Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].N12CCCN=C1CCCCC2.[C:29]([N:36]1[CH2:41][CH2:40][CH:39]([CH:42]=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[F:9]/[C:8](=[CH:42]/[CH:39]1[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:37][CH2:38]1)/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(F)=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 9 was prepared using the methods described in Scheme AE. Intermediate AE1 was prepared as follows. Lithium chloride (0.39 g) was added to a solution cooled to 0° C. of triethyl-2-fluoro-2-phophonoacetate (1.84 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.15 mL) in acetonitrile (6 mL). The mixture was stirred until the lithium chloride was dissolved to form a homogeneous solution. N-Boc-piperidine-4-carboxaldehyde (1.61 g) in acetonitrile (2.0 mL) was added to the mixture and stirred for 24 h at room temperature. The reaction was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate) and evaporated to yield 2.27 g of (E)-ethyl 2-fluoro-3-(N-Boc-piperdin-4-yl)propenoate (AE1). AE1 was carried forward as shown in Scheme AA to afford 9. Compound 9 was isolated as white flakes: mp 147-150° C.; MS m/e 515 (MH+). Anal. calcd. for C25H31FN6O5•2.3 HCl•1.6 H2O (627.25): C, 47.88; H, 5.87; N, 13.40; Cl, 13.00. Found: C, 48.26; H, 6.02; N, 12.90; Cl, 12.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])[N:4]=1.[CH3:23][N:24]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)C(Cl)=O.[I-].[Na+].C(N(C(C)C)CC)(C)C>O.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([N:24]([CH3:23])[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc[n+]1[O-]
Reactant: CN(C(=O)Cl)C1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(N(C)C2CCCCC2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 50 %

Procedure:
11.0 g (36 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate N-oxide, 9.5 g (54 mmol) of N-methyl-N-cyclohexylcarbamoyl chloride, 10.5 g (70 mmol) of sodium iodide and 9.0 g (70 mmol) of diisopropylethylamine were added to 150 ml of acetonitrile and reacted at a temperature of from 60° to 70° C. for one hour. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate, dried and concentrated. The obtained oily product was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the desired product.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.C1COCC1.CO>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(-n2nccn2)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CNCc1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 60 g (347 mmol) of 4-[1,2,3]-triazol-2-yl-benzaldehyde in 1000 ml of CH2Cl2, 78.9 g (629 mmol) of glycine methylester hydrochloride, 104.2 ml (749 mmol) of triethylamine and 150 g of MgSO4 are successively added at 0-5° C. The mixture is stirred at r.t. for 18 h and filtered through celite. The filtrate is concentrated under reduced pressure and the residue is diluted with AcOEt. Et3N hydrochloride is filtered off and the filtrate is concentrated under reduced pressure in an azeotropic manner using toluene to give the crude imine. To a solution of the crude imine in 600 ml of THF and 600 ml of MeOH, 20 g (526 mmol) of NaBH4 is added portionwise at −20˜−10° C. and the mixture is stirred for 1 h. The reaction mixture is slowly quenched with sat. aqueous NH4Cl and then extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=2:1-1:1) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][CH2:13][C:14](Cl)=[O:15].CCOCC>O1CCCC1>[Cl:12][CH2:13][C:14]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride (30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1 hour. The solution is cooled and concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL) is added and the yellow solid is collected.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:13]([OH:26])[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[CH2:9][CH2:10][CH2:11][CH3:12])(C)(C)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:7][C@@H:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:13]([C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:15][CH2:16][CH2:17][CH2:18][S:19]1)[OH:26]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCC[C@H](N)C(O)C1(c2ccccc2)SCCCS1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To {1-[hydroxy-(2-phenyl-[1,3]dithian-2-yl)methyl]pentyl}carbamic acid tert-butyl ester (608 mg, 1.47 mmol) in dioxane (2.7 mL) at 10° C. was added hydrochloric acid (2.7 mL, 4 M in dioxane). The solution was warmed to 23° C. After 3 h, the solution was diluted with toluene (5 ml) and concentrated under reduced pressure. The gummy solid was washed with diethyl ether resulting in the hydrochloride salt of 2(8)-amino-1-(2-phenyl-[1,3]dithian-2-yl)hexan-1-ol, (414 mg, 82%) as a free flowing solid after removal of excess ether under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C1COCC1.O>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(O)c1C(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2cccc(OC)c2C(C)=O)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A flask is charged with 1-(2-hydroxy-6-methoxyphenyl)ethanone (30 g, 180.5 mmol), potassium carbonate, (49.9 g, 361 mmol), sodium iodide (2.68 g, 18.1 mmol), and 4-methoxybenzylchloride (27.0 mL, 198.6 mmol) in THF and the mixture is heated to reflux overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine and dried over anhydrous MgSO4, filtered, and concentrated. The crude product is purified by silica gel chromatography with an eluent of ethyl acetate/hexanes to give 32.51 g (57%) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:32]([C:31]2[S:30][C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]=2[Cl:26])=[O:33])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Nc2ccccc2NC(=O)c2sc3ccccc3c2Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol) and triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 3-chlorobenzo[b]thiophene-2-carbonyl chloride (490 mg, 2.1 mmol). After stirring for 20 h, the mixture was concentrated in vacuo and chromatographed (silica gel, 25% ethyl acetate/75% hexane) to give 660 mg (73%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([C:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CN1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C2=CCN(C)CC2)c1C
Temperature: 95 °C
Yield: 85.4 %

Procedure:
To a solution of 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (836 mg, 5 mmol) in acetic acid (10 mL) and TFA (5 mL) under nitrogen was added 1-methyl-piperidin-4-one (0.8 mL, 6.67 mmol). The mixture was then heated in a 95° C. oil bath for overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.12 g (85%) of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([OH:17])=O)[N:13]=1)=[O:7].Cl.[NH2:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH2:32][Cl:33])[CH2:30][S:31][C@H:26]12.C[Si](NC(N[Si](C)(C)C)=O)(C)C>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([NH:24][CH:25]2[C:50](=[O:51])[N:27]3[C:28]([C:34]([O:36][CH:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:35])=[C:29]([CH2:32][Cl:33])[CH2:30][S:31][C@H:26]23)=[O:17])[N:13]=1)=[O:7]
Reactant: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
Phosphorus oxychloride (7.0 ml) was added under ice-cooling to a solution of N,N-dimethylformamide (5.8 ml) in tetrahydrofuran (11 ml). The mixture was cooled until the precipitate appeared. Tetrahydrofuran (107 ml) was then added to this mixture, and the mixture was stirred for 20 minutes at 0° C. 2-(2-Formamidothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer) (13.2 g) was added to the mixture. The resultant mixture was stirred at 0° C. to give an activated acid solution. On the other hand, to a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate monohydrochloride (20 g) in tetrahydrofuran (200 ml) was added bis(trimethylsilyl)urea (36.2 g) at ambient temperature. The mixture was stirred at 36°-38° C. for 40 minutes to give a clear solution. To this solution was added the activated acid solution obtained above at once at -20° C. The mixture was stirred at -20°~12° C. for 40 minutes. To this mixture was added a mixture of ethyl acetate (700 ml) and water. The separated organic layer was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated to give a solid. The solid was recrystallized from diisopropyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (25.5 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:34]([OH:36])=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=2[NH:3]1.C(N(CC)CC)C>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:34]([OH:36])=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 24 h

Procedure:
220 mg 10% Pd/C were added to a solution of 2.2 g (4.1 mmol) of (R)-1-carboxy-2-(4-benzyloxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 450 mg (4.4 mmol) triethylamine in 90 mL MeOH and the reaction mixture was hydrogenated at 3 bar H2 for 24 h. The catalyst was filtered, washed twice with MeOH and the filtrate was evaporated down i.vac. The residue was taken up in 20 mL water and adjusted to pH 2-3 with 10% HCl. The precipitate formed was filtered, washed with a little water and dried at 50° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH:37]([F:39])[F:38])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:39][CH:37]([F:38])[O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1OC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1OC(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.44 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[2-(difluoromethoxy)phenyl]ethoxy}thiophene-2-carboxamide in 25 ml THF is cooled to 0° C. At 0° C., 0.91 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:23]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccccc2N2CCN(C3CCCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (25 mg, 0.0832 mmol) produced in Example (8b), cyclopentanone (9.1 mg, 0.108 mmol), sodium triacetoxyborohydride (33.5 mg, 0.158 mmol) and acetic acid (0.009 mL, 0.158 mmol) was stirred for 1 hour and 40 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-cyclopentyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil. δ: 0.92 (s, 6H), 1.13 (s, 6H), 1.16-1.36 (m, 6H), 1.39-1.51 (m, 4H), 1.66-1.76 (m, 2H), 1.86-1.96 (m, 2H), 2.48-2.58 (m, 1H), 2.67 (brs, 4H), 2.89-2.98 (m, 4H), 3.52-3.61 (m, 1H), 7.04-7.14 (m, 3H), 7.21 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl:31][C:32]1[CH:33]=[CH:34][C:35](OS(C(F)(F)F)(=O)=O)=[N:36][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1COCC1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:35]1[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][N:36]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(Oc1ccc(Cl)cn1)C(F)(F)F
Reactant: CCOC(=O)c1c(Cl)c2cc(B(O)O)ccc2n1-c1ccc(OC2CCCC2)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(Cl)cn3)ccc2n1-c1ccc(OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
To a stirred suspension of 3-chloro-5-(dihydroxyboryl)-1-(4-cyclopentoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see step (b) above; 214 mg, 0.5 mmol), trifluoromethanesulfonic acid 5-chloropyrid-2-yl ester (see step (c) above; 130.0 mg, 0.5 mmol) and K3PO4 (200 mg, 0.95 mmol) in THF (2.0 mL) under argon at room temperature was added a mixture of Pd(OAc)2 (23.0 mg, 0.1 mmol) and tricyclohexylphosphine (34 mg, 0.12 mmol) in THF (2.0 mL). The reaction was stirred at ambient temperature for 12 h, diluted with Et2O (10 mL), washed with brine and dried (Na2SO4). Concentration and purification by chromatography afforded the sub-title product (100 mg, 40%).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:19]([O:21][CH:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])[CH3:23])[CH:20]=2)=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([NH2:33])=[C:19]([O:21][CH:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])[CH3:23])[CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 3 h
Yield: 105.9 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl-bis-(tert-butoxycarbonyl)-amine (1.3 g, 2.0 mmol) in dichloromethane (15 mL). After 3 hours, equal portions of water and saturated aqueous sodium bicarbonate were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation to give 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine (968 mg, 106%).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:25]=[C:26]=[O:27]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:26]([NH:25][CH2:3][CH2:4][CH2:5][CH3:6])=[O:27])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: CCCCNC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][C:3]=1[C:4]#[N:5].CO.[C:18](=O)([O-])[O-:19].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)C>[C:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][CH3:18])=[C:3]([CH:6]=1)[C:4]#[N:5])#[CH:11]
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(OC)c(C#N)c1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-Fluoro-5-trimethylsilanylethynyl-benzonitrile (0.935 g, 4.3 mmol), in dry methylene chloride (10 mL) and methanol (10 mL) was added cesium carbonate (1.7 g, 5.2 mmol) and stirred for 2 h under a nitrogen atmosphere. The mixture was diluted with diethyl ether (100 mL), and partitioned between diethyl ether and H2O (100 mL), and the aqueous layer was extracted with diethyl ether (50 mL), washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (20-30% ethyl acetate/petroleum ether) gave the title compound as a tan solid (0.468 g, 69%), identified by NMR and mass spectral analyses. Mp: 100-101° C. MS (EI+): 157 (M+).
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:15]#[N:16])=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)[OH:26].C(=O)(O)[O-].[Na+]>O>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:15]([NH2:16])=[O:26])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=S(=O)(O)O
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C#N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C(N)=O)ccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carbonitrile from Example 8 step A (174 mg, 0.5 mmol) were added concentrated sulfuric acid (2.88 mL) and water (0.32 mL). The mixture was stirred at 65° C. for 1 h and then allowed to cool to rt. The mixture was neutralized by slow addition of saturated aq sodium bicarbonate and then extracted with EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carboxamide (178 mg, 98%), which was used without further purification. LC-MS (ESI) m/z 365 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:30][CH2:31][CH2:32][OH:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:30][CH2:31][CH2:32][OH:33])=[O:18])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-methylphenyl)sulfonyl]meth yl]-4-methylpyridine-2-carboxylic acid (208 mg, 0.5 mmol), 2-aminoethanol (46 μl, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.75 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), and triethylamine (209 μl, 1.5 mmol) were dissolved in methylene chloride (35 ml), and the resulting solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 6% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (125 mg, 0.27 mmol, 54%) as a white amorphous substance.