Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][N:14]=[C:15]=[O:16].N12CCN(CC1)CC2.C1C=CC=CC=1>O>[CH3:13][NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: c1ccccc1
Product: CNC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Reaction time: 24 h

Procedure:
A mixture of 16.4 parts of 1,2,2,6,6-pentamethyl-piperidin-4-ol, 6.27 parts of methyl isocyanate and 0.5 parts of 1,4-diazabicyclo[2,2,2]octane was refluxed in 150 parts of dry benzene for 24 hours. Removal of the benzene solvent by distillation under reduced pressure yielded an oily solid which was poured on to 200 parts of water and allowed to stand for 24 hours. The solid formed was collected by filtration, dried and crystallised from n-hexane to give 14.2 parts of 4-methylcarbamoyloxy-1,2,2,6,6-pentamethylpiperidine having a melting point of 96°-7° C. and the following elemental analysis by weight:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[O:18]1[CH:20]2[CH2:21][CH2:22][C:23]3[C:28]([CH:19]12)=[CH:27][CH:26]=[CH:25][CH:24]=3.C(N(CC)CC)C.[ClH:36]>C(O)C.O.C(OCC)(=O)C.C(OCC)C>[ClH:36].[CH3:17][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([O:16][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C@H:20]2[OH:18])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4]
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cn2c1C
Reactant: c1ccc2c(c1)CCC1OC21
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1nc2c(O[C@@H]3c4ccccc4CC[C@H]3O)cc(C(=O)N(C)C)cn2c1C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 1.0 g (4.3 mmol) 6-(N,N-dimethylamino-carbonyl)-8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine in 20 ml ethanol and 5 ml water are added 1.25 g (8.6 mmol) 1,2-epoxy-1,2,3,4-tetrahydro-naphthalene and 1.2 ml triethylamine. After 16 h at 80° C., the mixture is cooled down and partitioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer is separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue is achieved by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1), then dichloro-methane:methanol (20:1). The oil thus obtained is dissolved in ethyl acetate and treated with saturated hydrogen chloride in diethyl ether to give a precipitate which is collected and dried to yield 0.6 g (34%) of the title compound as a colourless solid (m.p. 129° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-one (1.4 g prepared as described in Example 214) sodium borohydride (1.5 g) and propan-2-ol (30 ml) was heated under reflux for 4.25 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The extract was dried and evaporated to give a residue which was heated at 90°/20 mm to leave 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-ol as an oil the boiling point which was not determined.
Reaction SMILES: [F:1][C@@:2]([CH3:29])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[F:1][C@:2]([CH3:29])([C:3]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:5])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-2-fluoro-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (71%). MS: m/e=532(M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CO.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[N:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 197 mg of 4-chlorobenzaldehyde in place of the benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml of H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.33, 258 mg of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][C:18]([CH3:36])([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH3:19]>CC(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:18]([CH3:17])([CH3:19])[CH3:36])=[O:22])[C@@H:24]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)NC(=O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC

Procedure:
A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (94.4 mg, 0.3939 mmol) and (R)-4-[(1,1-dimethylethoxy)carbonyl]-3-(1,1-dimethylethylamino) carbonyl piperazine (see Askin, D. et al., Tetrahedron Letters 1994, 35, 673-676) (112.4 mg, 0.3939 mol) in 2-propanol (1 mL) was heated at 90° C. (24 h). The solvent was removed in vacuo and the residue subjected to PCTLC (SiO2, 2 mm, 0-10% MeOH/CH2Cl2) which afforded ((R)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(1,1-dimethylethoxy)carbonyl]-3-(1,1-dimethylethylamino)carbonyl piperazine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:29]=[CH:28][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]=[CH:20][C:21]3C=CC=CC=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.O1CCN=C1C1C=CC(C=C2CCNCC2)=CC=1.C1(C=CCC(O)=O)C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH2:19][C:20]#[CH:21])[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: O=C(CC=Cc1ccccc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Agent: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Agent: O=C(O)CC=Cc1ccccc1
Product: C#CCCC(=O)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-phenyl-3-butenoyl)piperidine from 4-[4-(2-oxazolin-2-yl)benzylidene]piperidine, 4-phenyl-3-butenoic acid and N,N'-carbonyldiimidazole. Melting point: 139° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2].CCN=C=NCCCN(C)C.[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:29][C:27](=[S:28])[NH:26][N:25]=2)=[C:5]([O:12][CH3:13])[CH:4]=1)[CH3:2]
Reactant: NNC(N)=S
Reactant: CCc1ccc(C(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-ethyl-2-methoxybenzoic acid (example 18b) (1 g, 6.1 mmol) in pyridine (6 mL) was added EDCI (1.2 g, 6.3 mmol) and the suspension was stirred at r.t. for 2 h. Then thiosemicarbazide (547 mg, 6 mmol) was added and the reaction was stirred at r.t. for 24 h. The mixture was evaporated to dryness and then diluted with water. A white solid was collected and washed with water. The solid was suspended in aq. NaHCO3 (1M, 20 mL) and heated at reflux for 2 days. The suspension was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was collected washed with water and dried to give 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione as a white powder (55%). MS (M+H, 236).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([NH:9][C:10](=[O:27])[CH:11]([NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[OH:3][CH:1]([C:4]1[O:8][C:7]([NH:9][C:10](=[O:27])[CH:11]([NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)[CH3:2]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncc(C(C)=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncc(C(C)O)o1
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To a solution of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-acetyl-oxazol-2-yl)-amide (130 mg, 0.34 mmol) in a mixture of MeOH (5 ml) and THF (5 mL) was added NaBH4 (130 mg, 3.9 mmol) at room temperature. After stirring for 10 min, the mixture was concentrated to a small volume, quenched with water and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give 131 mg of the title compound as a colorless oil. LC-MS, RT=1.7 min, M+1=382.2, M−1=380.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4])(=[O:15])[CH3:14]
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC(=O)N1CC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-(2-aminoacetyl)-2.2-dimethyl-4-imidazolidinone (5 g) in acetic anhydride (20 ml) was stirred at room temperature for 1 hour. Evaporation under vacuum and crystallization of the residue from 2-propanol gave 4.63 g of the title compound, m.p. 214°-215° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([C:24]4([OH:28])CO[CH2:25]4)[N:19]3[CH2:22]C)=[C:15]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:14]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].ClC1N=C2C(N=C(C3(O)C[N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]3)N2C)=C(N2CCOC[C@@H]2C)N=1>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([C:24]4([OH:28])[CH2:25][N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]4)[N:19]3[CH3:22])=[C:15]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[N:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)COC4)n(CC)c3n2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CN(C(=O)OC(C)(C)C)C1)n2C
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3nc(C4(O)CN(C(=O)OC(C)(C)C)C4)n(C)c3n2)cc1

Procedure:
This compound (w-2) was prepared in an analogous fashion to (S)-1-ethyl-3-(4-(8-(3-hydroxyoxetan-3-yl)-9-ethyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)urea, using (S)-tert-butyl 3-(2-chloro-9-methyl-6-(3-methylmorpho-lino)-9H-purin-8-yl)-3-hydroxyazetidine-1-carboxylate as the starting material. LC-MS m/z (method A)=567.4 [M+H]+, RT=2.44 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(O)C.[Pd]>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][N:3]=[C:4]([NH2:10])[N:5]=1
Reactant: COc1cc(Cl)nc(N)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(N)n1
Reaction time: 14 h
Yield: 89.4 %

Procedure:
To a solution of 4-chloro-6-methoxypyrimidine-2-ylamine (4.4 g, 27.7 mmol) in EtOAc (200 mL) and ethanol (150 mL), was added diisopropylethylamine (9.6 mL, 55.3 mmol) and 10% palladium on carbon (2.9 g, 2.77 mmol). The heterogeneous solution was stirred under a balloon atmosphere of H2 for 14 hours, at which time the solution was filtered through a Celite pad and the volatiles were removed in vacuo. The residue was dissolved in EtOAc (200 mL), washed with Na2CO3(sat.) (100 mL) and with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 3.1 g (90%) of 4-methoxypyrimidine-2-ylamine. LCMS (m/z): 126 (MH+). 1H NMR (CDCl3): δ 8.00 (d, J=5.7 Hz, 1H), 6.08 (d, J=5.7 Hz, 1H), 4.98 (bs, 2H), 3.84 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[C:29]([C:36]2[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:43])=[N:30][O:31][C:32]=1[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:43])[C:36]=1[C:29]1[C:28]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:32]([CH:33]([CH3:35])[CH3:34])[O:31][N:30]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(O)cc3)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2n1
Yield: 46.5 %

Procedure:
A solution of 75 mg (0.22 mmol) of dimethyl 7-(4-hydroxyphenyl)-2,4-quinolinedicarboxylate, 135 mg (0.44 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 125 mg (0.89 mmol) of K2CO3 in 2 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 62 mg (46%) of dimethyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 8.88 (d, J=9.0 Hz, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=9 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.31 (m, 1H), 6.91 (d, J=9 Hz, 2H), 4.79 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 3.36 (septet, J=7 Hz, 1H), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 606 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9])[OH:21]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: Cc1ccc(C)c(C2(O)C(=O)Nc3ccc(Cl)cc32)c1
Yield: 88.8 %

Procedure:
With 8.00 g of 1-bromo-2,5-dimethyl benzene and 5.79 g of 5-chloroisatin as starting materials, 8.15 g of the title compound (colorless amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([CH3:25])([OH:24])[CH3:23]>CN(C=O)C>[OH:24][C:22]([CH3:25])([CH3:23])[CH2:21][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(C)(O)CCl
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(C)(C)O)c1
Temperature: 80 °C
Yield: 25.8 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (5.07 g, 36.72 mmol) and 1-chloro-2-methylpropan-2-ol (0.75 mL, 7.34 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under vacuum to an oil. Purification by column chromatography on silica gel using EtOAc/hexane (0-50%) gave the product (0.5 g, 26%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([F:15])[CH2:9]1)#[CH:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:13][CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:16]=[C:3]([C:1]#[CH:2])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[F:15])(=[O:21])[CH3:20]
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred solution of 2',3'-dideoxy-5-ethynyl-3'-fluorouridine (1.106 g 0.4 mmol) in dry pyridine (5 ml) at 0° C. was added acetic anhydride (0.05 ml, 0.48 mmol) and stirring maintained at 0° C. for 1.5 hours. After stirring at room temperature for 24 hours, a further aliquot of acetic anhydride (0.02 ml, 0.2 mmol) was added and the mixture stirred at room temperature for 3 hours. After quenching with methanol (1 ml) the solvent was removed by evaporation under reduced pressure and co-evaporated with portions of ethanol (2×30 ml). The residue was recrystallised from ethanol to give a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I-:10].[NH4+].OO.ClCCl>C(O)(=O)C.CCCCCC>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: [I-]
Agent: OO
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1cc(I)ccc1N
Reaction time: 12 h
Yield: 48.2 %

Procedure:
2-Amino-benzonitrile (10 g, 0.085 mol) and ammonium iodide (13.5 g, 0.094 mol) were dissolved in acetic acid (200 mL). 30% aqueous hydrogen peroxide solution (5.3 mL, 0.094 mL) was slowly added at room temperature and stirred for 12 h. After completion of the reaction, the reaction solution was filtered through celite. The filtrate was treated with aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The solid obtained using dichloromethane (10 mL) and hexane (200 mL) was filtered and dried under nitrogen gas to give the title compound (10 g, Yield 48%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:16].[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1Cl
Yield: 25 %

Procedure:
A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (4.69 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (0.97 g), m.p. 149°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[S:8])=[C:4]([F:18])[CH:3]=1.[C-]#N.[K+].Cl.[CH2:23]([OH:25])C>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]2[C:23](=[O:25])[C:10]3([OH:15])[CH:9]([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:7]2=[S:8])=[C:4]([F:18])[CH:3]=1
Reactant: CCO
Reactant: O=C1CCCCC1C(=S)Nc1ccc(Br)cc1F
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C1N(c2ccc(Br)cc2F)C(=S)C2CCCCC12O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
In 350 ml of ethanol was dissolved 33.0 g of 4'-bromo-2'-fluoro-2-oxocyclohexane-1-thiocarboxanilide, and a solution of 7.0 g of potassium cyanide in 35 ml of water was added to the solution with stirring at room temperature over a 10-minute period, followed by adding 9.2 ml of concentrated hydrochloric acid at 10° to 20° C. over a 1 hour period, while cooling. After stirring was continued at room temperature for 1 hour, 30 ml of concentrated hydrochloric acid and 30 ml of water were added to the reaction mixture, and the mixture was warmed and stirred at 50° to 60° C. for 10 minutes. Upon cooling, there resulted crystals, which were collected by filtration, washed with dilute ethanol and dried, thereby producing 24.5 g (yield of 68%) of the subject compound. Recrystallization from ethanol yielded slightly yellow crystals, m.p. 163°-164° C.
Reaction SMILES: N1CCCC(CC(OCC)=O)C1.[CH3:13][N:14]([CH3:23])[C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.FC(F)(F)C(O)=O>[Pt]=O>[CH3:13][N:14]([CH3:23])[C:15]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:22]
Reactant: CN(C)C(=O)c1cccnc1
Agent: O=[Pt]
Agent: CCOC(=O)CC1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1CCCNC1
Yield: 38.4 %

Procedure:
This reaction was run in the same manner as ethyl 3-piperidinylacetate, starting with commercially available N,N-dimethylnicotinamide (10 g; 66.7 mmol) and platinum oxide (1.02 g; 4.49 mmol). Trifluoroacetic acid (5.1 ml; 66.2 mmol) was used in place of L(+) tartaric acid. Crude product was purified by distillation at approximately 150° C./10 torr, giving N,N-dimethyl-3-piperidinecarboxamide (4.0 g) as a colorless oil. MS m/z (positive ion) 157 (MH+: 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:36]=2)=[O:33])[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([OH:43])=[O:42])[CH:36]=2)=[O:33])[N:9]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)N=C(c2ccccc2F)c2cccc(C)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)N=C(c2ccccc2F)c2cccc(C)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]- N′-(3-tert-butoxycarbonylphenyl)urea (170 mg) and trifluoroacetic acid (1.0 ml) in methylene chloride (2.0 ml) was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give a residue, which was washed with diisopropyl ether to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-carboxyphenyl)urea (152.0 mg,98.0%) as a crystalline powder.