Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et3N (160 μL, 1.15 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 min before a solution of ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and then saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)propanoate (0.081 g, 50%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.67 (s, 1H), 7.23-7.19 (m, 2H), 7.04-7.01 (m, 3H), 6.89 (d, J=0.0 Hz, 1H), 6.28 (s, 1H), 6.06 (s, 2H), 4.25-4.17 (m, 2H), 3.91 (q, J=7.2 Hz, 1H), 1.72-1.70 (m, 2H), 1.61 (s, 2H), 1.29 (t, J=7.1 Hz, 4H), 1.13-1.11 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1.[OH:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH:30]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.CO>[OH:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:18]2[CH2:19][CH2:20][C:14]3([O:13][CH2:12][CH2:11][N:10]([C:8]([C:6]4[N:7]=[C:3]([CH3:2])[S:4][CH:5]=4)=[O:9])[CH2:15]3)[CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=CCOc1ccc(CCO)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.63 g) was added to a solution of 2-(4-(2-hydroxyethyl)phenoxy)acetaldehyde (example 3, step b) (0.541 g) in a mixture of NMP (10 mL) and acetic acid (0.11 mL). The resulting mixture was stirred at room temperature for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.64 g) was then added and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (100 mL) and eluted with 3M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo and the residue purified by silica gel chromatography, eluting with 95:5 ethyl acetate:triethylamine to give the subtitled compound as a brown oil. Yield 0.74 g.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49]>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCC(=O)Cl
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5 mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and valeryl chloride (5 μL, 42 μmole, 1.05 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.21 (s, 1H), 7.62 (t, 1H), 7.36 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.42 (s, 2H), 3.30 (water), 3.00 (s, 2H), 2.74 (t, 2H), 2.48 (DMSO), 1.99 (t, 2H), 1.56 (m, 4H), 1.41 (m, 2H), 1.26 (m, 1H), 1.20 (m, 3H), 0.81 (t, 3H), 0.60 (m, 4H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:13][CH:12]=1
Reactant: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCOc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
Methanesulfonylchloride (93 mg, 63 μL, 0.82 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl N-{4-[(3-methylbutyl)oxy]phenyl}glycinate (intermediate 6, 0.20 g, 0.68 mmol) and triethylamine (138 mg, 189 μL, 1.36 mmol) in dichloromethane (2 mL) at room temperature under a nitrogen atmosphere. Stirring was continued for 3 h then aqueous hydrochloric acid (1.0 M; 2 mL) was added. The organic phase was separated and the aqueous phase washed with dichloromethane (3×5 mL). The organic phases were combined, dried (magnesium sulfate) then evaporated to dryness. The residue was chromatographed on silica gel (30% diethyl ether:cyclohexane) to give the title compound as a white solid (140 mg, 56%). LC/MS: 3.72 min; z/e 389, calcd (M+18) 389. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.45 (9H), 1.70 (2H), 1.85 (1H), 3.10 (3H), 3.95 (2H), 4.30 (2H), 6.85 (2H), 7.35 (2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34](F)[CH:33]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[C:36]([NH:1][C:2]3[S:3][C:4]([C:14](=[O:15])[NH2:16])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=4)[N:6]=3)[CH:37]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Yield: 18.5 %

Procedure:
To a mixture of 0.35 g (1.38 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 0.59 g (1.66 mmole) of 4-(3-fluoro-4-nitro-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (IV.23) and 10 mL of dimethylformamide was added 2.24 g (6.90 mmole) of cesium carbonate. The mixture was heated at 70 degrees for 5 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 0.15 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (VI.23).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8](Cl)=[CH:9][C:10]=1[CH3:11])=[O:4].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1OC
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1OC
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 5.0 g (21.8 mmol) 6-chloro-2-methoxy-4-methylpyridine-3-carboxylic acid methylester, 2.0 g (24.0 mmol) morpholine and 6.0 ml (43.5 mmol) NEt3 in NMP (21 ml) was heated at 90° C. for 2 d. After cooling to RT the mixture was partiotionated between EtOAc and a 1M aq. NaHCO3 sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 2.7 g (9.8 mmol, 45%) 2-methoxy-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.I[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][CH3:34])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Product: COCCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 10 above, using 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 51 and iodomethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:67])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]([CH2:44][C:45]5[C:54]6[C:49](=[CH:50][C:51]([Br:55])=[CH:52][CH:53]=6)[CH:48]=[CH:47][C:46]=5[O:56][CH3:57])[C:36](=[O:58])[C@@H:35]([NH:59]C(OC(C)(C)C)=O)[CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[CH2:16][C@H:15]([NH:68]C(=O)OC(C)(C)C)[C:14]1=[O:76])=[C:7]([O:77][CH3:78])[CH:6]=[CH:5]2.C([Cl:82])(=O)C>CO>[ClH:82].[ClH:82].[NH2:59][C@H:35]1[CH2:34][N:33]([C:31](=[O:32])[C:28]2[CH:27]=[CH:26][C:25]([C:24]([N:17]3[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:13]([CH2:12][C:8]4[C:9]5[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=5)[CH:5]=[CH:6][C:7]=4[O:77][CH3:78])[C:14](=[O:76])[C@@H:15]([NH2:68])[CH2:16]3)=[O:67])=[CH:30][CH:29]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]([CH2:44][C:45]2[C:54]3[C:49](=[CH:50][C:51]([Br:55])=[CH:52][CH:53]=3)[CH:48]=[CH:47][C:46]=2[O:56][CH3:57])[C:36]1=[O:58]
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CO
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CN(C(=O)c2ccc(C(=O)N3C[C@H](N)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cc2)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
tert-Butyl N-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[4-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-(tert-butoxycarbonylamino)-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]carbamate (31 mg, 0.026 mmol) and acetyl chloride (9.3 μL, 0.131 mmol) were combined in MeOH (2 mL) and stirred at room temperature for 16 h. The mixture was concentrated to give (3S)-3-amino-1-[4-[(3S)-3-amino-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-2,3-dihydro-1,5-benzodiazepin-4-one dihydrochloride as a white solid (27 mg, 98%) that was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1.[CH2:25]([CH:33]([CH2:36]O)[CH2:34][OH:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:7]([CH:8]2[O:35][CH2:34][CH:33]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:36][O:9]2)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)c(F)n2)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2ccc(C3OCC(CCCCCCCC)CO3)c(F)n2)cc1
Yield: 41.9 %

Procedure:
2.20 g (6.68 mmol) of 2-fluoro-3-formyl-6-(4-octyloxyphenyl)pyridine, 1.26 g (6.68 mmol) of 2-octylpropane-1,3-diol, 0.02g (0.10mmol) of p-toluenesulfonic acid and 3.00 g of sodium sulfate are stirred in 100 ml of toluene at room temperature for 68 hours. 0.14 ml (1.00 mmol) of triethylamine is then added, sodium sulfate is filtered off, the filtrate is concentrated, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.40 g of 2-fluoro-3-(5-octyl-1,3-dioxane-2-yl)-6-(4-octyloxyphenyl)pyridine. ##STR63##
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)=O)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:32][C:31]4[C:26]([N:25]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(c3nc4ncccc4[nH]3)CC2)c1C
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (compound 26, 50 mg, 0.15 mmol) and 2,3-diaminopyridine (33 mg, 0.30 mmol) in CH2Cl2 (0.5 mL) is added polyphosphoric acid (1 mL). The mixture is concentrated to remove CH2Cl2. After being stirred at 150° C. for 1.5 h, the mixture is cooled to 25° C., diluted with water (10 mL), and basified by 10% aqueous solution of sodium hydroxide to pH ˜8. The aqueous solution is extracted with CH2Cl2 (5×15 mL). The combined organic layers are concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 2-[1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidin-4-yl]-1H-imidazo[4,5-b]pyridine (33.8 mg, 55%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.C(N(CC)CC)C.[CH:46]1([N:52]=[C:53]=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>O1CCOCC1>[CH2:32]([O:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:53]([NH:52][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:54])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[S:21]1(=[O:23])=[O:22])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C=NC1CCCCC1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNC(=O)NC3CCCCC3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 85 °C

Procedure:
To 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.25 g, 0.434 mmol) (Example 67, step A) in 5 mL dioxane is added triethylamine (0.12 mL, 0.87 mmol), followed by cyclohexyl isocyanate (0.11 mL, 0.87 mmol) and the mixture heated to 85° C. for 1 h. The reaction mixture is concentrated and then partitioned between EtOAc and 1N HCl. The combined organic layers are washed with saturated sodium bicarbonate and brine, dried, and evaporated to afford a crude orange oil which is purified by flash chromatography to afford the title compound as a foam.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:4].O.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[C:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:14][NH:15][C:3]=1[NH2:4]
Reactant: NN
Reactant: CC(C#N)C(=O)c1cccnc1
Solvent: CCO
Solvent: O
Product: Cc1c(-c2cccnc2)n[nH]c1N
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-3-oxo-3-(pyridin-3-yl) propanenitrile (1.5 g, 9.4 mmol) in EtOH (20 mL) was added 85% hydrazine hydrate (2 mL). The resulting mixture was heated to reflux for 2 hours. After cooling to rt, the solvent was removed in vacuo and the crude product purified by column chromatography (DCM:MeOH=10:1) to give the desired product: MS (m/z): 175.0 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.71 (d, 1H, J=2.0 Hz), 8.50-8.51 (m, 1H), 7.99 (d, 1H, J=8.0 Hz), 7.50-7.55 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]2[CH:20]=[N:21][O:22][C:18]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.46 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.48 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 111–112° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:37]#[N:38])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 70 %

Procedure:
2-(3-Bromoimidazo[1,2-a]pyrimidin-7-yl)propan-2-ol was coupled with 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 4-fluoro-3′-[7-(2-hydroxyprop-2-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (260 mg, 70%) as a yellow powder: δH (360 MHz, CDCl3) 1.61 (6H, s), 4.51 (1H, s), 7.07 (1H, d, J 7), 7.45 (1H, ddd, J 8, 1 and 1), 7.51-7.60 (3H, m), 7.63-7.69 (2H, m), 7.73 (1H, s), 7.90 (1H, s), 8.94 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19]([Cl:27])=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:27].[O:34]1[C:33]2[CH:38]=[CH:39][C:30]([CH2:29][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=5)[C:19]([Cl:27])=[CH:18][C:17]4=[O:28])[CH2:12][CH2:13]3)=[CH:31][C:32]=2[O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(F)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1cc(Cl)c2ccc(F)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 5 mL of an ethyl acetate solution containing 0.76 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 5 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 572 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-chloro-7-fluoroquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[N:11](CC2C=CC=CC=2)[C@@H:10]([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([C@H:8]1[CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)N1

Procedure:
267 mg (0.7 mmol) of stereochemically pure trans- or cis-N-benzylazetidine-2,4-dicarboxylic acid benzyl t-butyl ester, 50mg of 10% Pd/C, and 20 ml of methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 4 hours. The catalyst is filtered off and thoroughly washed, and the solution evaporated to dryness and dried in vacuo to afford as off-white solids the trans- or cis-azetidine-2,4-dicarboxylic acid mono-t-butyl ester.