Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[CH3:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11]([CH:13]=[CH2:14])=[CH2:12].[CH3:16][C:17](=[CH:20][CH3:21])[CH:18]=[O:19].O>C1C=CC=CC=1.[Cl-].[Cl-].C([Al+2])C>[CH3:16][C:17]1([CH:18]=[O:19])[CH:20]([CH3:21])[CH2:12][C:11]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:15])[CH3:6])=[CH:13][CH2:14]1
Reactant: C=CC(=C)CCC=C(C)C
Reactant: CC=C(C)C=O
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)=CCCC1=CCC(C)(C=O)C(C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A 3-neck reaction vessel is charged with 100 ml benzene and 50 grams of 25% ethyl aluminum dichloride in benzene. A solution containing 320 grams myrcene (85% pure), 170 grams 2-methyl-2-butenal, and 200 ml benzene is fed in at 40°-50° C. over a 1 hour period. The temperature is then raised to 60° C. and held there for 1/2 hour. An additional 10 grams ethyl aluminum dichloride solution mixed with 20 ml benzene is added and heating is continued for an additional 1/2 hour. The mixture is then cooled, water is added and the layers are separated. The organic layer is washed with water and distilled without fractionation to free the material of residue. Redistillation through an 18" Goodloe packed column provides 199 grams of 1,6-dimethyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carboxaldehyde (b.p. 105° C., 0.9 mm).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[C:20]1[N:26]([CH3:39])[C:27](=[O:38])[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[CH:29][C:19]2=1)=O)=[O:11])C1C=CC=CC=1.O.CCOC(C)=O>OS(O)(=O)=O>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[C:28]1[C:27](=[O:38])[N:26]([CH3:39])[C:20]2[N:21]([CH3:25])[C:22]3[C:18]([C:19]=2[CH:29]=1)=[CH:17][C:16]([C:14]1[O:11][C:10]([CH2:9][OH:8])=[N:12][CH:13]=1)=[CH:24][CH:23]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CNC(=O)COCc4ccccc4)ccc3n(C)c21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cnc(CO)o4)ccc3n(C)c21

Procedure:
A solution of compound A 2-benzyloxy-N-{2-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2-oxoethyl}acetamide (454 mg, 0.81 mmol) in 2 ml of H2SO4 is stirred at ambient temperature for 20 h. A mixture of H2O and EtOAc is added, the green solid obtained is filtered off, the filtrate is taken up and extracted with EtOAc, and these combined organic phases are concentrated with the precipitate without drying. The product is adsorbed onto silica with a minimum amount of pyridine and purification is carried out by chromatography on a silica column, elution being carried out with EtOAc and then EtOAc/5% MeOH. The residue is taken up in MeOH and the product is filtered and washed with a minimum amount of MeOH and then of Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.018 g, 9%). MS (ISP) 413.1 [(M+H)+]; mp 226° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1([CH3:28])[S:21][CH:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]=[CH:18]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:16][C:17]1([CH3:28])[S:21][C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:24][CH2:23]2)=[N:19][CH2:18]1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Reactant: CC1(C)C=NC(N2CCNCC2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CN=C(N2CCN(c3ncnc4sc(CC(F)(F)F)cc34)CC2)S1
Yield: 82.2 %

Procedure:
A solution of 0.5 g of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (2.4 mmol), 0.56 g of 5,5-dimethyl-2-(piperazin-1-yl)-2,5-dihydrothiazole (2.8 mmol), and 0.91 g of N,N-diisopropylethylamine (7.1 mmol) in 20 mL of THF was refluxed for 6 h. After cooling, the mixture was partitioned between ethyl acetate and H2O. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated to a pale yellow solid. Purification by silica gel column chromatography using dichloromethane/methanol (97:3) as eluent gave 0.82 g of 4-(4-(5,5-dimethyl-4,5-dihydrothiazol-2-yl)piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (compound 1) as a pale yellow solid. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. 1H NMR (400 MHz DMSO-d6): δ 8.46 (s, 1H), 7.70 (s, 1H), 4.37 (s, 1H), 4.09 (m, 4H), 3.81, (m, 4H), 3.45 (q, 2H, J=10.1 Hz), 1.61 (s, 6H). ESI MS [MH+]: 416.1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[S:17][C:16]([CH:18]=[CH:19][CH2:20][OH:21])=[CH:15][CH:14]=1>ClCCl>[O:9]1[CH:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:19]1[CH2:20][OH:21]
Reactant: OCC=Cc1ccc(Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OCC1OC1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.75 g of m-chloroperbenzoic acid is added to a stirred solution of 0.6 g of 3-(5-chlorothiophen-2-yl)-prop-2-enol according to c) in 50 ml of dichloromethane. The solution is stirred at room temperature for 5 hours, washed with 10% sodium carbonate solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ether and the title compound is obtained in the form of a light-yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:4].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>N1C=CC=CC=1>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=C(N1CCCC1c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C(N1CCCC1c1ccc(S(=O)(=O)Nc2nccs2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 31.9 %

Procedure:
Prepared using general procedure 37. Under an N2 atmosphere, a mixture of the 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride (1.1 g, 5.8 mmol), 2-aminothiazole (0.58 g, 5.8 mmol), and pyridine (4.0 mL) was stirred at RT for 19 h. The crude product was purified via silica gel chromatography using 3% MeOH in CH2Cl2. The resulting oil was taken up in a 2:1 mixture of CH2Cl2:Et2O (12 mL) and cooled to 0° C. for 20 minutes. The formed precipitate was filtered off and dried under vacuum to obtain N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-sulfonamide as a white solid (750 mg, 32%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=405.1; tR=2.68 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]>CN(C=O)C>[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH:67][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([CH2:14][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)=[CH:16][CH:17]=2)=[O:27])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)c2ccccc12
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (130 mg) obtained in Example 36-4 was dissolved in DMF (3.0 ml) and then added with DCC (60.0 mg) and HOBt (40.0 mg), followed by stirring at room temperature for 2 hours. The compound (50.0 mg) obtained in Example 19-2 was added to the solution at room temperature, and the whole was stirred overnight. After completion of the reaction, insoluble matter was removed from the solution through a G4 glass filter and the solvent was distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l hydrochloric acid. The organic layer was added with hydrochloric acid to separate the solution into layers. Then, the aqueous layer was added with a sodium hydroxide aqueous solution to adjust it to pH 12. The aqueous layer was subjected to extraction with chloroform, and the organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water) thereby obtaining hydrochloride (17.4 mg) of the subject compound as a white foamed compound.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25]([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 76 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C19H19FN2O3, 342.13804; found (ESI+), 343.14480.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([NH2:29])[CH:5]=1.Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CN(C)[C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2N(C)C)C=CC=1.[Na]>CN(C=O)C.C(#N)C>[C:37]1([CH2:36][O:35][C:33](=[O:34])[CH2:32][N:29]([C:6]2[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:30])[CH:5]=2)[CH2:4][C:3](=[O:2])[O:30][CH2:45][C:54]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(=O)OC)c1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 93.8 %

Procedure:
A mixture of 3.25 g (7.74 mmol) of 3-amino-5-(octadecyloxy)benzoic acid methyl ester, 3.7 ml (23 mmol) of benzyl bromoacetate, 4.2 g (19.4 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.3 g (2.2 mmol) of sodium iodidein 65 ml of acetonitrile and 20 ml of DMF was stirred and heated at reflux under argon for 48 hours. The reaction mixture was concentrated at reducedpressure and ethyl acetate was added to the residue. The extract was washedwith 0.05N HCl, with saturated NaHCO3 solution, dried and concentratedat reduced pressure to a solid which was purified by HPLC using 15% ethyl acetate-hexane to give 2.6 g (48% yield, mp 62°-63°) of N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy) ethyl]glycine phenylmethyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].Cl[C:19]1[C:20]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:25][C:21]=2[N:22]=[CH:23][N:24]=1.O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:20]3[C:19]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]#[N:10])=[N:24][CH:23]=[N:22][C:21]=3[O:25][C:26]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: N#CCCCCCN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC#N)c23)cc1

Procedure:
Add 1.15 g (8.9 mmol) DIEA and 0.67 g (5.9 mmol) 6-aminocapronitrile to 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 10 ml DMF and heat for 2 h to 120° C. After cooling, add water to the mixture and extract three times with ethyl acetate. Wash the organic phase with water, with dilute hydrochloric acid and with saturated sodium chloride solution, dry, and concentrate by evaporation. 1.2 g (98% of theor.) of a yellow oil is obtained, and is used as the raw product in further reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([O:28]C)[CH:27]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:14][C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23]O)[CH:18]=[CH:19][CH:20]=2)[N:8]=1.C(Cl)Cl.B(Br)(Br)[Br:34].C([O-])(O)=O.[Na+]>C(=O)=O>[Br:1][C:2]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:4]([CH2:5][NH:6][C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][Br:34])[CH:16]=3)[N:8]=2)[CH:3]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(Br)cc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(Br)cc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Into a reaction flask was added 3-[3-({4-[(3-bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}amino)phenyl]propan-1-ol (2.70 g, 5.65 mmol), methylene chloride (30 mL), and a solution of boron tribromide in methylene chloride (17.0 mL, 17.0 mmol, 1.0 M). The mixture was stirred at rt overnight. The resultant mixture was cooled in dry ice when NaHCO3 (saturated aqueous solution) was added. After removal of the organic solvent, the aqueous layer was extracted with methylene chloride twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product (2.97 g, 100%). LCMS for C20H19Br2ClN4O (M+H)+: m/z=526.9, 528.8.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[ClH:14].[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=4)[NH:3][C:2]=3[CH3:1])=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccnc2cc(Cl)ccc12
Temperature: 160 °C
Yield: 95.6 %

Procedure:
A mixture of 2-methyl-5-nitroindole (1.34 g) and 4,7-dichloroquinoline (1.53 g) in NMP (1 ml) and 4M HCl in dioxane (0.1 ml) was heated at 145° C. for 2 hours and at 160° C. for 4 hours. After cooling the mixture triturated with ether and the solid collected to give the sub-title compound (2.72 g) as a green solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2)=[O:31]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4cccc(Cl)c4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 3-chlorobenzoyl chloride (0.25 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 3-chloro-N-[2-(2,6-dioxo-piperidin-3yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.49 g, 88% yield); mp 293-295° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.50 (98.62%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.45 (m, 1H), 2.57-2.63 (m, 1H), 2.85-2.98 (m, 1H), 4.31 (d, 1H, J=17.4 Hz), 4.45 (d, 1H, J=17.4 Hz), 4.60 (d, 2H, J=6.0 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.46-7.50 (m, 1H), 7.53-7.55 (m, 2H), 7.61-7.65 (m, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.85-7.89 (m, 1H), 7.95 (t, 1H, J=1.7 Hz), 9.27 (t, 1H, J=6.0 Hz), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.0, 127.1, 127.2, 130.4, 130.5, 131.2, 133.2, 136.1, 142.2, 143.6, 164.9, 167.9, 170.9, 172.8; LCMS: MH=412, 414; Anal. Calcd for C21H18ClN3O4+0.1H2O: C, 60.98; H, 4.43; N, 10.16. Found: C, 60.71; H, 4.36; N, 10.30.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[N:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[N:30][CH:29]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cncc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cncc(N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.030 g, 0.054 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated to give the desired product (21 mg, 95%). LCMS for C18H20ClN6 (M+H)+: m/z=355.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C=O.[C:29]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-5-Chloro-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-indazole (40 mg, 0.11 mmol) and formaldehyde (37 wt. % solution in water, 156 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (34 mg, 0.54 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 30 mg (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.34-7.37 (m, 1H), 7.27 (m, 2H), 6.97 (d, J=1.5 Hz, 1H), 4.52 (q, J=6.7 Hz, 1H), 3.35 (d, J=9.2 Hz, 1H), 3.23 (d, J=8.9 Hz, 1H), 3.11-3.26 (m, 2H), 2.45-2.53 (m, 2H), 2.49 (s, 3H), 2.38-2.40 (m, 2H), 2.25-2.30 (m, 2H), 1.46 (d, J=6.7 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 135.5, 133.6, 129.3, 127.5, 127.4, 126.9, 126.0, 124.9, 124.4, 119.1, 78.2, 51.5, 51.4, 44.4, 40.5, 30.2, 22.0. Mass spec.: 384.16 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])[OH:20].[Na+].[CH:24]1([C:30]2C(CCC=O)=C(S([O-])(=O)=O)C=[CH:34][C:35]=2Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(OCC)C>COC(OC)COCC(OC)OC.O>[NH3:5].[CH:24]1([C:30](=[O:20])[CH2:35][CH2:34][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CCCc1c(S(=O)(=O)[O-])ccc(Br)c1C1CCCCC1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C([O-])O
Agent: COC(COCC(OC)OC)OC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCC(=O)C3CCCCC3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) in dimethoxyethyl ether (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol), and 3-cyclohexyl-3-oxopropyl-4-bromobenzenesulfonate (Preparation 91, 75 mg, 0.2 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (42 mg, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.33 mmol) to afford the desired product (41 mg, 28%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.46 (d, J=8.0 Hz, 1H), 8.96 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.64-7.57 (m, 2H), 4.13-4.07 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.22-2.15 (m, 2H), 2.13 (s, 6H), 1.87 (d, J=12.9 Hz, 2H), 1.57-1.42 (m, 3H), 1.16-0.99 (m, 5H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC 98.5% (AUC), tR=8.36 min.