Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[Cl:13])[CH:6]=[CH:5]1)(=[O:3])[CH3:2].C(O)(=O)C>[Pt].CO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([O:18][CH3:19])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c2c(ccn2C(C)=O)c1OC
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c2c(c1OC)CCN2C(C)=O
Reaction time: 48 h

Procedure:
The mixture of the indole of step 8 above (0.9 g) and Pt-C (0.2 g), acetic acid and MeOH (100 ml) is stirred under H2 at 1 atm. pressure for 48 hours. The catalyst is filtered (celite), the filtered material is washed (MeOH) and the reaction mixture and methanol washings are evaporated. The residue is diluted with CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated affording a colorless, semicrystalline material which is determined to be the desired compound by NMR. M.P. 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:29])[CH:12]=1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: Cc1cccc(Cl)c1N
Product: COc1ccc2c(Nc3c(C)cccc3Cl)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 2-chloro-6-methylaniline and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16. 1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 7.94 (d, 1H), 7.50 (dd, 1H), 7.42-7.34 (m, 2H), 7.16 (d, 1H), 4.82 (m, 1H), 4.28 (s, 1H), 3.90 (s, 3H), 2.21 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 399.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:26]=1)[C:7]([N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)=[N:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cc(Br)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3-n3ccc4cc(Br)cc2c43)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A mixture 4,9-dibromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine (4.5 g, 9.45 mmoles) and manganese(IV) dioxide (7.0 g) in chloroform (150 ml) was heated under reflux for 3.5 hours. An additional 4.5 g of manganese dioxide was added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography over a silica gel column (140 gm), eluted with 2% methanol:98% dichloromethane (2 l). The appropriate fractions were collected and evaporated. Crystallization of the residue from isopropanol (10 ml) yielded 3.37 g (75%) of product, mp 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reaction time: 1 h

Procedure:
A mixture of 2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1.77 g, 6.3 mmol), 2-aminomethylpyridine (Aldrich, 782 μl, 7.6 mmol), and triethylamine (VWR, 1.06 ml, 7.63 mmol) were refluxed in ethanol (30 ml) for 3 hrs. On cooling, the reaction was poured into water (300 ml) and stirred for 1 hr. The resulting precipitate was filtered, washed with water (2×30 ml) and dried under vacuum at 40° C. to give (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine as a pale-yellow solid. Yield=(1.55 g, 70%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (133 mg, 0.51 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (90 mg, 0.51 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid (125 mg, 0.42 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (88 mg, 0.93 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide as a pink foam. The impure foam was dissolved in methylene chloride (40 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×40 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford pure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide (75 mg, 48%) as a pink foam: mp 139-140° C.; EI-HRMS m/e calcd for C24H25N3O (M+) 371.1998, found 371.2006.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([NH:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)[CH:6]=[C:5]([CH3:32])[N:4]=1>[Pt].CO>[ClH:1].[NH2:9][C:8]1[C:3]([CH3:2])=[N:4][C:5]([CH3:32])=[CH:6][C:7]=1[NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:30][CH:31]=1
Reactant: Cc1cc(Nc2ccc(CCNC(=O)OCc3ccccc3)cc2)c([N+](=O)[O-])c(C)n1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2ccc(CCNC(=O)OCc3ccccc3)cc2)c(N)c(C)n1
Yield: 89.9 %

Procedure:
To a clean, nitrogen-purged 1 L hydrogenation reactor were charged 5% Pt/C (625 mg), benzyl 4-(2,6-dimethyl-3-nitropyridin-4-ylamino)phenethylcarbamate hydrochloride (25.0 g, 54.7 mmoles) and methanol (550 mL). The reaction was stirred for at least 15 minutes and then purged sequentially with nitrogen and hydrogen. The reaction was then pressurized with hydrogen to between 18 and 25 psi at between 22° C. and 28° C. until HPLC showed no starting material remained. The reaction was purged with nitrogen and the catalyst was filtered on a water-wet celite-coated filter and the cake was washed with methanol (125 mL). The resulting solution of benzyl 4-(3-amino-2,6-dimethylpyridin-4-ylamino)phenethylcarbamate hydrochloride was transferred to a clean and dry nitrogen-purged 1 L round-bottom flask. Methanol was displaced atmospherically with 2-propanol to a final volume of approximately 125 mL. The reaction was then cooled to between 15° C. and 25° C. over at least 60 minutes and sampled for KF. The reaction was then filtered and washed with 2-propanol (75 mL). After blowing the cake with nitrogen for at least 15 minutes and drying under vacuum at 40° C. to 50° C. with nitrogen bleed for at least 12 hours, 21.0 g (49.2 mmoles) of benzyl 4-(3-amino-2,6-dimethylpyridin-4-ylamino)phenethylcarbamate hydrochloride was isolated in 89.9% yield.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[C:37]([C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[F:46])[NH2:42])#[CH:38]>ClCCCl>[C:37]([C:39]1[CH:40]=[C:41]([NH:42][C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:43]=[CH:44][C:45]=1[F:46])#[CH:38]
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Reactant: C#Cc1cc(N)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C#Cc1cc(Nc2ncnc3cnc(C)cc23)ccc1F
Temperature: 60 °C
Reaction time: 6 h
Yield: 13.3 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4-one (44 mg, 0.27 mmol), polymer -supported triphenylphosphine (0.462 g of about 3.0 mmol P/g resin, 1.55 mmol) and anhydrous carbon tetrachloride (0.261 mL, 2.71 mmol) were combined in 1,2-dichloroethane (1.25 mL). The reaction mixture was heated to 60° C. under an atmosphere of dry nitrogen for 2 hours. 3-Ethynyl-4-fluoro-aniline (55 mg, 0.407 mmol) was added and heating was continued at 60° C. for 6 hours. The polymer was filtered off and washed several times with 50% methanol/chloroform. The filtrate and washings were concentrated in vacuo and flash chromatographed on silica with gradient from 0 to 10% methanol/methylene chloride to afford the title product (10 mg; M.P. 225° C.; LC-MS: 279 (MH+); anal. RP-HPLC: 3.94 min.).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11].[CH3:12][Sn](C)(C)C>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1ccc2nc[nH]c2c1Br
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(N)ccc2nc[nH]c12
Temperature: 145 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A solution of 4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol), tetramethyltin (330 mg, 2.4 mmol) and bis (triphenylphosphine) palladium (11) chloride (20 mg) in 5 ml of anhydrous DMF was placed in sealed tube and stirred for 12 h at 145° C. The reaction mixture was concentrated in vacuo, yielding an oily residue which was subjected to column chromatographic separation (NH, sat'd 10% MeOH/EtOAc) to yield 140 mg (0.83 mmol, >95%) of 4-methyl-5-aminobenzimidazole.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@@H:8]([NH:16][C:17]([C:19]1[N:20]=[C:21]([C:37]#[N:38])[C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:23]=2)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:37]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:16][C@@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][C:6]([OH:39])=[O:5])=[O:18])[N:20]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)N[C@H](CC(=O)O)Cc2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
(S)-3-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-4-phenyl-butyric acid tert-butyl ester (50 mg, 0.096 mmol) was dissolved in CH2Cl2 (4 mL) and cooled in an ice bath. Trifluoroacetic acid (4 mL) was added, and the mixture was stirred at r.t. for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between saturated NaHCO3 and EtOAc. Hydrochloric acid (1 M) was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was first purified by column chromatography (0-40% EtOAc/hexanes+2% AcOH), then by preparative TLC (60% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound as a pale brown solid. MS: (+) m/z 468.14 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:13][C:10]4[CH:11]=[CH:12][C:7]([C:4]5[N:3]=[C:2]([CH3:1])[O:6][N:5]=5)=[CH:8][CH:9]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1nc(-c2ccc(O)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(Oc3ncnc4c3cnn4C3CCN(C(=O)OC(C)(C)C)CC3)cc2)no1
Temperature: 160 °C
Yield: 20 %

Procedure:
A mixture of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenol (Enamine Ltd., Kiev, Ukraine; 32 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-{4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (17 mg, 20%) as an off white solid. Mass spectrum M+H-Boc=378.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]I)[CH:5]=1)([O-:3])=[O:2].[O:24]1CCC[CH2:25]1>CO.C(=O)([O-])[O-].[Ag+2]>[CH3:25][O:24][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]2[C:11]1=[O:21]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI
Reactant: C1CCOC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The solution of 2 g of N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide in 40 ml of tetrahydrofuran and 40 ml of methanol, is treated with 8.7 g of freshly prepared silver carbonate for 20 hours, with protection from light. The mixture is filtered and the filtrate evaporated, to yield the N-(2-methoxymethyl-4-nitrophenyl)-4-chlorophthalimide melting at 125°-128°.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH:24]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:24]1([CH2:30][C:31]([N:19]2[CH2:20][CH2:21][CH:16]([C@H:14]3[CH2:15][C@H:13]3[CH2:12][CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[N:4][N:3]=[N:2]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CC1CCCCC1
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCCCC1)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23 mg (0.071 mmol) of 4-((1R,2S)-2-{2-[4-(1H-tetrazol-1-yl)phenoxy]ethyl}cyclopropyl)piperidine in 0.6 ml anhydrous N,N-dimethylformamide at ambient temperature was added 0.020 ml (0.14 mmol) cyclohexylacetic acid, followed by 27 mg (0.14 mmol) EDC, 9.6 mg (0.071 mmol) HOBt, and 0.062 ml (0.35 mmol) diisopropylethylamine. The solution was stirred overnight at ambient temperature. The crude in N,N-dimethylformamide was purified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% acetonitrile/0.1% formic acid in water gradient). The pure fractions were lyophilized to yield the title compound as white solid.
Reaction SMILES: [CH:1]1([S:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][S:19]([CH3:22])(=[O:20])=[O:21])(=[O:31])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1S(=O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)C1CCCCC1
Temperature: 0 °C
Yield: 87.6 %

Procedure:
To 20 ml of a chloroform solution containing 1.2 g of N-(2-cyclohexylsulfinyl-4-nitrophenyl)methanesulfonamide obtained in Example 3 was added dropwise 60 ml of a chloroform solution containing 3.9 g of m-chloroperbenzoic acid under ice cooling with stirring. The mixture was stirred for 3 hours. The reaction solution was poured into ice water, neutralized with a dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude crystals, which were washed with ethyl ether and then recrystallized from ethyl acetate-n-hexane to give 1.1 g of N-(2-cyclohexylsulfonyl-4-nitrophenyl)methanesulfonamide as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1cccc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-methylacetophenone (R. Yveline, G. Gerard, and M. Geroges, Chem.Pharm.Bull., 1992,40, 1170.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Mg].II.[CH:10]([SiH:13]([CH:15]([CH3:17])[CH3:16])Cl)([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[CH:10]([SiH:13]([CH:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][O:5][CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: COCCCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCC[SiH](C(C)C)C(C)C
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 103.1 %

Procedure:
1-Bromo-3-methoxypropane (9.18 g, 60.0 mmol) was dissolved in THF (55 mL), and magnesium (1.53 g, 62.9 mmol) and iodine (catalytic amount) were added thereto, followed by stirring at room temperature for 20 minutes and at 55° C. for 5 minutes. The resultant mixture was added dropwise to diisopropylchlorosilane (8.88 mL, 52.0 mmol) in THF (65 mL) for 5 minutes, followed by stirring at room temperature for 1 hour. After termination of exothermic reaction, the resultant mixture was further stirred at 50° C. for 1.5 hours, and saturated aqueous ammonium chloride was added thereto. The resultant mixture was extracted with pentane, followed by washing with water six times and drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, whereby the Compound 60a was obtained as an yellow liquid (10.1 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][NH2:29]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: COc1ccc(CN)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2I)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-iodobenzoic acid (1-1, 500 mg, 1.529 mmol, 1.0 equiv) in dichloromethane (8 mL) was added catalytic DMF (0.012 mL, 0.153 mmol, 0.1 equiv) and oxalyl chloride (0.161 mL, 1.835 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred for 1 hour and concentrated. The crude residue was dissolved in dichloromethane (15 mL) and to the reaction was added 3,4-dimethoxybenzylamine (281 mg, 1.682 mmol, 1.2 equiv), and TEA (0.682 mL, 4.59 mmol, 3.0 equiv) at 0° C. After stirring for 10 min, the mixture was removed from the cold bath, diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes) to afford the product (1-2) as a tan solid. ESI+ MS [M+H]− C16H15BrINO3: 476.9 found, 476.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].[H-].[Na+]>C(Cl)Cl.C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1(c2ccc(Br)cc2)CC1
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (22 g, 91.3 mmol) and SOCl2 (13.6 mL, 183 mmol) in CH2Cl2 were heated together for 1.5 hours then evaporated to afford a dark oil. This oil was added via syringe over 30 minutes to a mixture of MeSO2NH2 (19 g, 200 mmol) in THF (250 mL) that was pre-treated at room temperature with NaH (60% in oil; 8.0 g, 200 mmol) for 1.5 hours. After a further 20 minutes, the mixture was poured into water, acidified and extracted with CH2Cl2, washed with water (2×) and evaporated to ˜100 mL. Hexane (300 mL) was added and the product collected by filtration to yield the title compound (25 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:37]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][C:40]=1[F:47])#[N:38]>C1COCC1>[NH2:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([C:37]#[N:38])=[C:40]([F:47])[CH:41]=1)[C:20]([OH:22])=[O:21])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(CC[C@H](N)C(=O)O)C(=O)O)cc1F
Temperature: -70 °C
Reaction time: 2 h

Procedure:
1.49 g (4 mmol) of di-tert-Butyl (2S)-2-[(tert-butoxycarbonyl)amino]hexanedioate 7a were dissolved in 50 mL of THF and cooled to −70° C. 8.8 mL (8.8 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise over a period of two hours at this temperature and the mixture was stirred at −70° C. for another 2 hours. 0.985 g (4.6 mmol) of 4-Cyano-3-fluorobenzyl bromide were then added dropwise, and after 2 h at this temperature, the cooling bath was removed and 20 mL of 2N aqueous hydrochloric acid and 100 mL of dichloromethane added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated (150 mg) MS (ESIpos): m/z=507 [M+H]+