Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)#[N:10]>O1CCOCC1>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:18][C:1]([O:4][CH3:5])=[O:6])=[O:19])=[CH:13][CH:12]=1)#[N:10]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC(=O)c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
Dimethyl carbonate (126 g, 1.4 moles) was added dropwise to a slurry of NaH (50% in mineral oil, 13.44 g, 0.28 mole) slurried in 280 ml of dry dioxane. The reaction mixture was warmed to 80°-85° and p-cyanoacetophenone (40.7 g, 0.28 mole) in 140 ml dioxane added dropwise (at about 3/4 addition, mechanical loss due to foaming occurred; such losses are avoided by slower addition, e.g., over 1 hour). After addition was complete, heating at 80° was continued for 2 hours and crude product recovered by hot filtration. The cake was distributed between dilute CH3CO2H and ether. The ether layer was separated; washed in sequence with H2O, saturated NaHCO3, H2O and brine; dried; and stripped to yield title product: 39 g, (68.6%); m.p. 93°-98°; tlc (4:1 toluene:ethyl acetate) Rf 0.58. Recrystallization of 0.5 g from 2-propanol gave 0.403 g; m.p. 96°-99°.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:27][CH:26]1[CH3:38])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH:37][C:2]3[N:3]=[CH:4][C:5]4[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:6]=4[N:7]=3)=[CH:35][CH:36]=2)[CH2:27][CH:26]1[CH3:38])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Product: CC1CN(c2ccc(Nc3ncc4cc(C#N)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 66.1 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.424 mmol) gave 4-[6-(6-cyano-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (128 mg) [following SiO2 chromatography eluting with 1-2.5% MeOH/dichloromethane and subsequent trituration with diethyl ether]. The material is used directly in the next step.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([CH3:5])=[CH2:4].[Br:16][CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:3]([CH3:5])=[CH2:4])[C:7]1=[O:15].[Cl:20][CH2:19][CH2:18][CH2:17][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:3]([CH3:5])=[CH2:4])[C:7]1=[O:15]
Reactant: ClCCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)n1c(=O)n(CCCBr)c2ccccc21
Product: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reaction time: 2 h
Yield: 215 %

Procedure:
Add sodium hydride (600 mg, 16.5 mmol of 60% dispersion in oil) to a solution of 1-isopropenyl-1,3-dihydro-benzoimidazol-2-one (1.311 g, 7.53 mmol) in anhydrous DMF (10 mL) under nitrogen at room temperature and stir for 2 h. Add 1-bromo-3-chloropropane (900 μL, 9.03 mmol) and stir for 3 days. Pour the suspension into water (100 mL), extract with diethyl ether (2×50 mL). Wash the organic extract with brine (100 mL), dry over MgSO4 and concentrate in vacuo to give the title compound impurified with 1-(3-chloro-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (2.03 g, 1:1 mixture). MS (ES+) m/z: 251 (M+H)+, 293 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24]C=C[CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].CS(Cl)(=O)=[O:34]>>[CH3:14][N:12]1[CH:13]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])[CH:3]=[CH:4][C:5]=2[O:19][CH:20]2[CH2:25][CH2:24][O:34][CH2:21]2)[C:9]2[CH:18]=[CH:17][NH:16][C:10]=2[C:11]1=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: CCS(=O)(=O)Nc1ccc(OC2CCOC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1

Procedure:
Example 66 was prepared according to the procedure used in method A of Example 4, substituting the product of Example 31b for the product of Example 3, and ethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, J=7.3 Hz, 3H), 1.93-1.80 (m, 1H), 2.20-2.04 (m, 1H), 3.02 (q, J=7.3 Hz, 2H), 3.55 (s, 3H), 3.65 (m, 3H), 3.82 (dd, J=10.0, 4.5 Hz, 1H), 5.00-4.91 (m, 1H), 6.16 (t, J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.16 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (s, 1H), 7.31-7.25 (m, 3H), 9.53 (s, 1H), 12.01 (bs, 1H), MS (ESI+) m/z 418.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CS(C)=O.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1>O.CCOC(C)=O.[Cl-].[Na+].O>[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1
Reactant: CC(C)(C)CO
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Temperature: 25 °C

Procedure:
A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL) to give a clear solution. Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added and the vial was placed in a 100° C. oil bath for 5 min, then was removed from the heat and cooled to RT. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 1B, 86 mg, 0.226 mmol) was added to give an orange solution. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][O:23][C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>C(O)C>[CH2:25]([N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(c1ccccc1)CO2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1c1ccccc1
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (336 mg, 1.01 mmol) in ethanol (3 mL) was added acetaldehyde (62 μL, 1.11 mmol) then sodium cyanoborohydride (89 mg, 1.42 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, partitioned between DCM (50 mL) and 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was further extracted with DCM (2×25 mL). The combined organics were dried with MgSO4 and concentrated in vacuo to give tert-butyl 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (298 mg, 82%). ESI-MS m/z calc. 360.5. found 361.7 (M+1)+; Retention time: 1.30 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.03 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.22 g, 0.025 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-m-tolyloxy-but-2-enoic acid ethyl ester (1.50 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (495 mg, 25%) as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][C:26]([F:28])([F:27])[CH:23]([C:20]1[CH:21]=[CH:22][C:15]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)=[N:18][C:17]=3[C:16]=2[CH:19]=1)[OH:24]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C=O)cc1-2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C(O)C(F)(F)F)cc1-2
Yield: 6 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carbaldehyde (0.354 g, 1.04 mmol) was dissolved in THF (7 mL) and treated with (trifluoromethyl)trimethylsilane (0.154 mL, 1.04 mmol) followed by TBAF (1M, 0.02 mL, 0.02 mmol). Stirred the resulting reaction mixture at ambient temperature for 2 h. Concentrated in vacuo and re-dissolved in DMF and purified by reverse phase HPLC to give 25.6 mg (6% yield) of 329. LC/MS (ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.10 (s, 1H), 7.41 (d, J=8.4, 1H), 7.10 (d, J=8.3, 1H), 6.80 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 5.21 (d, J=6.7, 1H), 4.39 (t, J=4.9, 2H), 3.45 (t, J=4.9, 2H), 1.55 (d, J=6.5, 6H)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][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][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[CH:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][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[CH2:24][C:25]([NH:38][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:26])=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: O=C(Br)CBr
Reactant: NC1CCCc2ccccc21
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CC(=O)NC1CCCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[CH2:21](C(CC)(CC)C([O-])([O-])[O-])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
A mixture of 2.9 g. of 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine, 50 ml. of ethanol, 2 ml. of triethylorthoacetate and 0.2 g. of p-toluenesulfonic acid was refluxed for 20 minutes. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and aqueous sodium carbonate solution. The organic phase was dried and evaporated. Crystallization from methylene chloride/hexane yielded 8-bromo-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine, having a melting point of 245°-248°. Chromatography of the mother liquor on 60 g. of silica gel using 10 percent ethanol in methylene chloride afforded additional product, m.p. 248°-250°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:31]1[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1>C(O)C>[OH:31][C@@H:32]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1)[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(NCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNC(=O)c4ccc(C(F)(F)F)cc4)CC3)ccc2s1

Procedure:
To a solution of N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2 g, 0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml, 1.5 mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (0.09 g, 0.42 mmol). The reaction was heated to 85 degrees for four hours. The mixture was then concentrated in vacuo and purified using preparative thin layer chromatography (10:1 DCM:MeOH) to yield N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=523.0).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([F:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([O:38]CC)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([F:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([OH:38])=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2F)c2c1[nH]c1cc(OCCOC)ccc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
To a light orange, homogeneous solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.8002 g, 1.435 mmol) in THF (30.8 mL) and MeOH (10.25 mL) was added a solution of LiOH hydrate (0.241 g, 5.74 mmol) in water (2 mL). After 1.5 hr. the reaction was concentrated in vacuo. Water (10 mL) was added followed by 1 N aqueous HCl to pH 4-5 by litmus paper. The precipitate was filtered and washed with water, dried over Drierite under vacuum to give the desired product (0.705 g, 1.331 mmol, 93% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:13]1([S:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]nc(Sc2ccccc2)c2ccccc12
Yield: 83.3 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (2.1 g, 12 mmol), thiophenol (2.6 g, 23 mmol), and K2CO3 (2.4 g, 17 mmol) in DMF (40 mL) was microwaved at 125° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated, and triturated with Et2O to give the title compound (2.5 g, 10 mmol): 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.28 (dd, J=7.8, 1.1, 1H), 8.06-7.99 (m, 1H), 7.98-7.92 (m, 1H), 7.92-7.85 (m, 1H), 7.44 (d, J=1.2, 2H), 7.38 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:37]=1)[N:34]=[C:33]([CH:44]=O)[CH:32]=[CH:31]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:44]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[C:36]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:34]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCCOc1cc(F)cc2ccc(C=O)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.15 g, 0.36 mmol) and 6-fluoro-8-(3-methoxypropoxy)quinoline-2-carbaldehyde (0.095 g, 0.36 mmol) in ethanol (1.8 mL, 0.36 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (1.8 mL) and iodosobenzene diacetate (0.13 g, 0.39 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.12 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH2:10][CH2:11][CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCCc1cc2cc(OCC(=O)OCC)c(Cl)c(Cl)c2s1
Reaction time: 72 h
Yield: 58.9 %

Procedure:
A mixture of 11.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, 8.82 g of ethyl bromoacetate, 7.52 g of potassium carbonate, 135 ml of 2-butanone and 9 ml of dimethylformamide is stirred for 3 days. The reaction mixture is filtered and 100 ml of water and 100 ml of ether are added. The layers are separated and the aqueous layer is extracted 2 times with 100-ml portions of ether. The combined organic layers are dried, filtered and the filtrate is evaporated to give an oil which crystallizes from hexane. Recrystallization from ether-hexane gives 9 g of ethyl[(6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetate, mp 62°-63°.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C(Cl)(=O)C(Cl)=O.[NH3:38].O1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:2][O:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH2:38])=[O:24])=[N:20][CH:21]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: N
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)nc3)no2)ccc1-c1ccccc1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccc(C(N)=O)nc3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}pyridine-2-carboxylic acid hydrochloride (100 mg, 0.23 mmol) in anhydrous DCM (5 mL) was added oxalyl chloride (0.058 mL, 0.69 mmol) and DMF (1 drop). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was taken up with anhydrous THF (2 mL) and a 0.5N solution of ammonia in dioxane (4.5 mL, 2.25 mmol) was added. The mixture was stirred at RT for 1 hour, and then concentrated under reduced pressure. The residue was taken up with Et2O. The precipitate was filtered off, washed with Et2O and dried under reduced pressure to give the title compound as a beige powder (88 mg, 96%). HPLC (Method A), Rt: 4.7 min (purity: 95.4%). UPLC/MS, M+(ESI): 401.2. 1H NMR (CD3OD, 300 MHz) δ 9.41 (dd, J=2.1, 0.9 Hz, 1H), 8.71 (dd, J=8.2, 2.1 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 0.9 Hz, 1H), 8.24 (dd, J=7.9, 1.8 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.34 (m, 2H), 7.28 (m, 1H), 7.13 (d, J=7.1 Hz, 1H), 4.24 (s, 2H), 3.32 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[C:14]=1[C:15]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(NC1CCCC1N1CCCC1)c1c(Cl)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=429.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-chloro-4,6-bis-trifluoromethyl-benzoic acid