Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)=[N:17][C:16]=1[C:30]1[N:34](COCC[Si](C)(C)C)[CH:33]=[N:32][N:31]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)=[N:17][C:16]=1[C:30]1[N:34]=[CH:33][NH:32][N:31]=1
Reactant: CC(=O)Nc1ccc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(-c2nc(-c3nc[nH]n3)c(-c3ccccc3Cl)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
TFA (0.6 mL) was added to a solution of N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (0.10 g, 0.20 mmol) in DCM (3 mL). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (Compound I-8) (0.026 g, 32%). LCMS (FA): m/z=380 (M+H).
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C@H:11]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])[NH2:12].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (32%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].N.[CH3:26][N:27](C)C=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CN(C)C=O
Reactant: CCCCC[C@H]1CC[C@H](C2C=CC(c3ccc(Br)cc3)=CC2)CC1
Agent: N
Product: CCCCC[C@H]1CC[C@H](C2C=CC(c3ccc(C#N)cc3)=CC2)CC1

Procedure:
In 20 ml of N,N-dimethylformamide, 7 g of the 1-(trans-4-pentylcyclohexyl)-4-(4-bromophenyl)dihydrobenzene, which had been obtained in Example 18, were dissolved, followed by the addition of 2.0 g of cuprous cyanide. The resulting mixture was reacted for 6 hours at reflux temperature. After the completion of the reaction, aqueous ammonia was added to the reaction mixture, followed by extraction with toluene. The extract was washed with aqueous ammonia and then with saturated NaCl. Anhydrous sodium sulfate was thereafter added to dry the extract. The toluene was distilled off under reduced pressure. The reaction product so obtained was recrystallized from ethanol, whereby 0.7 g of 1-(trans-4-pentylcyclohexyl)-4-(4-cyanophenyl)dihydrobenzene was obtained.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:7]=[CH:6]S[CH:4]=[CH:3]1.Br[C:25]1C=C2C(=CC=1)NC=C2CCN1CCCC1>>[OH:1][C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:7][CH2:6][CH2:25][CH2:4][CH2:3]1
Reactant: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)C=CSC=C1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Product: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCCC1

Procedure:
5-(4-Hydroxythiapyran-4-yl)-3-(2-pyrrolidinylethyl)-1H-indole: (56%) from 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b); mp 66-78° C.; HRMS-FAB+ for C19H27N2OS: calculated MH+ :331.18442; found MH+ :331.18568.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[N:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[N:17]=[C:26]([CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:28][N:29]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1nc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Yield: 13.8 %

Procedure:
A mixture of N-benzyl-2-cyano-4-methylthiazole-5-carboxamide (0.085 g, 0.33 mmol), phenylacetic hydrazide (0.02 g, 0.13 mmol) and potassium carbonate (0.037 g, 0.27 mmol) in 1-butanol (2 mL) was subjected to a microwave irradiation (150° C., 100 W) for 30 minutes. The reaction mixture was purified by column chromatography (0-10% methanol in dichloromethane). Less polar fractions were combined and concentrated in vacuo. The residue was purified by preparative thin layer chromatography plate (60% ethyl acetate in hexanes) to afford the title compound as a yellow solid (0.007 g, 15%): mp 235-237° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.6 Hz, 1H), 7.38-7.21 (m, 11H), 4.43 (d, J=5.6 Hz, 2H), 4.15 (s, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.8, 156.8, 155.4, 139.1, 136.4, 128.6, 128.6, 128.3, 127.2, 126.8, 42.7, 31.7, 17.0; MS (ES+) m/z 390.3 (M+1).
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]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.FC(F)(F)S(O)(=O)=O>>[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]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2-hydroxyethoxy)-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 (41.7 mg in 0.6 ml 33% methylene chloride in cyclohexane), benzyl trichloroacetimidate (15.8 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 7 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (24 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)=[O:7])(C)(C)C.[C:26]([O:30][C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1C(O)=O)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:25])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)=[O:7])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Yield: 68.1 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)1-(tert-butoxycarbonyl)-2-{1-hydroxy-2-[(3,4-methylenedioxy)phenoxy]ethyl} pyrrolidine (2.38 g) and N-(tert-butoxycarbonyl)-L-proline (1.60 g), there was obtained 2.07 g of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.N([O-])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)nc1
Temperature: -8 °C
Yield: 72.1 %

Procedure:
3-Amino-6-trifluoromethylpyridine (9.86 g, 61 mmol) was dissolved in concentrated sulphuric acid (70 ml) and diluted with water (70 ml), then cooled to −8° C. A solution of sodium nitrite (5.18 g, 75 mmol) in water (50 ml) was slowly added, and the mixture warmed to 0° C. for 15 minutes. The solution was then poured into sulphuric acid (10 M, 250 ml) and heated to 110° C. for 1 h. After cooling, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solution extracted with ethyl acetate (2×300 ml). The extracts were dried (MgSO4) and concentrated to give the product as a yellow solid (7.15 g, 44 mmol, 72% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7](O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]([OH:15])(=[S:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([S:14][C:12](=[O:15])[CH3:13])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CC2(CCS1)OCCO2
Reactant: CC(O)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)SC1CC2(CCS1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.545 g of product from Example 394, 0.23 ml of thioacetic acid, 0.16 g of p-toluene-sulfonic acid and 8 ml of carbon tetrachloride is stirred at room temperature for 1 hour. After work up concentration in vacuo gives 0.556 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
reacting said 2-methyl-3-nitrobenzoic acid in refluxing thionyl chloride to form 2-methyl-3-nitrobenzoyl chloride,
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][O:32]CC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31](=[O:32])[CH3:30])[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.220 g, 0.000543 mol), tributyl-ethoxyvinyl-tin (0.202 mL, 0.000597 mol), and bis(triphenylphosphine)palladium(II) chloride (0.0190 g, 0.0271 mmol) was degassed with N2. The reaction was heated to 100° C. overnight. The crude was hydrolyzed with 10% HCl and extracted 3 times with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated. The crude was loaded as a solid onto silica and purified by flash chromatography (45-100% ethyl acetate in hexanes) to give 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanone as a white solid (126 mg). MS(ESI+) 369.2
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16].CCOCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])[OH:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Oc1ccc(C2CO2)c(C(F)(F)F)c1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccc(C(O)CNCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g; 79.2 mmol) was dissolved in benzylamine (26 mL). The resulting mixture was stirred at 80° C. for 4 h. After cooling to RT, Et2O was added and the mixture cooled to 0° C. The formed precipitate was collected by filtration, washed with Et2O, and dried under vacuum, at 40° C., to afford methanesulfonic acid 4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester as a white solid (26.87 g) which was used as such.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1
Temperature: 150 °C
Yield: 45.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.279 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.069 g (45% yield) of pure product: MS (ES) m/z 496 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O>>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 64.2 %

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 1) (0.70 g, 2.5 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.25 g, 7.5 mmol, 3 eq) and TFA (0.93 mL, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 20 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.66 g, 64%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[C:11](=[O:29])[CH:10]=1)C1C=CC=CC=1>CO.[Rh]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[C:11](=[O:29])[CH:10]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CN2CCCC2)cc1
Agent: [Rh]
Solvent: CO
Product: O=c1cc(O)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To 1.20 g (3.09 mmol) 4-benzyloxy-1-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 1.4) in 80 mL MeOH is added 400 mg Rh/C. The reaction mixture is stirred under a hydrogen atmosphere of 3500 hPa at RT for 11 h. The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@@H:7]([CH2:9][CH3:10])[CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:4]1)[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH2:9]([C@H:7]1[O:8][C@@H:3]([CH2:1][CH3:2])[C@@H:4]2[C:28]3([CH2:13][C:12]4[C:11]([N:5]2[CH2:6]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30])[CH3:10]
Reactant: CC[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](CC)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: CC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](CC)O1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
2-(cis-2,6-Diethylmorpholin-4-yl)-5-nitrobenzaldehyde (1.58 g, 5.39 mmol) is combined with barbituric acid (767 mg, 5.39 mmol, Aldrich) in a flask with MeOH (17 mL). The sealed reaction is stirred with heating at 80° C. overnight. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using a 10% MTBE in CH2Cl2 as eluent. The product is dried under vacuum and re-crystallized from CH3OH/heptane. The large crystals are crushed and dried under vacuum @ 100° C. yielding 1.04 g (48%) of bright yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86, 0.97, 1.08, 1.24, 1.45, 1.58, 2.84, 3.03, 3.34, 3.60, 3.97, 4.26, 7.01, 7.84, 7.98, 11.56, 11.87.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:11][NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCCc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCCc1ccccc1
Temperature: 7 °C
Yield: 53 %

Procedure:
N-(3-Phenylpropyl)formamide (5.70 g, 34.9 mmol) was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of sodium borohydride (1.58 g, 41.91 mmol) in tetrahydrofuran (100 ml), which was cooled to 7° C. A solution of iodine (4.42 g, 17.46 mmol) in tetrahydrofuran was added dropwise, while the temperature was kept at 7° C. After the addition was finished, the reaction mixture was warmed to reflux for 16 h. The reaction mixture was cooled to 7° C., and methanol (250 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in 20% aqueous sodium hydroxide solution (250 ml) and tert-butyl methyl ether (100 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using dichicromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 2.76 g of N-methyl-N-(3-phenylpropyl)amine.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=O)=[CH:6][CH:5]=1>>[CH2:1]([NH:3][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:5][CH:6]=1)[CH3:2]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCN
Product: CCNCc1ccnc2ccccc12

Procedure:
prepared by reaction of ethylamine with quinoline-4-carbaldehyde
Reaction SMILES: FC1C(O[C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=3)=[O:10])=C(F)C(F)=C(F)C=1F.[CH:39]1([CH2:42][NH2:43])[CH2:41][CH2:40]1>C1COCC1>[CH:39]1([CH2:42][NH:43][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=3)=[O:10])[CH2:41][CH2:40]1
Reactant: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)Oc5c(F)c(F)c(F)c(F)c5F)cc4c3)c2cc1OC
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)NCC5CC5)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid pentafluorophenyl ester (0.5 g, above) in 5 mL of THF was added cyclopropylmethylamine (0.175 g, 2.46 mmol, Aldrich) and resulting solution was stirred at RT for 8 h. The mixture was concentrated in vacuo. The residue was diluted with 50 mL of EtOAc and washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (30% to 100% EtOAc/hexane) to afford white solid as desired product. MS (ESI pos. ion) m/z: 418 (M+H). Calc'd Exact Mass for C24H23N3O4: 417.46.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[C:18]1([C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-biphenyl isocyanate. m/z (ES+) 340 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(O)Cl
Reactant: Fc1cccc2ncccc12
Product: O=S(=O)(Cl)c1ccc(F)c2cccnc12
Temperature: 130 °C

Procedure:
5-fluoroquinoline (800 mg, 5.4 mmol) was added slowly to 10 mL of chlorosulfonic acid at 0° C. When the addition was complete, the reaction mixture was heated at 130° C. overnight. The solution was allowed to cool and was slowly poured over ice. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and evaporated to give the crude product, which was purified by column chromatography (5% EtOAc/PE) to afford 400 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 7.40 (t, J=8.46 Hz, 1H), 7.74 (dd, J=8.60, 4.30 Hz, 1H), 8.55-8.64 (m, 2H), 9.32 (dd, J=4.30, 1.88 Hz, 1H). LC-MS: m/z 4.246 (M+H)+