Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@H:19]([OH:22])[CH2:20][O:21][C@H:15]23)=[O:12])[CH2:7][CH2:6]1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31]([O:22][C@H:19]2[C@H:16]3[O:17][CH2:18][C@@H:14]([O:13][C:11]([N:8]4[CH2:7][CH2:6][CH:5]([O:4][N+:1]([O-:3])=[O:2])[CH2:10][CH2:9]4)=[O:12])[C@H:15]3[O:21][CH2:20]2)=[O:32])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)piperidine-1-carboxylate (0.47 g, 1.48 mmol) and Et3N (0.45 g, 4.44 mmol) in THF (25 mL) was added 4-Nitrophenyl chloroformate (0.30 g, 1.48 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; 60% EtOAc in n-hexane), affording the title product as a white solid. 1H-NMR (300 MHz, CDCl3); δ 8.33-8.29 (2H, m), 7.45-7.40 (2H, m), 5.22-5.07 (3H, m), 4.88-4.80 (1H, m), 4.79-4.71 (1H, m), 4.20-3.71 (6H, m), 3.60-3.30 (2H, m), 2.12-1.98 (2H, m), 1.88-1.73 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[OH:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][CH2:34][C@H:35]([OH:41])[CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1>>[ClH:1].[ClH:1].[ClH:1].[CH3:40][CH:38]([NH:37][CH2:36][C@@H:35]([OH:41])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:29]([O:28][CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:5]3[C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:13]=4[S:12][C:11]4[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:24][CH2:23]2)=[CH:43][CH:42]=1)[CH3:39]
Reactant: CC(C)NC[C@@H](O)COc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Product: CC(C)NC[C@@H](O)COc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl

Procedure:
Using the conditions outlined in method A, 11.7 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine was reacted with 7.5 g of (R)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol to give, after recrystallization from methanol-ethyl acetate and from methanol-ethanol, the trihydrochloride salt of (S)-1-(1-methylethylamino)-3-[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethoxy]phenoxy]-2-propanol, trihydrochloride, mp 251.5°-253°; [α]D25 +10.37° (c, 1.0, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Br)cc1
Temperature: 60 °C
Yield: 85.2 %

Procedure:
To a solution of 5.31 g (0.0307 moles) of 4-bromophenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 60° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 4 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried, which gave 8.1 g of crude product. The crude product was dissolved in CH2Cl2 and washed with 10% aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo gave 7.5 g (85% yield) of product. Recrystallization from ethanol afforded purified 2-(4-bromophenoxy)-5-nitrobenzonitrile, mp 171°-172° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.S(Cl)([Cl:14])=O.O>C(Cl)(Cl)Cl.ClCCl>[Cl:14][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2ccccc2o1
Yield: 80 %

Procedure:
A three-necked flask is charged with 33.2 g of 2-benzofuranylmethanol dissolved in 450 ml of anhydrous chloroform, 48.8 ml of thionyl chloride are then introduced dropwise and the temperature is raised gently to reflux and maintained for 3 hours 30 minutes. The reaction medium is then cooled and poured into 1 l of water, and is thereafter diluted with 500 ml of dichloromethane. After settling has taken place, the organic phase is washed to neutrality and dried over anhydrous magnesium sulfate, the solvent is evaporated off and the residue is distilled under vacuum to obtain the expected compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH:31]=1)[CH2:26][CH2:27][F:28])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:46])[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH2:37][OH:38])[CH:31]=1)[CH2:26][CH2:27][F:28])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
TBAF (1M in THF, 8.84 mL, 8.84 mmol) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (1.91 g, 4.42 mmol) in THF (44.2 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (100 mL) was added, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 30:70) yielded the title compound (901 mg, 64%). LC-MS: tR=0.64 min; ES+: 318.07.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12>CN(C)C=O>[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([CH2:5][CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12
Reactant: ClCCN1CCCC1
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of N-(2-chloroethyl)pyrrolidine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water, and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which crystallizes on trituration with ether. Recrystallization from ethyl acetate-hexane gives white crystals, m.p. 139°-141°C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([Cl:16])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2ncsc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2ncsc2c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
Under a nitrogen atmosphere, benzothiazole-6-carboxylic acid (1.014 g, 5.6 mmol) was dissolved in methylene chloride (25 mL). Five drops of N,N-dimethylforamide was added. Oxalyl chloride (0.5 mL, 5.6 mmol) was slowly added. After 2 hrs, the reaction was heated to 30° C. for 16 hrs. The reaction was concentrated in vacuo to yield benzothiazole-6-carbonyl chloride (19A) (1.665 g, quant., light yellow powder).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(NC(C)C)(C)C.C1C=CC(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(O)ccc1CN1CCCCC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-methoxy-4-piperidin-1-ylmethylphenol (456 mg, 2.06 mmol) and diisopropylamine (0.77 mL, 4.54 mmol) in DCM (10 mL) at 0° C. was added N-phenyltriflamide (958 mg, 2.68 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a colourless oil (408 mg, 56%). NMR (CDCl3, 300 MHz): 7.60 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 3H), 2.87-2.74 (m, 4H), 1.82-1.75 (m, 4H), 1.57-1.50 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-n2ccnc2)n(CCCCCCO)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(-n2ccnc2)n(CCCCCCCl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 1-(6-hydroxyhexyl)-3-methyl-2-(1-imidazolyl)indole (1.3 g) at 0°. The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration to dryness and purification by chromatography gives 1-(6-chlorohexyl)-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: O[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.P(Cl)(Cl)([Cl:21])=O.O>CN(C)C=O>[Cl:21][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (15 g) in dimethyl-formamide (170 ml) was added dropwise phosphorus oxychloride (7.4 ml) under ice-cooling. The reaction solution was heated at 100° C., and stirred for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give methyl 4-chloro-5-nitro-2-(trifluoromethyl)benzoate (14.78 g).
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[C@H:3]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:23]=[S:24](Cl)Cl.N1C=CC=CC=1>C1COCC1>[CH3:21][C:2]1([CH3:22])[O:1][S@:24](=[O:23])[N:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[C@@H:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)C(C)(C)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2[C@H](c3ccccc3)C(C)(C)O[S@@]2=O)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of (1R)-N-(2-hydroxy-2-methyl-1-phenyl-propyl)-4-methyl-benzene sulfonamide (2.0 g, 6.3 mmol) in THF 8 mL at −45° C. was added SOCl2 (1.12 g, 9.4 mmol), followed by slow addition of pyridine (1.24 g, 12.9 mmol) in THF (8 mL) over a period of 2 h. The reaction was monitored on TLC. The reaction was quenched by addition of saturated aqueous NaHCO3 and the mixture was extracted with EtOAc (30 ml), and organic phase washed with brine (20 mL) and evaporated to dryness. The residue was added hexane (40 mL) and stirred at ambient for 2 h. The precipitate formed was filtered and wet cake washed with hexane to afford the title compound (2.0 g, 87.5%) with 99% de.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]([NH:28][C@H:29]([C:33]([NH:35][CH:36]([CH:45]([OH:48])[CH2:46][F:47])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]([NH:28][C@H:29]([C:33]([NH:35][CH:36]([C:45](=[O:48])[CH2:46][F:47])[CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[O:34])[CH:30]([CH3:31])[CH3:32])=[O:27])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (0.13 mL, 1.9 mmol) was added to a methylene chloride solution of oxalyl chloride (0.29 mL, 2.0 M, 0.58 mmol in 4 mL of methylene chloride), and the resultant solution was stirred for 10 minutes under a nitrogen atmosphere at 78° C. A methylene chloride solution of N-[(1-phenylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (200 mg, 0.38 mmol in 2 mL of dry methylene chloride) was added dropwise and resulting mixture stirred for 15 minutes at −78° C. Triethylamine (0.30 mL, 2.1 mmol) was added dropwise to the mixture, and the resultant mixture was stirred for 10 minutes at −78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give a crude product. The crude product was triturated to yield the title product as a slightly yellow powder (181 mg). TLC (ethyl acetate/hexanes 1:1): Rf=0.43.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH2:10])=[NH:9])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1.C([O-])(=O)C.[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:10][C:21]3[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]=3[CH:14]([C:13]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=3[Cl:11])[N:9]=2)[CH:3]=1
Reactant: N=C(N)c1cccnc1
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCC2=C1C(c1ccc(F)cc1Cl)N=C(c1cccnc1)N2
Reaction time: 18 h
Yield: 27 %

Procedure:
3-pyridinecarboxamidine hydrochloride (Schaefer F. C., Peters G. A., et al. J. Org. Chem.; 1961; 26(2); 412-418.) 2.164 mmol, 2-chloro-4-fluorobenzaldehyde 2.164 mmol, 1,3-cyclohexanedione 2.164 mmol and sodium acetate 3.2 mmol were reacted in 8 ml of anhydrous ethanol under reflexing for 18 hr, condensed, to which ethyl acetate, water and 1N HCl were added and then the layers were separated. The water layer was adjusted with concentrated NaOH solution until the pH to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate and separated by column chromatography to obtain a yellow solid of 0.21 g (yield 27%); 1H-NMR (400 MHz, CDCl3) δ 2.13-2.17 (2H, m, CH2); 2.43-2.51 (2H, m, CH2); 2.63-2.83 (2H, m, CH2); 6.06 (1H, s, CH); 7.15-7.22 (2H, m, ArH); 7.34-7.38 (1H, m, ArH); 8.07-8.09 (1H, m, ArH); 8.70-8.71 (1H, m, ArH); 8.89 (1H, m, ArH). MS (HREI) 355.0887 (M+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 87.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.49 g, 0.84 mmol) prepared in Example 44a, triethylsilane (0.67 mL), trifluoroacetic acid (0.84 mL) and dichloromethane (8.4 mL), to yield the title compound (318 mg, 88%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.OS(O)(=O)=O.[NH3:17]>C(O)CCC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:17])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: N
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: CO
Product: NC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1 H), 7.54 (m, 2 H), 6.97 (d, J=12 Hz, 1 H), 6.00 (broad, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C@H:33]1CCCCN[C:34]1=O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:34][CH2:33][CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: N[C@H]1CCCCNC1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 300 mg, 0.677 mmol) in dichloromethane (3 mL) was added (S)-3-aminoazepan-2-one (prepared according to Example 4; 173 mg, 1.35 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 80% ethyl acetate/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (Ic) (290 mg, 94%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 9.11 (br, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 6.14 (br, 1H), 4.78 (ddd, 1H), 4.22 (d, 2H), 3.34 (m, 1H), 3.24 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.89 (m, 2H), 1.57 (m, 1H), 1.42 (m, 1H), 0.93 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-ditert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.021 ml) and pyridine (0.025 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (100 mg).
Reaction SMILES: CO[CH:3](OC)[CH2:4]OC.Cl.[CH3:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>>[CH2:28]([NH:17][C:16]1[C:11]([CH3:10])=[C:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)[CH2:29][CH2:4][CH3:3]
Reactant: Cc1c(N)cccc1-c1ccc(C(F)(F)F)cc1
Reactant: COCC(OC)OC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,1,2-trimethoxyethane (0.162 mL, 1.26 mL) was added to 0.5N HCl (2.52 mL, 1.26 mmol) and the resultant solution heated for 1 h at 50° C. The cooled reaction mixture was extracted with CH2Cl2. The organic solution was passed through a hydrophobic frit, dried for 2 h (3A molecular sieves). 2-Methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.32 g, 1.26 mmol) was added to the organic solution and the solution stirred for 20 min at rt. Sodium triacetoxyborohydride (0.325 g, 1.77 mmol) and acetic acid (0.072 mL, 1.26 mmol) were then added, and the resultant mixture stirred for 16 h at rt. Saturated sodium bicarbonate was added to the reaction mixture and once effervescence had ceased the mixture was extracted with CH2Cl2. The organic solution was passed through a hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (silica, 40 g) eluted with 10% EtOAc/cyclohexane afforded the title compound (42 mg).