Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([CH3:49])[CH3:48])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:10][C:3]1([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[N:2]1[O:1][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)([CH3:48])[CH3:49])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(N)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(ON5C(C)(C)CCCC5(C)C)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Yield: 87.3 %

Procedure:
The title compound is prepared reacting 0.59 g (3.75 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 1.0 g (10 mmol) of tert-butyl nitrite, 2.3 mg (0.0037 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 24.0 g (75 mmol) of 5-(4-aminophenyl)-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole, prepared in Example 17, in 10 mL of pyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (2% ethyl acetate/heptane) to give 2.20 g of the title compound as a colorless oil in 87.3% yield. M/S [M+1]673.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:2].[H-].[Na+].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl.O>CN(C)C=O.C1COCC1>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH:1]=[O:2])[CH:8]=[CH:9]1
Reactant: ClCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc2ccn(Cc3cccc(/C=C/c4ccc5ccccc5n4)c3)c12
Reaction time: 0.5 h

Procedure:
A solution of 7-formyl indole (Example 10a (iv) (2 g, 13.8 mmole) in dry dimethyl formamide (40 ml) was cooled in an ice bath and stirred as sodium hydride (60% dispersion in mineral oil) (0.66 g, 16.5 mmole) was added in portions over 10 minutes. The mixture was stirred for a further 30 minutes, then a solution of 3-[2-(E)-quinolin-2-yl ethenyl]benzyl chloride (Example 1b) (4.24 g, 15.2 mmole) in dry THF (12 ml) was added over 2 minutes. The reaction mixture was stirred at room temperature for 3 days, then poured into water, extracted into ethyl acetate, dried and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:40]([O:42][CH3:43])=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To 1.5 g (3.3 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 1.2 g (15 mmole) of pyridine and, finally, 1.3 g (13 mmole) of methyl chloroformate in 10 ml of ethyl acetate was added over 30 minutes. After an additional 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.7 g of the desired compound, mp 142°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:47])[CH2:26][C@@H:27]([C:42](OCC)=[O:43])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[BH4-].[Li+].CO.O>C1COCC1>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:28]([CH:29]([CH3:31])[CH3:30])[C@H:27]([CH2:42][OH:43])[CH2:26][CH:25]([F:47])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C@H:6]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NCCC(F)C[C@@H](CO)N(C(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of the material from Step 7 (23 mg, 0.034 mmol) in THF (343 μL) at 0° C. were added a solution of 2 M lithium borohydride in THF (69 μL, 0.137 mmol) and methanol (6 μL, 0.137 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC showed not complete reaction. Additional 2 equiv of lithium borohydride was added, stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 100:0) to afford 18 mg of the title compound as a colorless foam. LCMS (M+1)=629. 1H NMR (Acetone-d6): δ 7.60 (d, J=8.34 Hz, 1H), 7.53 (d, J=8.34 Hz, 1H), 7.46-7.36 (m, 4H), 7.33-7.24 (m, 4H), 7.23-7.15 (m, 2H), 7.16-7.08 (m, 1H), 6.77 (d, J=8.34 Hz, 2H), 6.38 (d, J=9.19 Hz, 1H), 5.52-5.44 (m, 1H), 4.97 (t, J=10.18 Hz, 1H), 4.49-4.38 (m, 1H), 4.35-4.12 (2×b, 1H), 3.94-3.83 (m, 2H), 3.81-3.67 (m, 2H), 3.50 (s, 3H), 3.42 (q, J=7.00 Hz, 1H), 3.29-3.03 (2×b, 1H), 2.98-2.88 (m, 1H), 2.17-2.05 (m, 1H), 1.88-1.71 (m, 1H), 1.45-1.24 (m, 2H), 1.20 (d, J=7.00 Hz, 3H), 1.10 (d, J=7.00 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CN=C1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: Nc1cccnc1
Agent: c1c[nH]cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1cccnc1)C2=O
Temperature: 190 °C
Yield: 62.2 %

Procedure:
5-Amino-6-nitroisoindoline-1,3-dione (3.00 g, 14.48 mmol), 3-aminopyridine (5.45 g, 57.92 mmol) and imidazole (3.94 g, 57.92 mmol) were suspended in diphenyl ether (50 mL). The mixture was stirred and heated to 190° C. for 3 days under argon. Then, the solid was filtered, washed with hexanes and purified by column chromatography (silica-gel, CH2Cl2/Acetone=7/3 v/v) to give a yellow solid product, 2.56 g, 62.2% yield. MS: 282.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.65 (d, 1H, J=2.0 Hz), 8.62 (dd, 1H, J=5.0 Hz, J2=1.0 Hz), 8.46 (S, 2H), 8.42 (s, 1H), 7.89 (m, 1H), 7.60-7.58 (m, 1H), 7.55 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)CC2C=CC(OC)=CC=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.IC.[C:51](=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:51])[CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([NH:31][CH:41]2[CH2:42][CH2:43]2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC5CC(=O)N(C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1CC(N(C)C2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A vial was charged with 2-((2-chloro-5-cyano-3-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg, 0.053 mmol) and iodomethane (3.94 μl, 0.063 mmol) in tetrahydrofuran (263 μl). Cesium carbonate (34.2 mg, 0.105 mmol) was added and the reaction mixture was stirred at room temperature 5 h. The reaction mixture was quenched with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was used as is in the final deprotection.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38].[NH2:42][C@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([C:52]([N:54]([CH3:67])[CH:55]3[CH2:60][CH2:59][N:58]([C:61]4[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=4)[CH2:57][CH2:56]3)=[O:53])[CH:50]=2)[CH2:45][CH2:44]1>C1COCC1.ClCCl>[CH3:67][N:54]([CH:55]1[CH2:60][CH2:59][N:58]([C:61]2[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)[C:52]([C:49]1[CH:50]=[C:51]2[C:46](=[CH:47][CH:48]=1)[CH2:45][CH2:44][C@H:43]2[NH:42][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])=[O:53]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](N)CC2)C1CCN(c2ccncc2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)CC(F)(F)F)CC2)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
HATU (168 mg, 0.44 mmol, 1 eq) and DIPEA (200 μl, 1.1 mmol, 2.5 eq) were added to an ice-cooled solution of 3,3,3-trifluoropropionic acid (67.5 mg, 0.528 mmol, 1.2 eq) in THF (5 ml), and the mixture was stirred for 30 min. (R)-3-Amino-N-methyl-N-(1-(pyridin-4-yl)piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (154 mg, 0.44 mmol, 1 eq) was dissolved in THF (2 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with sat. sodium hydrogen carbonate solution (40 ml), sat. ammonium chloride solution (40 ml), water (40 ml) and sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 59% (120 mg, 0.26 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:18][CH2:19][CH:20]([CH3:22])[CH3:21].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.[H-].[Na+].Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:12]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Under an argon atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methanol (587 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (587 mg) in THF (9.6 mL) was added 60% sodium hydride (100 mg) at 0° C., and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (890 mg) as a colorless oil.
Reaction SMILES: CO.[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27](OC)=[O:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].[ClH:33]>C(O)C.C(O)(=O)C.O.C(O)(C)(C)C>[ClH:33].[ClH:33].[CH3:3][N:4]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[N:25][CH:26]=2)=[O:20])[CH2:17][CH2:18]1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(CO)nc2)CC1
Reaction time: 0.08 h

Procedure:
1 ml of methanol was dropwise added, at about 80° C., to a mixture of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(2-methoxycarbonylpyridin-5-yl)carbonylpiperidine, 0.12 g of sodium borohydride and 3.88 g of tert-butanol. (This gave rise to foaming.) In this state, the mixture was refluxed by heating, for 1.5 hours. The reaction mixture was returned to room temperature and mixed with 1 ml of water and 1 ml of acetic acid. The mixture was stirred for 5 minutes and then subjected to distillation to remove the solvent. The residue was mixed with water for dissolution. The solution was made basic with an aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The resiude was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=45/1 to 25/1). The product was converted to a hydrochloride with 2 equivalents of 5 N hydrochloric acid, in ethanol. The hydrochloride was crystallized from ethyl acetateethanol and recrystallized from ethanol-water to obtain 0.32 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(2-hydroxymethylpyridin-5-yl)carbonylpiperidine dihydrochloride as colorless prism-like crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].S(=O)(=O)(O)O.Cl[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1.O.CN(C)C1C=CC=CC=1>CO.ClCCl>[CH3:1][C:2]1[CH:8]=[C:7]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:3]=1[N:4]=[C:22]1[NH:26][CH2:25][CH2:24][NH:23]1
Reactant: ClC1=NCCN1
Reactant: Cc1cc(Sc2ccccc2)ccc1N
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Sc2ccccc2)ccc1N=C1NCCN1
Reaction time: 72 h

Procedure:
The aniline derivative from Step C (3.0 g, 14 mmoles) is allowed to react with 2-chloro-2-imidazoline bisulfate (4.04 g, 20 mmoles) in methanol (60 ml) containing water (10 ml) and N,N-dimethylaniline (2.67 g, 22 mmoles). After 72 hours the reaction is worked up in the manner described in Example 2, except that the initial dichloromethane extracts are evaporated to a residue and triturated with hexane before extraction with 2 N acetic acid. The yield of pure product is 2.95 g, m.p. 140°-141° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: OCc1cccc2cn[nH]c12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCc1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a round-bottomed flask, (1H-indazol-7-yl)-methanol (572 mg, 3.09 mmol) was dissolved in DMF (8 ml) and potassium hydroxide (671 mg, 12.0 mmol) and iodine (1.57 g, 6.18 mmol) were added. The dark brown suspension was stirred at room temperature overnight then quenched with aqueous 10% Na2S2O3 and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 433 mg (51%) of (3-iodo-1H-indazol-7-yl)-methanol as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:6]#[N:7])=[C:4]([F:20])[CH:3]=1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([C:6]#[N:7])=[C:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])[CH:9]=1
Reactant: CC(C)(C)S(N)=O
Reactant: COc1cccc(C(=O)c2cc(Cl)cc(F)c2C#N)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(C(=NS(=O)C(C)(C)C)c2cc(Cl)cc(F)c2C#N)c1
Temperature: 75 °C
Yield: 58.7 %

Procedure:
4-Chloro-2-fluoro-6-(3-methoxybenzoyl)benzonitrile (2.56 g, 8.84 mmol), 2-methyl-2-propanesulfinamide (1.392 g, 11.49 mmol) and titanium(IV) ethoxide (4.62 mL, 22.09 mmol) were dissolved in THF (30 mL) and stirred at 75° C. over weekend. When cooled to rt, the mixture was diluted with DCM (25 mL). Saturated aqueous NaHCO3 (3 mL) was added followed by silica and the mixture concentrated under reduced pressure until a free flowing powder was obtained. Purification on a silica gel column (0-40% EtOAc in heptane as eluent) gave 2.04 g (59% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]3[CH3:22])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+]>[Cl-].[Cl-].[Zn+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:18][C@@H:17]3[CH3:22])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)n[nH]c2=O)nc1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)n[nH]c2=O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer was charged with 253c (321 mg, 1.0 mmol), 3-oxetanone (142 mg, 2.0 mmol), NaBH3CN (125 mg, 2.0 mmol), ZnCl2 (272 mg, 2.0 mmol), and methanol (10 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Water (20 mL) was added to the residue and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 253d (210 mg, 56%) as yellow solid. MS-ESI: [M+H]+ 377.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:25][CH:24]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1Cc1ccccc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-benzylpiperazine-2-carboxylate (Helv. Chim. Acta, 1962, 45, 2383) to give 1-benzyl-2-ethoxycarbonyl-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine in 67% yield.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:25])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCOC(=O)Cl
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)n1cc(F)c(N(C)Cc2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a stirred solution of 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (0.200 g, 0.858 mmol) in CH2Cl2 (18 mL) were added N-pentyl chloroformate (0.142 g, 0.944 mmol) and Et3N (0.263 mL, 1.88 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred an additional 3 h. The crude reaction mixture was evaporated to dryness and the residue was triturated with methyl t-butyl ether (MTBE; 4×5 mL) to remove triethylamine hydrochloride. The combined organic layers were evaporated in vacuo. The crude product was purified by reverse phase chromatography. Pentyl 4-(benzyl(methyl)amino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (20.1 mg, 6.7%) was isolated as a yellow gum: 1H NMR (methanol-d4) δ 8.04 (d, J=6.2 Hz, 1H), 7.38-7.25 (m, 5H), 4.24 (t, J=6.6 Hz, 2H), 3.21 (d, J=3.3 Hz, 2H), 1.78-1.65 (m, 3H), 1.37 (dd, J=9.2, 5.5 Hz, 6H), 0.92 (t, J=7.1 Hz, 3H); ESIMS m/z 348 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:3]=1[C:18]#[N:19].[I-].F[P-](F)(F)(F)(F)F.[CH2:28]([O+](CC)CC)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7](=[NH:9])[O:8][CH2:28][CH3:29])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:3]=1[C:18]#[N:19]
Reactant: N#Cc1c(Br)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Product: CCOC(=N)c1sc(Br)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 104 %

Procedure:
To a solution of 5-bromo-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (prepared in an analogous way to the iodide intermediate shown in Example 3-A; 0.500 g, 1.33 mmol) in dichloromethane (28 mL) at 0° C. was added triethyloxonium hexafluorophosphate (2.31 g, 9.31 mmol). The mixture was allowed to slowly warm to room temperature, and stirred for 16 hours. The solution was poured into 1M sodium carbonate solution at 0° C., then the layers were separated, and the aqueous layer was extracted 3 times with dichloromethane. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.558 g, 104%). LCMS: (FA) ES+, 405. 1H NMR (400 MHz, d1-chloroform) δ: 7.60-7.57 (m, 1H), 7.43-7.38 (m, 1H), 7.29-7.25 (m, 1H), 4.30-4.22 (m, 2H), 1.40-1.37 (m, 3H).