Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:27])[N:20]([CH3:28])[CH2:19]2)[C:9]1=[O:29])[CH3:7]>O1CCOCC1.O>[CH3:28][N:20]1[C:21]2[C:26](=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]([CH:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:9]2=[O:29])=[CH:19]1
Reactant: COC(=O)CCC(C)n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n(C(C)CCC(=O)O)c3ccccc31)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
To a solution of 4-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester (120 mg, 0.3 mmol) in dioxane (2.5 ml) was added a solution of LiOH monohydrate (25 mg, 0.6 mmol) in H2O (2.5 mL). The solution was stirred at room temperature for 4 hours. The reaction mixture was quenched with 4M HCl in dioxane (250 □L) and concentrated. The resulting residue was purified by CombiFlash with 10% MeOH in dichloromethane as the eluent to afford the desired 4-{3-[(1,4-dimethyl-1H-indol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}pentanoic acid (17 mg, 15%). LCMS (ESMS): 392.26 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)[CH3:6])[CH3:2].C1COCC1.[Li+].C[Si]([N-:24][Si](C)(C)C)(C)C.C1(P(ON)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:24][C:5]([C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CCOC(=O)C(C)c1noc(C)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(N)c1noc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-propionic acid ethyl ester (CAN168704-76-5, 0.5 g, 2.71 mmol) in a mixture of dry THF (15 ml)/dry DMF (4 ml) cooled down to 0° C. under an argon atmosphere was slowly added LiHMDS 1.0M solution in THF (2.85 ml, 2.85 mmol). The reaction mixture was stirred at 0° C. for 30 minutes followed by addition of O-(diphenylphosphoryl)hydroxylamine (696 mg, 2.99 mmol). The resulting suspension was let to warm up to room temperature and stirred at room temperature overnight (a white suspension formed). The reaction mixture was filtered through a pad of Celite and the filter cake was washed twice with THF. The filtrate was concentrated in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with 5 mL aqueous Na2CO3 2M. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of dichloromethane/methanol to yield the title compound (450 mg, 83%). MS (ESI, m/z): 200.2 (M+H+).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.O1CCOCC1.[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]([NH:30][NH2:31])=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[C:21]([CH3:22])=[CH:20][S:19][C:18]=1[C:23]1([C:28]2[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:31][N:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Reactant: COC1=NCCCCC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1csc(C2(c3nnc4n3CCCCC4)CCCC2)c1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
7-Methoxy-3,4,5,6-tetrahydro-2H-azepine (0.5 ml) was added to a dioxane (20 ml) and toluene (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentane-carbohydrazide (800 mg), followed by stirring at 100° C. for 3 days. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product was purified by column chromatography (chloroform:methanol=40:1). The resulting solid was washed with hexane to obtain 770 mg of 3-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine (colorless solid).
Reaction SMILES: CSC1C=CC(C=C([N+]([O-])=O)C)=CC=1.CSC1C=CC([CH2:23][C:24](=[O:26])C)=CC=1.[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][C:24](=[O:26])[CH3:23])=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CSc1ccc(CC(C)=O)cc1
Agent: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Product: CC(=O)Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound is prepared by the procedures described in experiments 27a and 27b, replacing 4-methylsulfanyl-benzaldehyde with 4-methanesulfonyl-benzaldehyde (31a).
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=[O:35])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C=O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (417 mg, 0.86 mmol) in THF (10 mL) was added NaIO4 (468 mg, 2.19 mmol) and H2O (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, filtered and concentrated in vacuo to yield 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carbaldehyde (384 mg, 99%) as a white solid. ESI-MS m/z calc. 450.3. found 451.3 (M+1)+; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[CH2:12][C:13]([NH2:15])=[O:14]>O>[NH2:7][C:6]1[CH:5]=[C:4]([CH:10]=[CH:9][CH:8]=1)[O:3][CH2:12][C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CCl
Reactant: Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)COc1cccc(N)c1

Procedure:
A solution of 50% sodium hydride (5.76 g., 0.12 M), 3-hydroxyaniline (13.09 g., 0.12 M) and chloroacetamide (11.22 g., 0.12 M) is stirred at room temperature for 18 hours. The mixture is diluted with water to decompose residual sodium hydride and is then extracted with chloroform. The chloroform extract is dried (MgSO4) and concentrated to an oil under reduced pressure. The addition of chloroform causes it to crystallize. Yield = 10.0g. (50%); m.p. 107°-111° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)(C)[CH2:8][OH:9])(=[O:4])=[O:3].C1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.Cl.NC(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][CH:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)CO
Agent: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Product: CS(=O)(=O)OCC(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-6-carbaldehyde (1A) and 2-amino-1,3-propanediol hydrochloride (Sigma) gave 2-((6-chrysenylmethyl)amino)-1,3-propanediol methanesulfonate mp 208°-209°, (CH3OH/Et2O), (C,H,N,S).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:25]=O)=[CH:10][N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:25]=[CH2:1])=[CH:10][N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(Cn2cc(C=O)c3c(Br)cccc32)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cn(Cc2ccc(OC)cc2)c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyltriphenylphosphonium bromide (1.14 g) was suspended in tetrahydrofuran (6.0 mL), and to this solution was added n-butyl lithium (in 2.64 M hexane solution of 1.16 mL) at −78° C. The mixture was stirred at 0° C. for 1 hour and then a solution of compound (48a) (0.91 g) in tetrahydrofuran (2.0 mL) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was partitioned with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (48b) (0.864 g, 95%) as a colorless oily substance.
Reaction SMILES: CN(C=O)C.[Na+].[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([O-:29])(=O)=[O:27])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([Cl:32])(=[O:29])=[O:27])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)[O-])cc2)c2ccccc2n1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 97.5 %

Procedure:
A catalytic amount of DMF was added to a solution of the 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonic acid sodium salt (1.0 g, 2.8 mmol) from step (2a) in thionyl chloride (3.0 ml, 41.0 mmol). The reaction was heated to 60° C. for 2 h, allowed to cool to room temperature, diluted with methylene chloride, concentrated in vacuo, diluted with THF, concentrated in vacuo to give 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonyl chloride (0.95 g, 97%) as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:24][O:23][C:7]1[C:8]([CH3:22])=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=3)=[N:10]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1C
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Yield: 73 %

Procedure:
Compound 65b was synthesized from compound 64b as a yellow powder in 73% yield, following the procedure as described for compound 43a.
Reaction SMILES: N([CH2:3]NC(N)=O)=O.[OH-].[K+].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=[O:14]>C(OCC)C.CO>[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([O:15][CH3:3])=[O:14]
Reactant: NC(=O)NCN=O
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Nitrosomethyl urea (8 g, 78.16 mmol), taken in diethyl ether (30 ml) was cooled to 0° C. and 25% aqueous KOH solution was added slowly under cooling. The ether layer was collected, dried over KOH and added dropwise to a stirring solution of 2,4-Dichloronicotinic acid (3 g, 15.62 mmol) in methanol (5 mL) at 0° C. The reaction mixture was allowed to come to room temperature within 1 hour. The organic solvent was removed under reduced pressure and the crude residue was purified by column chromatography (5-10% EtOAc in hexane) to obtain the pure methyl 2,4-dichloronicotinate (3.00 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.3 Hz, 1H), 7.33 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[NH:8][C:9]2=O)=[CH:4][CH:3]=1.O(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([CH3:13])[N:8]=1
Reactant: ClOCl
Reactant: Cc1cc2ccc(Cl)cc2c(=O)[nH]1
Product: Cc1cc2ccc(Cl)cc2c(Cl)n1
Reaction time: 5 h

Procedure:
A solution of 7-chloro-3-methyl-2H-isoquinoline-1-one (7.1 g, 36.7 mmol) in 100 mL of phosporous oxychloride is heated to 100° C. After 5 h, the solution is concentrated to dryness. The residue is dissolved in CH2Cl2. The solution is washed with H2O. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 3% EtOAc/hexanes to 5% EtOAc/hexanes. The title compound is obtained as a white solid (6.0 g, 28 mmol). 1H NMR (CDCl3, 300 MHz) δ8.23 (s, 1H), 7.68 (m, 1H), 7.63 (m, 1H), 7.40 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH2:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(N)c3O2)cc1
Reactant: Clc1ccc(Br)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccc(Cl)cc4)c3O2)cc1
Yield: 59.7 %

Procedure:
Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 1-bromo-4-chlorobenzene (0.570 g, 3.0 mmol) generally according to the procedure described for Intermediate 37 provided 0.77 g (57%) of (±)-{7-[(4-chlorophenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 132-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: O=S(Cl)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Solvent: CCCCCC
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) and thionyl chloride (31 mL, 424 mmol) are heated to reflux for 5 h then allowed to cool to room temperature. To this mixture is added hexane and the resulting solid is filtered, washed with hexane and dried in vacuo to yield 52.3 g (97%) of the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.FC1C([I:31])=C(F)C(F)=C(F)C=1F.O.C1COCC1>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:31])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.Cl.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>O>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:17][C:16]([OH:20])([CH3:19])[CH3:18])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: Cl
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 50 mL of water and a solution of 25.3 g (0.37 mol) of 50% aqueous hydrogen peroxide are added simultaneously over 3-3.5 hours at 40° C. to a mixture of 0.27 g (1.0 mmol) of ferric chloride hexahydrate, 25 mL of water, 1.1 mL of 37% hydrochloric acid and 200 mL of tert-butyl alcohol. About two hours into the addition, 0.5 mL of 37% hydrochloric acid is added to the reaction mixture. After the peroxide addition is complete, 1.2 mL of 37% hydrochloric acid is added and the reaction mixture is heated at 40-50° C. for 3.5 hours. The reaction mixture is stirred overnight at room temperature. The reaction is completed by adding two portions of 0.3 mL of 37% hydrochloric acid while heating the reaction mixture at 45° C. for 5.5 hours. Work-up is done as in Example 20 and affords 21.5 g (88% yield) of the title compound as a white solid. Gas chromatography shows the product has a purity greater than 96%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([OH:31])=O)=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[Cl:47][C:43]1[CH:42]=[C:41]([C@@H:33]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:32][N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([C:29]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:31])=[CH:22][N:23]4[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1cc(C(=O)NS(C)(=O)=O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
To a solution of 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylic acid (131 mg) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (35 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 hours. To this one were added methanesulfonamide (46 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (72 mg) at room temperature, and the mixture was stirred at 60° C. for 10 hours. The resulting mixture was poured into 0.1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=200/1 to 100/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl][2-[4-[1-isopropyl-3-[[(methylsulfonyl)amino]-carbonyl]-1H-indol-6-yl]phenyl]ethyl]carbamate (134 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.O1CCN(CCN=C=N)CC1.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]3[CH2:14][CH2:13]3)[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: S=C=NC1CC1
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C=NCCN1CCOCC1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Br)c1Cl
Yield: 34.7 %

Procedure:
3-Bromo-4,5-dichloro-1,2-phenylenediamine (5.12 g, 20.0 mmol), cyclopropyl isothiocyanate (2.18 g, 21.98 mmol), 1-cyclohexyl-3-(2-morpholinoethylcarbodiimide metho-p-toluenesulfonate (11.0 g, 25.97 mmol) and pyridine (75 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid. MS (CI): m/z 319 amu. Anal. Calcd for C10H8BrCl2N3(0.35 C4H8O2): C, 38.92; H, 3.09; N, 11.94. Found: C, 39.17; H, 3.05; N, 11.94.
Reaction SMILES: [Br:1][C:2]([CH:9]=[CH2:10])=[CH:3][O:4][Si](C)(C)C.[O:11]([CH:14](OCC)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13]>>[Br:1][C:2](=[CH:3][CH2:4][CH:14]([O:11][CH2:12][CH3:13])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=[O:10]
Reactant: CCOC(C=Cc1ccccc1)OCC
Reactant: C=CC(Br)=CO[Si](C)(C)C
Product: CCOC(C=Cc1ccccc1)CC=C(Br)C=O
Reaction time: 2 h

Procedure:
One starts with 2.21 g of 2-bromo-1-trimethylsiloxybut-1,3-diene and 2.06 g of 3,3-diethoxyl-1-phenylprop-1-ene and proceeds in the same manner as in Example 3, except that the reaction is carried out for two hours.