Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)=[CH:19][C:18]([Cl:33])=[CH:17][N:16]=2)[C:6]1=[O:34])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][OH:22])=[CH:19][C:18]([Cl:33])=[CH:17][N:16]=2)[C:6]1=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OCc1cc(Cl)cnc1CC1C(=O)N(C(C)(C)C)c2ncccc21)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Reaction time: 0.33 h
Yield: 77.7 %

Procedure:
A solution of 69 (max 60.7 mmol) in THF (50 mL) obtained from the previous step was degassed with vacuum/flush N2, cooled below 5° C. followed by charged TBAF (79 ml, 1.0 N in THF). The reaction aged at room temperature for 1 h 20 min, cooled below 10° C., quenched with water (100 ml), and diluted with AcOEt (200 mL). Aqueous layer was extracted with AcOEt (100 mL). The combined organic layer was dried with MgSO4, filtered, concentrated and purified by silica gel column (50 to 100% AcOEt/hexane) to give 56 (16.3 g, 78% from 65) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[NH2:10].[CH2:11]([N:13]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1)[CH3:12]>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:10]=[C:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:11][CH3:12])[CH:17]=1)[N:8]2[CH3:9]
Reactant: CCn1cc(C=O)cn1
Reactant: CNc1ncnc(Cl)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 103 %

Procedure:
To a solution of 6-chloro-N4-methylpyrimidine-4,5-diamine (300 mg, 1.9 mmol) in anhydrous DMF (8 mL) were added 1-ethyl-1H-pyrazole-4-carbaldehyde (236 mg, 1.9 mmol) and Iron (III) chloride hexahydrate (0.51 g, 1.9 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (20 g). The resulting precipitate was collected by vacuum filtration, and triturated with 10 mL of ethanol at 50° C. for 30 min. The solids were collected by vacuum filtration to give 514 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, 2H), 8.19 (s, 1H), 4.25 (q, 2H), 3.95 (s, 3H), 1.43 (t, 3H); MS (EI) for C11H11ClN6: 263.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.00 g, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at room temperature was added 2M trimethylsilyldiazomethane (8.75 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (1.06 g, 4.38 mmol, 100% yield) as a white solid. MS m/z 243 (MH+). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3H) 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[CH2:21]([S:23][CH:24]([CH3:39])[CH2:25][CH:26]1[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[CH2:29][C:28](=[O:38])[CH2:27]1)[CH3:22].CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:29]2[C:28](=[O:38])[CH2:27][CH:26]([CH2:25][CH:24]([S:23][CH2:21][CH3:22])[CH3:39])[CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]2=[O:37])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1CC(C)SCC
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)CC1CC(C)SCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (1 g) in dry dichloromethane (5 ml) was added at 0°-10° C. to a stirred solution of triethylamine (0.62 ml) and 5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (1.3 g) in dry dichloromethane (20 ml) and the mixture stirred at ambient temperature for 2 hours. Triethylamine (1.9 g) and acetone cyanohydrin (0.1 ml) were added successively to the solution and the mixture stirred at ambient temperature for a further 18 hours. The mixture was washed successively with 2N hydrochloric acid (10 ml) and water (2×10 ml) dried over magnesium sulphate and evaporated under reduced pressure to give 2-(4-chloro-2-nitrobenzoyl)-5-(2-ethylthiopropyl)-6-carbethoxycyclohexane-1,3-dione (0.6 g), mp 102°-104° C., as an orange crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[F:27][C:28]1([F:33])[CH2:30][CH:29]1[CH:31]=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:31][CH:29]3[CH2:30][C:28]3([F:33])[F:27])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=CC1CC1(F)F
Solvent: C1CCOC1
Product: COc1cn(C(=CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg (purity 78%, 30% of theory)
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:37]([O:39][CH3:40])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(c2ccc(OC)c(OC3CCC3)c2)C[C@@H]1Cc1ccccc1
Yield: 48.7 %

Procedure:
Prepared using the same procedure described in Example 89 from (S)-3-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (188 mg, 0.535 mmol), diisopropylethylamine (200 μL, 1.15 mmol), and methyl chloroformate (62 μL, 0.81 mmol) to afford the title compound as a yellow solid (107 mg, 49%). LC/MS (Method B) 4.17 min, [M+1]+ 411.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccccc1)OC

Procedure:
A mixture of 31.3 g of phenol, 60.0 g of bromoacetaldehyde dimethyl acetal and 80 g of potassium carbonate was heated at 150° C. in 300 ml of dimethylformamide. After 4.5 hours the reaction mixture was cooled, added to water, and extracted with diethyl ether. Separation, drying and evaporation of the organic phase gave the crude product. Vacuum distillation, bp 88°-98° C./1 mm yielded the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and nonanoic acid to yield (3aR,4S,7aR)-4-nonanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=476; RT 9.818 min; LC-MS Method III
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.CCOCC>[F:10][C:9]([F:11])([F:12])[C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:7][CH2:6]1)([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: NC1CCC(C(O)(C(F)(F)F)C(F)(F)F)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=S(=O)(NC1CCC(C(O)(C(F)(F)F)C(F)(F)F)CC1)c1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of 100 mg (0.37 mmol) of the acetate salt of 2-(4-amino-cyclohexyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 5 mL of DMF was treated with 0.2 mL (1.16 mmol) of DIPEA and 0.144 mL (1.1 mmol) of benzenesulfonyl chloride. The mixture was stirred for 1 hr and distributed between a diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. Column chromatography on silica gel with EtOAc/heptane 1:1 gave 90 mg (72%) of N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a pink solid, MS: 404 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][O:42][C:43](=[O:62])[C@@H:44]([NH2:61])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=2[CH3:60])=[CH:48][CH:47]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:61][C@H:44]([C:43]([O:42][CH3:41])=[O:62])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=3[CH3:60])=[CH:50][CH:51]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedure L furnished (3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester. This compound was converted to (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedure C. LCMS (m/z) 707.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Br:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Br)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Br)=CC1=O
Temperature: 0 °C
Yield: 74.6 %

Procedure:
To a solution of (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.260 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.180 g, 0.91 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.200 g, 1.55 mmol) was added. The mixture was stirred at room temperature for 5 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.290 g, 75%) as a yellow solid: HR-ES-MS m/z calculated for C25H31BrN4O5 [M+H]+ 547.1551, observed 547.1549, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.37-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.83 (m, 1H), 3.73 (dd, J=8.4, 5.8 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.77 (s, 1H), 4.90 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.24-7.35 (m, 1H), 7.50 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[OH:35])=[CH:32][C:31]=1[Br:38])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2ccc(OCc3ccccc3)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Then, 1.6 M n-butyllithium hexane solution (22.9 mL) was added to a mixture of 4-bromophenetole (7.3 g, 0.037 mol) and tetrahydrofuran (70 mL) at −78° C. After stirred for 0.5 hours, 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0.024 mol) in a tetrahydrofuran (70 mL) solution was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain colorless oily [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:42]([N:39]2[CH2:38][CH2:37][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:41][CH2:40]2)=[O:43])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 67.1 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.376 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.10 ml, 0.56 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (94 mg, 0.41 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 3:1) afforded 135 mg (66%) of the title compound as a white solid. ES-MS m/e: 535.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[C:6]1[CH3:29].O1CCCC1.[OH-].[Li+].Cl>O>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:30])=[O:2])[C:6]([CH3:29])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}acetic acid methyl ester (0.17 g), tetrahydrofuran (0.35 mL) and water (0.35 mL) was treated with lithium hydroxide (0.088 g), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C., pH adjusted to 5 by the addition of 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 by volume) to afford the title compound as a white solid (0.089 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.8 g.), anisole (2.8 ml.) and trifluoroacetic acid (11.2 ml.) was stirred at room temperature for an hour. Ethyl acetate and water were added to the resultant solution and adjusted to pH 7.0 with sodium bicarbonate. The aqueous layer was separated, and the ethyl acetate layer was extracted with water. The aqueous extracts were combined, washed with ethyl acetate and diethyl ether in turn, and then adjusted to pH 2.0 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.43 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC(C)([O-])C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[C:4]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)c3)nc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)C)CC4)c3)nc2c1
Temperature: 100 °C
Yield: 14.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (0.5 g, 1.38 mmol), 1-isopropyl-piperazine (0.24 mL, 1.66 mmol), potassium t-butoxide (0.32 g, 3.31 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (60.1 mg, 0.096 mmol) and tris(dibenzylideneacetone)dipalladium(0) (31.6 mg, 0.034 mmol) in nitrogen saturated toluene (10 mL) was heated at 100° C. for 48 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 97:3 dichloromethane/methanol) to give 2-(3-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.080 g, 14%) as a yellow solid: mp 251-253° C.; 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.42-7.38 (m, 2H), 7.13-7.09 (m, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.38-3.28 (m, 4H), 2.78-2.68 (m, 4H), 1.11 (d, 6H); ESI MS m/z 407 (M−1)−
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4F)cc(F)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3F)cc(F)c2O1

Procedure:
The title compound was prepared (0.132 g, 92%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.48 mmol) and methylamine (0.30 g, 9.6 mmol). mp >250° C. (dec).