Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH3:5].[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=2)=[N:26]1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (4.11 mmol) in DMF (10 mL) was treated with the 1,5-dimethyl-1H-pyrazol-3-ylamine (4.52 mmol), DIPEA (5.93 mmol) and HATU (3.85 mmol) and stirred at RT overnight, under an argon atmosphere. The mixture was poured onto water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (20 mL) and evaporated in vacuo before chromatography on silica, eluting with 20-80% ethyl acetate in isohexane, to afford the desired compound as a yellow oil (1.05 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[O:40])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[C:39]([NH:41][CH2:42][C:43](=[O:45])[CH3:44])=[O:40])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Dess-Martin reagent (814 mg) was added to a stirred solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-hydroxypropyl)-2-piperidinecarboxamide (548 mg) [see Preparation 80) and triethylamine (0.89 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 1 hr after which time the mixture was filtered through a pad of basic alumina and washed through with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-oxopropyl)-2-piperidinecarboxamide (300 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)([N:15]=[C:16]=[O:17])=[O:14]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]1([CH:7]2[C:8]3[O:12][C:16](=[O:17])[NH:15][C:13](=[O:14])[C:9]=3[CH2:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CC2
Yield: 13.1 %

Procedure:
A solution of 2-phenylcyclopentanone (19.995 g, 125 mmol) and carbonisocyanatidic chloride (23.70 g, 225 mmol) was stirred at 58° C. for 1 h and at 130° C. for 45 min. The resulting tar was dissolved in ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The product was purified by column chromatography on silica gel to give 7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g, 16.36 mmol, 13% yield) as a brownish solid. LC-MS (M+H)+=230.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18 (2H, d, J=7.3 Hz), 4.20 (1H, t, J=7.6 Hz), 2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([N:44]([CH3:45])[CH3:46])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (Example 339 step 4, 0.0475 g, 0.111 mmol) and N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (Example 384, Step 2 0.0380 g, 0.152 mmol) in THF (1 mL) in 20 mL scintillation vial, NaHMDS (Aldrich, 1 M in THF, 0.445 mL, 0.445 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (20 mL) and EtOAc (20 mL) resulted in having insoluble materials. The biphase mixture was filtered and the solid was collected and washed with water to afford N′-(2-chloro-5-((3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-(4-morpholinyl)ethyl)-2-pyridinyl)amino)-3-pyridinyl)-N,N-dimethylsulfamide (0.0472 g, 65% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.12 (s, 1H) 9.76 (s, 1H) 8.86 (d, J=2.35 Hz, 1H) 8.50 (d, J=1.96 Hz, 1H) 8.32 (s, 2H) 6.79 (br. s., 1H) 5.87 (d, J=8.22 Hz, 1H) 4.16-4.26 (m, 1H) 3.79-3.90 (m, 1H) 3.73 (br. s., 4H) 3.55 (br. s., 1H) 2.87-3.04 (m, 9H) 2.50 (br. s., 4H) 1.98-2.21 (m, 3H) 1.69-1.92 (m, 3H) 1.48 (d, J=6.46 Hz, 3H). m/z (ESI, positive ion): 657.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>C(OCC)(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: CN(c1cccc(C(F)(F)F)c1)c1cc(Cl)ncn1
Temperature: 126 °C
Yield: 61.9 %

Procedure:
4,6-Dichloropyrimidine (1.55 g, 0.01 mol) and N-metyl-3-trifluoromethylaniline (2.0 g, 0.11 mol) are combined and heated to 126° C. under N2 for 1.5 hours. The resulting oil is taken up in ethyl acetate, is washed with 10% sodium carbonate and dried over sodium sulphate. The organic phase is concentrated under reduced pressure to yield a yellow oil which is purified by column chromatography to give 4-chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (1.78 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[C:23](#[N:25])[CH3:24].ClCCl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12][C:23](=[NH:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClNCc1cc(Br)ccc1OCc1ccccc1
Reactant: CC#N
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=N)NCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-benzyloxy-5-bromobenzylamino hydrochloride (10 g) in toluene (75 ml) at 4° C. was added a solution of trimethylaluminium in toluene (2M, 15.2 ml). The mixture was stirred at ambient temperature for 2 hours, acetonitrile (6.5 ml) added and the mixture heated at 80° C. for 18 hours. The mixture was cooled and poured onto a slurry of silica gel (300 g), and dichloromethane. The solvent was filtered off and the product eluted from the silica gel with methanol to give N1 -[2-benzyloxy-5-bromobenzyl]acetamidine (5.51 g).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH:5]([NH:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]3[N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=23)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([NH:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[C:18]3[C:23](=[CH:22][N:21]=[C:20]4[C:19]=3[CH:27]=[CH:26][N:25]4[S:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:30])[N:24]=[N:1]2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)NC(=O)[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)NC(=O)[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Reaction time: 0.75 h

Procedure:
Sodium nitrite (12 mg, 0.17 mmol) was added to a solution of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarboxylic acid isopropylamide (70 mg, 0.15 mmol) in acetic acid (1 mL) and stirred for 45 minutes. The mixture was concentrated under vacuum affording trans 4-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanecarboxylic acid isopropylamide which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.58 min, m+H=467.35.
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:2][C:3]3[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=3)=[C:14]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:15]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(C(O)c2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1csc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
Under an argon atmosphere, to an ice-cooled solution of ethyl 2-[hydroxy(6-methoxy-2-phenyl-1H-indol-3-yl)methyl]thiazole-4-carboxylate (69.0 mg) and triethylsilane (0.135 mL) in methylene chloride (1.7 mL) was slowly added dropwise a boron trifluoride diethyl ether complex (0.107 mL). After stirring for 10 minutes, the mixture was stirred at room temperature for additional 15 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (17.0 mg). 1H-NMR (CDCl3) δ ppm: 1.43 (3H, t, J=7.2 Hz), 3.87 (3H, s), 4.45 (2H, q, J=7.2 Hz), 4.61 (2H, s), 6.79 (1H, dd, J=2.1, 8.7 Hz), 6.93 (1H, d, J=2.1 Hz), 7.30-7.60 (6H, m), 7.99 (1H, s), 8.13 (1H, br s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([NH:11][C:12]([N:14]1[C:18]2[CH2:19][CH2:20][O:21][CH2:22][C:17]=2C(C2C=CC(F)=C(F)C=2)=[N:15]1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=O)=[C:35]([F:42])[CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]2[C:19]3[CH2:20][O:21][CH2:22][CH2:17][C:18]=3[N:14]([C:12]([NH:11][C@@H:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:31])=[O:13])[N:15]=2)=[C:35]([F:42])[CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(Cl)cc2F)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 88 was prepared according to the procedure for the synthesis of compound 36 by replacing 3,4-difluorobenzoyl chloride with 4-chloro-2-fluorobenzoyl chloride. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.16-7.24 (m, 2H), 6.45 (br, 1H), 4.65 (s, 2H), 4.18 (d, J=9.1 Hz, 1H), 3.94 (t, J=5.6 Hz, 2H), 3.73 (br, 2H), 3.45 (br, 2H), 3.17 (br, 2H), 1.10 (s, 9H). Purity: 98%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCCC4)c3)n2)n1
Yield: 71.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with pyrrolidine (0.131 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.230 g, 71%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 174° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1)[C:7]#[N:8])([O-:3])=[O:2].[CH:17]12[CH2:25][CH:21]([CH2:22][NH:23][CH2:24]1)[CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2.O>CC(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:23]2[CH2:24][CH:17]3[CH2:25][CH:21]([CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]3)[CH2:22]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3[N+](=O)[O-])C2)C1
Yield: 54 %

Procedure:
3-Nitro-4-(2-oxiranylmethoxy)benzonitrile (2.9 g; 13.2 mmol; from step (a) above) was added to a stirred solution of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3 g; 13.2 mmol; see Example F above) in IPA:H2O (12.5 mL; 9:1), and the reaction mixture was refluxed for 3 h. Concentration of the reaction mixture and purification by column chromatography (DCM:MeOH; 15:1) gave the title compound in a 54% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(Cl)c2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Nc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc2c(c(Nc3ccc(Cl)cc3Cl)n1)CN(C(=O)OC(C)(C)C)CC2
Yield: 60.8 %

Procedure:
A mixture of tert-butyl 4-chloro-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (100 mg, 0.317 mmol), 2,4-dichloroaniline (56 mg, 0.348 mmol) and sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 412 □l, 0.412 mmol) in tetrahydrofuran (2 ml) was heated at reflux over night. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product, which was purified by flash chromatography (0.5% methanol in dichloromethane as eluent) to give tert-butyl 4-[(2,4-dichlorophenyl)amino]-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate as a light yellow oil (85 mg, yield 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:6]1[CH:5]=[C:4]([CH3:18])[C:3]([O:19][CH2:21][C:22]#[N:23])=[C:2]([CH3:1])[CH:7]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC#N

Procedure:
To 2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenol (12.0 g=42 mmol) in 150 ml acetonitrile add chloroacetonitrile (3.8 g=50 mmol) and potassium carbonate (11.5 g=83 mmol). Reflux 6 hours, add more chloroacetonitrile (0.8 g=10 mmol), reflux 1/2 hour, and allow to cool. Filter, concentrate and partition between ether and water. Dry and concentrate the ether. Partition between 1:9 ether-hexane and 1.0 N NaOH. Acidify the aqueous layer with concentrated HCl and extract with ether. Dry and concentrate the combined ether extracts to leave a residue comprising 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetonitrile, together with some of the corresponding acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1)#[N:2].[H-].[Na+].[Na].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH3:25])[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1)#[N:2]
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cn1c2c(c3cc(C#N)ccc31)CC(NC(=O)C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Follow the procedures essentially as described in Example 104, above, using N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (3.38 g, 12 mmol) and treating with sodium hydride (580 mg, 14A mmol). Cool the formed sodium salt in a dry ice/acetonitrile bath and add 2-methoxybenzylchloride (1.84 mL, 13.2 mmol) in DMF (2 mL) at −35 to −30° C. Remove the bath and allow the reaction to warm to ambient temperature over 3 h with stifling. Add water (250 mL) dropwise, cooling in an ice bath while stirring for 30 min. Filter the resulting precipitate and dry under house vacuum at 45° C. for 18 h. Triturate and sonicate the material in diethyl ether for 1.5 h, filter and dry to provide 3.98 g (83%) of an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[N:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:21]=[S:22].O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:21]([NH:20][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:22])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: ClCCl
Solvent: O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=S)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide. obtained in step VIII of Example 1 (1 eq) in dichloromethane, a solution of isothiocynato benzene (1 eq) in dichloromethane was added and the reaction was stirred at room temperature for 3 h. Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]#[N:24])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](I)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]#[N:24])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1CCCCN1C(=O)c1ccccc1
Reactant: ICCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 ml of a solution of lithium diisopropylamide (140 mmol) in tetrahydrofuran was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78° C. and the mixture was stirred for 30 minutes. Then, 100 ml of a solution of 33.2 g of phenethyl iodide in tetrahydrofuran was added dropwise at -78° C. After completion of dropwise addition, the temperature of the reaction mixture was gradually increased to 0° C. The reaction mixture was diluted with water and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The pooled organic layer was dried over magnesium sulfate and filtered and the solvent was distilled off. The group was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as the eluent. The active fraction was concentrated under reduced pressure and the solid group was recrystallized from ethyl acetate-hexane to provide 17.3 g of colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([NH:13][C:14](=[O:34])[C:15]3[CH:20]=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([CH:28]5[CH2:30][CH2:29]5)[CH2:24][CH2:23]4)[CH:18]=[CH:17][C:16]=3[N+:31]([O-])=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.N[C:37]1C=CC(OC2CCN(C3CC3)CC2)=CC=1C(NC1C=C(C(NC2CC2)=O)C=CC=1C)=O>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([N:13]3[C:14](=[O:34])[C:15]4[C:16](=[CH:17][CH:18]=[C:19]([O:21][CH:22]5[CH2:27][CH2:26][N:25]([CH:28]6[CH2:30][CH2:29]6)[CH2:24][CH2:23]5)[CH:20]=4)[N:31]=[CH:37]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 15 which is concerned with the preparation of starting material, N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]-2-nitrobenzamide was reduced to 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]benzamide; Mass Spectrum: M+H+ 449.