Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([C:29](=[O:35])[CH:30](Br)[CH:31]([CH3:33])[CH3:32])[CH2:21][CH2:20]2>C(OCC)(=O)C.CCCCCC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([C:29](=[O:35])[CH:30]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:31]([CH3:33])[CH3:32])[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C(Br)C(C)C)CC2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)CN(C(=O)C(Oc1ccccc1)C(C)C)CC2
Temperature: 80 °C
Reaction time: 10 h
Yield: 54.7 %

Procedure:
Phenol (50 μl, 0.569 mmol) and sodium hydride (60% in a mineral oil, 10 mg) were added to a DMF (2 ml) solution of 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-methyl-2-bromobutan-1-one (54 mg, 0.152 mmol) obtained in Reference example 16, and the mixture was stirred at 80° C. for 10 hours and cooled to room temperature. The reaction solution was diluted with ethyl acetate and hexane (1:1, 50 ml), washed with a 1 N aqueous sodium hydroxide solution (30 ml) and 1 N hydrochloric acid (30 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography using ethyl acetate and hexane (1:1) as an eluent to obtain the captioned compound (30.7 mg, 55%) as a yellow oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[N:4]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[ClH:20].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:35][CH2:36][N:37]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([C:5]4[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=4)=[CH:18][CH:17]=3)[CH2:38][CH2:39]1)(=[O:32])=[O:33])[CH:25]=[CH:24]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1cc(-c2ccc(C(=O)O)cc2)nc(N)n1
Agent: Cl
Product: Nc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)nc(N)n1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 4-(2,4-diamino-6-pyrimidyl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH2:18]([O:25][CH2:26][C@H:27]([OH:30])[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@H:27]([OH:30])[CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H](O)COCc3ccccc3)ccc2c1

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[CH3:30]O>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:30])=[O:6]
Reactant: CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 92 %

Procedure:
100 g of deoxycholic acid was dissolved in 300 ml of methanol, and then 2 ml of hydrochloric acid was added thereto. The resulting mixture was refluxed for 1 hour. The methanol was distilled off. After the resulting mixture was dissolved in 400 ml of ethylether, it was washed with distilled water, sodium bicarbonate and brine several times. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to prepare 95 g (yield: 92%) of methyl deoxycholate represented by the following formula:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][F:46])[C:36]=1[F:47])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:37]([O:43][CH2:44][CH2:45][F:46])=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After adding 1.09 g of 2-hydrazinopyrimidine [CAS No. 7504-94-1] and 1.37 ml of triethylamine to a solution of 5.0 g of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of DMF, the mixture was stirred at 85° C. for 20 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of methanol, 10 ml of THF and 3 ml of acetic acid. Next, 2.0 g of sodium cyanotrihydroborate was added to the solution, and after stirring at room temperature for 3 hours, 1.0 g of sodium cyanotrihydroborate was further added and stirring was continued for 2 hours and 30 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the insoluble portion was filtered off to give the title compound as a white solid. The filtrate was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (total: 4.88 g) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[CH3:14].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 25.2 g of indoline-2-carboxylic acid, 50 ml of ethanol and 200 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at room temperature for 3 days. At the end of this time, the reaction mixture was poured into an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 28.1 g of the title compound having Rf=0.81 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2].[Br:12]Br.O>C(O)C>[CH2:1]([N:3]1[C:11]([Br:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: CCn1cc2ccccc2n1
Reactant: BrBr
Solvent: CCO
Solvent: O
Product: CCn1nc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 2-ethylindazole (2.32 g, 15.87 mmol) in ethanol (20 mL) was added bromine (2.54 g, 15.87 mmol) in ethanol (1 mL)/water (1 mL) at 0° C. After stirring at 0° C. for 10 min. and at rt for 1 h, the reaction was quenched with aq. sodium bicarbonate. The mixture was partitioned between ethyl acetate and aq. sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, and dried over anhydrous magnesium sulfate. Purification by flash chromatography (hexanes:ethyl acetate=1:1, then 100% ethyl acetate) gave 2.34 g of the title compound as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][O:12][C:13]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1)#[N:2].[Li+].[BH4-]>C1COCC1>[OH:15][CH2:14][C:13]1[O:12][CH:11]=[N:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1ocnc1-c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ncoc2CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a stirred solution of ethyl 4-(4-cyanophenyl)-1,3-oxazole-5-carboxylate (347 mg, 1.43 mmol, 1.00 equiv) in anhydrous THF (5 mL) maintained at −5° C. was added LiBH4 (157 mg, 7.14 mmol, 4.98 equiv) in several portions. The resulting solution was stirred at room temperature for 3 h then quenched by the addition of 10 mL of saturated NH4Cl solution. The mixture was extracted with 2×10 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum to give 190 mg (66%) of 4-(5-(hydroxymethyl)oxazol-4-yl)benzonitrile as a yellow solid. LCMS (method D, ESI): RT=1.13 min, m/z=201.0 [M+H]+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-methylpiperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10]Br>>[Br:10][C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Reactant: BrBr
Product: O=C(O)C1(Br)CCCCC1

Procedure:
35 g (0.275 mol) cyclohexanecarboxylic acid and 28.4 ml (0.548 mol) bromine with the addition of 3 g red phosphorus.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[C:14]([O:20][CH2:21][CH3:22])=[CH:13][C:5]=1[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[O:7])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[C:14]([O:20][CH2:21][CH3:22])=[CH:13][C:5]=1[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH3:2]
Reactant: CCOc1cc(OCC)c(C(=O)/C=C/C(=O)O)cc1OCC
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(OCC)c(C(=O)CCC(=O)O)cc1OCC
Reaction time: 1 h

Procedure:
A mixture of 1.0 part by weight of 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid, 50 parts by volume of methanol and 0.2 part by weight of 5% palladium-charcoal is subjected to catalytic reduction at 25° C under atmospheric pressure for 1 hour. After removal of the catalyst by filtration, the filtrate is evaporated and the residue is recrystallized from aqueous ethanol to give 0.85 part by weight of 3-(2',4',5'-triethoxybenzoyl)-propionic acid as pale yellow needles melting at 150°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: Fc1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1

Procedure:
A 2.3 g. portion of 3-(4-fluorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.1 g. of potassium carbonate and 1.2 ml. of methanesulfonyl chloride were added. The mixture was stirred under reflux for 2 days, and was then cooled and diluted with 20 ml. of aqueous sodium bicarbonate and 5 ml. of 2N sodium hydroxide. The organic phase was washed again with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hot diethyl ether, and the solids were filtered and dried to obtain 2.6 g. of the desired product, m.p. 112°-113°.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][S@@](C(C)(C)C)=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.O1CCOCC1>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH2:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](N[S@](=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of (R)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (53 mg, 0.111 mmol) in THF (200 μL) was added MeOH (55.6 μL) and 4 M HCl in dioxane (55.6 μL, 0.222 mmol). The reaction mixture was stirred at room temperature for 1 h. After quenched with saturated Na2CO3 solution and diluted with EtOAc, the reaction mixture was stirred for 15 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude (R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropan-1-amine was obtained in 99% yield (41 mg), which was used for the next step without further purification (a major side product, methyl 2-methylpropane-2-sulfinate, was completely removed under high vacuum). 1H NMR (CDCl3, 400 MHz): δ 7.96 (1H, m), 7.35-7.29 (2H, m), 7.28-7.22 (3H, m), 7.08 (1H, m), 7.0 (1H, m), 4.18 (2H, m), 3.8 (1H, s), 1.73 (2H, bs), 1.02 (9H, s). LC/MS (uplc): MH+ 356.2, 1.08 min.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[C:13](Cl)(Cl)=[O:14]>>[CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([N:12]=[C:13]=[O:14])[CH2:5][CH2:4]1
Reactant: COC1CCC(N)c2ccsc21
Reactant: O=C(Cl)Cl
Product: COC1CCC(N=C=O)c2ccsc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 1 g sample of 4,5,6,7-tetrahydro-7-methoxybenzo[b]thiophen-4-amine is added to 18 ml of 12.5% phosgene solution (benzene) in a nitrogen atmosphere at 20° C. After stirring at room temperature for an hour, the mixture is heated to 60° C and kept at this temperature for 7 hours. The mixture is cooled to room temperature and evaporated to dryness in vacuo to afford the crude 4,5,6,7-tetrahydro-7-methoxybenzo[b]thien-4-ylisocyanate.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:22]([Cl:21])=[O:24])[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(Nc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 258.1 %

Procedure:
To a solution of 3-chlorodiphenylamine (3.0 g) and pyridine (1.43 mL) in CH2Cl2 (30 mL) was added triphosgene (1.75 g) at 5° C. After stirring at room temperature for 6 hours, the mixture was evaporated, diluted with EtOAc, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1) to give N-(3-chlorophenyl)-N-phenylcarbamoyl chloride (4.05 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:42]([CH2:41][CH2:40][O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH:43]([CH3:44])[CH3:45])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3-chlorophenyl)cyclo-pentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (502) was synthesized from 5-(benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (501) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (245).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33](O)=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]([C:41]1([O:44][S:45](=[O:48])(=[O:47])[NH2:46])[CH2:43][CH2:42]1)=[O:40].S(=O)(=O)(O)N>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:46][S:45]([O:44][C:41]2([C:39]([O:38][CH3:37])=[O:40])[CH2:42][CH2:43]2)(=[O:48])=[O:47])=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1(OS(N)(=O)=O)CC1
Agent: NS(=O)(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(C(=O)OC)CC1

Procedure:
2-[2-Ethyl-1-(1-methoxycarbonyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.10 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 1-sulfamoyloxy-cyclopropanecarboxylic acid methyl ester (40 mg, 60%): LCMS found 676.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:1][C:2]2[CH:3]=[C:4]([C:14]3[N:15]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:16]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:17][CH:18]=3)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (117 mg, 0.272 mmol) synthesized in Example (38d) was dissolved in dichloromethane (20 mL), and 4-methoxycarbonylphenyl boronic acid (100 mg, 0.556 mmol), copper (II) acetate (80 mg, 0.440 mmol), triethylamine (0.20 mL, 1.435 mmol) and molecular sieves 4A (100 mg) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. The deposit of this reaction solution was Celite filtered. This mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-25%) to afford the desired compound (70 mg, yield 46%) as a yellow oil.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC1CCCCC1
Reactant: O=C(O)CNc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CN(c2ccccc2)C(=O)N1C1CCCCC1
Yield: 60 %

Procedure:
A mixture of N-phenyl glycine (0.1 mole), cyclohexyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for about 6 hours and then cooled. The crude product was recrystallized from ethanol to produce a 60% yield of the above-identified product having a melting point of approximately 196° C.