Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][CH2:30][C:29]2[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.3 %

Procedure:
To a solution of (3S,4R)-4-(4-fluoro-phenyl)-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 5.11 mmol) in 30 ml DMF were added 0. 29 g (6.0 mmol) sodium hydride (50% in mineral oil) at 0° C. The reaction mixture was allowed to warm to room temperature. After 20 min. 3,5-bis(trifluoromethyl)benzyl bromide (3.14 g, 10.2 mmol) was added. Stirring at room temperature for 2 h was followed by quenching with water and extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, heptane/ethyl acetate) to give 3.4 g (>100%) of the title compound as a white solid.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[Mg].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][CH2:21][C:22]2=O.Cl>C1COCC1.O.CCOCC>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:12]=1[CH2:22][CH:21]=[C:20]2[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:18]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCc2c(Br)cccc21
Agent: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1cccc2c1CC=C2c1ccccc1
Temperature: -10 °C

Procedure:
Under an argon atmosphere, to a solution of PhMgBr in THF [obtained from 7.60 g (0.312 mol) of magnesium turnings, 50.0 g (0.318 mmol) of bromobenzene, and 200 ml of THF], a solution of 43.9 g (0.208 mol) of 4-bromoindan-1-one in 400 ml of THF was added dropwise with vigorous stirring at −10° C. This mixture was stirred overnight at room temperature; and, then, 300 ml of ether was added. The resulting mixture was cooled to 0° C., and 200 ml of cold water and then 200 ml of 12 M HCl were added. The organic layer was separated; and the aqueous layer was extracted with 2×200 ml of dichloromethane. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 65 mm, 400 mm, eluant:hexanes) and then recrystallized from hexanes. Yield, 48.4 g (86%) of a white crystalline solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(CC1CCCCC1)Nc1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)CC2CCCCC2)cn1)c1ccccc1
Yield: 71.7 %

Procedure:
A solution of 2-cyclohexyl-N-(6-hydroxy-pyridin-3-yl)-acetamide (0.70 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.79 g, 72% yield) as a brown solid.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[C:43](=[O:44])[CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][N:48]=3)[CH:40]=[N:39]2)=[C:32]([CH3:56])[CH:31]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>COC(C)(C)C>[Br:25][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[C:43](=[O:44])[CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][N:48]=3)[CH:40]=[N:39]2)=[C:32]([CH3:56])[CH:31]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Solvent: COC(C)(C)C
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9c) instead of preparation 1c. The reaction mixture is stirred overnight. Tert-butyl methyl ether is added and the resulting precipitate is filtered off and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7[C:51](=[O:61])[CH:52]([CH:58]7[CH2:60][CH2:59]7)[NH:53][C:54]([O:56][CH3:57])=[O:55])=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(NC(C(C)C)C(O)=O)=O>>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:52]([C:51]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:61])[CH:58]([CH3:59])[CH3:60]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 65 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using 2-Methoxycarbonylamino-3-methyl-butyric acid to provide [1-(3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.070 g, 65%) as a white powder.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[N:9]=[C:10]([C:28]2([CH3:31])[CH2:30][CH2:29]2)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][C:44]#[N:45]>CN1C(=O)CCC1.CCOC(C)=O>[Br:7][C:8]1[N:9]=[C:10]([C:28]2([CH3:31])[CH2:30][CH2:29]2)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:45][CH2:44][CH2:43][C:42]#[N:41])[N:14]=1
Reactant: N#CCCN
Reactant: CC1(c2nc(Br)c(-c3ccnc(Cl)n3)n2COCC[Si](C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(c2nc(Br)c(-c3ccnc(NCCC#N)n3)n2COCC[Si](C)(C)C)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Solid Na2CO3 (1.11 g, 10.5 mmol) was added to a solution of 4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-3a, step 4, 2.33 g, 5.2 mmol), DIEA (1.8 mL, 10.5 mmol), and 3-aminopropionitrile (1.2 mL, 15.7 mmol) in NMP (3 mL) and the resulting reaction mixture was heated to 90° C. After 5 hours, LCMS indicated complete reaction and the reaction was allowed to cool to room temperature. EtOAc (75 mL) was added the organic phase was washed with water (100 mL), dilute aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4), and concentrated. Purification of the resulting residue by flash chromatograhpy (SiO2, 0-50% EtOAc in heptane) provided 3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (2.47 g, 5.2 mmol, 99% yield) as a foamy off-white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:30].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:30])[C:13]([C:27]([OH:29])=[O:28])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=3)=[CH:10][C:9]=2[F:31])[CH2:37]1
Reactant: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 100 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 102 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 76.3 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 4-aminobutyric acid (0.54 g, 0.0052 mol) were refluxed as above for 7 hours. Crystallisation of the product from EtOH yielded 1.1 g (76%) of 102 as a white solid: mp=218–220° C.; Rf 0.78 (A): Rf 0.84 (C): Rf 0.28 (D): 1H NMR (DMSO-d6); IR (cm−1): 2800–3250 (OH), 3050 (C═CH), 2680 (C—H), 1760 (C═O), 1712 (bs, C═O), 1560 (C═C), 1430 (C═C), 1397 (C—O), 1305 (C—O), 727 (C═CH); MS m/z (rel intensity) 277 (18), 276 (100).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([N:14]=[C:15]=[S:16])[CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:13]=1
Reactant: NCC(N)=O
Reactant: Cc1ccc(F)cc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenylisothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: CN(C)C1CCCCC1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClC1C=CC=CC=1.O>[OH:16][C:15]1[CH:14]=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Solvent: CN(C)C1CCCCC1
Product: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Temperature: 50 °C
Yield: 81 %

Procedure:
##STR19## 38 g (0.3 mol) of dimethylcyclohexylamine and 27 g (0.25 mol) of p-cresol in 150 ml of chlorobenzene were initially taken. 35.1 g (0.25 mol) of benzoyl chloride were added dropwise over one hour, the temperature increasing to 50° C. After cooling to room temperature, the suspension was added to 100 ml of water in order to separate off the dimethylcyclohexylamine hydrochloride. The organic phase was separated off and was dried by partial distillation. 33 g (0.25 mol) of aluminum trichloride were then added a little at a time at room temperature in the course of 30 minutes. During this procedure, the internal temperature increased to 50° C. The batch was stirred at 130° C. for about 10 hours until the evolution of HCl gas had ceased. After cooling to 60° C., the reaction mixture was poured onto ice water. The phases were separated and the aqueous phase was extracted twice with chlorobenzene. The combined organic phases were dried over magnesium sulfate and then evaporated down. 43 g (corresponding to a yield of 81%) of 2-hydroxy-5-methylbenzophenone were obtained. 25 g (0.12 mol) of the compound were then dissolved in 150 ml of methanol, and 4.1 g of sodium hydroxide in 30 ml of methanol were then added. The refluxing reaction mixture was stirred for 3 hours and then evaporated down in a rotary evaporator. 27 g (corresponding to a yield of 98%) of the title compound were obtained in the form of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:18]([C:19]([NH:21][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[N:25]=2)[CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:32])[N:10]1[C@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:39][S:40]([CH3:43])(=[O:42])=[O:41].C(N(CC)CC)C.[C:51](OC(=O)C)(=[O:53])[CH3:52]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[C:51]([O:31][CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:22]([NH:21][C:19]([C@@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:32])[N:10]([C@H:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]3[NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[C@H:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:20])[CH3:23])[N:25]=1)(=[O:53])[CH3:52]
Reactant: CC(NC(=O)[C@@H]1c2ccccc2C(=O)N([C@H]2CCCC[C@@H]2NS(C)(=O)=O)[C@H]1c1ccc(Cl)cc1Cl)c1cccc(CO)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cccc(C(C)NC(=O)[C@@H]2c3ccccc3C(=O)N([C@H]3CCCC[C@@H]3NS(C)(=O)=O)[C@H]2c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 714 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml of triethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP were added thereto in this order, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate-water was added thereto for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methyl acetate.
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][C:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:8][CH:7]=1)([CH3:3])[CH3:2].I(C1C=CC=CC=1)=O.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>ClCCl>[N:35]([CH:8]1[CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:10][CH2:11][C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])=[CH:7]1)=[N+:36]=[N-:37]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Agent: O=Ic1ccccc1
Solvent: ClCCl
Product: CC(C)[Si](OC1=CC(N=[N+]=[N-])C(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a three-neck flask a stirred solution of triisopropyl {[4-(2,4,5-trifluorophenyl)cyclohex-1-en-1-yl]oxy}silane (26.06 g, 0.068 mol) in dichloromethane (260 mL) was cooled to −15° C. and treated with iodosobenzene (19.5 g, 0.089 mol) in four portions followed by azidotrimethylsilane (24 mL, 0.116 mol) while maintaining the temperature below −10° C. Stirring was continued for 1.5 h. The reaction mixture was allowed to warm to room temperature briefly, then cooled again back to −15° C. and filtered. The filtrate was evaporated under vacuum below 25° C. to give the title compound which was used directly in the next step.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[N+](C(C)C)([O-])=O.ClC[C:13]1[CH:18]=[CH:17][CH:16]=C[C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)=[O:24])(=[O:21])=[O:20]>C(O)C>[CH:2]([C:3]1[CH:16]=[CH:17][CH:18]=[CH:13][C:14]=1[S:19]([NH:22][C:23]([NH:25][C:26]1[N:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[N:31]=1)=[O:24])(=[O:21])=[O:20])=[O:1]
Reactant: CC[O-]
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCl)n1
Agent: [Na+]
Solvent: CC(C)[N+](=O)[O-]
Solvent: CCO
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1

Procedure:
To a solution of 6.26 mmol of sodium ethoxide in 10 ml of absolute ethanol under an argon atmosphere was added 0.80 ml of 2-nitropropane. Next 0.74 g (2.09 mmol) of 2-chloromethyl-N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide was added and the solution was heated to reflux. The mixture became pasty shortly after heating was begun and an additional 3 ml of ethanol was added to facilitate stirring. After heating for 4 hours, the solvent was removed under reduced pressure and the residue was dissolved in 12 ml of water. The crude product was precipitated by neutralizaiton of the solution with 3 N hydrochloric acid. The crude product was purified by preparative thin layer chromatography on silica gel and subsequent recrystallization from acetone to provide the title compound, m.p. 157° C. (decomp.). The infrared spectrum showed a new carbonyl band at 1675 cm-1, indicative of the formation of an aldehyde, in addition to the urea carbonyl band at 1710 cm-1. The nuclear magnetic resonance spectrum showed peaks at 10.57 ppm and 10.67 ppm which are consistent with an aromatic aldehyde with restricted rotation.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCOC(C)=O>[CH2:1]([NH:9][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenethylamine (60.5 g, 0.5 mol) and Na2CO3 (63.6 g, 0.6 mol) in EtOAc/H 0 (800 mL, 4:1) was added ethyl chloroformate, dropwise, (65.1 g, 0.6 mol) at 0° C. during a period of 1 h. The mixture was warmed to RT and stirred for an additional 1 h. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried (Na2SO4), concentrated in vacuo and purified by flash chromatography to afford ethyl phenethylcarbamate (90.2 g). 1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 4.73 (brs, 1H), 4.14-4.08 (q, J=6.8 Hz, 2H), 3.44-3.43 (m, 2H), 2.83-2.79 (t, J=6.8 Hz, 2H), 1.26-1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:26]2[CH2:25][CH2:24][N:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:28][CH2:27]2)[N:12]=1)[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(N2CCN(c3ccc(Cl)cc3)CC2)n1
Yield: 62.5 %

Procedure:
A mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 3.9 g of N-(p-chlorophenyl)piperazine and 2.1 g of sodium carbonate in 120 ml. of ethanol was warmed on a steam bath for 10 minutes. The reaction mixture was filtered and the filtrate was diluted with water in order to cause precipitation. The precipitate was recrystallized from ethanol to afford 5.3 g of product, mp. 117°-120°C.
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Product: CCOC1OC(=O)C=C1N
Yield: 100.9 %

Procedure:
A mixture of 4-azido-5-ethoxy-5H-furan-2-one (0.62 g, 3.67 mmol) and 10% palladium on charcoal (0.31 g) in de-oxygenated ethyl acetate (20 mL) was stirred at 1 atm hydrogen for 24 h. The reaction was filtered (Celite) and evaporated to provide 4-amino-5-ethoxy-5H-furan -2-one (0.53 g, 100% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 5.60 (s, 1H), 4.85 (br s, 2H), 4.81 (s, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 1.22 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: N[C:2]1[C:3](C2C=CC=CC=2Cl)=[C:4]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:5]2=[N:6][CH:7]=1.CN(C)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl:29]CCl>>[Cl:29][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[CH:2][CH:3]=2)[S:8][C:9]=1[CH2:11][CH3:12]
Reactant: ClCCl
Reactant: CN(C)c1ccccc1
Reactant: CCc1cc2c(-c3ccccc3Cl)c(N)cnc2s1
Product: CCc1sc2ncccc2c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture o 4-acetoxy-3,5-dimethoxycinnamic acid (638 mg), dimethylformamide (2 drops) and tetrahydrofuran (8 ml) was added oxazolyl chloride (0.25 ml). The mixture was stirred at room temperature for one hour and then the solvent was distilled off to obtain 4-acetoxy-3,5-dimethoxycinnamic acid chloride as crystals. To a solution of the crystals in dichloromethane (15 ml) were added 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (576 mg) and N,N-dimethylaniline (0.25 ml) with ice cooling. After warming to room temperature, the mixture was stirred for 5 hours, washed in turn with water, aqueous saturated NaHCO3 solution and water, and then dried over MgSO4. The solvent was distilled off and the residue was crystallized from ethanol (729 mg, 67.4%). 5-(4-Acetoxy-3,5-dimethoxycinnamoylamino)-4-(2-chloropheny ethylthieno[2,3-b]pyridine was obtained as colorless prisms by recrystallization from acetone, mp: 133°-135° C.