Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:7]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][C:5](=[S:15])[N:4]1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]=[C:39]=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>O1CCCC1>[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([O:1][N:2]=[C:3]2[C:7]([CH3:14])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:6][C:5](=[S:15])[N:4]2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NOC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxyimino-5-methyl-5-phenyl-3-phenylamino-thiazolidine-2-thione (0.19 g), triethylamine (0.06 g) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 ml) was stirred for 2 days at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform) to yield 4-(3,4-Dichlorophenylcarbamoyl)oxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (0.13 g) having a melting point of 95-96° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:29]([C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1)([CH3:31])[CH3:30]>>[CH:29]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)([CH3:31])[CH3:30]
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine from Example 111 (0.1 g) was reacted with 2-isopropyl-1H-benzo[d]imidazole via General Procedure C to produce 10.2 mg of 113 following reverse phase HPLC purification. MS (Q1) 528.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14](O)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 59.5 g of 3,4-dichlorophenylacetic acid in 500 ml of absolute ethanol is saturated with anhydrous hydrogen chloride and then heated at reflux for 2 hours. The mixture is concentrated under reduced pressure to 200 ml, diluted with 200 ml of water and neutralized with concentrated ammonium hydroxide. This aqueous mixture is extracted 3 times with chloroform. Concentration and decolorization of the chloroform extracts gives ethyl 3,4-dichlorophenylacetate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10](=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24](O)=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:20]=1[Cl:29].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:18][C:19]1[C:24]([O:15][C:14](=[O:16])[CH2:13][N:11]2[CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][C:10]2=[O:17])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:20]=1[Cl:29]
Reactant: O=C(O)CN1CC(c2ccc(Cl)cc2)CC1=O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CN1CC(c2ccc(Cl)cc2)CC1=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73.5 g (290 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid are suspended in 900 ml of tetrahydrofuran; 92.5 g (350 mmol) of pentachlorophenol are added and the whole is stirred at room temperature until a clear solution is obtained. The solution is cooled in an ice bath, 65.8 g (319 mmol) of dicyclohexylcarbodiimide dissolved in 180 ml of tetrahydrofuran are added dropwise thereto within a period of 30 minutes and the whole is stirred for a further 1 hour in the ice bath and for a further 16 hours at room temperature; the resulting dicyclohexylurea is filtered off and the filtrate is concentrated to dryness by evaporation under reduced pressure at 60° and recrystallised from 400 ml of ethyl acetate. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester having a melting point of 135°-136° is obtained. Additional product can be obtained by concentrating the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Br)c(O)c1C(=O)O
Temperature: 100 °C
Yield: 121.9 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett, 2007, 17, 2817, 5.41 g) and lithium hydroxide monohydrate (9.23 g) was suspended in dioxane (100 mL) and water (100 mL) and heated at 80° C. overnight. The temperature was then increased to 100° C. for 4 hours. Further lithium hydroxide monohydrate (4.61 g) was added and the reaction mixture was heated at 100° C. for a further 1 hour. After cooling, the mixture was concentrated in vacuo and the residue was acidified to pH3 with formic acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered and the filtrate was concentrated in vacuo to give 6-amino-3-bromo-2-hydroxybenzoic acid (6.22 g) as a black/grey solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(O)(O)=O>C(#N)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=1)=[N:3]2
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.0000 g, 4.424 mmol), 3-fluorophenylboronic acid (0.6808 g, 4.866 mmol), tetrakis(triphenylphosphine)-palladium (0.2556 g, 0.2212 mmol), and sodium carbonate anhydrous (2.344 g, 22.12 mmol) in acetonitrile-water (3:1) (0.04000 mL) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-2-(3-fluorophenyl)-quinoline-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.14 (1 H, s), 9.06 (1 H, d, J=0.8 Hz), 8.13-8.18 (1 H, m), 7.92-8.00 (2 H, m), 7.59-7.67 (2 H, m), 7.53-7.58 (1 H, m), 7.39-7.47 (1 H, m); LC-MS (ESI) m/z 286.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C([N:15](CC)[CH:16]([CH3:18])[CH3:17])(C)C.C1(N)CC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH:16]2[CH2:18][CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: NC1CC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To 10.0 g (53 mmol, 1.0 eq.) of 2,4-dichloro-5-nitropyrimidine in 40 mL of THF at −78° C. was added 22 mL (120 mmol, 2.2 eq.) of N,N-diisopropylethylamine and 3.7 mL (53 mmol, 1.0 eq.) of cyclopropylamine. The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature and stirred for an additional 1 h. The solvent was removed in vacuo to afford a yellow solid. The product was purified by flash chromatography (15% EtOAc/hexanes) to provide 8.8 g (8.1 mmol, 77%) of 2-chloro-N-cyclopropyl-5-nitropyrimidin-4-amine (I-1) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11]Br.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:11][C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To a solution of ethyl 1H-pyrrole-2-carboxylate (1.17 g) in carbon tetrachloride (40 ml), a solution of bromine (1.48 g) in carbon tetrachloride (80 ml) was added dropwise at −15° C., and the mixture was stirred for one hour. The mixture was warmed to a room temperature, and a 2-N sodium hydroxide aqueous solution (80 ml) was added thereto. The resulting mixture was subjected to extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:6) to give ethyl 4-bromo-1H-pyrrole-2-carboxylate (700 mg, 38%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:31])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.N>N1C=CC=CC=1>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][N:6]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:31]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.9 %

Procedure:
A solution of (2S,4S)-2-azidomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.18 g) and triphenylphosphine (3.75 g) in pyridine (15 ml) was stirred at ambient temperature for 1 hour. To a reaction mixture was added conc. ammonia water (1.2 ml) with stirring at ambient temperature and the mixture was allowed to stand overnight at the same temperature. The solution was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-aminomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.13 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N+:54]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])([O-:56])=[O:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[N+:54]([O-:56])=[O:55])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccccc1[N+](=O)[O-])O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with 2-nitro-benzenesulfonyl chloride to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-nitro-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (21 mg) was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 919.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][C:20](=O)[CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]([CH3:21])=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: COc1ccc2c(c1)nc(C)n2-c1ccccc1

Procedure:
Method A applied to 4-chloro-3-nitroanisol (84 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a pale yellow solid. mp 88-90° C. 1H NMR (DMSO) δ 2.61 (s, 3H), 3.88 (s, 3H), 7.07 (d, J=8.9Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.38 (br s, 1H), 7.65-7.73 (m, 5H); 13C NMR δ 12.5, 55.9, 97.7, 112.6, 114.7, 126.9, 127.8, 130.2, 130.3, 132.8, 133.1, 151.2, 157.6, 157.8. HRMS (FAB): cal. for C15H15N2O [M+H+]: 239.1184; found: 239.1180.
Reaction SMILES: BrN1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[CH2:11][CH2:10]1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[CH:11]=[CH:10]1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccc2occc2c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
N-bromosuccinimide (0.89 g, 5.0 mmol) was added to a solution of 2,3-dihydrobenzofuran-5-ylacetic acid (0.89 g, 5.0 mmol) and benzoyl peroxide (10 mg) in carbon tetrachloride (100 mL) and refluxed for 3 hours. The mixture was cooled to room temperature, filtered and concentrated. The product was recrystallized from ethyl acetate:hexane (2:1) to give a 0.39 g (44%) of white solid. 1H NMR (CD3OD) δ 7.62 (1H, d, J=2.4 Hz), 7.52 (1H, d, J=0.8 Hz), 7.46 (1H, d, J=8.4 Hz), 7.21 (1H, dd, J=1.6, 8.4 Hz), 6.74 (1H, d, J=3.2 Hz), 3.74 (2H, s).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=O)[C:6]([S:9][C:10](=[O:12])[CH3:11])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:16]([NH:19][CH:20]([C:26]([OH:28])=[O:27])[CH2:21]SC(=O)C)(=O)[CH3:17]>>[C:6]([O:28][C:26](=[O:27])[C@@H:20]1[CH2:21][CH2:17][CH2:16][N:19]1[C:13](=[O:15])[C@H:5]([C:6]([S:9][C:10](=[O:12])[CH3:11])([CH3:7])[CH3:8])[NH:4][C:1](=[O:3])[CH3:2])([CH3:8])([CH3:7])[CH3:5]
Reactant: CC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)=O
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Product: CC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)(C)SC(C)=O

Procedure:
By substituting N,S-diacetyl-penicillamine for the N,S-diacetyl-D,L-cysteine in the procedure of Example 53, N-acetyl-3-acetylthiovalyl-L-proline t-butyl ester is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH3:48])=[C:17]([C:21]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[NH2:35])=[C:30]4[C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([NH:37]C(=O)OCC5C=CC=CC=5)=[CH:27][C:28]=3[NH:29]4)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Br>C(Cl)Cl>[NH2:37][C:26]1[CH:27]=[C:28]2[C:23]([C:22]3[C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([N:9]5[CH2:8][C:7]6[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=6)[C:10]5=[O:14])[C:16]=4[CH3:48])=[CH:33][CH:32]=[C:31]([C:34]([NH2:35])=[O:36])[C:30]=3[NH:29]2)=[CH:24][CH:25]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NC(=O)OCc5ccccc5)ccc4c23)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: Br
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O

Procedure:
A solution of benzyl 5-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-8-carbamoyl-9H-carbazol-2-ylcarbamate (Example 51-4, 65 mg, 0.102 mmol) in hydrogen bromide (30-35% in acetic acid, 5 mL, 27.6 mmol) was stirred at rt for 1.5 h. The mixture was diluted with DCM and concentrated. The residue was dissolved in DCM containing a small amount of methanol and the solution was mixed with 1 M aqueous sodium hydroxide. The organic phase was separated, washed with water, dried and concentrated, and the residue was triturated with hexane. The residue was purified by column chromatography (eluting with a gradient from 97:2.7:0.3 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 7-amino-4-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide as a white solid (Example 54-3, 45 mg, 88%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 10.32 (1H, s), 7.89 (1H, d, J=8.35 Hz), 7.57 (1H, d, J=7.91 Hz), 7.49-7.55 (2H, m), 7.35-7.47 (3H, m), 7.04 (1H, d, J=7.47 Hz), 6.93 (1H, d, J=8.35 Hz), 6.74 (1H, d, J=1.76 Hz), 6.46 (1H, dd, J=8.57, 1.98 Hz), 4.79 (2H, d, J=2.20 Hz), 3.84 (2H, br. s.), 1.96 (3H, s), 1.40 (9H, s). Mass spectrum m/z 503.3 (M+H)+. Also obtained was 7-amino-6-bromo-4-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide as a white solid (Example 54-4, 5 mg, 8%). 1H NMR (400 MHz, chloroform-d) δ 10.34 (1H, s), 7.89 (1H, d, J=7.91 Hz), 7.53-7.59 (3H, m), 7.44-7.48 (2H, m), 7.35 (1H, dd, J=5.71, 3.08 Hz), 7.05-7.08 (2H, m), 6.84 (1H, s), 4.83 (2H, s), 4.22 (2H, br. s.), 1.95 (3H, s), 1.40 (9H, s). Mass spectrum m/z 581, 583 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1>CO>[Cl:14][C:15]1[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[S:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=3[CH:13]=2)[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CN1C(=O)CSc2ccc(N)cc21
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2c(c1)N(C)C(=O)CS2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A mixture of 1.3 g of 6-Amino-4-methyl-3-oxo-benzo[1,4]thiazine and 3.3 g of 2,4-Dichloro-5-methylpyrimidine in 100 mL methanol was stirred at RT overnight and was reduced in volume by rotary evaporation. The solution was filtered and the filtrate diluted with water and neutralized with sodium bicarbonate. The precipitate was collected by suction filtration washed with water and dried on the funnel to yield 660 mg 13% of the desired product 2-Chloro-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 8.06 (m, 2H), 7.62 (s, 1H), 7.37 (s, 1H), 3.51 (s, 2H), 2.16 (s, 3H) purity 97%; MS (m/e) 321 (MH+).
Reaction SMILES: Br[CH2:2][CH:3]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[K].[CH2:21]([O:23][C:24]([O:26][NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])=[O:25])[CH3:22]>CN(C)C=O>[CH2:30]([O:29][C:28]([N:27]([CH2:2][CH:3]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:32])[CH3:31]
Reactant: CCOP(=O)(CC(CBr)OC1CCCCO1)OCC
Reactant: CCOC(=O)NOC(=O)OCC
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.4 h
Yield: 36.7 %

Procedure:
To a solution of diethyl 3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (134.4 g.) in N,N-dimethylformamide (880 ml.) was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (88.45 g.) under ice-cooling, and the mixture was stirred at ambient temperature for half an hour, and then for additional 2.4 hours at 50° to 60° C. The solvent was distilled off under reduced pressure. The residue was dissolved in water (1300 ml.) and then extracted twice with ethyl acetate (1000 ml. and 800 ml.). The combined extracts were washed twice with a saturated aqueous sodium chloride solution (500 ml. and 300 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily residue (143.2 g.), which was subjected to column chromatography on silica gel (700 g.) and fractionated by elution with a mixture of chloroform and ethyl acetate (the ratio was gradually changed from 9:1 to 1:1 v/v respectively) and then ethyl acetate. The fractions containing an object compound were combined and evaporated to dryness under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (62.6 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cncc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ncc(Cl)cc1O
Temperature: 25 °C

Procedure:
5-Chloro-3-pyridinol (15.3 mmol) is dissolved in concentrated H2SO4 (15 ml). At 5° C. concentrated nitric acid (0.9 ml) is added. The reaction mixture is allowed to warm to room temperature over 6 days. The reaction solution is pored onto ice (50 ml) and diluted with water (200 ml). The precipitate is filtered, washed with water and dried at 40° C. in vacuo. 5-Chloro-2-nitro-pyridine-3-ol is obtained as yellow powder; mp. 97°; LC-MS (method B): 1.35 min, 175.1 (M+H+).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1>>[O:23]1[C:22]2[CH:21]=[CH:20][C:17]([CH2:18][O:1][NH2:2])=[CH:16][C:15]=2[O:14][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccc2c(c1)OCO2
Product: NOCc1ccc2c(c1)OCO2

Procedure:
Prepared by a similar procedure as described for preparation 15, starting from N-hydroxyphthalimide and 3,4-methylenedioxybenzyl chloride (Fluorochem). 13C-NMR (CDCl3) δ 147.5, 147.2, 131.0, 121.9, 108.7, 107.9, 100.8, 77.5.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:15]([F:18])([F:17])[F:16])=[N:8][N:9]2C(=O)C)=[CH:5][CH:4]=1.[OH-].[Na+]>Br>[F:18][C:15]([F:16])([F:17])[C:7]1[C:6]2[C:10](=[CH:11][C:3]([OH:2])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: COc1ccc2c(C(F)(F)F)nn(C(C)=O)c2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc2c(C(F)(F)F)n[nH]c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Hydrobromic acid (100 mL; manufactured by Wako Pure Chemical Industries, Ltd.) was added to 1-(6-methoxy-3-trifluoromethylindazol-1-yl)ethanone (2.5826 g) that can be produced by the method described in Reference Example 34 or the like, and the mixture was stirred overnight at 110° C. The reaction solution was cooled to 0° C., and then was neutralized with a 5 mol/L aqueous solution of sodium hydroxide to adjust the pH to about 7. The reaction solution was extracted once with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and thus the title compound (1.8583 g) was obtained.