Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C1CCCCC1.ClCCl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:53][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in cyclohexane (0.8 ml) and dichloromethane (0.4 ml) was added 2,2,2-benzyltrichloroacetimidate at 0° C. followed by triflic acid. The reaction was allowed to warm to room temperature and stir for 1.5 hours after which time it was poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic extracts were dried (MgSO4) and concentrated and the crude material was purified by column chromatography on silica gel eluting with 65% hexane:35% ethyl acetate to give the desired product (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:25])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N+:21]([O-:31])[CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:25])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccn(-c2nc(C)c(C(=O)NCc3cccnc3)s2)c(=O)c1
Solvent: ClCCl
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccc[n+]([O-])c3)s2)c(=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
To a stirred solution of 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g, 0.28 mmol) in anhydrous dichloromethane (10 mL) was added m-chloroperoxy benzoic acid (0.072 g, 0.42 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 hours, diluted with dichloromethane (100 mL), washed with saturated bicarbonate solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane to afford the title compound as a colorless solid in 34% yield (0.035 g): mp 255-257° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.8 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 8.09 (d, J=6.3 Hz, 1H), 7.37-7.23 (m, 2H), 6.33 (dd, J=8.1, 2.7 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.34 (d, J=5.7 Hz, 2H), 3.81 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.6, 162.2, 161.7, 154.1, 151.0, 139.3, 138.1, 137.7, 131.9, 126.7, 124.9, 123.0, 104.2, 96.5, 56.8, 42.1, 17.5; MS (ES+) m/z 373.3 (M+1), 395.2 (M+23).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(CC)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(OCC(=O)OCC)cc1

Procedure:
Analogously, to example 1.4, crude [4-(tert-butoxycarbonyl-ethyl-amino)-phenoxy]-acetic acid ethyl ester was deprotected with TFA to give (4-ethylamino-phenoxy)-acetic acid ethyl ester as light brown oil, MS: 224 (MH+).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1>C(O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]2[S:31][C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:3]=3[N:32]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)n1
Yield: 39 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (84 mg, 0.332 mmol, from preparation AAA) and 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (87 mg, 0.332 mmol, from step 4 of preparation F) was heated in ethanol (0.55 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 54 mg (39% yield) of the titled compound as a white solid. LC-MS (M+H)+ 418.0. 1H NMR (400 MHz, chloroform-d) δ ppm 8.44 (s, 1 H) 7.49 (dd, J=5.41, 3.15 Hz, 2 H) 7.23-7.35 (m, 2 H) 7.12-7.21 (m, 3 H) 6.60 (dd, J=8.56, 2.27 Hz, 1H) 3.98-4.08 (m, 1 H) 3.49 (s, 3 H) 2.66-2.85 (m, 2 H) 2.46 (s, 3 H) 2.17-2.26 (m, 1 H) 1.92-2.05 (m, 1 H) 1.78-1.91 (m, 2 H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C=CC=CC=1.[NH2:34][OH:35].Cl>CCO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:34][OH:35])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: NO
Reactant: O=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 88 °C
Yield: 71.1 %

Procedure:
(R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone from Example 54 (70 mg, 0.19 mmol) was stirred in EtOH. Pyridine (100 μL, excess) and NH2OH.HCl (100 mg, excess) were added and the resulting mixture was heated at 88° C. for 1 h. LCMS showed that the reaction was complete. The mixture was then cooled to rt and purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone oxime (53 mg, 73%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.60 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.13-8.27 (m, 1H), 8.09 (dd, J=0.8, 7.9 Hz, 1H), 7.58-7.76 (m, 1H), 7.10-7.39 (m, 3H), 5.49 (s, 2H), 4.33-4.77 (m, 1H), 2.69-2.95 (m, 1H), 1.92-2.38 (m, 2H), 1.26-1.86 (m, 5H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].O>C(OCC)(=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CN(C)CCN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 42 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and a solution of 2 parts by volume of N,N-dimethyl-ethylenediamine in 3 parts by volume of water with a yield of 42% of theory. Orange yellow crystals; m.p. 123°-125° C. (ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([OH:22])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:24][CH3:25].O>CN(C)C=O>[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:22][CH2:24][CH3:25])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCC
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Sodium hydride (60%, oily, 1.28 g) was added to a solution of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (8.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 30 minutes. Iodoethane (2.82 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazol-4-yl)propionate (8.80 g, yield: 91%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:31]=[N:32][N:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:29][C:30]2[CH:31]=[N:32][N:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cnn(-c2ccccc2)c1
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cnn(-c3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 265-1 and 4-(chloromethyl)-1-phenyl-1H-pyrazole (3.47 g) synthesized in Reference Example 18 were dissolved in N,N-dimethylformamide (80 mL), potassium tert-butoxide (2.32 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1 to 3:1) to give the title compound (7.30 g) as a colorless oil.
Reaction SMILES: [C:1]12([C:8]3[C:9]([O:13][C:14]4[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[C@@:22]([CH3:26])([CH2:24][CH3:25])[NH2:23])=[CH:16][CH:15]=4)=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@@:22]1([CH3:26])[NH:23][C:29](=[O:31])[N:20]([C:17]2[CH:18]=[N:19][C:14]([O:13][C:9]3[C:8]4[C:1]5([CH2:4][O:5][CH2:6][C:7]=4[CH:12]=[CH:11][CH:10]=3)[CH2:2][CH2:3]5)=[CH:15][CH:16]=2)[C:21]1=[O:27])[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)COC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 129.7 %

Procedure:
To a solution of N1-[6-(1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-yloxy)-3-pyridinyl]-isovalinamide (Intermediate 141, 40 mg) in dry dichloromethane (8 mL) TEA (0.076 mL, 0.544 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (14.54 mg, 0.049 mmol) in dry dichloromethane (4 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The reaction was quenched with water (10 ml) and two phases separated. The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 7:3 to 3:7 as eluent. This afforded the title compound (25 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:27]=1)[C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]1[CH2:17][N:14]([CH:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH2:15]1)=[O:35]
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (Aldrich) and N-(azetidin-3-ylcarbamoylmethyl)-5-fluoro-3-trifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[CH2:24]1[N:17]2[C:18]3[C:14]([C@@H:15]4[CH2:28][NH:27][CH2:26][CH2:25][C@@H:16]42)=[CH:13][C:12]([NH:11][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:1]#[N:2])=[CH:20][C:19]=3[CH2:21][O:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: N#Cc1ccccc1C=O
Product: N#Cc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-cyanobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 138. 1H NMR (CDCl3) δ: 8.42 (d, 1H), 7.67-7.50 (m, 3H), 7.19 (d, 1H, J=2.2 Hz), 6.98 (d, 1H, J=2.2 Hz), 5.32 (s, 2H), 4.65 (ABq, 2H), 4.20-4.15 (m, 1H), 3.83-3.77 (m, 1H), 3.62-3.57 (m, 1H), 3.50-3.45 (m, 1H), 3.28 (dd, 1H), 3.20 (dd, 1H), 3.03-2.96 (m, 2H), 2.90-2.78 (m, 2H), 2.05-1.98 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][CH2:21][OH:22]>CC(O)C.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH2:21][OH:22])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(O)ccc1CNC(=O)OC(C)(C)C
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(OCCO)ccc1CNC(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a stirred solution of (4-hydroxy-2-methoxy-benzyl)-carbamic acid tert-butyl ester (22.8 mg, 0.09 mmol) in 2-propanol (1 mL) and 2 N aq. NaOH (0.15 mL) is added 2-bromoethanol (22.5 mg, 0.18 mmol). The reaction mixture is heated to 85° C. and stirred for 8 h. The mixture is cooled to rt and subjected to prep. HPLC purification to give [4-(2-hydroxy-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (10.3 mg) as a colourless oil. LC-MS: tR=0.85 min, [M+1]+=298.07.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Fc1cccc(S)c1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-fluoro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 351 (MH+).
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[C:6]([CH3:12])=[N:5]1)(=O)C.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[CH3:12][C:6]1[C:7](=[O:11])[N:8]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:9](=[O:10])[NH:4][N:5]=1
Reactant: CC(=O)n1nc(C)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1n[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-acetyl-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione (P1, 196 mg, 1.159 mmol) in 1,4-Dioxane (2 mL) and dry pyridine (0.281 mL, 3.48 mmol) at 5° C. was treated benzoyl chloride (0.155 mL, 1.333 mmol) was added dropwise, then the mixture was stirred at room temperature overnight. The day after 0.1 eq of Benzoyl chloride were added and the mixture stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the solvents evaporated under vacuum. The residue was dissolved in EtOH (5 mL), then HCl 37% (126 μL) was added and the reaction was refluxed for 15 minutes. Solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (eluent: DCM to DCM/MeOH 6:4) providing the title compound 6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (180 mg, 0.779 mmol, 67% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH:13]2[CH3:16])=[CH:9][CH:8]=1.C(=O)=O.CC(C)=O.[N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O1CCCC1>[CH3:16][C:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:15]=2)[CH2:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1CCc2ccc(Br)cc21
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1=CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 46.5 %

Procedure:
n-Butyllithium (8.6 mL, 13.76 mmol) was added to a three-neck flask under argon atmosphere. Upon cooling by a dry ice-acetone bath, 8 mL of tetrahydrofuran, 6-bromo-1-methyl-indan 38d (1.32 g, 6.26 mmol) were added successively under stirring. The reaction mixture was reacted in the dry ice-acetone bath for 2 hours followed by dropwise addition of a solution of di-tert-butyl azodicarboxylate (1.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran. The mixture was stirred for another 30 minutes and the ice-acetone bath was removed. The mixture was warmed up to room temperature and stirred for 20 hours. The reaction was quenched by addition of 20 mL of saturated ammonium chloride. The mixture was extracted with ethyl acetate (25 mL×3). The combined organic extracts were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3-methyl-inden-5-yl)hydrazine-1,2-dicarboxylate 38e (1.05 g, yield 46.7%) as a yellow oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Br:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10](CO)[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH2:1][Br:5])[CH:9]=1
Reactant: COc1cc(CO)cc(CBr)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)cc(CBr)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 31.8 %

Procedure:
Carbon tetrabromide (663 mg) was added to a stirred solution of 1-bromomethyl-3-hydroxymethyl-5-methoxy-benzene (420 mg) in anhydrous dichloromethane (10 mL) under argon. After cooling the resulting solution at 0° C., a solution of triphenylphosphine (500 mg) in anhydrous dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioFlash 30 g column, Si60 15-40 μm, eluted with dichloromethane/heptane, 40:60) to give 1,3-bis-bromomethyl-5-methoxy-benzene (170 mg):
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH3:11])[CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:9]([N:5]1[CH2:6][CH2:7][O:8][CH:3]([CH2:2][O:1][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH2:4]1)[CH2:10][CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCOC(CO)C1
Solvent: c1ccncc1
Product: CCCN1CCOC(COS(=O)(=O)c2ccc(C)cc2)C1
Yield: 11.3 %

Procedure:
2-Hydroxymethyl-4-n-propylmorpholine (16.2 g.) is dissolved in dry pyridine (50 ml.) and a solution of toluene-p-sulphonylchloride (21.4 g.) in dry pyridine (50 ml.) is added dropwise with stirring. The mixture is stirred at 20°-25°C. for 3 hours. The pyridine is removed under reduced pressure, water (100 ml.) is added to the residue and the product is extracted into ether (3 × 150 ml.). The ethereal solution is washed with water, dried (MgSO4), filtered and the ether evaporated to give 4-n-propyl-2-toluene-p-sulphonyloxymethylmorpholine (3.6 g.) as an oil which forms a hydrochloride, m.p. 172°-173°C. on recrystallisation from methanol/ether.