Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.Br[C:19]1C=CC=CC=1.[Li].[C:26](=[O:28])=[O:27]>CCOCC>[CH3:19][O:27][C:26]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)=[O:28]
Reactant: O=C=O
Reactant: Brc1ccccc1
Reactant: c1cnc2c(c1)CCCC2
Agent: [Li]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC(=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (14 g.) in dry ether (100 ml.) was added dropwise over 1/2 hour to an ethereal solution of phenyl lithium (prepared from bromobenzene (42 g.) and lithium (3.7 g.) in dry ether (300 ml.) and the reaction mixture stirred at room temperature for a further 1 hour. The cooled reaction mixture was saturated with dry CO2 gas, evaporated in vacuo and the residue treated with methanol previously saturated with dry HCl (500 ml.) and the solution heated at reflux for 12 hours. The solvent was removed in vacuo and the residue dissolved in water (50 ml.), extracted with ether (3 × 150 ml.) and the extracts discarded. The aqueous solution was made basic and extracted with ether (3 × 100 ml.). The combined ethereal extracts were dried, evaporated in vacuo and the residual oil distilled giving methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate as a colourless oil (13 g.) b.p. 92° C/0.05 mm. The hydrochloride was prepared by saturating an ethereal solution with dry HCl gas and recrystallising the resultant solid from methanol-ether to give the hydrochloride of the title compound as colourless needles mpt. 173° C. Found: C, 58.2; H, 6.3; N, 6.3%. C11H13NO2.HCl requires C, 58.0; H, 6.2; N, 6.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.CC1(C)C2C(=CC=CC=2Br)SCC1.C([Li])(C)(C)C.[C:32](=[O:34])=[O:33]>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([C:32]([OH:34])=[O:33])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2cc(Br)ccc21
Reactant: O=C=O
Agent: CC1(C)CCSc2cccc(Br)c21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)CCSc2cc(C(=O)O)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 g (3.9 mmol) of the 4,4-dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman mixture in 12 ml of anhydrous ether at -78° C. was added, dropwise under nitrogen, 6.0 ml of 1.7 M 10.2 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at -78° C. for 1 hour and then a rapid stream of dry carbon dioxide gas was passed through it with vigorous stirring. The reaction mixture was warmed to -20° C. and then quenched with water. The mixture was warmed to room temperature and its pH adjusted to 10 with ammonium hydroxide. The basic solution was washed with 2×10 ml ether and then acidified with dilute HCl. The mixture was extracted with 3×20 ml of ether. The ether extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO4). The ether solution was filtered and the solvent removed in-vacuo. The residue was recrystallized from a mixture of ethyl acetate and hexane to give the captioned compound as a white solid. PMR (CDCl3): δ1.33 (6H, s), 1.96 (2H, s), 3.04 (2H, m), 7.42 (1H, d, J~8.1 Hz), 7.66 (1H, dd, J~8.1 Hz, 1.8 Hz), 7.77 (1H, d, J~1.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH:26]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]([O:29][CH3:30])=[O:28])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: COC(=O)C(Oc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2)c1ccccc1
Yield: 82 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and methyl α-bromophenylacetate, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:5]=1[F:13].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH2:10]([C:9]1[C:8]([F:12])=[CH:7][CH:6]=[C:5]([F:13])[C:4]=1[CH2:3][C:2]1[NH:17][CH2:16][CH2:15][N:18]=1)[CH3:11]
Reactant: NCCN
Reactant: CCc1c(F)ccc(F)c1C=C(Br)Br
Product: CCc1c(F)ccc(F)c1CC1=NCCN1

Procedure:
2-(2-Ethyl-3,6-difluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-3-ethyl-1,4-difluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 225.3 ([M+H]+, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([N:20]3[C:28]4[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[CH:15]=[C:16]([N:20]3[C:28]4[C:23](=[CH:24][C:25]([CH2:29][OH:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[N:17]=[CH:18][N:19]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(CO)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19c was dissolved in 1 mL of THF with 0.5 mL of triethylamine (3.59 mmol). Isopropyl chloroformate (1M in toluene, 2.25 mL, 2.25 mmol) was added and the mixture was stirred at room temperature for 2 h. Water (1 mL) was added followed by NaBH4 (0.5 g, 13.2 mmol) and the mixture was sonicated for 2 minutes and stirred at room temperature for 1 h. THF was removed under vacuum and the aqueous mixture was acidified with 1N HCl, extracted with DCM (3×10 mL) and the combined extracts were washed with brine (10 mL). The solution was dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 19-1 (tR=3.0, Method 5) as well as a small amount of 4-[6-(5-hydroxymethyl-2,3-dihydro-indol-1-yl)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 19-2. tR=5.21 (Method 5).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=1.C(Cl)Cl>COCCOC.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:1]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(Br)ccn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (164 mg, 0.14 mmol) was added to a stirred suspension of phenylboronic acid (345 mg, 2.84 mmol) and 4-bromo-2-hydroxypyridine (494 mg, 2.84 mmol) in DME (10 mL). The reaction mixture was stirred under an argon atmosphere for 90 min. Degassed 2N potassium carbonate solution (aq) (10 mL) was added and the reaction mixture stirred with heating at 90° C. for 72 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (×2). The organics were combined, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanol:DCM afforded 4-phenylpyridin-2-ol (311 mg, 1.82 mmol, 64%) M.S. (ESI) (m/z): 172 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43][CH2:44][CH:45]([OH:49])[CH2:46][CH2:47][CH3:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:49][CH:45]([CH2:44][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:46][CH2:47][CH3:48])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCC(O)CCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(CCN1CCCCC1)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 90.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-piperidino-3-hexanol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 82%).
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.C(OCC)(=O)C>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of phenyl(piperidin-4-yl)methanone hydrochloride 86 (1.97 g, 8.73 mmol) and potassium carbonate (3.62 g, 26.2 mmol) in THF (40 mL) at 0° C. was added benzyl chloroformate (1.433 mL, 10.04 mmol) and the reaction mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was diluted with ethyl acetate, washed with brine, water, dried over Na2SO4, filtered and concentrated to afford compound 87 quantitative yield. LRMS (ESI): (calc) 323.39 (found) 324.31 (MH)+
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=1)=O.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[CH2:46][C@H:45]2[NH2:47])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH4-].[Na+]>ClC(Cl)C>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]2[CH2:46][C@H:45]2[NH:47][CH2:1][C:3]2[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:5][N:4]=2)=[CH:42][CH:43]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1nnc(C=O)o1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nnc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.4 %

Procedure:
Tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate (Intermediate O, 220 mg, 1.041 mmol) and sodium triacetoxy borohyride (441 mg, 2.08 mmol) was added to a solution of Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine (Intermediate B, 250 mg, 1.041 mmol) in dry Dichloro ethane (2.5 mL) at 0° C. and stirred at RT for 24 h, then the solvent was evaporated. The residue was taken in MeOH (2.5 mL) and NaBH4 (116 mg, 3.138 mmol) was added at 0° C. and stirred for 2 h at RT. After completion, the solvent was evaporated, the residue was taken in water (10 mL) and extracted with EtOAc (4×10 mL) Combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography (SiO2) using MeOH:CHCl3 (1:99) to get tert-butyl (5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (70 mg, 15.3%) as pale green liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:13]1([S:19]([C:22]#[N:23])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(OCCCC)(OCCCC)OCCCC>>[C:13]1([S:19]([C:22]2[CH:1]=[C:2]([CH3:12])[CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:23]=2)(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)=CC(=O)c1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Product: Cc1cc(-c2ccccc2)nc(S(=O)(=O)c2ccccc2)c1
Temperature: 112 °C
Yield: 27.2 %

Procedure:
First, 0.96 g (6.00 mmol) of 3-methyl-1-phenyl-2-buten-1-one and 0.84 g (5.00 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.12 g (0.50 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 8 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was recrystallized with 5 ml of ethyl acetate to give 0.42 g of 2-benzenesulfonyl-4-methyl-6-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 28% based on benzenesulfonyl cyanide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:38]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[C:38]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:11](=[O:13])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:51][CH2:52]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(O)/C=C/c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (E)-3-(3,5-dichlorophenyl)acrylic acid (step 2) (1.365 g, 6.29 mmol) in NMP (12 ml) was added HATU (2.87 g, 7.55 mmol) and the mixture was stirred for 5 minutes at RT. tert-Butyl(2-(piperidin-4-yl)ethyl)carbamate (1.436 g, 6.29 mmol) was added followed by DIPEA (3.30 ml, 18.87 mmol) and stirring continued at RT overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic portion was washed with water, saturated sodium bicarbonate solution, water, brine and dried using a phase separating column and the solvent removed under reduced pressure. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of the product of above-mentioned (13-a) (5.5 g, 20 mmol) in methylene chloride (1.4.0 ml) was added triethylamine (5.4 ml, 29 mmol) and methanesulfonyl chloride (2.4 ml, 21 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 5.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH:32][C:33]#[N:34].C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[N:5]=[C:4]([N:32]([C:33]#[N:34])[CH3:31])[N:3]=1
Reactant: CNC#N
Reactant: CC1CCN(c2nc(S(C)(=O)=O)nc(Cl)c2-c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCN(c2nc(N(C)C#N)nc(Cl)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83.3 %

Procedure:
To a solution of 4-chloro-6-[(4-methyl)-piperidin-1-yl]-2-methylsulfonyl-5-phenyl-pyrimidine (0.5 g, 1.37 mmol) in dimethylformamide (6 ml) was added potassium carbonate (0.38 g, 2.73 mmol) followed by methyl cyanamide (0.31 g, 5.47 mmol). After stirring the reaction mixture at room temperature for 19 hours the reaction mixture was diluted with water (75 ml), and extracted with ethyl acetate (75 ml). The organic phase was washed with water (75 ml), followed by saturated brine (75 ml), dried over magnesium sulfate and concentrated in vacuo to afford a yellow syrup. The crude product was chromatographed an silica gel eluting with 90:10 v/v hexane: ethyl acetate to afford 0.39 g (84% yield) of the title compound as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:18]=[C:17]([N:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:15][C:11]=3[C:12]=2[CH:13]=O)=[CH:4][CH:3]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39].BrN1C(=O)CCC1=O>ClCCl>[NH:39]1[CH2:38][CH2:37][N:40]=[C:13]1[C:12]1[C:11]2[CH:15]=[C:16]([O:33][CH:34]([CH3:36])[CH3:35])[C:17]([N:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:10]=2[O:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NCCN
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=O)c3cc2OC(C)C)S(C)(=O)=O)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NCCN4)c3cc2OC(C)C)S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
N-(2-(4-fluorophenyl)-3-formyl-5-isopropoxybenzofuran-6-yl)-N-(4-methoxybenzyl)methanesulfonamide (0.65 g, 1.27 mmol) was dissolved in dichloromethane, and powdered 4 A molecular sieves (0.7 g) were added. The slurry was cooled to 0° C. in an ice bath and treated with dropwise addition of ethylenediamine (0.1 mL, 1.4 mmol). The resulting slurry was stirred under nitrogen for 30 minutes, then solid N-bromosuccinimide was added in one portion and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with 100 mL dichloromethane and filtered through diatomaceous earth. The organic filtrate was washed with 10% aqueous sodium bicarbonate, 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving a foamy solid (0.54 g, 77%) which was placed under vacuum for 24 hours. The title compound was used without purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][SH:10])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:13][O:14][C:15](=[O:28])[C:16]1[C:17](=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[NH:18][C:19](=[O:22])[CH2:20]Br.C(OCC)(=O)C>O1CCCC1>[C:15]([O-:28])(=[O:14])[CH3:16].[CH3:13][O:14][C:15](=[O:28])[C:16]1[C:17](=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[NH:18][C:19](=[O:22])[CH2:20][S:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CBr
Reactant: SCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)[O-]
Product: COC(=O)c1ccc(Cl)cc1NC(=O)CSCCCc1ccccc1
Reaction time: 0.5 h

Procedure:
4.3 g (28.7 mmol) of 3-phenylpropylthiol are added dropwise at 0° to a mixture of 1.4 g (31.6 mmol) of sodium hydride dispersion in oil (55%) and 30 ml of tetrahydrofuran. The mixture is then stirred for 30 minutes at 0°. A solution of 4-chloro-N-(bromoacetyl)-anthranilic acid methyl ester in 30 ml of tetrahydrofuran is added dropwise and the mixture is then stirred for one hour at 0° and for three hours at room temperature. Ethyl acetate is added and the reaction mixture is extracted with water and brine. The aqueous phases are washed with ethyl acetate and the organic phases are combined, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexanelethyl acetate (4:1) yields 4-chloro-N-(3-phenylpropylthio)acetylanthranilic acid methyl ester in the form of a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=O)[CH2:3][SH:4].B.O1CCCC1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[NH2:1][C@H:2]([CH2:3][S:4][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:5][OH:7]
Reactant: N[C@H](CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: N[C@@H](CO)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
D-Cysteine (2.36 g, 19.48 mmol) was suspended in THF (40 mL) and cooled to 0° C. Borane-tetrahydrofuran complex (1 M in THF, 78 mL, 78 mmol) was added over 20 mins and the mixture was stirred at RT for 6 hours. The reaction was quenched with DMF (7 mL) and stirred for 25 mins. Trityl chloride (5.97 g, 21.43 mmol) was added and the mixture stirred for a further 16 hours. The reaction mixture was evaporated under vacuum. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 50% EtOAc/hexane, EtOAc, 10% MeOH/EtOAc and 20% MeOH/EtOAc gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c(C)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)c(C)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(2,4-dimethylanilino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 241°-241.5°C after recrystallization from ethanol.