Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[OH:9]/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=1.[CH:28]([S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]([CH:47]=[CH2:48])[C:43]([NH2:46])=[N:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:30])[CH3:29].CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C.O>[NH2:46][C:43]1[C:42]([CH:47]2[O:9][N:10]=[C:11]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:16][CH:17]=3)[CH2:48]2)=[N:41][C:40]([C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH:28]([CH3:29])[CH3:30])(=[O:33])=[O:32])=[CH:39][CH:38]=2)=[CH:45][N:44]=1
Reactant: CN(Cc1ccc(/C=N/O)cc1)C(=O)OC(C)(C)C
Reactant: C=Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C3CC(c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)=NO3)n2)cc1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
NCS (75.43 mg, 0.5649 mmol) was added to a solution of tert-butyl N-[[4-[(E)-hydroxyiminomethyl]phenyl]methyl]-N-methyl-carbamate (129.4 mg, 0.4896 mmol) in DMF (571.5 μL) and the reaction mixture heated at 55° C. for 15 min. After the reaction mixture was allowed to cool to room temperature, 5-(4-isopropylsulfonylphenyl)-3-vinyl-pyrazin-2-amine (114.3 mg, 0.3766 mmol) was added followed by the dropwsie addition of Et3N (76.22 mg, 105.0 μL, 0.7532 mmol). The reaction mixture was stirred at rt for 45 mins followed by heating to 65° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic extracts washed with water (3×10 mL), dried over MgSO4, and concentrated in vacuo to a solid. The residue was purified by column chromatography on silica using with 0-100% Ethylacetate/petroleum ether as elaunt to yield tert-butyl 4-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl(methyl)carbamate. LC/MS m/z 510.1 [M+1-56]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH2:17][C:18]([NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[O:19]
Reactant: Nc1ccncc1F
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-pyridin-4-ylamine (0.2 g) in dry dichloromethane (2 mL) under nitrogen at 0° C. was treated with triethylamine (0.28 mL) followed by slow addition of chloroacetyl chloride (0.16 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane. The relevant fractions were combined and evaporated to give the title compound (0.11 g) as a pink solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:5]=1[CH:14]([CH3:17])[C:15]#[N:16].[CH3:18]N(C=O)C>>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:5]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]
Reactant: CN(C)C=O
Reactant: CC(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH 80% (0.0918 mole) was added portionwise at 0° C. under N2 flow to a solution of intermediate (1) (0.0612 mole) in DMF (100 ml). The mixture was stirred at 0° C. under N2 flow for 1 hour. CH3l (0.0918 mole) was added dropwise at 0° C. The mixture was stirred at 50° C. for 12 hours, then poured out on ice and extracted with EtOAc. The organic layer was separated, washed with H2O, dried, filtered and the solvent was evaporated, yielding 17.1 g of 2,6-dichloro-α,α-dimethyl-4-nitrobenzeneacetonitrile (intermediate 2).
Reaction SMILES: O[C@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.CS([Cl:37])(=O)=O.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:37][C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(N2CCC3(CCN(C[C@@H](Cl)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reaction time: 0.33 h

Procedure:
To a solution of 8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 7) (1.1 g, 2.5 mmol) and methanesulfonyl chloride (0.584 mL, 7.49 mmol) in DCM (30 mL) was added triethylamine (1.22 mL, 8.74 mmol) and N,N-dimethylpyridin-4-amine (0.031 g, 0.250 mmol) at −10 to −15° C. (ice-NaCl). The mixture was stirred at the same temperature for 20 min, quenched with NH4Cl aqueous. The organic layer was separated, and the aqueous was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product was used in the next step without further purification. LCMS: 459.05 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1C=CC(S(O)=O)=[CH:22][C:18]=1C(O)=O.C1(CN)CC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH2:13][CH:22]2[CH2:18][CH2:17]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: NCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Yield: 81 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and cyclopropylmethylamine and obtained in 81% yield. MS (m/e): 288.0 (MH−, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[C:22](=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][CH2:14][C:13]=2[CH:29]=1>C1COCC1>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][N:26]1[CH2:25][CH2:24][C:23](=[C:22]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][CH2:14][C:13]3[CH:29]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]2=3)[CH2:28][CH2:27]1)[CH3:6]
Reactant: CC(=O)OCCBr
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
2-Bromoethyl acetate (267 mg, 1.6 mmol) was added dropwise to a stirred solution of 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}piperidine (500 mg, 1.6 mmol) in THF (12 ml) and the reaction stirred at room temperature overnight. THF was removed under reduced pressure and the residue partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate, filtered and solvent removed to leave a white solid. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield ethyl-(4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)acetate as a white solid (214 mg, 34%)
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>>[C:15]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: CCCCCCCCCCCCCO
Reactant: O=C(O)c1cccnc1
Product: CCCCCCCCCCCCCOC(=O)c1cccnc1

Procedure:
Tridecyl nicotinate was prepared using the method of Example 1 from commercial tridecanol (an isomeric mixture) and nicotinic acid. The product had a boiling point of 136° to 140° C. under 0.05 mm pressure and an estimated purity of 100% based on a molecular weight of 305.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: BrCCOc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 1-bromo-4-(2-bromoethoxy)benzene (19.9 g, 100 mmol; see step (a) above) in THF (120 mL) was portion-wise added t-BuOK (14.0 g, 125 mmol) over 10 min at 0° C. After stirring at room temperature for 16 h, the mixture was diluted with water (400 mL) and the product was extracted with light petrol (4×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and distilled under vacuum to yield the sub-title compound (11.5 g, 58%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[S:37][C:16]2[NH:17][C:18]([C:20]([NH:22][C@@H:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]3[NH:32][C:33](=[O:36])[CH2:34]Cl)=[O:21])=[CH:19][C:15]=2[CH:14]=1.CCN(CC)CC>C1COCC1>[Cl:12][C:13]1[S:37][C:16]2[NH:17][C:18]([C:20]([NH:22][C@@H:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]3[NH:32][C:33](=[O:36])[CH2:34][N:8]([CH2:9][CH2:10][OH:11])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:21])=[CH:19][C:15]=2[CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CN(CCO)Cc1ccccc1)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
2-(Benzylamino)ethanol (160 mg, 1.06 mmol) was added to a solution of 2-chloro-N-{(1R,2R)-1-[(chloroacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 23; 216 mg, 0.53 mmol) and Et3N (500 μL, 3.60 mmol) in anhydrous THF (5 mL) and the reaction stirred for approximately 16 hours at room temperature then for a further 16 h at 50° C. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with H2O (2×10 mL) and dried (MgSO4). The solvent was removed under reduced pressure, the residue triturated (EtOAc:isohexane, 1:5), collected by filtration, washed with isohexane (10 mL) and dried to give the title compound (100 mg, 36%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Br:15])[C:9]([Br:14])=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[OH-].[Na+].I[CH2:19][CH3:20]>C(#N)C>[Br:1][C:2]1[N:6]([CH2:19][CH3:20])[C:5]2[CH:7]=[C:8]([Br:15])[C:9]([Br:14])=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)c(Br)cc2[nH]c(Br)nc12
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCn1c(Br)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2,5,6-tribromo-4-nitro-1H-1,3-benzodiazole (Method 2) (28 mmol, 10 g) was dissolved in acetonitrile (200 ml), and then NaOH (33.8 mmol, 1.35 g) was added. The resulting mixture was stirred at temperature for 0.5 h. Next 2-iodoethane (225 mmol, 35.16 g) was added, and the mixture was heated to 85° C. until the reaction was complete (20 h) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was taken up into ethyl acetate and washed with water. The organic extract was dried over MgSO4, filtered and concentrated. The product was purified on silica gel using EA/hex (1:1) to afford compound 2,5,6-tribromo-1-ethyl-4-nitro-1H-1,3-benzodiazole (mg). 1H NMR (600 MHz, DMSO) δ 8.58 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); m/z 427.8; rt 3.5 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](O)([CH3:11])[CH2:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[CH:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:14])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1C(C)=CCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
The pyrrolidine oil 82 (10.5 g, 32.11 mmol) was dissolved in pyridine (86 mL). POCl3 (7.48 mL, 80.27 mmol) was added dropwise and the resulting mixture stirred overnight at room temperature. The mixture was poured over ice, extracted with ether and washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The ether layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the crude solid 83 (8.80 g, 88%). 1H-NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 1.69 (m, 3H), 2.43 (s, 3H), 4.10 (m, 1H), 4.20 (q, 2H), 4.21 (m, 1H), 7.31 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.58, 14.10, 21.56, 54.64, 61.62, 70.55, 110.02, 122.51, 127.51, 129.73, 169.87 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 13.58, 14.10, 21.56; CH2 carbons: 54.64, 61.62; CH carbons: 70.55, 122.51, 127.51, 129.73 ppm. LC/MS: 100%, m/z=309.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[N:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[CH:7][CH:8]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(-c2cc[nH]n2)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
4-(1H-Pyrazol-3-yl)aniline (0.159 g, 1.003 mmol), triethylamine (0.101 g, 1.003 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.170 g, 1.003 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.180 g, 0.350 mmol, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[S:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[S:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([C:27]([NH:1][C:2]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=2[C:4]([OH:6])=[O:5])=[O:28])=[CH:26]1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=C(O)c1csc2ccccc12
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(O)c1ccc(Cl)cc1NC(=O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). Benzo[b]thiophene-3-carboxylic acid (21.4 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (2.9 mg, 95% purity). MS (EI) for C16H10ClNO3S: 332 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]([C@:8]1([OH:29])[C@@:12]2([CH3:28])[CH2:13][C@H:14](O)[C@@H:15]3[C@:25]4([CH3:26])[C:19](=[CH:20][C:21]([CH2:23][CH2:24]4)=[O:22])[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:7])=[O:3].CN(C)C=O.N1C=CC=CC=1.CS(Cl)(=O)=O>CO>[C:2]([O:4][CH2:5][C:6]([C@:8]1([OH:29])[C@:12]2([CH3:28])[CH:11]([CH:16]3[C:15](=[CH:14][CH2:13]2)[C@:25]2([CH3:26])[C:19](=[CH:20][C:21](=[O:22])[CH2:23][CH2:24]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)OCC(=O)[C@@]1(O)CCC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 25 °C

Procedure:
The title compound can be synthesized from hydrocortisone acetate according to the procedure disclosed in EP 0097328.405 g (1 mol) of hydrocortisone acetate is added to a mixture of 2 liters of N,N-dimethylformamide and 350 ml of pyridine, and with stirring at room temperature, 260 g of methanesulfonyl chloride is added. The reaction mixture is heated, maintained at 80 to 85° C. for 1 hour, and then cooled to room temperature. Methanol (7 liters) is added. The precipitated crystals are separated by filtration, washed with methanol and water, and dried under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:29])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[F:28])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:29])=[C:22]([F:28])[CH:23]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1F)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(Cl)cc1F)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-chloro-2-fluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:16])=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[O:17]1CCC[CH2:18]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:1]1[C:2]2[CH:15]=[C:6]3[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:5]3=[CH:4][C:3]=2[NH:16][C:18]1=[O:17]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2cc(O)c(N)cc2o1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc3oc(=O)[nH]c3cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 0.9 g (4.2 mmol) of ethyl 5-hydroxy-6-aminobenzofuran-2-carboxylate [Helv. Chim. Acta 77, 100. (1994)], 60 ml of tetrahydrofuran, 3.1 ml of 20% phosgene in toluene solution and 2.0 ml of triethylamine is stirred at room temperature for 1 h. The tetrahydrofuran is distilled off in vacuum, water is added to the residue and the product is extracted with ethyl acetate. The combined organic layers are washed with 5% aqueous sodium hydrogencarbonate solution, water, 1 N hydrochloric acid solution and again with water, dried over sodium sulfate and concentrated to yield 1.0 g (96%) of the title compound as oil.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=2)=[C:13]([CH3:26])[CH:12]=1)C1C=CC=CC=1.CC(C)=O.C(Cl)Cl>CO.C1COCC1.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH:24][CH3:25])[CH:23]=2)=[C:13]([CH3:26])[CH:12]=1
Reactant: CNc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2C)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNc1cc(Oc2ccc(N)cc2C)ncn1

Procedure:
The title compound is prepared from [3-methyl-4-(6-methylamino-pyrimidin-4-yloxy)-phenyl]-carbamic acid benzyl ester by hydrogenation in the presence of Pd/C in MeOH/THF: M+H=230.9; Rf (acetone/CH2Cl2=1:1): 0.20.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Cl:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(=O)[nH]c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc2ncccc12
Temperature: 120 °C
Yield: 67 %

Procedure:
To a solution of 4-methyl-1,8-naphthyridin-2(1H)-one (440 mg, 2.75 mmol) in toluene was added 302 uL of POCl3 (1.2 eq). The resulting mixture was refluxed at 120° C. for 3 hours. After cooling to room temperature the reaction mixture was quenched into ice-H2O and extracted with EtOAc (3×10 mL). The combined organic extracts was washed with H2O (2×15 mL), brine (1×20 mL), and then dried over MgSO4. Concentration and purification by MPLC gave the desired 2-chloro-4-methyl-1,8-naphthyridine (330 mg, 67%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.72 (s, 3 H) 7.35 (d, J=1.17 Hz, 1 H) 7.53 (dd, J=8.20, 4.40 Hz, 1 H) 8.36 (dd, J=8.35, 1.90 Hz, 1 H) 9.10 (dd, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)Oc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 48.7 %

Procedure:
By a method similar to Example 31, using 4-methoxybenzenesulfonyl chloride (248 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (230 mg, 1.0 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 225 mg of crude product. The crude product was recrystallized from ethyl acetate to give 195 mg (49%) of the title compound as a white powder: mp=186-187° C.; MS(m/e): 400 (M+); Calculated for C21H24N2O4S: Calcd: C, 62.98; H, 6.04; N, 6.99. Found: C, 63.10; H, 6.18; N, 7.04.