Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]C#N.[BH4-].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11]
Reactant: N#CSc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(S)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-nitrophenyl thiocyanate (4.38 g, 20.4 mmole) in dry DMF (70 mL) under inert atmosphere, excess sodium borohydride (1.1 g) was added. The mixture was stirred for half hour and poured over crushed ice. The mixture was acidified with 1 N HCl and left at 0° C. for 1 hr. The precipitate were collected by filtration and redissolved in CH2Cl2. The organic layer was further washed with water and dried with MgSO4. The solvent was removed in vacuo to afford yellow crystals. The product was used in the next step without further purification. 1H NMR (300 MHz, d6-acetone) δ: 8.42 (d, 1H, J=2.7 Hz), 7.98 (dd, 1H, J=8.7, 2.7 Hz), 7.68 (d, 1H, J=8.7 Hz), 5.26 (bs, 1H). 13C NMR (75 MHz, d6-acetone) δ: 147.5, 137.9, 136.4, 131.2, 124.8, 121.7. HR-MS (EI): calcd. for C6H4ClNO2S 189.9646 [M+]. found 189.9646.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:21][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[C:19]#[N:20])[CH2:11][CH:6]2[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC.Cl>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][CH:3]2[CH2:21][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[C:19]#[N:20])[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:44][CH:43]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1cc(F)ccc1N1CCN2CC(CO)CCC2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cc(F)ccc1N1CCN2CC(COc3ccc(F)cc3)CCC2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A solution of 0.51 g (1.8 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.555 g (2.12 mmol) of triphenylphosphine, and 0.296 g (2.64 mmol) of 4-fluorophenol in 8 mL of dry THF was treated with 0.368 g (2.12 mmol) of diethyl azodicarboxylate and stirred at ambient temperature for 24 h. The mixture was diluted with ether, and 1M HCl was added until a gummy residue formed. The layers were separated and the aqueous layer was washed with ether (3×). The aqueous layer was combined with the gummy residue and dissolved in a mixture of ethyl acetate and 10% ammonium hydroxide, the layers were separated and the aqueous layer was extracted with more ethyl acetate (2×). The organic layers were evaporated, the residue dissolved in chloroform, washed with 1M NaOH (3×), dried (magnesium sulfate), filtered and evaporated. The product was dissolved in absolute ethanol, filtered and evaporated to give 0.21 g of the title compound. mp (—HCl) 235-240° C. HRMS calcd for C22H23F2N3O: 383.1809, found: 383.1796.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:12](O)[CH3:13]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc(Br)n1
Yield: 92 %

Procedure:
6-Bromo-2-pyridinecarboxylic acid (925 mg, 4.95 mmol) (Aldrich) was dissolved in hydrochloric acid/ethanol (1.25 M, 20 ml) and stirred under reflux for 3 h. Then the solvent was evaporated under reduced pressure. The remaining residue was taken up with DCM and washed with saturated aqueous NaHCO3 solution. Evaporation of the solvent afforded the title compound (1.045 g, 92%). The material was used in the following step without any further purification; 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.1-8.0 (m, 1H), 7.8-7.5 (m, 2H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 30 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-tert-butylaniline (51.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1,1-dimethylethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (21.1 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([N:21]([CH2:24][CH3:25])CC)C>O1CCOCC1>[C:11]1([C@H:24]([NH:21][C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:25])[CH:18]=[CH:17][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(C#N)cc3)cc12)c1ccccc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A mixture of 1.27 g (5 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile, 1.4 ml (10 mol) triethylamine and 0.955 ml (7.5 mmol) R(+)-1-phenyl-ethylamine in 25 ml dioxane is heated under reflux for 24 h. A second portion of R(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) is added and heating is continued for 24 h. After addition of a third portion of R(+)-1-phenyl-ethylamine (0.32 ml, 2.5 mmol) and additional 24 h the reaction mixture is cooled to 10° C. and the title compound filtered off and washed with dioxane. From the mother liquor a second crop is obtained after concentration of the solution; m.p. 333-336° C.; MS-ES+: (M+H)+=340.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:12]([NH:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-chloro-2-fluoronitrobenzene (250 mg) and t-butylamine (0.40 mL) were dissolved in dimethyl sulfoxide (3.0 mL) and stirred at room temperature overnight. Then, the mixture was added with water and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine, and the water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The subsequent reaction was proceeded without further purification of the thus obtained compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(NCc1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Triethylamine (0.77 ml) and 4-chlorobenzenesulfonyl chloride (1.2 g) were added to a solution of 4-hydroxybenzylamine (0.68 g) in ethanol(10 ml), respectively. The reaction mixture was stirred at room temperature for 4 hours and evaporated in vacuo to remove the solvent. The residual solid was washed with water then recrystallized from ethanol to give N-(4-hydroxybenzyl)-4-chlorobenzenesulfonamide (1.2 g), mp 187-189° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=O)[CH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:19][CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1Cl)N(CCO)Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: OCCN(CCc1cccnc1Cl)Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of the compound (2.00 g) obtained in step 5 in THF (30 mL) was added 1M BH3.THF complex/THF solution (32.0 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 6N hydrochloric acid (32 mL), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 33→50% ethyl acetate/hexane) to give 2-(benzyl(2-(2-chloropyridin-3-yl)ethyl)amino)ethanol (0.88 g, 46%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].Cl.[NH2:9][OH:10].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[N:9][OH:10])[NH2:2]
Reactant: N#Cc1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cccs1
Yield: 78.8 %

Procedure:
To a solution of 21.8 g (0.20 mole) of 2-cyanothiophene in 500 ml of ethanol, 13.9 g (0.20 mole) of hydroxylamine HCl is added, followed by the addition of 13.8 g (0.10 mole) of K2CO3 in 50 ml of water. The mixture is refluxed for 16 hours, cooled and diluted with 200 ml of water. After removing the ethanol in vacuo, the product precipitates out of the aqueous residue. It is collected by filtration, washed with water and dried to yield 22.4 g (80%) of product, m.p. 70°-75°.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:8]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.6 g, 14.0 mL, 138.0 mmol). The reaction mixture was then stirred at r.t. for 1 h before cooling to 5° C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 10° C. was maintained. After addition, the reaction mixture was allowed to stir at 5° C. for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5° C. and a further portion of NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of <10° C. was maintained. The ice bath was removed on completion of addition and the reaction mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with Et2O (3×100 mL) and the aqueous phase acidified to pH 5 with conc. HCl. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. δH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=O)[N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:20]2[N:19]=1
Reactant: Cc1nc2cccc(C=O)n2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a suspension of sodium hydride (0.570 g, 13.0 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (2.36 mL, 11.8 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde (1.90 g, 11.8 mmol) in tetrahydrofuran (58 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.50 g, yield 92%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1CN(c2ccccc2)C(=O)N1C1CCCCC1
Yield: 60 %

Procedure:
A mixture of N-phenyl glycine (0.1 mole), cyclohexyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for about 6 hours and then cooled. The crude product was recrystallized from ethanol to produce a 60% yield of the above-identified product having a melting point of approximately 196° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C.CO>C(O)CCC>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[C:5]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][N:3]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCCCO
Solvent: CO
Product: O=c1[nH][nH]c2cc(Nc3ncc(-c4ccccc4)c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To ((2-Chloro-5-phenyl-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (75 mg, 0.241 mmol), was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (180 mg, 0.72 mmol) in n-butanol and the solution was heated to 95° C. in a sealed tube. After 12 hr, the solution was concentrated and the title compound was isolated by preparative HPLC as a white solid (5.2 mg, 5% yield) HNMR (500 MHz, MeOH d-6). □17.82–7.80 (2H, m), 7.59–7.50 (6H, m), 7.19–7.17 (1H, m), 6.08 (1H, s), 2.65 (1H, m), 0.91–0.89 (2H, m), 0.45 (2H, m); LCMS m/e: 1.9 min, 425.1 (M+H), 423.1 (M−H).
Reaction SMILES: S(=O)(=O)(O)O.O.[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23](CC#N)=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8].C(OCC)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44]>>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:44][C:43]([OH:46])=[O:45])=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of 5 ml of concentrated sulphuric acid and 5 ml of water is added dropwise to a solution of 0.35 g (0.82 mmol) of nitrile derivative from Example VIII in 5 ml of acetic acid (100% strength). The reaction solution is stirred at 105° C. for 4 hours, then cooled to room temperature and treated with ice-cold water and ethyl acetate. The organic phase is separated off, the aqueous solution is extracted again with ethyl acetate, and the combined organic phases are dried over sodium sulphate, filtered and concentrated to give an oil. The crude product (120.3 mg) is chromatographed on silica gel 60 by means of methylene chloride/methanol (95:5 and95:11).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][C@@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (S)-methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride in dioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RT for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([NH:24][CH2:23][CH2:21][OH:22])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: NCCO
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(NCCO)nc21

Procedure:
The title compound, m.p. 241°-244° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and ethanolamine using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 260° C. for 50 min., and the product was crystallized from chloroform/ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC[CH2:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:31][CH2:27][CH2:28]3)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCOCC3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCCCC3)cc2)CC1

Procedure:
Same procedure as described for the preparation of compound 82, but using piperidine in place of morpholine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:16]([NH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O-:33])=[O:32])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[Cs+]>>[C:16]([NH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:32])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(CCCCBr)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1

Procedure:
This compound was prepared from the products of 8a (0.73 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The crude product was purified on a 75×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. Fractions containing the product (5-8) were collected, and after evaporation 0.82 g (72%) product was obtained (yellowish solid, mp 53-56° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:10]=2[N:11]=1.C1C(=O)N([Br:24])C(=O)C1>C1COCC1>[Br:24][C:14]1[C:13]([CH3:16])=[N:12][C:10]2[N:11]=[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:7]=[CH:8][C:9]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCNc1ncc2ccc(C)nc2n1
Solvent: C1CCOC1
Product: COCCNc1ncc2cc(Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
Heat a solution of 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine (2.6 g, 13.6 mmol) and 2-methoxyethanamine (6 mL) with microwave irradiation at 180° C. for 2 h. Cool the mixture to RT, dissolve in EtOAc, wash with water, then brine, dry over Na2SO4 and concentrate under reduced pressure to give N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.7 g, 91%). Treat a solution of N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.35 g, 10.7 mmol) in THF (100 mL) portion wise with NBS (1.8 g, 10.7 mmol) and stir at RT for 2 h. Concentrate the reaction mixture to dryness, dissolve in EtOAc, wash with water, then brine, dry the organics over Na2SO4, concentrate and purify by HPLC to afford the title compound (0.55 g, 26%). MS (m/z): 297.0 (M+1+).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[C:11]([N:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2/[CH:42]=[CH:43]\[CH2:44]O)(=[O:34])=[O:33])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][CH2:17][C:16]1[O:20][CH:21]=[CH:22][C:15]2=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:23]([C:11]2[C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:19]3[C:14]([C:15]4[CH:22]=[CH:21][O:20][C:16]=4[CH2:17][O:18]3)=[CH:13][CH:12]=2)[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])(=[O:33])=[O:34])=[C:36](/[CH:42]=[CH:43]\[CH2:44][N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:37]=1
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (0.100 g) was added to an ice-cooled, stirred solution of methyl-7-{N-[4-fluoro-2-((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 48, 1.57 g) and diisopropylethylamine (0.859 g) in DCM (25 mL) and the mixture was stirred in an ice bath for 20 minutes. Morpholine (0.689 g) was added and the reaction mixture was stirred at room temperature for 90 minutes. It was washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-80% to give methyl 7-{N-[4-fluoro-2((Z)-3-{morpholin-4-yl}prop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxy-methyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (1.15 g) as a yellow gum.