Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:16]2[C:20]3[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=3[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]2[CH3:31])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[CH:24][C:19]=3[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:17]2[CH3:31])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Cl)ncc12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ncncc12
Yield: 75 %

Procedure:
A mixture of compound ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (75 mg, 0.16 mmol) and Pd/C (10 mg) in methanol (10 mL) was stirred under 50 psi of hydrogen at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give product ethyl 7-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, yield: 72%). LRMS (M+H+) m/z: calcd 450.2. found 451.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.O1CCOCC1>CO>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3[nH]ncc3c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc2[nH]ncc2cc1OC1CCCNC1
Reaction time: 3 h
Yield: 101.2 %

Procedure:
To a solution of the tert-butyl 3-(1H-indazol-5-yloxy)piperidine-1-carboxylate (150 mg, 0.473 mmol) obtained in Example 376 in methanol (2 ml) was added a 4N-hydrochloric acid-dioxane solution (1 ml) at room temperature. After 3 hours, the mixture thus obtained was concentrated under reduced pressure, and the resulting residue was dissolved in methanol. The resulting solution was adjusted to pH 8 to 9 with a 2M-aqueous sodium hydroxide solution and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/chloroform/methanol/(1%-aqueous ammonia)) to obtain 5-(piperidin-3-yloxy)-1H-indazole (104 mg, 65%).
Reaction SMILES: CCOCC.[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+:19]([O-])([OH:21])=[O:20]>O>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(C2CCCCC2)ccc1O
Temperature: 25 °C

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 10.0 g of 4-cyclohexylphenol, was added dropwise 12.6 ml of 60% nitric acid while cooling with ice. The temperature of the mixture was raised to room temperature and the reaction was carried out for a day. After 500 ml of water was added, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 6.92 g of 4-cyclohexyl-2-nitrophenol.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(C=O)cc3OC)c(C)s2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(CO)cc3OC)c(C)s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of ethyl 1-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (1.56 g) in tetrahydrofuran (30 mL)-ethanol (5 mL) was gradually added sodium borohydride (70 mg) at 0° C. After stirring at 0° C. for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (1.48 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 84-85° C.
Reaction SMILES: ClC1C=CC=CC=1Cl.[N+:9]([C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[C:19]([OH:30])[CH:20]=[CH:21][C:22]=3[N+:27]([O-])=O)[C:17](=[O:31])[C:16]=2[C:15]([OH:32])=[CH:14][CH:13]=1)([O-:11])=[O:10].C1(C=CC=C(O)C=1O)O>CO>[NH2:27][C:22]1[C:23]2[C:24](=[O:26])[C:25]3[C:16](=[C:15]([OH:32])[CH:14]=[CH:13][C:12]=3[N+:9]([O-:11])=[O:10])[C:17](=[O:31])[C:18]=2[C:19]([OH:30])=[CH:20][CH:21]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Agent: Oc1cccc(O)c1O
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(O)c2c1C(=O)c1c([N+](=O)[O-])ccc(O)c1C2=O
Temperature: 150 °C

Procedure:
50 parts of o-dichlorobenzene, 8.25 parts of 1,8-dinitro-4,5-dihydroxyanthraquinone and 3.5 parts of pyrogallol are heated for 3 hours at 150° C while stirring. Then 3.5 parts of pyrogallol is introduced and the reaction mixture is heated for another 7 hours at 150° C. After the reaction mixture has been cooled to 60° C it is diluted with 120 parts of methanol and cooled to ambient temperature. The precipitated reduction product is suction filtered, washed with methanol and hot water and dried. 5.3 parts of 1-amino-8-nitro-4,5-dihydroxyanthraquinone is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.5 %

Procedure:
A stirred mixture of 5-chloro-thiophene-2-boronic acid (5.15 g, 0.0317 mol), 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (8.00 g, 0.0294 mol), and tetrakis(triphenylphosphine)palladium(0) (1.09 g, 0.00094 mol) in a two-phase mixture of toluene (62 mL) and 2.0 M aqueous sodium carbonate (31 mL, 0.062 mol) was heated at 70° C. for 20 hours and allowed to cool to room temperature. Additional 5-chloro-thiophene-2-boronic acid (0.369 g, 0.00227 mol) was added, and the mixture was reheated at 65° C. for 20 hours. The mixture was cooled to room temperature and filtered through Celite, eluting with dichloromethane. Filtrate and washings were combined, and the mixture was washed with 0.10 M aqueous sodium hydroxide (100 mL), 3% aqueous ammonium hydroxide (100 mL), water, and brine. The organics were dried (Na2SO4), and rotary evaporated to a solid. The residue was dissolved in chloroform. silica gel (101 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The residue was purified by chromatography on silica gel (1450 g, 230-400 mesh), eluting with hexanes-acetone (12:1, 16×1L; 9:1, 12×1L) to give 6.04 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid, methyl ester as a bright yellow solid; mp 117-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][C:21]([O:27][CH3:28])=[CH:22][CH:23]=2)[N:18]=1>O>[CH3:28][O:27][C:21]1[N:20]=[C:19]2[C:24]([CH:25]=[CH:26][C:17]([NH:16][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: CCOC(=O)Nc1cccc(C(=O)O)c1
Solvent: O
Product: CCOC(=O)Nc1cccc(C(=O)Nc2ccc3ccc(OC)nc3n2)c1
Yield: 58.7 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 3-ethoxycarbonylaminobenzoic acid (10 g), N,N'-carbonyldiimidazole (7.6 g) and 2-amino-7-methoxy-1,8-naphthyridine (5.95 g). The reaction mixture is then poured into water (1000 cc) and the precipitate formed is separated by filtration, washed with water (10 cc) and dried in the air. On recrystallization in ethyl acetate (100 cc) of the product thereby obtained, N-(7-methoxy-1,8-naphthyridin-2-yl)-3-ethoxycarbonylaminobenzamide (7.3 g), m.p. 120° C., is obtained.
Reaction SMILES: [C:1]1(C(N)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16](CC)CC)C.S(=O)(=O)=O>C(N(CC)CC)C>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:14]#[N:16]
Reactant: NC(=O)c1cccc2ccccc12
Reactant: CCN(CC)CC
Agent: O=S(=O)=O
Product: N#Cc1ccc2ccccc2c1
Temperature: 89 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A suspension of 10 mmol of naphthalenecarboxamide and 25 mmol of triethylamine-sulphur trioxide in 30 ml of triethylamine was stirred at 89° C. for 2 hours. The working up was effected as described under Example 1a). Yield: 91% of theory.
Reaction SMILES: [C:1]1([S:7]([CH2:9][CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:12]2=3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([S:7]([CH2:9][CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:12]2=3)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)c3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(CCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
tert-Butyl 6-[2-(phenylsulfinyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was dissolved in trifluoroacetic acid and stirred for 5 min. The reaction mixture was concentrated to dryness, and the residue was dissolved in 10% aqueous acetic acid. This aqueous solution was extracted with CH2Cl2 (3×). The aqueous layer was adjusted to pH 10 with NaOH, then extracted with EtOAc (3×). The combined EtOAc extracts was dried over MgSO4, filtered, and concentrated. The product was chromatographed (SiO2, 10% methanol in CH2Cl2) to give 6-[2-(phenylsulfinyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.116 g) in 70% yield as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.09-3.24, 3.28-3.44, 4.40, 4.62, 7.05, 7.13, 7.25, 7.43, 7.50-7.59; 13C NMR (75 MHz, CD3OD) δ 22.79, 24.84, 37.04, 46.77, 48.66, 56.93, 110.42, 112.81, 116.30, 118.82, 120.17, 120.93, 122.91, 125.18, 128.93, 130.72, 132.72, 136.17, 136.92, 143.37.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][OH:16]>>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Product: O=[N+]([O-])c1ccc(CCNCCO)cc1
Temperature: 150 °C

Procedure:
A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (86.9 mmoles) and 2-amino-ethanol (869 mmoles) is heated at 150° C. under microwave activation for 10 minutes. The reaction mixture is evaporated to dryness and the residue obtained is purified on silica gel (SiO2; gradient DCM/MeOH) to yield the title product, which is used directly in the next Step.
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc2c(ccn2COCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc2c(ccn2CO)c1
Yield: 46.5 %

Procedure:
The 1-benzyloxymethyl-1H-indole-5-carboxylic acid (380 mg) obtained in Intermediate Example 47 was suspended in ethanol (6.5 ml). 10% Palladium on carbon (190 mg) was added thereto and stirred for 47 hours at 60° C. in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (120 mg, Y.:48%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:51]([O-:53])=[O:52])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH:5]1[CH3:50].[Na+]>C(OCC)(=O)C.O1CCOCC1>[CH3:1][CH2:2][CH:3]([C:51]([OH:53])=[O:52])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH:5]1[CH3:50]
Reactant: CCC(C(=O)[O-])C1OC(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)C(C)CC1C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(C(=O)O)C1OC(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)C(C)CC1C
Yield: 71.8 %

Procedure:
20-Deoxynarasin sodium salt (200 mg) was dissolved in ethyl acetate (10 ml). This solution was washed with 0.1 N HCl (10 ml) and then twice with water (5 ml). The resulting organic layer was evaporated to dryness to give a residue which was redissolved in dioxane and lyophilized to give 139.6 mg of 20-deoxynarasin free acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11][CH2:10]2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[NH2:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:11][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)ccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 100 %

Procedure:
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)-amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 20 parts (100%) of 1-[3-{4-[(2-amino-4-chlorophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([O:11][C@@H:12]2[CH2:17][C@@H:16]([CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[O:15][C@@:14]([O:38]C)([C@@H:23]3[CH2:27][S:26][C:25](=[O:28])[N:24]3CC3C=CC(OC)=CC=3)[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C@@H:12]2[CH2:17][C@@H:16]([CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[O:15][C@@:14]([OH:38])([C@@H:23]3[CH2:27][S:26][C:25](=[O:28])[NH:24]3)[CH2:13]2)=[O:10])=[CH:40][CH:41]=1)(=[O:3])=[O:4]
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccc(S(C)(=O)=O)cc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccc(S(C)(=O)=O)cc2)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl 4-(methylsulfonyl)benzoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>ClCCl>[CH2:1]([O:4][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of allyl alcohol (2.27 g, 39.0 mmol) in dichloromethane (60 ml), triethylamine (6.27 ml, 4.55 mmol) was added, then succinic anhydride (3.00 g, 30.0 mmol) was slowly added; the mixture was stirred at rt overnight. Then the mixture was diluted in dichloromethane and washed with 5% solution of NaH2PO4 (2×80 mL). The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo, affording 3.90 g of desired product as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
188 (1 mole) g of 2-amino-4-chloro-5-nitrophenol and 79 g (1 mole) of pyridine were added to 500 ml of N-dimethylacetamide, followed by dropping 140 g (1 mole) of benzoyl chloride at about 5° C. in about 30 minutes and agitating for further 30 minutes. The resulting crystals were filtered and washed with 500 ml of methanol to obtain 260 g (yield 89%) of an isomer of exemplified compound [IV]-(1) (2-benzamido-4-chloro-5-nitrophenol). From the melting point of below 250° C. and an IR spectrum (νC=O, 1654 cm-1), this compound was found to be 2-benzamide compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[S:19]1[CH:23]=[C:22](B(O)O)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[S:19]1[CH:23]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1csc2ccccc12
Product: Cc1cc(Nc2cc3ccccc3c(-c3csc4ccccc34)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and benzo[b]thiophene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: CCNCC
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Solvent: ClCCl
Product: CCN(CC)CC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (2.3 g, 8.8 millimoles), prepared as described in Example 4a was dissolved in 100 ml CH2Cl2, to which solution was added diethylamine (6.5 g; 88.0 millimoles). The resulting solution was allowed to stir at room temperature for 18 hours after which the solvent was removed. The residue was extracted with diethyl ether. The ethereal solution was washed with three portions of H2O, with brine, and was dried over Na2So4, filtered and evaporated, thereby affording crude 7-chloro-4-(2-diethylaminoacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as a viscous oil. The crude material was reduced with LiAlH4 (0.55 g; 14.6 millimoles) in diethyl ether by the general procedure of Example 5. The dihydrochloride salt was prepared, thereby affording a 52% yield of the title compound; mp 113° C (dec).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[CH:7]=[N:8][CH:9]=1)[CH3:3].[Cl:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23](Cl)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:20][C:21]1[N:22]=[C:23]([NH:1][C@H:2]([C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[CH:7]=[N:8][CH:9]=2)[CH3:3])[CH:24]=[N:25][CH:26]=1
Reactant: Cc1cccc(C(=O)Nc2cncc([C@H](C)N)c2)c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)Nc2cncc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Temperature: 150 °C
Yield: 6 %

Procedure:
A mixture of N-{5-[(1S)-1-aminoethyl]pyridin-3-yl}-3-methylbenzamide (65 mg, 0.27 mmol), 2,6-dichloropyrazine (61 mg, 0.41 mmol) and potassium carbonate (76 mg, 0.54 mmol) in dioxane (2 mL) was heated in a microwave reactor at 150° C. for 1.5 hours. After this time the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give N-(5-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}pyridin-3-yl)-3-methylbenzamide (6 mg, 6%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:23]([C:25]#[N:26])[Na]>C(O)(=O)C.CCOC(C)=O>[CH2:20]1[O:21][C:16]2=[CH:15][C:14]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH2:26])=[O:23])=[CH:3][CH:4]=4)=[N:9][NH:10][C:11](=[O:22])[CH2:12][C:13]=3[CH:18]=[C:17]2[O:19]1
Reactant: N#CO[Na]
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (119 mg, 0.403 mmol) in acetic acid (2 mL) was added NaOCN (38 mg, 0.58 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, diluted with EtOAc (80 mL), washed with 2 N NaOH, water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography to afford the title compound as a yellow solid (40 mg, 0.12 mmol, 30%), mp: 238°-241° C. 1H NMR (DMSO-d6) 10.79 (s, 1H), 8.77 (s, 1H), 7.47 (d, J=8.7, 2H), 7.40 (d, J=8.7, 2H), 7.07 (s, 1H), 6.61 (s, 1H), 6.10 (s, 2H), 5.95 (s, 2H), 3.33 (s, 2H).