Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1([NH2:28])[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:28][C:25]5([CH3:24])[CH2:27][CH2:26]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CC4)c3n2)c2ccc(F)cc21
Yield: 53.7 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 1-methylcyclopropanamine (21 mg, 0.29 mmol), HATU (110 mmol, 0.29 mmol) and DIPEA (46 mg, 0.36 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 54.9%) as a white solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 9.09 (s, 1H), 8.54 (s, 1H), 8.48-8.42 (m, 2H), 7.71 (dd, 1H, J=9.9, 2.1 Hz), 7.25-7.24 (m, 1H), 4.16 (s, 3H), 1.49 (s, 3H), 0.81 (brs, 2H), 0.80 (brs, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2CCCCN2CC(C2C=CC=C(Br)C=2)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C([O:31]CC)C>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:31])[CH3:8]
Reactant: CCOCC
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Agent: [Li]CCCC
Product: CC(=O)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 3, 37.8 g. (0.1 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.18 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 27 g. (0.23 mole) of acetophenone to give 11.8 g. of 2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([OH:33])[C:26]=1[CH3:34].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([O:33][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:26]=1[CH3:34]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Pyridine (64 μl) and benzoyl chloride (45 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in CH2Cl2 (5 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was poured into a KHSO4 aqueous solution and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→4/1) to obtain 6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH3:20].O>CN(C)C=O>[F:17][C:14]([F:15])([F:16])[C:13]([NH:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][CH3:20])[CH:3]=1)=[O:18]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(CCNC(=O)C(F)(F)F)ccc1OC
Yield: 22.1 %

Procedure:
N-[2-[3-Amino-4-methoxyphenyl]ethyl]-2,2,2-trifluoro acetamide (26.2 g., 0.1 mole) and iodomethane (14.0 g., 6.2 ml., 0.1 mole) in dry dimethylformamide (500 ml) were stirred under nitrogen for 3 hr. The solution was poured into water and the suspension extracted with ethyl acetate. Evaporation of the extracts afforded an oil which was separated by high pressure liquid chromatography on silica using 1% methanol in dichloromethane as eluant. Evaporation of the fractions containing the major bond afforded the sub-title compound (6.1 g) as a white solid mp 65°-67°. The hydrochloride, prepared in the usual way, had mp 153°-155°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N+:12]=[N-:13])[C:5](=[O:11])[NH:6]2.[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC>[Cl:1][C:2]1[C:3]2[C:4]3[N:12]([N:13]=[C:15]([CH2:14][OH:17])[CH:16]=3)[C:5](=[O:11])[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2cccc(Cl)c21
Reactant: C#CCO
Solvent: CCOCC
Product: O=c1[nH]c2cccc(Cl)c2c2cc(CO)nn12
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
2.0 g (0.0103 mole) of 4-chloro-3-diazooxindole, and 11.95 g (0.207 mole or 20 equivalents) of 97% propargyl alcohol are refluxed under N2 for hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 20 minutes. The cream-colored precipitates are filtered off, washed with ether and dried in vacuo over the weekend at 50°. Yield: 2.44 g, mp 295°-296°; 94.9% crude yield. The crude product is taken up in absolute ethanol, filtered while hot and the filtrate is concentrated to a volume of 150 ml. The solution is cooled and the precipitates filtered off, washed with ether and dried in vacuo at room temperature for 24 hours to give 1.4 g of title compound, mp 309°-311°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:34][CH2:33][CH2:32][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:9]([O:14][CH:15]([CH3:16])[CH3:17])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:19][CH2:20]1
Reactant: CC(C)Oc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCCNc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)Oc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylic acid (100 mg, 0.296 mmol), N-2-pyridyl-1,2-ethanediamine (60.9 mg, 0.444 mmol) and triethylamine (0.0619 mL, 0.444 mmol) in DMSO (3 mL) was stirred at 100° C. for 8 h. After the reaction mixture was poured into ice-water, NH4Cl was added and stirred for 30 min. The resulting precipitate was collected by filtration in vacuo and washed with water. The crude product was purified by preparative thin layer chromatography (Hexane:EtOAc 1:4) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-isopropoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (80.6 mg, 60%) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[C:6]([C:23]([NH:25][CH3:26])=[O:24])=[C:7]([C:9]3[CH:10]=[N:11][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:29][C:28]1[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[N:11][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)=[CH:13][CH:14]=3)=[C:6]([C:23]([NH:25][CH3:26])=[O:24])[C:5]=2[CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N)c(Br)cc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 85.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.22 mmol) and DMAP (10 mg, 0.02 mmol) in Pyridine (5 ml) under N2 was added MsCl (32 mg, 0.38 mmol) at 0° C. Then it was stirred at 20° C. for 15 h. The reaction mixture was concentrated and extracted with DCM. After it was washed with brine, dried over Na2SO4 and concentrated, the residue was purified by prep-TLC to give 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 85%). 1H-NMR (CDCl3, 400 MHz) δ 9.65 (s, 1H), 8.73 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.33˜7.38 (m, 4H), 7.28 (d, J=8.8 Hz, 1H). (M+H)+: 534/536.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]([OH:48])[C:24]2(O)[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23](=[O:48])[CH:24]2[CH2:29][CH2:30][O:31][C:32](=[O:46])[N:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(O)C2(O)CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(=O)C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 51.4 %

Procedure:
A solution of 5-t-butyldiphenylsilyloxy-1,2-dihydroxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene (2.0 g) and p-toluenesulfonic acid (20 mg) in toluene (40 ml) was stirred for 30 minutes under reflux. The mixture was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyl-diphenylsilyloxy-1-[2-(N,N-diphenylcarbamoyloxy)ethyl]-2-oxo-1,2,3,4-tetrahydronaphthalene (1.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].B([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH:3]=[N:4][CH:5]=1)#[N:8]
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Reactant: N#Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-bromonicotinonitrile (8.8 g, 48.08 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (11.50 g, 52.89 mmol) and K2CO3 (13.3 g, 96.16 mmol were dissolved in a mixture of DME (120 mL) and water (30 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (2.7 g, 2.40 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aq. 0.5 N NaOH (100 mL) and stirred for about 30 min., and then the mixture was extracted with ether (30 mL×3) The aqueous layer was cooled to 0° C., acidified with 2 N HCl, and then extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 9.4 g of 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid as a white solid in 73% yield.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)#[N:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1cc(C#N)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1OC
Yield: 367.6 %

Procedure:
To a mixture of 4-cyano-2-methoxybenzoic acid (1.00 g, 5.648 mmol, Biogene) in methanol (15.0 mL) was added p-toluenesulfonic acid monohydrate (286 mg, 1.48 mmol, Aldrich) and it was heated to reflux under an argon atmosphere for 16 hrs. The solvent was removed and the reaction mixture was extracted with EtOAc, washed with saturated Na2CO3, water, and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96.4%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[C:6]([O:27][CH2:28][CH3:29])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)[CH3:4].Br[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][NH:35]2.CCN(C(C)C)C(C)C>C(O)C.C([O-])(O)=O.[Na+]>[Cl:11][C:9]1[C:8]([CH3:12])=[C:7]([CH:13]2[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14]2)[C:6]([O:27][CH2:28][CH3:29])=[C:5]([CH:3]([NH:2][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][NH:35]3)[CH3:4])[CH:10]=1
Reactant: CCOc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (65 mg, 0.13 mmol, second peak from chiral separation in previous step) was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylene chloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give benzyl 3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate hydrochloride. LCMS calculated for C22H28ClN2O3 (M+H)+: m/z=4012. found: 403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16 mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at 100° C. overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (83 mg). LCMS calculated for C27H30ClN6O3 (M+H)+: m/z=521.2. found: 521.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH2:32][O:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH2:32][O:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CCOC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COCCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
1.80 g (3.40 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate (racemate) in 45 ml of methanol/water (4/1) were reacted with 2.24 g (6.87 mmol) of caesium carbonate according to General Method 4, giving the title compound. Yield: 1.66 g (88% of theory)
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CCN(CC)C(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCN(CC)C(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-N, N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide (10.0 g, 0.037 mol) in methanol (220 mL) containing anhydrous ammonia (3.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000(4.2 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.2 g of (4R -cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide as an oil.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1)([CH3:5])=[O:4].[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][C:24]=2[F:33])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[CH3:1][O:2][P:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:14][C:15]2[S:16][C:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][C:24]=3[F:33])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[N:8]=1)([CH3:5])=[O:4]
Reactant: COP(C)(=O)Cc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COP(C)(=O)Cc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was synthesized from methyl[(6-bromopyridin-2-yl)methyl]methylphosphinate (90 mg, 0.34 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH2:3]1.[N:18]#CBr>C1C=CC=CC=1>[C:1]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])[CH2:3]1)#[N:18]
Reactant: N#CBr
Reactant: CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Solvent: c1ccccc1
Product: N#CN1CCCC(CC(=O)c2ccc(F)cc2)C1

Procedure:
The above reaction scheme generally follows the procedure of E. L. Engelhardt, J. Med. Chem., 11, 325 (1968). Briefly, 1-methyl-3-(4-fluorophenacyl)piperidine in benzene solution is treated at essentially ambient temperature with excess cyanogen bromide under a nitrogen purge. Volatile materials are distilled under reduced pressure and the residue is dissolved in chloroform. The chloroform solution is washed, dried, and filtered. Distillation of the chloroform gives 1-cyano-3-(4-fluorophenacyl)piperidine. Hydrolysis of the cyano compound with hydrochloric acid-containing aqueous acetic acid gives the 1-carbamoyl derivative and the completely hydrolyzed and decarboxylated piperidine derivative (wherein the cyano group effectively is replaced with hydrogen). Increasing the amount of hydrochloric acid employed and increasing reaction time appear to favor complete hydrolysis and decarboxylation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:26])=[O:18])[CH2:20][CH2:21]2)[CH2:30][CH2:29]1
Reactant: CN1CCCNCC1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCN(C2CCN(C(=O)Nc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1
Reaction time: 15 h

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(4-oxo-piperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and 4-methyl(hexahydro-1,4-diazepine) (0.03 mL, 0.241 mmol) in 10% acetic acid in methanol (2.2 mL) was treated with sodium cyanoborohydride (20 mg, 0.268 mmol). After 15 h, the mixture was loaded onto a SCX column, which was pretreated with a solution of 5% acetic acid in methanol. The column was eluted with methanol followed by 2 N ammonia in methanol. The eluent was concentrated to afford title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:20]2[C:12](=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)[CH:11]([N:21]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:22]2[N:23]=[N:24][NH:25][N:26]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CO.[C:44]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH:1]([O:4][C:5]([N:7]1[C:20]2[C:12](=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)[CH:11]([N:21]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=2)[C:22]2[N:23]=[N:24][N:25]([CH3:44])[N:26]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of (+/−)-isopropyl 9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (Example 49) (48 mg, 0.082 mmol) and methanol (0.015 mL, 0.36 mmol) in dichloromethane (1 mL) at room temperature, under nitrogen atmosphere, add triphenyl phosphine (22 mg, 0.082 mmol) in one portion. Add diethyl azodicarboxylate (0.015 mL, 0.082 mmol). The reaction mixture was allowed to stir at room temperature overnight. Add methanol (0.015 mL, 0.36 mmol), triphenyl phosphine (22 mg, 0.082 mmol) and diethyl azodicarboxylate (0.015 mL, 0.082 mmol). After stirring for 6 h, remove the solvents under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (25 mg, 51%). MS (ES+): 597 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:37][CH:27]([CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (1 g; 4.36 mmol) is dissolved in methylene chloride (50 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) [1.33 g; 4.36 mmol], triethylamine (0.61 mL; 4.36 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.84 g; 4.4 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then concentrated in vacuo at 30° C. The residue is diluted with ethyl acetate (100 mL) and washed successively with water (200 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (5%→40% ethyl acetate in hexanes) affording the desired product (1.30 g) as a viscous oil. ESMS: MH+ 479.4