Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([CH3:11])[C:6]=2[CH:12]=1.[H][H]>O1CCOCC1.[Pd]>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:12][C:6]2[CH:7]([CH3:11])[C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: CC1C(=O)Oc2cc(N(Cc3ccccc3)Cc3ccccc3)c(Cl)cc21
Agent: [Pd]
Solvent: C1COCCO1
Product: CC1C(=O)Oc2cc(N)c(Cl)cc21

Procedure:
A solution of 21.8 g (0.058 mole) of 5-chloro-6-dibenzylamino-3-methylbenzofuran-2(3H)-one in 220 ml of dioxane is reduced with 2.0 g of palladium-on-carbon (5% strength) at room temperature with hydrogen without superatmospheric pressure. After absorption of the theoretical amount of hydrogen the catalyst is removed by filtration and the dioxane is evaporated off in vacuo. 20 ml of cold methanol are added to the residue and the precipitate is filtered off. 6-amino-5-chloro-3-methylbenzofuran-2(3H)-one is obtained in the form of colourless crystals having a melting point of 139°-140°.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1C=CC=CC=1>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Yield: 44.3 %

Procedure:
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 47a), to obtain 36.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate as a non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 47b), with 7.5 g of ethyldiisopropylamine and 10.1 g of p-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2% of theory) of ethyl 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, MP 93° to 95°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[O:14])[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[N:6][CH:7]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([N:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)=[O:14])[N:10]=[C:9]2[C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CC(c2ccc(Cl)cn2)C(c2ccc(F)cc2)=N1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N(C(=O)N1CC(c2ccc(Cl)cn2)C(c2ccc(F)cc2)=N1)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Sodium hydride (240 mg, 6.00 mmol as a 60 percent slurry in mineral oil) was extracted 3 times with 2 mL portions of dry hexane under an inert atmosphere and then 15 mL of tetrahydrofuran was added and the mixture cooled by stirring in an ice bath. 4-(5-Chloro-2-pyridinyl)-4,5-dihydro-3-(4-fluorophenyl)-N-(4-trifluoromethoxyphenyl)-1H-pyrazole-1-carboxamide (958 mg, 2.00 mmol) was then added in one portion and the mixture allowed to react for 30 min. Ethyl chloro-formate (0.573 mL, 6.00 mmol) was then added with cooling and stirring and the mixture allowed to react at 0°-10° C. for 30 min. The resulting mixture was partitioned between saturated aqueous ammonium chloride and ether. The ethereal phase was dried over magnesium sulfate, and then concentrated by evaporation under reduced pressure. The residue was triturated with 20 mL of ether, refrigerated for about 1 hr, and then recovered by filtration. It was then recrystallized from a mixture of hexane and acetone to obtain 660 mg of the title compound as white crystals melting at 159.5°-161° C. (60 percent yield)
Reaction SMILES: [CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][N:4]=1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[O:5][N:4]=1
Reactant: CSc1noc(-c2ccc(O)cc2)c1C#N
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1noc(-c2ccc(OCCc3ccccc3)cc2)c1C#N
Yield: 80 %

Procedure:
Equimolecular amounts of (III), 2-phenyl-ethyl bromide and K2CO3 were refluxed in acetone for 48 h. The mixture was concentrated to small volume and shaken with diethyl ether and water. The ether phase was washed with 2 M NaOH, then with water, evaporated to dryness and the residue was recrystallized from ethanol. The title product was obtained in an 80% yield (abbreviation ON-6), m.p. 93-940° C. (ethanol); IR (KBr) 2227 (CN) cm1; 1H NMR (CDCl3) (δ, ppm) 2.66 (s, 3H, SCH3); 3.14 (t, 2H, CH2—Ph); 4.26 (t, 2H, O—CH2); 7.30 (m, 5H, arom.); 6.99-8.00 (m, 4H, arom.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10]C2=O)=[CH:4][CH:3]=1.FC1C=CC(CO)=CC=1OC1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:12]([C:11]([OH:16])=[O:10])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: C1CCOC1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2, 5-dione (336 mg, 1.32 mmol) and 4-dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of 4-fluoro3-phenoxybenzyl alcohol (275 mg, 1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product, yellow liquid, is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give the 4-fluoro-3-phenoxybenzyl ester of N-(4-chlorophenyl) valine.
Reaction SMILES: C(=O)(OC(C)CC)[O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[Na+].[Cl-].[OH-].[Na+].[CH3:25][C:26]([O:29][OH:30])([CH3:28])[CH3:27]>C(OCC)C>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([O:2][O:30][O:29][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:14])=[CH:11][CH:10]=1
Reactant: CCC(C)OC(=O)OC(=O)COc1ccc(OC)cc1
Reactant: CC(C)(C)OO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc(OCC(=O)OOOC(C)(C)C)cc1
Yield: 70 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 2-(4-methoxyphenoxy)acetyl 1-methyl-1-propyl carbonate (0.012 mole), 20 ml of diethyl ether, and 20 ml of a 25 wt % aqueous NaCl solution. The reaction mixture was cooled to below 10° C. and the pH was increased to a value above 11 using a 25 wt % aqueous NaOH solution. Then, TBHP (0.013 mole) was dosed with this temperature and pH being maintained. The mixture was post-reacted for 90 min at a temperature between 0 and 10° C. and a pH of above 11. Working up was as described in Example 1. After evaporation of the diethyl ether, 2.3 g of tert-butylperoxy 4-methoxyphenoxyacetate (an orange oil) having a content of 92.5% were obtained in a yield of 70%.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH:3]=[CH:2][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C(N2C=CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 0.819 mmol) in DCM (8.2 mL) at 0° C. was added DBU (370 μA, 2.46 mmol), and XtalFluor-E® (562 mg, 2.46 mmol). The mixture was stirred overnight while warming up to rt, and quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1)]+=349
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[Se](=O)=[O:20]>O1CCOCC1>[OH:1][C@H:2]1[C@@H:16]([OH:20])[CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CC1=C2C[C@@]3(C)C(=C[C@H](O)[C@H](O)[C@@H]3C)C=C2OC1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 85.8 %

Procedure:
The compound prepared in Example B1 (5 mg, 0.02 mmol) was dissolved in dioxane (1 ml), selenium dioxide (22 mg, 0.20 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 days. The reaction solution was filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give the title compound (4.5 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>C1(O)CCCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:4][CH2:3][CH2:2][CH2:7][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: OC1CCCCC1
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
12 g (35 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1 g of powdered potassium cyanide in 120 ml of cyclohexanol are stirred at 130° for 18 hours, in each case about 10 ml of cyclohexanol being distilled off three times in the course of the reaction. The mixture is subsequently evaporated, the residue is taken up in chloroform, washed with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained cyclohexyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 166°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:13])=[C:5]2[C:14]([OH:16])=O.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:13])=[C:5]2[C:14]([Cl:19])=[O:16]
Reactant: Cc1c(C(=O)O)c2cc(Cl)ccc2[nH]c1=O
Reactant: O=S(Cl)Cl
Product: Cc1c(C(=O)Cl)c2cc(Cl)ccc2[nH]c1=O

Procedure:
6.5 g (0.027 mol) of the carboxylic acid prepared in Example 1 are dissolved in 80 ml of thionyl chloride and heated under reflux for two hours. For working-up, the reaction mixture is concentrated under reduced pressure on a rotary evaporator and the residue which remains is stirred with diethyl ether. The reaction product is filtered off and the solid obtained is dried in vacuo.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:34])[NH:16][C:17]1[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:18]=1[O:32][CH3:33])[N:9]2[CH3:14])(=[O:3])[CH3:2].Br[C:36]1[N:37]=[C:38]([C@H:46]2[CH2:51][CH2:50][C@H:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[N:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[C:40]=12>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:34])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:36]3[N:37]=[C:38]([C@H:46]4[CH2:47][CH2:48][C@H:49]([N:52]5[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]5)[CH2:50][CH2:51]4)[N:39]4[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[C:40]=34)=[CH:19][C:18]=1[O:32][CH3:33])[N:9]2[CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC(C)=O)cccc2n1C
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC(C)=O)cccc2n1C

Procedure:
Reaction of 2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoyl)-1-methyl-1H-indol-4-yl acetate (36 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% methanol (+ few drops ammonia)) gave 2-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamoyl)-1-methyl-1H-indol-4-yl acetate. This product was stirred with 7N ammonia in methanol for 1 h by room temperature, concentrated in vacuo, solved in acetonitril and filtered. The filtrate was concentrated in vacuo to give 4-hydroxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (15 mg)
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([F:23])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(F)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and α-methylthio-4-fluoroacetophenone (6.5 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-fluorophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (9 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][C@@H:8]2[CH3:13])[C:3]1=[O:14].[Cl:15][C:16]1[C:17]([C:23]#[N:24])=[N:18][CH:19]=[C:20](Cl)[N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:15][C:16]1[C:17]([C:23]#[N:24])=[N:18][CH:19]=[C:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[O:14])[C@H:8]2[CH3:13])[N:21]=1
Reactant: C[C@H]1NCCC[C@H]1N1CCN(C)C1=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Compound 356 from above was dissolved in 10 mL DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (250 mg, 1.42 mmol) and DIEA (500 μL, 2.84 mmol). The mixture was stirred at RT for 2 hours, diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (357, 200 mg, 42% yield).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1COCC1.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[C:36]([Si:40]([CH3:43])([CH3:42])Cl)([CH3:39])([CH3:38])[CH3:37]>O>[C:36]([Si:40]([O:33]/[C:30](/[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]2[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)=[CH:31]\[CH3:32])([CH3:43])[CH3:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
With cooling with ice, potassium hexamethyldisilazide (0.5 M toluene solution, 89 mL) was dropwise added to a stirring THF (100 mL) solution of the compound (10.0 g, 37.0 mmol) synthesized in the above (1) and t-butyldimethylchlorosilane (6.13 g, 40.7 mmol), and then the reaction solution was stirred at room temperature for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane) to obtain the entitled compound (13.5 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][S:21]3(=[O:27])=[O:26])[N:13]([CH3:19])[C:14](=[O:18])[C:15]=2[O:16]C)=[O:9])=[CH:4][CH:3]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][S:21]3(=[O:27])=[O:26])[N:13]([CH3:19])[C:14](=[O:18])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1c(C(=O)NCc2ccc(F)cc2)nc(N2CCCCS2(=O)=O)n(C)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 120 °C
Yield: 52.3 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid 4-fluoro-benzylamide (0.115 g, 0.27 mmol) in 2,4,6-collidine (3 ml) was treated with lithium iodide (0.060 g) and the resulting mixture was heated at 120° C. for 30 min. The collidine was then evaporated in vacuo, the residue was diluted with a small volume of water and the pH was adjusted to a value of 7 with 0.1 N hydrochloric acid. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on reversed phase silica gel (Waters, C-18, 125 A, elution with water-acetonitrile 7:3 to 6:4) to give 0.058 g (52% yield) of the title amide as a white solid; mp 226–227° C. (dichloromethane-ethanol).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11](=[O:14])[CH2:12]Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:9][CH2:10][C:11]1([OH:14])[CH2:12][S:7][C:6]([CH2:5][N:3]([CH3:4])[CH3:2])=[N:8]1
Reactant: O=C(CCl)CCl
Reactant: CN(C)CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CC1=NC(O)(CCl)CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask were added 44.5 g. of dimethylaminothioacetamide, hydrochloride, 40.4 g. of 1,3-dichloropropanone, 224 ml. of 1,2-dichloroethane and 53.4 g. of sodium bicarbonate. An endothermic reaction took place and cooled the mixture to 13° on initial mixing. The mixture was then stirred overnight at ambient temperature, and the reaction was found to be essentially complete after 24 hours, by thin layer chromatography. The tlc system is silica gel, eluting with chloroform:methanol:ammonium hydroxide, 36:4:1. The mixture was then filtered, and the filter cake was washed with 1,2-dichloroethane. The filtrate was evaporated to dryness under vacuum to obtain 59.5 g. of crude product, which was washed with ethyl acetate. The washed solids were dried in air, to obtain 52.5 g. of substantially pure product, m.p. 90°-92°.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=[O:23])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([OH:23])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:20])([CH3:21])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)C2CCC(C2)C1CCC(O)CCC1C2CCC(C2)C1(C)C

Procedure:
The ketone, 1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanone (2 grams) was dissolved in 100 ml. of ethanol and stirred with 2 grams of sodium borohydride overnight. The solvent was removed in vacuo and the residue partitioned between ethyl ether and water. The organic layer was dried over sodium sulfate. After filtration, and removal of solvent a colorless oil was obtained that crystallized on standing, m.p. 55° C.-56° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:13][CH3:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(OCC)C.ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH3:14])[CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CO)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(COCc1ccccc1)COS(C)(=O)=O
Yield: 72.9 %

Procedure:
To a solution of 5.88 g (30 mmol) of 3b and 10 ml of triethylamine in 100 ml of dry diethyl ether and 50 ml of dichloromethane, was added under stirring 6.84 g (60 mmol) of methanesulphonyl chloride in 50 ml of dichloromethane, and the mixture was refluxed for 5 hours. Water was then added, and the organic phase was decanted, dried and evaporated. The crude product was chromatographed (eluent petroleum ether/diethyl ether 80:20 by volume), to yield 6 g (74%) of 4b.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33][CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C([CH:41]1CC[CH2:43][NH:42]1)CC>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[C:32]5[CH:41]=[N:42][CH:43]=[CH:34][CH:33]=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCCC1CCCN1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5cccnc5)c4)cc23)CC1
Yield: 22.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 3-(2-pyrrolidinyl)pyridine (148 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 13.0 mg of the title compound (22.5%).