Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[O:10]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 2-benzoxazolinone (2.0 g, 14.8 mmol) and potassium carbonate (3.07 g, 22.2 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (4.4 mL, 44.4 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.1 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24](=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Yield: 70 %

Procedure:
Intermediate 6 was coupled with 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure J. The product was purified on silica gel using 1:1 ethyl acetate:hexanes as eluent. Yield: 70%. LC-MS showed the product had the expected M+H+ of 375.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)[CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:23])[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=1.[H][H]>N.[Ni]>[NH2:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:23])[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)[CH3:20]
Reactant: [H][H]
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Agent: [Ni]
Agent: N
Product: CC1N=C(c2ccccc2F)c2cc(C(C)N)ccc2N(C)C1=O

Procedure:
A solution of 4.1 g (12.08 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 150 ml of 2 N methanolic ammonia is treated with 5 g of Raney-nickel paste and the suspension is stirred in a hydrogen atmosphere for 24 hours. After filtration of the catalyst and removal of the solvent in vacuo, there is obtained 7-(1-aminoethyl)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one as a foam of melting point 48°-50°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=O)[CH3:2].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.Cl.N[C:34]1C=CC(NC(=O)C)=C[CH:35]=1.C(O)CCC>O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:34][CH3:35]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 400 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
3-(4-Cyclohexylphenyl)-3-oxo-propionic acid ethyl ester 50.25 g (0.183 moles), 4′-aminoacetanilide 25 g (0.167 moles), 4′-aminoacetanilide hydrochloride salt, 1.55 g (0.008 moles), and 500 mL of dry n-butanol were placed in a 1 liter single neck round bottom flask equipped with a Soxhlet extractor apparatus with condenser, magnetic stirrer and nitrogen inlet. In the Soxhlet thimble (33×118 mm) was placed highly activated 4A sieves (1.7-2.4 mm beads). The sieves were activated immediately before use under high vacuum with heating (400° C. for 30 min). The mixture was then brought to reflux such that the butanol azeotropically removed water, so as to drive the equilibrium reaction, and the water was removed from the butanol by the sieves before being returned to the reaction pot. The reaction was allowed to continue for 48 hrs. The charge of sieves was replaced after the first 24 hrs. Transesterification to the butyl ester along with removal of ethanol occurred concomitantly with enamine formation. After 48 hrs the reaction pot was cooled, placed in a −40° C. freezer and crystals were-allowed to form for 24 hrs. Crystals were collected by vacuum filtration and solids washed with cold ethanol. The product was then dried in a vacuum oven to give 73.8 g (98%) of the desired enamine.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[O:20])[CH2:13][CH2:12]1>C1COCC1>[OH:20][CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]1)[CH:5]1[S:6][CH2:7][CH2:8][NH:3][C:4]1=[O:9]
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C1CSCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C(O)C2SCCNC2=O)CC1
Temperature: 25 °C

Procedure:
Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) was washed with hexanes under a nitrogen atmosphere and suspended in 100 mL of anhydrous THF. Thiomorpholin-3-one (1.0 g, 8.55 mmol) was added, followed immediately by 2-(4-methylpiperazin-1-yl)-benzaldehyde (1.58 g, 7.75 mmol). The reaction was then heated to reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous ammonium chloride (NH4Cl) and saturated brine and then dried with MgSO4. Purification using flash chromatography gave 2-{hydroxy-[2-(4-methylpiperazin-1-yl)phenyl]-methyl}-thiomorpholin-3-one as a white solid, m.p. 137-139° C. Mass spectrum 322 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:18][O:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC
Yield: 64.4 %

Procedure:
A solution of the product from step (c) (40.2 g), potassium carbonate (46.5 g) and methyl iodide (20.9 ml) in dry dimethylformamide (150 ml) was stirred at 20° C. for 16 hours. The solvent was evaporated and the residue quenched with water. The aqueous phase was extracted with ethyl acetate which was washed with brine, dried, filtered and evaporated to leave a yellow oil (27.4 g), MS; m/e 283.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(C)(C)C>[ClH:1].[C:15]([C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1)#[CH:16]
Reactant: C#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Solvent: CC(C)(C)O
Product: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Product: Cl
Temperature: 25 °C

Procedure:
4-Chloro-7-nitroquinazoline (7.97 g, 38.0 mmol) and 3-ethynylaniline (4.54 g, 38.8 mmol) were refluxed in 125 mL of tert-butyl alcohol for 3 hours, cooled to room temperature and filtered to afford the title product as a solid which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 9.95 g (80%); mp 209°-210° C. dec.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:29]([OH:31])=[O:30])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1.C(Cl)Cl.C(NCC)C>C(#N)C>[NH2:1][C@H:2]([C:29]([OH:31])=[O:30])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(C(NCCCC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of Fmoc-Lys(MMT) (9.7336 g) in 100 ml of mixture of methylene chloride and acetonitrile (1:1) at room temperature was added diethylamine (100 ml). The mixture was stirred at room temperature for 1.5 hrs. After removal of solvent, the residue was flushed with acetonitrile at 60° C. (90 ml×2), washed with acetonitrile (20 ml×3) and ether (20 ml×3). The solid was then dissolved as far as possible in 1:1 CH2Cl2/CH3OH (200 ml) and some solid byproduct was removed by filtering through filter paper. After removal of solvent and being dried in vacuo, 4.7707 g (82.2%, based on Fmoc-Lys) of pale yellow foam was obtained. ES(+)-MS: 147(Lys+1), 273(MMT).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2].C(N(CC)CC)C.CS[C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]>CO>[C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH:20][C:30]([NH2:35])=[N:31][N+:32]([O-:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC(N)=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (200 mg, 0.689 mmol) was dissolved in absolute methanol (2.7 ml) by the addition of triethylamine (0.098 ml, 0.690 mmol). 2-Methyl-1-nitro-2-thiopseudourea (103 mg,0.757 mmol) was then added. The mixture was warmed to 40° C. with stirring under nitrogen for 2hrs, then stirred at 21° C. for 16 hr. The addition of reagent and heating and stirring was repeated twice more. The cooled mixture was then filtered and the white solid washed with methanol. Combined filtrate and washings were evaporated and the residue purified by ion exchange chromatography (Dowex 50 W×8(H+) resin, eluting with water. Appropriate fractions were combined and freeze dried. The residue was triturated with warm water (4 ml), and the off-white solid filtered and dried under high vacuum to give the title product (Yield =50 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.[OH:14][N:15]1[C:19]2C=CC=CC=2N=N1.Cl[CH2:25]Cl.C(N(CC)CC)C>O>[CH3:25][O:14][N:15]([CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: ClCCl
Reactant: CCCc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-n-propylbenzoic acid (10.0 g), 1-hydroxybenzotriazole hydrate (8.20 g), 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 g) and dichloromethane (1000 ml) was treated dropwise with triethylamine (42.6 ml) and N,-dimethylhydroxylamine hydrochloride (6.6 g). The mixture was stirred overnight at room temperature and then treated with water (700 ml). The organic layer was separated, washed with 2N aqueous hydrochloric acid (4×500 ml) and then saturated aqueous sodium bicarbonate solution (4×500 ml). The organic phase was dried (MgSO4) and concentrated to give the title compound as a clear oil (10.8 g).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)=[CH:22][CH:23]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](O)CC1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N([C@H]1CC[C@H](O)CC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-5-(trans-4-hydroxy-cyclohexyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate F) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 6.99 min (HPLC 2); ESI-MS: tR=1.18 min, [M+H]+ 479/481 (LC-MS 1); TLC: Rf=0.10 (EtOAc).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH:6]=[C:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:16](N(CC)CC)[CH3:17].[C:23]([O:26][C@@H:27]([C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1)[CH3:28])(=[O:25])[CH3:24]>ClCCl>[C:23]([O:26][C@@H:27]([C:29]1[N:34]=[C:33]([N:10]2[CH2:11][CH2:12][C:7](=[CH:6][C:5]3[CH:13]=[CH:14][CH:15]=[C:3]([Cl:2])[CH:4]=3)[CH2:8][CH2:9]2)[CH:32]=[CH:31][N:30]=1)[CH3:28])(=[O:25])[CH2:24][CH2:16][CH3:17]
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: CCN(CC)CC
Reactant: Clc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCC(=Cc3cccc(Cl)c3)CC2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(3-chlorobenzylidene)-piperidine hydrochloride (prepared according to the method of Example 176, Step: B, 0.46 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in dichloromethane (10 mL) was added (R)-1-(4-chloropyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 0.54 g, 2.2 mmol) and stirred at ambient temperature for 12 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 176, Step C as a viscous oil, 0.64 g (80%). 1H NMR (CDCl3, 300 MHz) δ 0.95 (d, 6H), 1.51 (d, 3H), 1.68 (m, 2H) 2.35 (m, 2H), 2.47-2.64 (m, 4H), 3.67-3.75 (m, 4H), 5.68 (q, 1H), 6.36 (s, 1H), 6.40 (d, 1H), 6.98 (m, 1H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); MS (Cl) 400 (MH+).
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.C(N(CC)CC)C.[C:57](Cl)(=[O:66])[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:27]2[CH:28]=[CH:29][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH3:34])=[CH:31][CH:32]=2)[C:57](=[O:66])[O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:12][CH2:11]1)=[O:43]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The compound (257 mg, 0.383 mmol) obtained in Example 83b was dissolved in dichloromethane (4 mL), triethylamine (107 mL, 0.766 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in tetrahydrofuran (4 mL), 55% sodium hydride-paraffin (25.0 mg, 0.573 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and dichloromethane was further added to separate the layers. The resulting organic layer was separated and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography to give the title compound (235 mg; yield, 76%) as a brown oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:24][CH:23]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH3:8].[N:11]1([C:14]([C:16]2([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:26][CH:27]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2(c3ccc(OCCCN4CCCOCC4)cc3)CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N
Product: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
4-{4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.48 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4M, 5 ml) and was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in DCM (10 ml) and washed with saturated sodium bicarbonate solution (15 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo before purifying the residue using column chromatography, eluting with a gradient of DCM:MeOH:NH3 (from 99:1:0.1 to 92:8:0.8) to afford the title compound as a white solid (80 mg, 37%). 1H NMR (400 MHz, d6-DMSO) δ 1.70-1.88 (m, 6H), 2.08 (m, 2H), 2.52-2.63 (m, 6H), 3.04-3.35 (m, 8H), 3.58 (m, 4H), 3.64 (m, 2H), 3.72 (m, 2H), 3.98 (t, 2H), 6.92 (d, 2H), 7.12 (d, 2H). LRMS ESI+ m/z 432 [MH]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][N:10]3COCC[Si](C)(C)C)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(C3CC3)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cn[nH]c2cc1C1CC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 91.1 %

Procedure:
In a round-bottomed flask, 6-cyclopropyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (668 mg, 2.2 mmol) was dissolved in dichloromethane (12 ml) and trifluoroacetic acid (6.5 ml, 84.4 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2.25 h then concentrated. The residue was redissolved in dichloromethane (12 ml) and ethylenediamine (9.0 ml, 133 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-25% EtOAc) to provide 317 mg (91%) of 6-cyclopropyl-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.99-8.08 (m, 1H), 7.59-7.70 (m, 1H), 7.16-7.25 (m, 1H), 6.88-7.01 (m, 1H), 1.94-2.14 (m, 1H), 0.96-1.11 (m, 2H), 0.71-0.84 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].CCN(CC)CC.Cl[S:44]([C:47]1[CH:48]=[CH:49][C:50]([CH3:56])=[C:51]([CH:55]=1)[C:52]([OH:54])=[O:53])(=[O:46])=[O:45]>C(Cl)Cl>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]([CH2:20][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:35]=[CH:34][CH:33]=2)[CH2:2][NH:1][S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:56])=[C:51]([CH:55]=2)[C:52]([OH:54])=[O:53])(=[O:46])=[O:45])[S:8]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[OH:19])(=[O:10])=[O:9])=[CH:22][CH:23]=1
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(-c4ccccc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1C(=O)O
Reaction time: 1.17 h
Yield: 58 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-N-(biphenyl-4-ylmethyl)-3,5-dichloro-2-hydroxybenzenesulfonamide (50 mg, 0.095 mmol) and Et3N (0.13 mL) in CH2Cl2 (4 mL) was added a solid of 5-(chlorosulfonyl)-2-methylbenzoic acid (22.24 mg, 0.095 mmol) at rt and it was stirred at it for 70 min. Direct purification of the mixture after concentration by prep HPLC provided the desired product (40 mg, 58.1%) as a white solid after lyophilization. 1H NMR (CD3OD): δ 8.17 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.3, 2.2 Hz, 1H), 7.56˜6.90 (m, 15H), 6.76 (s, 1H), 4.34 (s, 2H), 4.31 (s, 2H), 3.87 (s, 2H), 2.52 (s, 3H); MS (ESI): (M+H)+=725.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15].Cl.N1C=CC=CC=1>O>[CH2:10]([C:8]1[S:7][C:6]2[C:14]([Cl:15])=[C:2]([Cl:1])[C:3]([OH:16])=[CH:4][C:5]=2[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2-n-butyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride, under nitrogen, is heated with stirring in a 195° oil-bath for 5 hrs. After the reaction mixture has cooled, 1000 ml of water is added and the aqueous mixture is extracted with three 250-ml portions of ether. The organic layers are combined, washed with one 200-ml portion of 2N hydrochloric acid, two 250-ml portions of water, dried over anhydrous magnesium sulfate and filtered. The solvent is removed to give an oil. Crystallization with pentane and cooling gives 3.3 g of 2-n-butyl-6,7-dichloro-5-hydroxybenzo[b]thiophene, mp 35°.