Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[NH:33][CH:30]1[CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18FN5O2, 403.1
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([CH:17]3[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)=[O:16])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH2:30]([N:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:8]=2[CH:9]=1)[C:15]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:18]1)=[O:16])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN(Cc1ccc2c(c1)C(O)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN(Cc1ccc2c(c1)CCCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1

Procedure:
A mixture of 230 mg 0.50 mmol) of (±)-tert-butyl 2-{[[(9-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)methyl](isobutyl)amino]-carbonyl}morpholine-4-carboxylate, and 60 mg of 10% palladium on carbon catalyst in 5 mL of ethanol was stirred under of hydrogen (1 atmosphere) for four hours. The mixture was filtered and concentrated under reduced pressure. The residue was filtered through a pad of silica gel eluting with 33% ethyl acetate in hexanes. The filtrate was concentrated and the residue dried to give product as a gummy foam. MS (m+1)=445.4; H NMR (400 MHz, CDCl3) 7.04 (m, 1H), 6.89 (m, 2H), 4.7 (m, 1H), 4.45 (d, 1H, J 16 Hz), 4.18-4.02 (m, 2H), 3.90 (m, 2H), 3.51 (m, 1H), 3.22 (m, 2H), 3.03 (m, 2H), 2.77 (m, 4H), 2.00 (m, 1H), 1.82 (m, 2H), 1.63 (m, 4H), 1.45 (d, 9H, J 15 Hz), 0.91 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][NH:19][C:17]([C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][CH2:5][C:4]1[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[CH:3]=1)[CH:16]=2)=[O:18].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 1 h

Procedure:
To a cooled solution, 0° C., of tert-Butyl (2-(7-((3-chlorobenzyl)oxy)quinoline-3-carboxamido)ethyl)carbamate in DCM (1 mL) was added TFA (1 mL). The reaction was stirred for 1 hour, and concentrated under reduced pressure. The reaction mixture was taken up in MeOH and concentrated under reduced pressure to afford the title compound as a white solid, TFA salt (57 mg, 100%) 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=2.0 Hz, 1H), 8.88 (t, J=5.5 Hz, 1H), 8.76 (s, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.51-7.39 (m, 4H), 5.34 (s, 2H), 3.55 (q, J=6.3 Hz, 2H), 3.10-2.95 (m, 2H). [M+H]=356.3
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.[C:20]([O-])([O-])=O.[K+].[K+].IC>CS(C)=O>[CH3:20][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[C:7]([C:6]3[CH:5]=[CH:4][C:3]([OH:19])=[CH:2][CH:1]=3)=[CH:8][O:9]2)=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 5.1 g of daidzein (20.06 mmol) in 40 ml of DMSO was added 3.5 g of anhydrous K2CO3 (25.4 mmol) and 6 ml of iodomethane (96.4 mmol). The mixture was stirred at room temperature for 2 hours and then poured into ice water to precipitate product. Precipitates were extracted with ethyl acetate, dried by flash evaporation and purified on a Sephadex LH-20 column (chloroform:methanol/7:3). Final product was recrystallized from acetone to give 2.3 g of crystalline analog 2, a yield of 45.1% (w/w): mp 210-211° C.; 1H NMR (DMSO-d6) δ 3.89 (—OCH3), 6.81 (d, 2H, J=8.43 Hz, 3′, 5′-H), 7.05 (dd, 1H, J=8.89, 2.39 Hz, 6-H), 7.11 (d, 1H, J=2.07 Hz, 8-H), 7.39 (d, 2H, J=8.62 Hz, 2′, 6′-H), 8.01 (d, 1H, J=8.87 Hz; 5-H), 8.35 (s, 1H, 2-H), 9.54 (s, 1H, 4′-OH). Anal. (C16H12O4) for C, H. Cacld: 71.64, 4.51; found: 71.24, 4.47.
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5]1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1)[CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)CCC1CCN(CC(=O)c2ccc3c(c2)Nc2nccnc2S3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)CCC1CCN(CC(O)c2ccc3c(c2)Nc2nccnc2S3)CC1
Yield: 66 %

Procedure:
To a solution of 0.8 g of ethyl 4-[1-[2-oxo-2-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl]ethyl]piperidin-4-yl]-2-methylbutanoate in ethanol (30 ml) was added 70 mg of sodium borohydride and the resulting mixture was reacted at room temperature for 30 minutes. After adding ethyl acetate, the reaction mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.53 g of the title compound as a yellow oily substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[Cl:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:23])[C:17]=1[N:12]1[CH2:13][CH2:14][CH2:15][C:16]2=[C:8]([NH2:7])[N:9]([CH3:26])[N:10]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3NC(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a 0° C. solution of 287 mg of [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamic acid tert-butyl ester (Example 8c) in 9 mL of dichloromethane, was added 3 mL of trifluoroacetic acid. After 15 min, the cooling bath was removed and the reaction mixture was allowed to stir and warm to room temperature during 3 h. The reaction mixture was then diluted with dichloromethane and washed with dilute aqueous sodium hydroxide. The aqueous phase was washed with additional dichloromethane, after which the combined organics were dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a methanol/dichloromethane gradient to provide 182 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine, mp 234–236° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH2:34][C:35]2[CH:46]=[CH:45][C:38]([O:39][CH2:40][C:41]([O:43]C)=[O:42])=[CH:37][CH:36]=2)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]([CH2:34][C:35]2[CH:46]=[CH:45][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:37][CH:36]=2)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)Nc3ccc(C(C)(C)C)cc3)cc2)cc1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of methyl {4-[({[(4-tert-butylphenyl)amino]carbonyl}{4-[(4-butylphenyl)-ethynyl]benzyl}amino)methyl]phenoxy}acetate (70 mg, 0.11 mmol) in MeOH (1 mL) and THF (1 mL) was added an aqueous solution of NaOH (0.5 mL, 5N) and the resulting mixture was stirred at it for 3 hrs. Then the solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with an aqueous solution of HCl (1N) and brine. The organic layer was dried over MgSO4 and the solvent was removed to give 46 mg (67%) of the title compound. HPLC, Rt: 5.67 min (purity: 97.4%). 1H NMR (CD3OD) δ: 7.48 (d, J=8.3 Hz, 2H), 7.40 (d, J=7.5 Hz, 2H), 7.18-7.33 (m, 10H), 6.93 (d, J=8.7 Hz, 2H), 4.66 (s, 2H), 4.66 (s, 2H), 4.54 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 1.30 (s, 9H), 0.95 (t, J=7.2 Hz, 3H). M+(ESI): 603.4, M−(ESI): 601.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(N)cn2)CC1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
2-(1-Methylpiperidin-4-yloxy)-5-nitropyridine (100 mg, 0.42 mmol) was dissolved in 5 mL of methanol and placed under a nitrogen atmosphere. A catalytic amount of 10% palladium on carbon was added and a hydrogen balloon connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere. The solid was filtered and washed with methanol. The filtrate was evaporated under reduced pressure to yield 6-(1-methylpiperidin-4-yloxy)pyridin-3-amine as a brown solid (85 mg, 98%). LC/MS (m/z): 2082 (MH+), Rt 0.34 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[O:9]=[C:10]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:12]1([CH2:11][C:10]([N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)=[O:9])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(CN1CCOCC1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ncn1

Procedure:
7-2 (0.22 g, 1.76 mmol), 42-2 (0.37 g, 1.76 mmol) and DIEA (0.23 g, 1.76 mmol) were reacted to afford 42-3, which was purified on a silica column. 1H-NMR(CD3OD): 8.00(s, 1H); 5.75(s, 1H); 3.70(m, 6H); 3.65(m, 4H); 3.56(m, 2H); 3.30(s, 2H); 2.54(br s, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of alcohol 15 (1.94 g, 6.81 mmol) and triethylamine (1.25 g, 12.4 mmol) at 0° C. in Cl2CH2 (15 mL), methanesulfonyl chloride (0.96 g, 8.4 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 20 min. It was quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was removed in vacuo and the crude mesylate 16 was obtained as a foamy white solid, which was used in the next step without further purification. 1H NMR (CDCl3).δ1.394 (s, 9H), 2.916 (s, 3H), 3.718 (s, 3H), 4.878 (dd, J=8.7, 5.0 Hz, 1H, H-2), 5.231 (bd, J=8.7 Hz, 1H, H--N), 5.917 (d, J =5.0 Hz, 1H, H-3), 7.379-7.425 (m, 5H).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)=[C:11]([NH:24][CH3:25])[CH:10]=1>C(O)=O>[F:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15](=[O:23])[C:16]([C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)=[CH:25][N:24]2[CH3:1])=[CH:13][CH:14]=1
Reactant: CNc1cc(F)ccc1C(=O)Cc1nnnn1C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of acetic anhydride (0.8 ml) and formic acid (0.4 ml) was stirred at 50°-60° for 2 hours, then cooled to ambient temperature. 1-(4-Fluoro-2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone (1.03 g) was added. The mixture was stirred at ambient temperature for 5 hours, then kept at this temperature for 16 hours. The mixture was triturated under light petroleum to give a solid product. This product was extracted with boiling ethyl acetate (100 ml) and the extract cooled to give a solid product which was recrystallised from industrial methylated spirit to give the novel compound 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 264°-267°, identical to the product of Example 2(d).
Reaction SMILES: C([CH:4]([C@@H:14]1[CH2:17][C@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][C:23]=3[NH2:27])[CH2:15]1)[C:5](C(C)C)(C(C)C)[O:6][SiH3])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:5][CH2:4][C@@H:14]1[CH2:17][C@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][C:23]=3[NH2:27])[CH2:15]1
Reactant: CC(C)C([C@H]1C[C@@H](n2cnc3c(N)ncnc32)C1)C(O[SiH3])(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CCO)C1
Reaction time: 1 h
Yield: 95.3 %

Procedure:
In a 25 mL flask with 9-[cis-3-(triisopropyl-siloxyethyl)cyclobutyl]adenine (0.07 g, 0.18 mmol) inside, dry THF 1.5 mL was added to give a totally clear light-yellow solution. This was treated with TBAF (1.0 M in THF, 0.36 mL, 0.36 mmol) at room temperature. After 1 hr, the solvent was removed and the crude product was directly applied to the silica gel flash chromatography (CH2Cl2 to CH2Cl2: MeOH=5:1) to give 0.04 g (90%) the desired product. MS (FAB): expected for C11H15N5O (M+H)+ 234.27. Found 234.13482.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=S)[CH:21]=[CH:22][C:23]=1[F:24].CN(C)CCCN=C=NCC>>[F:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Fc1ccc(N=C=S)cc1F
Reactant: Nc1ccccc1Nc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Product: Fc1ccc(Nc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
The title compound was prepared by Procedure G from N-(3,4-difluorophenyl)-benzene-1,2-diamine (Scheme 5), 3,4-difluorophenyl isothiocyanate and, in the last step, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture was evaporated to dryness and the remaining crude product purified by preparative LCMS to give the title compound as the free base (solid, mp 115-117° C.). MS(ES+) m/z 358 ([M+1]+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28](Br)([CH3:30])[CH3:29]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:28]([CH3:30])[CH3:29])[N:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
A solution of N-(1-benzylpiperidin-4-yl)-indazole-3-carboxamide (3.34 g, 10.0 mmol) in dry DMF (70 ml) under argon atmosphere was added sodium hydride (0.25 g, 10.0 mmol) and stirred at room temperature for 3 h. The mixture was added isopropylbromide (1.37 g, 11.0 mmol) and stirred for additional 24 h. The reaction mixture was evaporated in vacuo and the residue added EtOAc (100 ml). The organic layer washed with brine (50 ml) and H2O (2×50 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave an oil that solidified upon standing. The oil was separated with flash chromatography (SiO2, Et2O/Hexane (2:1) to leave the product as a solid (1.22 g, 32.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:14](Cl)(Cl)=[O:15]>ClCCl.C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([N:1]=[C:14]=[O:15])=[C:3]([CH:9]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: O=C(Cl)Cl
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cc(Br)ccc1N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-amino-5-bromo-N,N-dimethyl-benzamide (1.48 g, 6.09 mmol) was dissolved in a mixture of dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (60 mL). 16 mL of 20% w/w phosgene in toluene was added and the mixture stirred at room temperature for 30 min. The layers were separated and the aqueous layer extracted three times with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate and evaporated. The residue was concentrated down several times from ether and dichloromethane to afford 5-bromo-2-isocyanato-N,N-dimethyl-benzamide as a yellow power. 1H-NMR (250 MHz, d6-DMSO) δ 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd, J=6.3, 2.7 Hz, 1H), 7.16 (d, J=8.88 Hz, 1H), 3.10 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH2:20])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[Cl:19].[F:22][C:23]([F:31])([F:30])[C:24]([F:29])([F:28])[C:25](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:10]=2[Cl:19])=[CH:6][C:5]2[NH:20][C:25]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[F:22])=[N:21][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 55 %

Procedure:
A solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) in pentafluoropropanoic acid (3 ml) was stirred overnight at 80° C. The reaction was then quenched by the addition of water (100 ml), pH value adjusted to 8 with potassium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Prep-HPLC to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a pink solid (38 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:21]=1[C:22]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3)=[O:23]
Reactant: CCCOC(=O)c1c(N)sc2c1CC1CCC2O1
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: CCCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 34A and commercially available 2-fluoro-6-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (DMSO-d6, 300 MHz) δ0.92 (t, J=7.1Hz, 3H), 1.60-1.72 (m, 3H), 1.98-2.17 (m, 3H), 2.57 (d, J=17.0Hz, 1H), 3.10 (dd, J=17.1, 4.9Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 4.69-4.73 (m, 1H), 5.14-5.16 (m, 1H), 7.73-7.87 (m, 3H), 11.53 (br s, 1H); MS (ESI+) m/z 458 (M+H)+. Anal. calcd. for C21H19F4NO4S: C, 55.14; H, 4.19; N; 3.06. Found: C, 55.19; H, 3.99; N, 3.08.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:18]1[C:24](=[O:25])[CH2:23][CH2:22][N:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH2:19]1)[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-]>CO>[Cl:36][C:28]1[CH:27]=[C:26]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:13][CH2:14]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[CH2:19][CH2:20]2)[CH:31]=[CH:30][C:29]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(C(F)(F)F)c(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: O=C(CC[C@@H](CO)N1CCN(c2ccc(C(F)(F)F)c(Cl)c2)CCC1=O)N1CCC2(CC2)[C@H](O)C1
Yield: 62 %

Procedure:
In analogy to the procedure described for intermediate 40C, (S)-2-[4-(3-Chloro-4-trifluoromethyl-phenyl)-7-oxo-[1,4]diazepan-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester (example 123) and LiBH4 (2 M in THF)/MeOH gave the title compound in 62% yield as yellow oil. MS: 518.20 (MH+, Cl).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:38]1[CH:39]=[CH:40][CH:41]=[N:42][C:37]=1[O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35]
Reactant: Clc1ncccn1
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(Oc3ncccn3)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-chloro-pyrimidine
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][CH:10]=[CH:11][N:12]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:6]([C:7]1[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][CH:10]=[CH:11][N:12]=1)#[CH:5]
Reactant: CCOC(=O)Cc1nccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1nccnc1CC(=O)OCC
Reaction time: 0.03 h
Yield: 74.8 %

Procedure:
Ethyl 2-(3-((trimethylsilyl)ethynyl)pyrazin-2-yl)acetate (I100) (0.386 g, 1.47 mmol) in THF (15 mL) was cooled to 0° C. and a 1.0 M solution of TBAF in THF (1.84 mL, 1.84 mmol) was added. The mixture was stirred for two minutes then poured into water (150 mL). The resulting mixture was extracted with diethyl ether (2×150 mL) and the combined ether phases washed with brine, dried (sodium sulphate) and evaporated to give the title compound (I101) (0.209 g, 75% yield) as a yellow-brown oil; 1H NMR (400 MHz, CDCl3) δ 8.50-8.47 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.08 (s, 2H), 3.49 (s, 1H), 1.26 (t, J=7.1 Hz, 3H). LCMS Method C: rt 4.88 min; m/z 191.1 [M+H]+.