Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1)=[CH2:16].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:14][C:9]1[CH:8]=[C:7]([CH:2]([C:3]([F:6])([F:5])[F:4])/[CH:16]=[CH:15]/[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH:12]=[C:11]([Cl:13])[CH:10]=1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
Reaction SMILES: [CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([OH:24])=[O:23])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH2:26](O)[CH3:27]>>[CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH2:26][CH3:27])=[O:23])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCCc1cc2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A solution of 2-(n-dodecyl)indole-6-carboxylic acid (14.0 g) in ethanol (70 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml, of strength 35% w/v) was refluxed for 5 hours. The solid, which crystallised on cooling, was collected, washed with light petroleum ether (b.p. 40°-60° C.) and was recrystallised from ethanol to give ethyl 2-(n-dodecyl)-indole-6-carboxylate (9.1 g), in the form of a pale pink solid, m.p. 83°-86° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (471 mg) and triethylamine (328 μl) in chloroform (4.7 ml) cooled to 0° C. was added methanesulfonyl chloride (118 μl), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 1M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (565 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[CH:16][C:15]=1[O:33][CH3:34]>CN(C)C=O>[CH:26]1([N:20]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:19])[C:17]2[CH:31]=[CH:32][C:14]([CH2:13][N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[CH:2]3)=[C:15]([O:33][CH3:34])[CH:16]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1cnc2nc[nH]c2c1
Reactant: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1Cn1cnc2ncccc21
Reaction time: 2 h

Procedure:
To a stirred solution of imidazo[4,5-b]pyridine (350 mg, 2.94 mmol) in N,N-dimethylformamide (25 mL), sodium hydride (118 mg, 60% dispersion in mineral oil, 2.94 mmol) was added. After stirring for 2 hr, 4-bromomethyl-3-methoxy-N,N-dicyclopentyl benzamide (1.4 g, 3.57 mmol) was added in small installments over 10 min. The reaction mixture was stirred under argon at 25° C. After 18 h, the reaction was quenched by adding acetic acid (0.5 mL) and the solvent was removed under reduced pressure at <45° C. The crude mixture (2 g) was chromatographed (silica gel, CH2Cl2 -MeOH-NH4OH 90-10-1) to give the title compound. (160 mg, 13%) DSC 198° C.; Anal calcd. for C25H30N4O2 ·0.7H2O: C, 69.65; H, 7.34; N, 12.99. Found C, 69.72; H, 7.39; N, 12.63.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:37])[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:38]([O:41][CH2:42][CH2:43]Br)(=[O:40])[CH3:39]>>[C:38]([O:41][CH2:42][CH2:43][N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:37])[C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:15])(=[O:40])[CH3:39]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Product: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Yield: 95 %

Procedure:
5-(2-Acetoxypropionylamino)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide was alkylated with 2-bromoethyl acetate according to the general procedure described in Example 25a. After work up the product was isolated in 95% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9]CC[CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:44])C=CC=2)N=1.Cl.N1CC[C@@H]1C(OC)=O>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:9][C@@H:4]3[C:3]([O:2][CH3:1])=[O:44])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])(=[O:25])[NH2:27]
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: COC(=O)[C@H]1CCN1
Agent: Cl
Product: COC(=O)[C@H]1CCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B36 was prepared following the general procedure reported for B4 using A1 and A7 and obtained as white crystals; yield: 60 mg (18%). MS (ES) C15H18N16O4S requires: 378. found: 379 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][OH:20])[C:10]1=[O:11].[CH3:21][C:22]1(C)NC(=O)N[C:23]1=[O:28].C1OC1>>[C:1]([O:5][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][O:20][C:23](=[O:28])[CH:22]=[CH2:21])[C:10]1=[O:11])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][N:9]1[C:15]([CH3:17])([CH3:16])[C:13](=[O:14])[N:12]([CH2:18][CH2:19][OH:20])[C:10]1=[O:11]
Reactant: C=CC(=O)O
Reactant: CC1(C)NC(=O)NC1=O
Agent: CC1(C)C(=O)N(CCO)C(=O)N1CCO
Solvent: C1CO1
Product: C=CC(=O)OCCN1C(=O)N(CCOC(=O)C=C)C(C)(C)C1=O

Procedure:
1,3-Bis(2-acryloyloxyethyl)-5,5-dimethylhydantoin is prepared by reaction of acrylic acid and 1,3-bis(2-hydroxyethyl)-5,5-dimethylhydantoin according to Example 4 of U.S. Pat. No. 3,852,302. 1,3-Bis(2-hydroxyethyl)-5,5-dimethylhydantoin is prepared by the reaction of 5,5-dimethylhydantoin and ethylene oxide according to Example C of U.S. Pat. No. 3,629,263.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=C(OC)C(OC)=C(OC)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COc1cc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc(OC)c1OC
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc(OC)c1OC
Yield: 7 %

Procedure:
The title compound (0.006 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4,5-trimethoxybenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C23H26ClN3O3, 427.17. found, m/z 428.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.49 (m, 2H), 7.46-7.44 (m, 2H), 6.44 (s, 2H), 5.32 (s, 2H), 3.78 (s, 6H), 3.74 (s, 3H), 2.95-2.89 (m, 6H), 2.81-2.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([NH2:20])#[C:18][CH3:19].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH2:17][C:18]#[CH:19])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC#CN
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolved in 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0 ml (86 mmol) of propynylamine are added. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO2, and the solvent is evaporated by means of underpressure. After the remaining material is recrystallized with diisopropyl ether/hexane, the yield is 10.6 g (87% of theory) of the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C(O)CCC>O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:15]=3[N:16]=1)[CH:6]=[CH:5]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCI
Reactant: CCCCc1ccc2oc(-c3ccc4cc(O)ccc4c3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCOc1ccc2cc(-c3nc4cc(CCCC)ccc4o3)ccc2c1
Yield: 56.6 %

Procedure:
In a 30ml round-bottom flask, 0.47 g (1.48 m mole) of 2-(6-hydroxy-2-naphthyl)-5-butylbenzooxazole, 0.43 g (1.79 m mole) of octyl iodide, 0.12 g (1.82 m mole) of potassium hydroxide and 5 ml of butanol were placed, followed by refluxing for 310 minutes. The reaction mixture was poured into water, extracted from ethyl acetate to obtain an organic layer. The organic layer was washed with water dried with mirabilite and dried under reduced pressure to obtain a resultant. The resultant was recrystallized from ethylacetate to obtain a crystal. The crystal was filtered, purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.36 g of 2-(6-octyloxy-2-naphthyl)-5-butylbenzooxazole (Yield: 56.6%). ##STR190##
Reaction SMILES: [Zn:1].C(Br)CBr.C[Si](Cl)(C)C.[I:11][CH2:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>C1COCC1>[I-:11].[CH2:12]([Zn+:1])[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: [Zn]
Reactant: CC(C)(CI)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C[Zn+])c1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round flask including nitrogen preparation, internal thermometer and septum cap, which was heated in a vacuum and rinsed with argon, zinc powder (1.57 g, 24.0 mmol) was covered with a layer of THF (6 ml) and presented, and 1,2-dibromomethane (0.2 ml) was slowly added dropwise from a single-use syringe with cannula. Upon addition, heating was effected by means of a hot-air blast until the solvent was slightly boiling. After the reaction mixture was cooled to room temperature, trimethylsilylchloride (0.2 ml) was slowly added dropwise. By means of a hot-air blast, the mixture was again heated until it was slightly boiling, and stirring was continued for 5 minutes. Subsequently, 1-(2-iodo-1,1-dimethylethyl)benzene (neophyl iodide, 1.56 g, 6.0 mmol) was added within 5 minutes. Upon completion of the addition, the mixture was heated to 50° C. for 3 hours. The zinc insertion was observed by means of a GC analysis via iodolysis and hydrolysis of an aliquot of the reaction mixture.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:30][N:29]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]=[C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=3)=[O:20])[CH2:37][CH2:38]2)[S:30][N:29]=1
Reactant: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4F)ns3)CC2)cc1
Yield: 22.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 60.5 mg (22.6%) of the desired product as a solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH:1]([C:4]1[N:5]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1ccnc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 2-isopropylimidazole (3.0 g, 27.2 mmol) and DIEA (5.28 g, 40.9 mmol) in DCM (75 mL) was treated drop-wise with methoxyethoxymethyl chloride [MEM-Cl] (4.24 g, 34.0 mmol) and stirred at RT for 16 h. The mixture was washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (3.91 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 7.11 (d, J=1.3 Hz, 1H), 6.74 (d, J=1.3 Hz, 1H), 5.30 (s, 2H), 3.47-3.46 (m, 2H), 3.38-3.37 (m, 2H), 3.19 (s, 3H), 3.08-3.07 (m, 1H), 1.18 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][S:49]([CH3:48])(=[O:51])=[O:50])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Preparation 23) (0.419 g, 0.70 mmol) in 10 ml of dry dichloromethane at 0° C. Add triethylamine (0.18 ml, 1.41 mmol) followed by methanesulfonyl chloride (0.06 ml, 0.77 mmol). Stir at room temperature for 5 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl, NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. Filter through a short silica plug to receive 0.45 g (95%) of the title compound: Mass spectrum (apci) m/z=675 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To 7-bromo-1,2,3,4-tetrahydroquinoline (1E) (1.0 g, 4.7 mmol) in DCM (30 mL) was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12 mmol), and pyridine (1.0 mL, 10.0 mmol). The reaction was allowed to stir at rt for 24 hours while monitoring by LCMS. To the reaction mixture was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12.0 mmol), and pyridine (1.0 mL, 10 mmol). The reaction was allowed to stir at rt for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 1.09 g (91%) of the desired product 1-(7-bromo-3,4-dihydroquinolin-1(2H)-yl)ethanone (1F): LC/MS (APCI): m/z 255.7 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[C:10]([C:11]2C=C[CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[C:7]([NH2:17])[C:6]1=[O:18].[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]([NH2:17])[C:6]1=[O:18]
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCc1ccc(N)c(=O)n1CC(=O)OC

Procedure:
Methyl[3-amino-1,2-dihydro-2-oxo-6-phenyl-1-pyridyl]acetate (50f), was isolated (86%) as a grey solid: mp. 207-9° C.; IR (KBr) 3473, 3345, 1750, 1644, 1600, 1536, 1443, 1366, 1309, 1212, 1184, 1156; 1H NMR (d6 -DMSO) δ 7.30 (5H, m), 6.54 (1H, d), 6.03 (1H, d), 5.25 (2H, s), 4.49 (2H, s), 3.61 (3H, s).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].COS([O:20][CH3:21])(=O)=O.[CH2:22]1COCC1>[Pd]>[CH3:22][O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([O:20][CH3:21])=[CH:2][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: COS(=O)(=O)OC
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Following the procedure of Evans et al.,23 1,4-naphthoquinone (31, 10.00 g, 63.20 mmol) and Pd/C (10 wt %, 0.994 g) were added to a flame-dried 500 mL round bottom flask at room temperature under Argon. THF (250.0 mL) was then added at room temperature, the reaction vessel was covered in foil, and then purged with H2 for 10 minutes. A balloon filled with H2 was attached and the reaction stirred for 4 hrs at room temperature. The reaction was then purged with Argon before adding NaH (5.66 g, 142 mmol) slowly at 0° C. After 10 minutes Me2SO4 (13.0 mL, 137 mmol) was added slowly at 0° C. The reaction became too thick to stir after adding Me2SO4, and 50 mL of THF were added to facilitate stirring. The dark green mixture was allowed to stir at room temperature for 4 hrs. The reaction was then filtered through celite, washed with brine, dried over MgSO4, and condensed. The resulting solid was then purified by flash chromatography (EtOAc:hexanes) or recrystallized from Et2O:hexanes to provide 32 (11.74 g, 62.42 mmol, 99%) as pink needles.
Reaction SMILES: [Cl:1][CH:2]1[CH2:10][CH2:9][C:8]2[C:7](=[NH:11])[NH:6][C:5](=N)[C:4]=2[CH2:3]1.Cl.[C:14]([N:18]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]1[S:20][CH2:21][C:22](=[NH:24])[N:23]=1)([CH3:17])([CH3:16])[CH3:15].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[NH:11]=[C:7]1[C:8]2[CH2:9][CH2:10][CH:2]([Cl:1])[CH2:3][C:4]=2[C:5](=[C:21]2[S:20][C:19]([N:18]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([CH3:15])([CH3:16])[CH3:17])=[N:23][C:22]2=[NH:24])[NH:6]1
Reactant: N=C1NC(=N)C2=C1CCC(Cl)C2
Reactant: CC(C)(C)N(C1=NC(=N)CS1)C(C)(C)C
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CC(C)(C)N(C1=NC(=N)C(=C2NC(=N)C3=C2CC(Cl)CC3)S1)C(C)(C)C

Procedure:
When equivalent amounts of 5-chloro-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-di-t-butylamino-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-5-chloro-4,5,6,7-tetrahydro-3-(2-di-t-butylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH:10]([CH3:13])[CH2:11][Cl:12].[OH-].[Na+]>C(O)C>[C:1]1([S:7][CH2:9][CH:10]([CH3:13])[CH2:11][Cl:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCl)CBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CCl)CSc1ccccc1
Temperature: 40 °C
Yield: 97.1 %

Procedure:
A mixture of 22 g (0.2 mol) of thiophenol and 37.7 g (0.22 mol) of 3-bromo-1-chloro-2-methylpropane in 200 ml of ethanol is stirred at 40° C and 40 ml (0.2 mol) of 5N sodium hydroxide solution is added dropwise. The mixture is stirred for a further 2 hours at 40° C and evaporated to dryness in vacuo, the residue is extracted with methylene chloride and the extract is washed with water, dried and evaporated in vacuo. 39 g (97%) of a yellow oil are obtained.