Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCCC1
Reactant: Oc1cccc(O)c1
Product: Oc1ccc(C2CCCCC2)c(O)c1
Temperature: 125 °C
Yield: 44.2 %

Procedure:
Resorcinol (2.2 g, 20 mmol) and cyclohexanol (6.33 ml, 6 g, 60 mmol) were suspended in 85% polyphosphoric acid (8 ml). The mixture was heated to 125° C. for 24 hours, after which time TLC appeared to show complete consumption of the starting materials. On cooling the mixture was partitioned between water (50 ml) and diethyl ether (50 ml). The aqueous layer was discarded, and the organic portion extracted with sodium hydroxide solution (2×50 ml, 2M). The base extract was washed with ether (3×50 ml), and then acidified with aqueous hydrochloric acid (120 ml, 2M). The organic components were then extracted into diethyl ether (2×50 ml), dried (magnesium sulfate), filtered and the solvent removed under reduced pressure. The resulting brown oil was then chromatographed on silica gel, eluting with ethyl acetate/petroleum ether (bp 60-80° C.) 1:2 to give the desired product as an off-white solid (1.7 g, 44%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Reaction time: 18 h
Yield: 24.5 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (89 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (0.079 mL, 0.56 mmol) was added, followed by methanesulfonyl chloride (0.022 mL, 0.28 mmol). The mixture was stirred at it for 18 h and then at 50° C. overnight. The mixture was concentrated, diluted with MeOH, filtered and the filtrate purified by HPLC eluting with 20-95% gradient acetonitrile/water to afford 24 mg (25%) of the title compound. 1H-NMR (CD2Cl2-d2) 8.13-8.06 (m, 2 H), 7.81 (dt, 1H), 7.77-7.76 (m, 1 H), 7.43 (s, 1H), 7.42-7.33, (m, 5 H), 7.19 (dd, 1 H), 5.64 (s, 1 H), 4.61-4.53 (m, 1 H), 3.74-3.65 (m, 2 H), 3.54-3.44 (m, 1 H), 3.39-3.31 (m, 1 H), 2.89 (s, 1 H), 2.46-2.28 (m, 2 H); LC-MS [M+H]+=516.2, RT=2.88 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19]([OH:21])=O)([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:23]1C2N=CC=CC=2N=N1.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19](=[O:21])[NH2:23])([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1OC2(C(=O)O)C=CC1CC2
Reactant: On1nnc2cccnc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C12C=CC(CC1)N(C(=O)OCc1ccccc1)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
The benzyl ester (d) (12.0 g, 41.5 mmol) and 1-hydroxy-7-azabenzotriazole (6.26 g, 46 mmol) were dissolved in DMF (100 ml) then I-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.79 g, 46 mmol) added. After stirring for 5 minutes ammonium hydrogen carbonate (8.22 g, 104 mmol) was added. Four further small portions of ammonium hydrogen carbonate were added over the next 7 hours. The mixture was then stirred overnight, diluted with water and extracted with ethyl acetate (×4). The combined organic extracts were washed with 5% aqueous citric acid then brine, dried and evaporated to give an off-white solid (9.9 g, 83%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)=[O:23]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-(4-aminophenyl)-propionate hydrochloride with 5-chloro-2-methoxybenzoyl chloride. there is obtained β-[4-(5-chloro-2-methoxybenzamido)-phenyl]-propionic acid; m.p. 188°-190° C., after recrystallization from ethanol.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]=[CH:9][C:8]2[N:7]=[C:6]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:4][C:3]1=2.FC(F)(F)C(O)=O.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[NH:45][C:44]([CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:43][N:42]=2)=[CH:37][N:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCN(CC)CC.CN(C=O)C.CC(O)=O>[CH3:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:41]2[NH:45][C:44]([CH:46]3[CH2:51][CH2:50][N:49]([CH2:16][C:15]4[CH:14]=[CH:13][C:12]([C:6]5[C:5]([C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=6)=[CH:4][C:3]6[C:2](=[O:1])[NH:11][CH:10]=[CH:9][C:8]=6[N:7]=5)=[CH:19][CH:18]=4)[CH2:48][CH2:47]3)=[N:43][N:42]=2)=[CH:39][CH:40]=1
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: COc1ccc(-c2nnc(C3CCNCC3)[nH]2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C3CCN(Cc4ccc(-c5nc6cc[nH]c(=O)c6cc5-c5ccccc5)cc4)CC3)[nH]2)cn1
Reaction time: 0.25 h

Procedure:
To a dry flask was added 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (308 mg, 0.94 mmol) and 2-methoxy-5-(5-piperidin-4-yl-4H-1,2,4-triazol-3-yl)pyridine trifluoroacetate (350 mg, 0.94 mmol) in 5% NEt3:DMF (5 mL). The solution was stirred for 15 min. then 5% AcOH:DMF (10 mL) was added. This was stirred for 1 h and sodium triacetoxyborohydride was added and the reaction mixture was stirred for 16 h at room temperature. The mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate solution and then extracted (×3) with CH2Cl2, the organic layers combined and dried over anhydrous Na2SO4. This was filtered, concentrated and purified by silica gel chromatography (2-4% MeOH in CH2Cl2) to give 2-[4-({4-[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}methyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one. NMR (MeOD): δ 8.73-8.72 (1H, d, J=3 Hz), 8.52 (1H, s) 8.25-824 (1H, d, J=3 Hz), 7.43-7.41 (1H, d, J=6), 7.33-714 (1H, m), 6.80 (2H, m), 3.93 (3H, s), 3.6 (2H, s), 3.02-2.98 (2H, m), 2.86 (1H, m), 2.27 (2H, m), 2.05 (2H, m), 1.93 (3H, m). m/e (m+1): 570.1.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[N:11]=[CH:10]1.[Na]>CO.O>[Br:1][CH2:22][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=2[N:11]=[CH:10]1
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: BrBr
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cn1c(=O)c2c(ncn2CCCCC(=O)CBr)n(C)c1=O
Reaction time: 0.5 h
Yield: 40 %

Procedure:
9.7 Grams (0.06 moles) of bromine were added to a solution of 15 g (0.054 moles) of 7-(5-keto-hexyl)-1,3-dimethylxanthine in 100 ml of anhydrous methanol, at 10° C. with stirring. After 30 minutes at the same temperature, stirring was continued for 7 more hours at room temperature. The mixture was then concentrated under reduced pressure till a residual volume of 30 ml, diluted with 30 ml of water, added with 3 drops of 96% sulphuric acid and stirred for 4 hours at room temperature, to hydrolyze any dimethylketal formed, then diluted with 100 ml of water and alkalized with a 10% sodium bicarbonte aqueous solution. The mixture was extracted with 2×80 ml of methylene chloride, the organic phase was washed with water, dried and evaporated under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate, cooled and crystallized at 5°-10° C. 7.5 Grams (40%) of the title compound were obtained, melting at 106°-109° C., which was directly used in the next step.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]=1[O:20][CH3:21])(=O)=O.[CH3:22][S-:23].[Na+]>O1CCOCC1>[C:13]([C:11]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([O:20][CH3:21])=[C:7]([CH2:6][S:23][CH3:22])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: C[S-]
Reactant: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(CSC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.64 g 5-tert-butyl-2-methoxy-3-nitro-benzyl methanesulphonate are dissolved in 50 ml of 1,4-dioxane, combined with 950 mg of sodium thiomethanolate and stirred for 12 hours at ambient temperature. A further 600 mg of sodium thiomethoxide are added and the mixture is stirred for 2 hours at 40° C. Then the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 98:2 to 60:40).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:23][CH:20]([CH3:22])[CH3:21])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)NC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 130 °C
Yield: 57.8 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), isopropylamine (0.041 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.108 g, 58%). 1H NMR (500 MHz, CDCl3): δ 7.52-7.46 (m, 2H), 7.44-7.38 (m, 3H), 5.16-5.04 (m, 1H), 3.34-3.22 (m, 1H), 1.71 (s, 9H), 0.94 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 160.1, 134.2, 131.7, 129.8, 128.9, 125.6, 106.5, 61.6, 44.8, 27.8, 23.0; Mass Spectrum: M−H+ 323.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>>[C:23]([O:25][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:24])/[CH:22]=[CH:21]\[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:26]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
A sample of mono octadecyl (monostearyl) maleate was prepared in a similar manner, but using 405 g octadecanol (1.5 moles) and 147 g maleic anhydride (1.5 moles).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].[Cl-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[N:10]=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]cnc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)c(Br)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
6-Bromo-7-chloro-3H-imidazo[4,5-b]pyridine (1.07 g, 4.60 mmol) in N,N-dimethylformamide (12 mL) was cooled to 0° C., mixed with sodium hydride (55 wt % dispersion in mineral oil, 300 mg, 6.88 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (12.0 mL, 6.78 mmol) and stirred at room temperature for 3 hours. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1 (v/v)) to give the title compound as a yellow oil (640 mg, yield 38%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[Cl:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(B(O)O)c1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 99 %

Procedure:
1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2-chloro-5-methylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 1.1 g of the title compound. Yield 99% ES MS (+) m/z 391.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4[CH2:22][CH2:23][S:24](=[O:41])(=[O:40])[C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=6)=[CH:28][C:26]=5[CH:27]=4)=[O:20])=[CH:14][CH:13]=3)[CH3:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][C:25]3[S:24](=[O:40])(=[O:41])[CH2:23][CH2:22][C:21]([C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:9]([CH3:10])[CH:6]5[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]5)=[CH:13][CH:14]=4)=[O:20])=[CH:27][C:26]=3[CH:28]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCS3(=O)=O)cc1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-methoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (112 mg) in THF (20 ml) was added at room temperature 3N hydrochloric acid (1 ml), and the mixture was stirred for 18 hours. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless solid, which was recrystallized from ethyl acetate/hexane to give colorless crystals of 7-(4-methoxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 17) (77.6 mg).
Reaction SMILES: S([O-])([O-])(=O)=O.[C:6]([OH:12])(=O)[CH2:7][CH2:8][CH2:9][CH3:10].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][C@@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31].C(N(CC)CC)C>C(#N)C.O>[C:6]([NH:28][C@@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31])(=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(=O)O
Reactant: N[C@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC(=O)N[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
4-hydroxyphenyldimethylsufomethyl sulfate (trade name: SANCELER-DSP, manufactured by Sanshin Kagaku Kogyo Co. Ltd.) 2.66 g (0.01 mole) was heated and dissolved in 40 ml of acetonitrile. Pentanoic acid 1.16 g (0.01 mol) was added to the solution obtained, and the mixture was stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-serine 1.05 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-pentanoyl-D-serine 1.7 g was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:38]([OH:40])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[C:45]([CH3:52])([CH3:51])[O:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([C:45]([OH:44])([CH3:52])[CH3:51])[CH2:48][CH2:49][NH:50][C:38]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:41])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]2([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[NH:17]1)=[O:40]
Reactant: CC1(C)O[C@@H](CCN)C(C)(C)O1
Reactant: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2NC(C(=O)NCC[C@H](O)C(C)(C)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Yield: 34.9 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.72 g, 1.15 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 131a (0.4 g, 2.3 mmol), HATU (0.79 g, 2.1 mmol) and iPr2NEt (1 mL, 5.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (0.25 g, 42%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15]C(=O)C)=[CH:10][C:9]=2Br)=[O:5])C.[ClH:20].[CH2:21]([OH:23])C>>[ClH:20].[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([O:23][CH3:21])[CH:10]=1)[NH:7][C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(NC(C)=O)cc(Br)c2[nH]1
Reactant: CCO
Agent: Cl
Product: COc1cc(N)cc2cc(C(=O)O)[nH]c12
Reaction time: 4.5 h

Procedure:
A mixture of 982 mg I.19 (5-acetylamino-7-bromo-1H-indole-2-carboxylic acid ethyl ester), 10 ml ethanol and 1.8 ml concentrated hydrochloric acid was stirred for 4.5 h at reflux. The reaction mixture was evaporated. The residue was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]([NH:16][C:17](=O)[CH3:18])=[CH:13][S:14][CH:15]=1)=[O:10].C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH3:18][C:17]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9](=[O:10])[C:11]2[C:12](=[CH:13][S:14][CH:15]=2)[N:16]=1
Reactant: CC(=O)Nc1cscc1C(=O)Nc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cscc2c(=O)n1-c1ccccc1Cl

Procedure:
A mixture of 3-acetamidothiophene-4-carboxylic acid 2-chlorophenylamide (0.36 g, 1.23 mmol), toluene (15 mL), and phosphorous oxychloride (0.35 mL, 3.7 mmol) was refluxed 8 hours with azeotropic removal of water (Dean-Stark apparatus). The reaction was cooled and partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was flash chromatographed on silica gel (20×85 mm) eluting with 10% ethyl acetate/hexane. After an unweighed forerun, 2-methyl-3-(2-chloro-phenyl)-3H-thieno[3,4-d]pyrimidin-4-one was isolated as an off white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([OH:29])=[O:28].[O:31]([C:38]1[S:39][CH:40]=[C:41]([CH2:43]O)[N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([O:29][CH2:43][C:41]1[N:42]=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:39][CH:40]=1)=[O:28]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Reactant: OCc1csc(Oc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 17 h
Yield: 71.6 %

Procedure:
0.11 g of 4-dimethylamino-pyridine and 2 g of dicyclohexylcarbodiimide was added to a solution of 2.04 g of (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid[described in French Pat. No. 70-21682] in 20 ml of methylene chloride and the mixture was stirred at 20° C. for 15 minutes. A solution of 1.7 g of (2-phenoxy-4-thiazolyl)-methanol in 10 ml of methylene chloride was added dropwise to the mixture which was stirred at 20° C. for 17 hours and was filtered. The organic phase of the filtrate was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 2.44 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate melting at 78° C.