Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].O.NN>>[CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Sc1ccc(SCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Product: CCC(C)Sc1ccc(SCCN)cc1

Procedure:
To 4-(1-methylpropylthio)benzenethiol (8.79 g, 44.3 mmol) in 25 ml of DMS is added, under N2, potassium carbonate (7.05 g, 51.0 mmol) followed by dropwise addition of N-(bromoethyl)-phthalimide (12.94 g, 51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solvent removed to give N-{2-[4-(1-methylpropylthio)-phenylthio]ethyl}phthalimide. Following the procedures of Example 13, the above phthalimide (2.12 g, 5.7 mmol is reacted with hydrazine hydrate (0.28 ml, 5.7 mmol) to give 2-[4-(1-methylpropylthio)phenylthio ethylamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[C:26]3[S:20][C:21](=[S:22])[NH:23][C:24]3=[O:25])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Sc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Sc2ccc(C=C3SC(=S)NC3=O)cc2)cc1
Yield: 51.9 %

Procedure:
The 4-[4-(t-butyl)phenylthio]benzaldehyde (1.5 g, 5.5 mmol) was coupled with rhodanine (0.87 g, 6.5 mmol) in the presence of sodium acetate (1.64 g, 20 mmol) and acetic acid (80 ml) essentially as previously described to yield 1.1 grams (52.3%) of the title product. mp 211°-212° C. NMR. FDMS (M+) 385.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[S:41])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(CNC(=S)c2ccc(CSc3c(Cl)ccc4c3CCNCC4)cc2)cc1
Temperature: 25 °C

Procedure:
Combine 7-chloro-6-[4-(4-fluorobenzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (23 mg, 0.05 mmol) with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (23 mg, 0.05 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100° C. for 2 h Cool the reaction mixture to room temperature, concentrate in vacuo and purify the residue by SCX chromatography to obtain 7-chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][C:23](O)=[O:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:21])[CH3:20])[CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C([Cl:32])=O>C1COCC1>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][C:23]([Cl:32])=[O:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:21])[CH3:20])[CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=C(CC(=O)O)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Product: CC1=C(CC(=O)Cl)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-1-(p-methylsulfonylbenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:20])[CH2:15][CH2:14][C:13]2(OCC[O:16]2)[CH2:12][CH2:11]1>C(O)(=O)C.Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:20])[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]1
Reactant: OC1(c2nc3ccccc3s2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCC(O)(c2nc3ccccc3s2)CC1
Yield: 73.5 %

Procedure:
A solution of 4-(benzothiazol-2-yl)-1,1-ethylenedioxy-4-hydroxycyclohexane (1.0 g, 3.4 mmol) in acetic acid (40 mL) and conc. HCl (10 mL) was heated at 80° C. for 2 h with stirring. The volume was reduced on a rotary evaporator and the remaining solution was carefully neutralized with saturated sodium hydrogen carbonate solution and then extracted with diethyl ether (3×50 mL). The organic layers were combined, washed with water (2×50 mL) and dried over magnesium sulphate. Removal of the solvent under vacuum gave the product 4-(benzothiazol-2-yl)-4-hydroxycyclohexan-1-one (0.618 g) as an off white solid (73%); mp 134° C.; 1H NMR (CDCl3) δ 8.00 (1H, m, benzothiazole H-4/7), 7.91 (1H, m, benzothiazole H-4/7), 7.49 (1H, m, benzothiazole H-5/6), 7.41 (1H, m, benzothiazole H-5/6), 3.66 (1H, s, OH), 2.97–2.85 (4H, m, cyclohexanone CH2), 2.53–2.34 (4H, m, cyclohexanone CH2); IR (KBr disc) 2913, 1690, 1505, 1427, 1312, 1198, 889, 768 cm−1; MS (AP+) 248 (M++1), 230 (M++1—H2O); Anal. (C13H13NO2S) C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:13](=O)[O:12][C:10](=O)[C:9]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]12.CSC1[NH:22][CH2:23][CH2:24][N:25]=1.[OH-].[K+]>O1CCOCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8]2[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10](=[O:12])[N:22]2[CH2:23][CH2:24][N:25]=[C:13]12
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(Cc2cccs2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2cccs2)C2=NCCN12

Procedure:
A mixture of 20 g. of N-(2-thienylmethyl)isatoic anhydride, 9 g. of 2-methylmercapto-imidazoline and 1 pellet of potassium hydroxide in about 300 ml. of dioxane is heated at reflux for 5 hours, the solvent then evaporated off and the residue dissolved in methylene chloride. After washing twice with water the solution is extracted 3 times with 1N. hydrochloric solution. Heating on a steam bath avoids precipitation and after filtering hot through celite, sodium bicarbonate solution is added and the resulting precipitate is recovered by filtering, washed with water, dissolved in methylene chloride and the methylene chloride exchanged for diethyl ether. The resulting precipitate is recovered by filtering, washed with diethyl ether and dried under reduced pressure at 40°C. to obtain 10-(2-thienylmethyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 124°-127°C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:37]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH2:38].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:19]=4)[CH2:16][N:15]([CH2:38][CH2:37][S:39]([CH3:42])(=[O:41])=[O:40])[C:14]3=[O:32])=[CH:11][CH:12]=2)=[CH:33][CH:34]=1
Reactant: C=CS(C)(=O)=O
Reactant: O=C1NCC(c2cccc(OCc3ccccc3)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCN1CC(c2cccc(OCc3ccccc3)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(benzyloxy)phenyl)imidazolidin-2-one (Example 288) (200 mg, 0.42 mmol) in 5 mL DMF is added sodium hydride (19 mg, 0.47 mmol) followed by methyl vinyl sulfone (41 μL, 0.47 mmol). After 30 minute, the reaction is cooled to 0° C. and sat. ammonium chloride is added slowly to the reaction mixture. The reaction mixture is extracted with ethyl acetate (2×) and purified by flash chromatography gives 171 mg (71%) of the title compound. HPLC-MS calculated for C31H29ClN2O5S (M+H+): 577.2, found 577.2.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13](C(=O)C)[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6](=[C:26](OCC)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]1=[O:36])(=O)C.[C:37]([N:40]([C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)[CH2:41][CH2:42][NH:43]C(=O)C(F)(F)F)(=[O:39])[CH3:38].CO.[OH-].[Na+]>CN(C=O)C.O>[C:37]([N:40]([C:50]1[CH:51]=[CH:52][C:53]([NH:54]/[C:26](=[C:6]2\[C:5](=[O:36])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:11]=3)/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:55][CH:56]=1)[CH2:41][CH2:42][NH2:43])(=[O:39])[CH3:38]
Reactant: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(=O)N(CCN)c1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g (1 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone and 0.3 g (1.2 mmol) of 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline are stirred in 5 ml of DMF for 6 hours at 120° C. After cooling to ambient temperature 5 ml of methanol and 3 ml (6 mmol) of 2 N sodium hydroxide solution are added, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with 50 ml of water and the crystalline precipitate is suction filtered and dried. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=9:1:0.1).
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]=[CH:8][CH2:9][NH2:10].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+].C(O)(=O)C>CO.O>[CH2:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]=[CH:8][CH2:9][NH2:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCC=CCc1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: NCC=CCc1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
A solution of (3-amino-4-phenoxy-5-sulfamylbenzyl)allylamine hydrate (3.3 g; prepared as described in Example 111) and benzaldehyde (1.2 g) in methanol (35 ml) is refluxed for 16 hours. Sodium borohydride (1.0 g) is then during 30 minutes added in portions while stirring at 0°-5° C. After additional stirring for 2 hours, acetic acid (1.0 ml) followed by water (120 ml) is cautiously added to precipitate crude (3-benzylamino-4-phenoxy-5-sulfamylbenzyl)allylamine. After filtration and recrystallization twice from aqueous ethanol, it is obtained with a melting point of 139°-140° C. The material (IR, analysis) is identical with the material prepared as in Example 150.
Reaction SMILES: [I-].[F:2][C:3]([F:40])([F:39])[C:4]1[CH:5]=[C:6]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:7][N:8]([CH3:31])[C:9]([C:11]1[N:21]([CH3:22])[C:20](=[O:23])[C:14]2=[N+:15]([CH3:19])[CH:16]=[CH:17][CH:18]=[C:13]2[C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:10].[BH4-].[Na+]>CO>[F:39][C:3]([F:2])([F:40])[C:4]1[CH:5]=[C:6]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[CH2:7][N:8]([CH3:31])[C:9]([C:11]1[N:21]([CH3:22])[C:20](=[O:23])[C:14]2[N:15]([CH3:19])[CH2:16][CH:17]=[CH:18][C:13]=2[C:12]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[O:10]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccc[n+](C)c2c(=O)n1C
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)N(C)CC=C2

Procedure:
To a solution of the compound (310 mg) obtained in Example 29 in methanol (15 ml) was added portionwise sodium borohydride (50 mg) at room temperature while stirring. This mixture was stirred for 15 minutes at room temperature, which was then concentrated. To the concentrate was added ethyl acetate, which was washed with water and dried, then the solvent was distilled off to leave N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-fluorophenyl)-1,2,7,8-tetrahydro-N,1,7-trimethyl-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide as a pale yellow oily product [NMR (200 MHz,CDCl3) ppm: 2.70(3H,s), 3.16(3H,s), 3.49(3H,s), 3.49(1H,m), 3.88(1H,m), 4.29(1H,d,J=14.6 Hz), 4.66(1H,d,J=14.6 Hz), 5.62(1H,m), 5.77(1H,d,J=13 Hz), 6.84-7.26(4H,m), 7.53(2H,s), 7.81(1H,s)].
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:20]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3OC(F)(F)F)noc2N)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (559 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.CC(C)([O-])C.[Na+].Cl.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH:32]2[CH2:37][CH2:36][CH:35]([O:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[O:41])[CH2:34][CH2:33]2)=[CH:27][C:26]=1[C:48]([F:51])([F:50])[F:49])([O-:24])=[O:23]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH:32]2[CH2:33][CH2:34][CH:35]([O:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([C:2]4[S:3][C:4]5[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=5[N:6]=4)[CH2:44][CH2:43]3)=[O:41])[CH2:36][CH2:37]2)=[CH:27][C:26]=1[C:48]([F:51])([F:50])[F:49])([O-:24])=[O:23]
Reactant: FC(F)(F)c1ccc2sc(Br)nc2c1
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2nc3cc(C(F)(F)F)ccc3s2)CC1
Temperature: 70 °C
Yield: 74.9 %

Procedure:
To a solution of 2-bromo-5-trifluoromethyl-benzothiazole (430 mg, 1.4 mmol, 1 eq.) in toluene (15 ml) was added sodium tert-butoxide (546 mg, 5.7 mmol, 4 eq.), BINAP (10 mg, 0.015 mmol, 0.01 eq.) and 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (1.33 g, 2.84 mmol, 2 eq.). The solution was flushed with nitrogen and evacuated three times before adding Pd2(dba)3-CHCl3 (31 mg, 0.03 mmol, 0.02 eq.) and flushing/evacuating a final time. The slurry was heated to for 18 hours at 70° C. before concentrating in vacuo. The residue was applied onto a silica gel column and eluted with Heptanes/EtOAc to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperazin-1-yl]-ethanone as a yellow solid (662 mg, 73.8%). (CI, m/z): [M+H]+ 632; 1H NMR (400 MHz, CDCl3): δ 1.29-1.38 (m, 2H), 1.41-1.56 (m, 2H), 2.16 (d, J=8.9 Hz, 4H), 3.26-3.53 (m, 2H), 3.55-3.90 (m, 8H), 4.26 (s, 2H), 4.47 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.81 (s, 1H), 8.01 (d, J=9.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:38])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][C:29]([O:32][CH3:33])=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (crude) (410 mg, 0.769 mmol) in DCM (1.5 mL) was added DIPEA (0.269 mL, 1.539 mmol) and MeI (0.072 mL, 1.154 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (120 mg, 28.5% yield). LCMS: rt=3.48 min, [M+H+]=547
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: O=Cc1ccccc1
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC(O)c1ccccc1
Yield: 95.2 %

Procedure:
125.40 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 60.00 g of benzaldehyde, 180 g of toluene, 240 g of 5% acetic acid and 73.88 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature of 3 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 98.23 g of 2-chloroallylphenylcarbinol. The results were as follows.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].[NH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][NH:24][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.66 g, 82 mmol) in 140 ml of water was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (4.20 g, 16.2 mmol) in 20 ml of absolute ethanol at room temperature. Upon completion of the addition, the mixture was stirred for 5 minutes, added with 2-amino-1-phenyl-ethanone (2.5 g, 14.6 mmol) and heated to reflux for 3 hours. The resulting mixture was added with water (300 ml), extracted with ethyl acetate (100 ml×3). The organic extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.0 g, 88.7%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH:1]([C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:27]1)=[O:20]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Reactant: O=C(NC1CCNCC1)c1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc2c(c1)NC(=O)CC2)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a MeOH solution (15 mL) of the compound (206 mg) obtained in Step 51-2, the compound (560 mg) obtained in Step 51-3 and AcOH (327 mg), NaBH3CN (274 mg) was added at room temperature and the mixture was refluxed for 12 hours. After the reaction mixture was cooled to room temperature, NaBH3CN (274 mg) was added and the mixture was refluxed for 72 hours. After a saturated aqueous NaHCO3 solution was added, a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 20/80; v/v) and (Chromatorex NH, mobile phase MeOH/CHCl3=0/100 to 10/90; v/v) in this order] to obtain the titled compound (7 mg, a colorless solid).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O:22][C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])C>C1(C)C=CC=CC=1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH2:25][C:23]([OH:24])=[O:22])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2O)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)O)cc1
Yield: 87.9 %

Procedure:
A solution of 3-hydroxy-2-(4-methoxyphenyl)isoindolin-1-one (12.0 g) and ethoxycarbonylmethylenetriphenylphosphorane (16.0 g) in toluene (200 ml) was refluxed for 3 hours. After cooling, the toluene was distilled off and the residue was dissolved in 100 ml of methanol. A solution of 10 g of potassium carbonate in 70 ml of water was added to the above methanol solution and the mixture was refluxed gently for an hour. After cooling, 200 ml of water and 300 ml of ether were added and the mixture was shaken well. The aqueous layer was separated and acidified with 5N hydrochloric acid to give 12 g of 3-oxo-2-(4-methoxyphenyl)isoindoline-1-acetic acid, which was described in (iv) of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: CN1CCN(CCCN)CC1
Reactant: COC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)sc2c1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methyl ester (2.08 g, 6.50 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (3.00 g, 19.0 mmol) in 1,4-dioxane (40 mL) is heated at 90° C. for 20 hours. The solvent is evaporated and the resulting residue is subjected to chromatography on silica gel, eluting with 2M NH3/CH3OH in dichloromethane 0-8%, to give the title compound (1.30 g, 72% yield). ES+(m/z) 460 [M+H].