Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18]([C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[O:20])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (80 mg, 0.276 mmol) was dissolved in N,N-dimethylformamide (1 mL) then added 4-chloroaniline (42 mg, 0.331 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (133 mg, 0.414 mmol), and N,N-diisopropylethylamine (56 mg, 0.552 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The remaining orange oil was purified by silica gel chromatography (1% to 3% 7N ammonia in methanol/dichloromethane) to afford N-(4-chlorophenyl)-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (89 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:4](=[O:11])[CH:5]([CH3:10])[CH:6]([CH3:9])[CH2:7][CH:8]=1>[Cu-]=O.C(O)(C)C>[CH3:10][C:5]1[C:6]([CH3:9])=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[OH:11].[Cl:1][C:7]1[CH:8]=[C:3]([CH3:2])[C:4]([OH:11])=[C:5]([CH3:10])[C:6]=1[CH3:9]
Reactant: CC1=CCC(C)C(C)C1=O
Reactant: Cl
Agent: O=[Cu-]
Solvent: CC(C)O
Product: Cc1cc(Cl)c(C)c(C)c1O
Product: Cc1ccc(C)c(O)c1C
Temperature: 70 °C

Procedure:
55 g of hydrogen chloride were passed into 400 ml of isopropanol at room temperature, and 28 g (0.2 mole) of 2,5,6-trimethylcyclohex-2-en-1-one and 4 g (0.028 mole) of copper(I) oxide were added to the resulting solution. Thereafter, the reaction mixture was heated to 70° C., and 75 liters/hour of air were passed in for 3 hours, while stirring. Gas chromatographic analysis (2 m OV 17, 200° C.) then showed that 2,5,6-trimethylcyclohex-2-en-1-one was no longer present, and that 2,3,6-trimethylphenol as well as a little 4-chloro-2,3,6-trimethylphenol had beed formed. 243 ml of a 30% strength solution of sodium methylate in methanol were then run in at room temperature, and a sample of the reaction mixture, after water had been added to it, had a pH of 4.2. The mixture was then heated at 62° C., and 75 liters/hour of air, which had been fed in uninterrupted throughout the entire process, was passed into the mixture at 62° C. for a further 16 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1Br
Product: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.16 (d, J=1.2, 1H), 7.96 (dd, J=8.0, 0.9, 1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.72-7.64 (m, 1H), 7.44 (s, 1H), 7.37 (dd, J=7.6, 0.9, 1H), 7.34 (s, 1H), 7.27 (dd, J=6.4, 1.3, 1H), 7.24 (s, 1H), 1.31 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21].C1C(=O)N([Br:33])C(=O)C1>ClCCl>[CH3:25][O:24][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:10]=[C:9]([Br:33])[C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(OC)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(OC)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 2 L flask equipped with a mechanic stirrer were charged with methyl 1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 23 as obtained above and 500 mL of dichloromethane. To this flask was added NBS (30 g, 0.17 mole) portion-wise. The reaction was stirred at room temperature until its completion (monitored by TLC, ˜6 hours). The mixture was then diluted with dichloromethane and washed with NaHCO3 (ss). The organic phase was dried over Na2SO4 before evaporation of the solvents. The crude product was purified by column chromatography (silica gel, EtOH/DCM: 0-40%) to afford methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 as a light brown solid (50 g, 60% over three steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.7 (s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3 (s, 2H), 4.4 (s, 1H), 3.8 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calcd 426. obsd 426.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:39])[CH3:38]>>[Cl:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:38])[CH3:39])=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CC(C)NCCC(O)CCN
Reactant: NC(=O)c1c(OCc2c(F)cc(Cl)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CC(C)NCCC(O)CCNC(=O)Nc1snc(OCc2c(F)cc(Cl)cc2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H), 3.34 (1, 2H, J=6.4 Hz), 2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][O:7][C:8]2=[O:9])([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.O>C1(C(F)(F)F)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:8](=[O:9])[O:7]1
Reactant: O=C1OCc2c1cccc2[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Yield: 93.6 %

Procedure:
5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are refluxed in 80 ml of benzotrifluoride and heated by exposure to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.76 g, 30 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (7.11 g, 30 mmols), potassium carbonate (4.14 g, 30 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an yellow oil of tert-butyl[2-[3-(3-nitro-2-pyridyloxy)phenyl]ethyl]carbamate (10.1 g, 92.5%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a15) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][C:14]([OH:16])=[O:15].CCOCC.Cl>C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.CO>[C:14]([CH2:13][NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:16])=[O:15]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CNc1ccc(Cl)cc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
To a solution of 2-amino-5-chlorobenzoic acid (2.0 g, 11.6 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was added dropwise. After stirred for 20 hours at 80° C., the reaction mixture was cooled down to room temperature. 50 ml ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After concentration, a light brown solid was obtained. A white solid (2-(N-carboxymethylamino)-5-chlorobenzoic acid) (1.58 g, yield: 59%; mp: 182-183° C.) was obtained through silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(O)([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1.[O:24]1CCCC1>>[C:1]([O:8][CH:13]1[CH2:14][CH2:15][CH:10]([OH:16])[CH2:11][CH2:12]1)(=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(O)CCCCC1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OC1CCC(O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of benzoyl chloride (50 mL), cyclohexanediol (150 g), pyridine (105 mL) and tetrahydrofuran (1300 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, successively washed with saturated aqueous sodium hydrogen carbonate, water, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (81.5 g, 86%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].O>CC(N(C)C)=O>[CH2:12]([C:11]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: NC(=O)c1ccccc1N
Reactant: CCCCC=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Anthranilamide (300 mg, 2.20 mmol) was dissolved under argon in dimethylacetamide (5 ml), valeraldehyde (199 mg, 2.31 mmol) and Na2S2O5 (628 mg, 3.31 mmol) were added, and the mixture was stirred under reflux conditions for 4 h. After cooling to room temperature, water was added to the reaction mixture. By suction-filtering and thoroughly drying the solid formed, 2-butylquinazolin-4(3H)-one (254 mg, 54% of theory) was obtained as a colorless solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.26 (d, 1H), 7.74 (dd, 1H), 7.69 (d, 1H), 7.46 (dd, 1H), 7.30 (br. s, 1H, NH), 2.75 (t, 2H), 1.82 (quint, 2H), 1.49 (sext, 2H), 1.00 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[NH2:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([I:23])[C:14]([NH2:13])=[CH:15][C:16]=2[O:24][CH3:25])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(N)c(I)cc1C(=O)O
Product: COc1cc(N)c(I)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-amino-5-iodo-2-methoxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23]CC[CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:14][NH:13][CH3:18])[O:5][CH2:2][CH2:20][O:19][CH3:23]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Product: CNCCOC(=O)OCCOC
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., 2-methoxyethyl 2-(methylamino)ethyl carbonate hydrochloride (1.07 g) obtained in Reference Example 18 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.85 g), triethylamine (1.05 mL) and 4-dimethylaminopyridine (0.061 g) were added, and the mixture was stirred at 60° C. for 6 hrs. and at room temperature for 8 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate). Crystallization from ethyl acetate-diethyl ether and recrystallization from ethyl acetate-diisopropyl ether gave the title compound (1.39 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](=O)([O:34]C1C=CC=CC=1)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:18](=[CH:17][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:15][CH:14]=3)[N:19]([C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:20]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C=O)c1ccc2c3ccc(OCc4ccccc4)cc3n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (140 mg, 0.42 mmol) in 5 mL dry THF at 0° C. under Ar atmosphere was added NaH (50 mg, 60% in oil, 1.26 mmol) in 4 portions. The mixture was then stirred at rt for 20 min followed by the addition of tert-butyl phenyl carbonate (244 mg, 1.26 mmol) with a syringe. The reaction was allowed to stir at rt for 3 h and quenched onto ice (30 g). The mixture was extracted with EtOAc (2×40 mL) and the combined organic phase was dried over MgSO4. After solvent removal, the residue was chromatographed to afford tert-butyl 2-(benzyloxy)-7-(N-methylformamido)-9H-carbazole-9-carboxylate as a white solid (120 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.50-7.49 (m, 2H), 7.43-7.39 (m., 2H), 7.37-7.32 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 1.75 (s, 9H); MS (ESI) m/z 431 (M+H+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH3:16])([CH3:15])[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][CH2:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)CBr
Reaction time: 1 h
Yield: 97.3 %

Procedure:
98.8 g (0.62 mol) of bromine are added dropwise to 130 g (0.62 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-3-butanone in 1000 ml of chloroform at room temperature. The reaction mixture is subsequently stirred for 1 hour and is then concentrated. 174.7 g (97.3% of theory) of 4-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone of refractive index nD20 1.5570 are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH:14]=1)[NH2:20]
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Cl)n2n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Cl)n2n1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To a stirred solution of 3-chloro-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.25 g, 0.784 mmol) in ethanol (50 mL) and water (10 mL) containing AcOH (4.70 mmol) is added iron (0.218 g, 3.92 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.201 g, 89%) as a yellow solid: Rf 0.32 (EtOAc); LCMS (m/z)=289.4, 291.2 [M+H]+, tR=2.21 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:18])[S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[CH3:18][C:8]1[S:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)c(Nc2cccnc2)s1
Temperature: 55 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
A solution of 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.24 g, 0.90 mmol) in methanol (1.6 ml) was treated with a 2.55 N solution of KOH in water (1.06 ml). The mixture was stirred at 55° C. for 40 min then cooled to room temperature. The volatiles were evaporated and the residue dissolved in water (2.00 ml) and treated with HCl 1N under vigorous stirring until pH 5 was reached. The mixture was stirred for 1 h, then the solids were filtered, washed with water and dried under high vacuum to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.15 g, 70%) as a light yellow solid, MS (ISP): m/e=234.1 (M−H).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH:21]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1H-indole-6-carboxylate in DCM/H2O (2:1; 0.15 M), a stoichiometric excess of TFA was added dropwise and the solution was stirred at RT overnight. The volatiles were removed in vacuo, the residue taken up in Et2O, scratched and concentrated in vacuo again (2×) to drive off residual TFA. The crude was used in the next step without further purification; MS (ES+) m/z. 492 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:38])[C:22](=[O:37])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:24]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:38])[C:22](=[O:37])[C:23]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:24]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1O
Reaction time: 5 h

Procedure:
To a solution of N-[4-(2-benzyloxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide (200 mg, 370 μmol, example 258) in MeOH (2 mL) and EtOAc (2.00 mL) was added 10% palladium on charcoal (30 mg, 370 μmol) under argon atmosphere. The reaction was evacuated and purged with hydrogen gas. The reaction was stirred for 5 hours at 1.7 bar under H2 atmosphere. The reaction mixture was filtered over dicalite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (150 mg, 90%). MS (ESI): m/z=451.094 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH3:11][NH:12][CH3:13]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:12]([CH3:13])[CH3:11])=[O:9]
Reactant: CNC
Reactant: O=c1[nH]c2ccccc2o1
Product: CN(C)C(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (200 g) was stirred with 1 liter of a 33% solution of dimethylamine in industrial alcohol at 50° C. for 48 hours. The alcohol and unchanged dimethylamine were distilled off under reduced pressure at below 60° C. and the product was recrystallised from a 1:1 by volume mixture of isopropanol and light petroleum ether (b.pt. 60°-80° C.). It melted at 148° C. (decomp.) as measured on a Kofler bench.