Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(C(F)(F)F)c2)C1

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (0.34 g, 2 mmol) in dichloroethane was added 3-(trifluoromethyl)benzaldehyde (0.45 g, 2.6 mmol) and sodium triacetoxyborohydride (0.64 g, 3 mmol). The resultant mixture was stirred at room temperature for 16 hours, and then the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-70% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:23][NH:24][CH2:25][C@H:26]([CH3:29])[CH2:27][OH:28].CS(OCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)(=O)=O.NC[C@H](C)CO.ClC1C(C(O)=O)=C(C2C=CC=CC=2)C=CN=1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCCO>C1COCC1>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:23][N:24]([CH2:25][C@H:26]([CH3:29])[CH2:27][OH:28])[C:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH3:17])[C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: C[C@H](CO)CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cnc(Cl)c(C(=O)O)c1-c1ccccc1
Agent: CS(=O)(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[C@@H](CN)CO
Agent: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Solvent: C1CCOC1
Product: Cc1cnc(Cl)c(C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H](C)CO)c1-c1ccccc1

Procedure:
The same process as in Step 2 in Reference Example 12 was repeated, except that 2-chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-[(S)-3-hydroxy-2-methylpropyl]amine [this was prepared by reacting 3,5-bis(trifluoromethyl)benzyl methanesulfonate with (S)-3-amino-2-methylpropanol in THF, and this is a colorless oily substance and was identified by NMR(200 MHz, CDCl3) ppm: 0.86(3H,d,J=6.8 Hz), 1.98(1H,m), 2.63(1H,dd,J=9.4,11.8 Hz), 2.70-2.90(3H,m), 3.56(1H,dd,J=8.6,10.6 Hz), 3.71(1H,ddd,J=1.4,4.0,10.6 Hz), 3.87(1H,d,J=13.8 Hz), 3.98(1H,d,J=13.8 Hz), 7.79(3H,s)] in place of reacting 2-chloro-4-phenyl-3-pyridinecarboxylic acid with N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[N:7]=1
Reactant: CC(C)(O)c1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1cccc(Br)n1
Reaction time: 3 h

Procedure:
A solution of 2-(6-bromopyridin-2-yl)propan-2-ol (2.44 g, 11.29 mmol) and methansulfonic anhydride (5.90 g, 33.9 mmol) in dichloromethane (35 mL) was charged with triethylamine (6.26 ml, 45.2 mmol). After three hours, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) and brine (2×25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting yellow liquid was purified by silica gel chromatography (2-20% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.70 (t, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 5.89 (s, 1H), 5.33 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reaction time: 16 h

Procedure:
5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example 10, step 2, (0.30 g, 1.01 mmol) was combined with K2CO3 (0.418 g, 3.03 mmol) and THF (6 mL). The mixture was cooled then isopropyl isocyanate (0.12 mL, 1.21 mmol) was warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with water, extracted into ethyl acetate, dried (MgSO4), filtered, and concentrated to dryness. The residue was stirred in methanol and dichloromethane for one hour then filtered to give 0.118 g of 5-amino-1-(4-fluorophenyl)-4-[3-isopropylaminocarbonyloxybenzoyl]pyrazole (mpt. 225.2-230.1° C.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([O:23][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:21][OH:22])([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(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:52]([O:56][C:57]([N:59]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:60]1[N:68]=[C:67]2[C:63]([N:64]=[CH:65][N:66]2O)=[C:62]([O:70][CH3:71])[N:61]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:75]([O:74][C:72]([N:59]([C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])[C:60]1[N:68]=[C:67]2[C:63]([N:64]=[CH:65][N:66]2[O:22][CH2:21][C@H:20]([O:23][CH2:24][P:25]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:32])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:62]([O:70][CH3:71])[N:61]=1)=[O:73])([CH3:78])([CH3:77])[CH3:76]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Reactant: CCOP(=O)(CO[C@@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@H](COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a stirred mixture of diethyl (S)-[1-(t-butyldiphenylsilyloxymethyl)-2-hydroxyethoxy]methylphosphonate (540 mg, 1.12 mmol), triphenylphosphine (440 mg, 1.68 mmol) and 2-[bis-(t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine (prepared as described in EF-A-319228) (428 mg, 1.12 mmol) in dry THF (20 ml), cooled in ice and under a nitrogen atmosphere, was added dropwise diethyl azodicarboxylate (0.27 ml, 1.68 mmol). Within five minutes complete dissolution had occurred and the ice bath was removed. After 1 hour, the solution was evaporated to dryness and the residue obtained chromatographed on silica gel (initial eluant hexane: ethyl acetate 2:1, then hexane:ethyl acetate in the proportions 1:1, 1:2, 1:3) to yield (S)-2-[bis-(t-butoxycarbonyl)amino]-9-[3-(t-butyldiphenylsilyloxy)-2-(diethoxyphosphorylmethoxy)propoxy]-6-methoxypurine as a colourless glass (310 mg, 32%). 1H NMR: δH [(CD3)2SO] 0.96 (9H, s, t-Bu), 1.18, 1.19 (2×3H, 2×t, J= 7 Hz, (OCH2CH3)2), 1.37 (18H, br.s, 2×t-Bu), 3.7-4.15 (12H, m, CHCH2, (OCH2CH3)2, OCH2P, OCH3), 4.45-4.70 (2H, m, NOCH2), 7.25-7.75 (10H, m, 2×Ph), 8.75 (1H, s, H-8). m/z: (FAB+ve ion, thioglycerol/HCl) 844 (MH+, 4%), 644 (100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[Cl:11])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:22]([NH2:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[C:22]([NH:23][S:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)(=[O:14])=[O:13])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: CC(C)(C)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 420 mg (1.57 mmol) of 3-tert-butyl-4-chloro-benzenesulfonyl chloride and 326 mg (1.57 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine using procedure x. Yield: 0.48 g of a white solid. LC-MSD, m/z for C15H15BrCl2N2O2S [M+H]+=436.9, 438.8, 440.8.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[NH2:8].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:7]=1[N:8]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N=C=S)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophosgen (4.0 mL) (supplied from Aldrich) was added dropwise to a solution of 2-fluoro-4-methylaniline (6.31 g) (supplied from Aldrich) in 70 mL of chloroform under ice cooling, and subsequently 15 mL of triethylamine was added dropwise thereto at the same temperature. The reaction solution was stirred at room temperature overnight. Then 70 mL of 1 N hydrochloric acid was added thereto, and the mixture was separated into two liquid phases. The organic layer was washed with 70 mL of water, dried on sodium sulfate anhydrate and subsequently concentrated The residue was applied onto the silica gel column and eluted with hexane, to yield 7.72 g of the title compound.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][CH:39]=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 264, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.76 (d, 2H), 7.43-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.14-6.85 (m, 8H), 5.29 (d, 1H), 5.18 (d, 1H), 4.76 (d, 1H), 3.74-3.68 (m, 1H), 3.33 (t, 1H), 3.03-2.77 (m, 3H), 2.58 (dd, 1H), 1.83-1.74 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][CH:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:41])[CH:47]=2)[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](COc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 45, 132 mg, 0.44 mmol), triphenylphosphine (172 mg, 0.66 mmol) and 3-chlorophenol (0.069 ml, 0.66 mmol) in tetrahydrofuran (5 ml) at 0° C. under a nitrogen atmosphere was added diisopropylazodicarboxylate (0.129 ml; 0.66 mmol) dropwise and allowed to stir to room temperature over 18 hours. The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel, eluting with 10% ethyl acetate/heptane to give the title compound as a colourless gum (66 mg, 37%).
Reaction SMILES: FC1C(O[C:9](=[O:32])[CH:10]([C:17]2[N:18]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][C:21]=23)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH:37]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([N:18]2[C:17]([CH:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]([NH:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:32])=[C:21]3[CH2:22][CH2:23][CH2:24][C:20]3=[N:19]2)=[CH:30][CH:29]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 40 %

Procedure:
To a suspension of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester (95 mg, 181 umol) in DMF (0.9 ml) was added cyclohexylamine (30 ul, 271 umol; CAS Reg. No. 108-91-8) and DMAP (66 mg, 543 umol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 h. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (32 mg, 75 umol; 40%) as brown oil. MS: m/e=440.3 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3nccn3c(N3CCN(c4ccc(F)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Yield: 64.6 %

Procedure:
The mixture of 5-chloro-7-(3,4-dimethoxyphenyl) imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol), 1-(4-fluorophenyl)piperazine.2HCl (55.69 mg, 0.22 mmol), and diisopropylethylamine (85.31 mg, 0.66 mmol) in 3 ml of 2-propanol was stirred at 90° C. for 3 h, and cooled to room temperature. To the obtained mixture, 3 ml of ice water was added, the produced white solid was collected by filtration, and dried to give the pure product (56 mg, 64.6%) of 7-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorophenyl)piperazin-1-yl]-imidazo[-1,2-c]pyrimidine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][N:22]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:29][CH:30]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 7.5 °C
Yield: 56.4 %

Procedure:
Lithium aluminium hydride (304 mg) was added to a solution of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (1.3 g) in THF (20 ml) with stirring at 5-10° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 4 hours. The reaction mixture was cooled at 5° C. and water (0.3 ml), 15% NaOH solution (0.3 ml) and water (0.9 ml) was added, the resultant mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give {6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}methanol (670 mg)
Reaction SMILES: [NH2:1][C:2](=[N:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:32]2[NH:36][C:35](=[O:37])[N:34]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:33]=2)[C:11]2[C:12]([F:31])=[C:13]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.Cl[CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58].C(=O)([O-])O.[K+].CN(C=O)C>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:32]2[N:36]=[C:35]([O:37][CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[N:34]([C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)[N:33]=2)[C:11]2[C:12]([F:31])=[C:13]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCCOC(=O)c2ccncc2)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCOC(=O)C(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 45 °C
Reaction time: 20 h
Yield: 33.5 %

Procedure:
Under nitrogen atmosphere, a mixture of isonicotinic acid 2-{3-[(4-{amino[benzoylimino]methyl}phenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (31.3 mg), 2,2-dimethylpropionic acid chloromethyl ester (9.1 mg), potassium hydrogen carbonate (6.7 mg), and DMF (2 mL) was stirred at 45° C. for 20 hours. The mixture was poured into ethyl acetate (100 mL) and water (20 mL). After shaking the mixture, the organic layer was collected, sequentially washed three times with water (20 mL) and with saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (12.2 mg).
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)CC1)C1C=CC=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(CCc1c[nH]c2cnc(-n3cncn3)cc12)NN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)CCc2c[nH]c3cnc(-n4cncn4)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl) propionic acid (0.34 g, 1.3 mmol) (prepared as described in Example 53 Step 7) in anhydrous DMF (5 ml) was added 1-tert-butyloxycarbonylpiperazine (0.5 g, 2.7 mmol), 1-hydroxybenzotriazole (225 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45 g, 2.3 mmol) and triethylamine (0.23 ml, 1.7 mmol). The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate (25 ml) and water (20 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The combined organic layers were dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (90:10) to afford the title compound, with some impurities, as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:37]1[CH:36]=[CH:35][N:27]2[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:8])=[CH:39][CH:38]=3)=[O:23])[CH2:25][C:26]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 113.5 %

Procedure:
To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 800 mg of solid. The solid is dissolved in methylene chloride washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is filtered through hydrous magnesium silicate, dried with Na2SO4 and concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 400 mg of the desired product as a white solid, m.p. 232°-235° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@H:13]([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[OH:23][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:24])[CH2:2][O:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12]1
Reactant: Oc1ccncc1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3ccncc3)CC[C@@H]12
Temperature: 25 °C
Yield: 7.7 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5β-pregnan-20-one (500 mg, 1.26 mmol), 4-hydroxypyridine (144 mg, 1.51 mmol), and triethyl amine (200 μL) in 10 mL of TBIF was heated under reflux for 4 h. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 50% acetone in CH2Cl2 yielded 3α-hydroxy-21-(pyrid-4-yloxy)-5β-pregnan-20-one (40 mg) as an oily solid; TLC Rf (acetone:CH2Cl2 1:1)=0.28.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=O)[CH3:2].[S:13]1[C:25]2C3C=CC=CC=3C=[N:17][C:16]=2[CH:15]=[CH:14]1>>[CH3:2][C:1]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:25]2[S:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: c1ccc2c(c1)cnc1ccsc12
Reactant: CC(=O)c1ccccc1B(O)O
Product: Cc1nc2ccsc2c2ccccc12
Yield: 86 %

Procedure:
Starting from 2-Acetylphenylboronic acid (15 g, 91 mmol) in place of 2-formylphenylboronic acid in Step 3, the title compound (12 g, 86%, m.p. 74-76° C.) was synthesized in essentially the same manner as described in Steps 1-3 for Thieno[3,2-c]isoquinoline.