Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:20]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:20]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Reactant: CC(C)(C)c1csc(N)n1
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Yield: 59.4 %

Procedure:
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:32]1[NH:33][CH:34]=[CH:35][CH:36]=1.[BH4-].[Na+].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>ClCCCl.CCOC(C)=O.CO.O>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:32]1[NH:33][C:34]([CH:1]([N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH3:2])=[CH:35][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)c2ccccc2)cc1-c1ccc[nH]1
Reactant: CC(=O)N1CCCCC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)c2ccccc2)cc1-c1ccc(C(C)N2CCCCC2)[nH]1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 1-acetylpiperidine (0.61 ml) under argon, was added phosphorus oxychloride (0.45 ml) at ambient temperature. After stirring for 0.5 h 1,2-dichloroethane (10 ml) was added and the mixture cooled to 0° C. A solution of 2-(2-methoxy-3-phenylsulphonylphenyl)-1H-pyrrole (D25) (1.0 g) in 1,2-dichloroethane (10 ml) was added dropwise over 0.3 h. Stirring was continued at 0° C. for 3 h and at ambient temperature for 18 h. The mixture was cooled to 0° C. and sodium borohydride (1 g) added portionwise over 0.16 h. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C. Water (5 ml) followed by MeOH (5 ml) was added dropwise followed by dilution with more water (50 ml). The mixture was extracted with dichloromethane (3×200 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo. Methanol (10 ml) and concentrated HCl (4.8 ml) were added and the mixture stirred for 4 h. Water (100ml) was added and the solution basified with NaOH (10%) and extracted with dichloromethane (3×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. This material was dissolved in EtOAc and added to a hot solution of oxalic acid (1 equivalent) in EtOAc. Sufficient MeOH was added to dissolve the precipitated solid and the resultant solution cooled to give the title compound (E38) (0.27 g).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:43])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][C:28]4[CH:32]=[N:33][N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:27]3=4)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:43])([CH3:1])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][C:28]4[CH:32]=[N:33][N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:27]3=4)=[CH:24][CH:25]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:13])=[O:14])[CH:11]=1
Reactant: C[Mg]Br
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (2 eq) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide (1 eq) in tetrahydrofuran (3 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[C:13]([O:18]CC4C=CC=CC=4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:18])[C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2ncc3c(O)cccc32)cc1
Temperature: -78 °C
Yield: 58.4 %

Procedure:
1-[4-(Methyloxy)phenyl]-4-[(phenylmethyl)oxy]-1H-indazole (D32) (40 mg, 0.121 mmol) was dissolved in dry DCM (1.5 mL) under argon and cooled to −78° C. in a dry ice-acetone bath. After 5 minutes BBr3 (1M in DCM, 0.242 mL, 0.242 mmol) was added dropwise and when the addition was complete the bath was removed and it was allowed to reach room temperature. The reaction was followed by LC-MS. After 4 hours more BBr3 (1M in DCM, 0.242 mL, 0.242 mmol) was added to the mixture and after 21 hours it was concentrated in vacuo. The residue was partitioned between EtOAc (25 mL)/water (25 mL), the pH adjusted to 7 by addition of a solution of NaHCO3 and the layers separated. The aqueous phase was extracted with EtOAc (2×25 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude material (28 mg) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 30 to 60% in hexane. The isolated material (28 mg) was further purified by MDAP to afford 16 mg of the title compound (E16).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[N+]=[N-])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.BrN1C(=O)CCC1=O.[N-]=[N+]=[N-].[Na+].[CH3:40][N:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1>>[CH3:40][N:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[CH:42]1
Reactant: Cn1ccc2ccccc21
Reactant: [N-]=[N+]=NCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1CCC(=O)N1Br
Agent: [N-]=[N+]=[N-]
Product: Cn1cc(NS(=O)(=O)c2ccc(CN=[N+]=[N-])cc2)c2ccccc21
Temperature: 55 °C

Procedure:
A mixture of 4-azidomethylphenylsulfonyl azide (2.93 g, 12.3 mmol), prepared by reaction of p-toluenesulfonyl chloride with N-bromosuccinimide followed by sodium azide, and 1-methylindole was heated at 55° C. for 6 hours. Pure 1-methyl-3-[4-(azidomethyl)phenylsulfonylamino]indole was obtained by chromatography on silica gel (1:1 CH2Cl2 /hexanes, then CH2Cl2, then 1.5% methanol/CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N+:7]=1[O-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH3:26]>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:26][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: Cc1nnc(-c2ccccc2)c[n+]1[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-6-phenyl-[1,2,4]triazine-4-oxide (3 g, 16 mmol) in chloroform (80 ml) was added p-toluenesulfonyl chloride (3.05 g, 16 mmol) and the mixture stirred under nitrogen at room temperature for 30 min. To this mixture was added aqueous ammonia (48 ml of 12%) and ammonia in dioxane (160 ml of a 0.5 M solution) and stirred at room temperature for 72 h. The organic layer was separated from the aqueous which was extracted with dichloromethane (2×20 ml), the combined organic layers dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 20% EtOAc in hexanes) to afford the title compound (1.7 g). δH (400 MHz; d6-DMSO) 2.42 (3H, s), 6.50-7.40 (2H, vbs), 7.49-7.63 (5H, m). m/z (ES+) 187 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+].Cl>CO>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:15]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:17][CH2:16]1
Reactant: COc1ccccc1C=O
Reactant: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCC3
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C=C1CCc2c1oc1ccc(C(=O)O)cc1c2=O
Temperature: 45 °C
Reaction time: 7 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 273°-275° C. (1.6 g) was reacted with 2-methoxy-benzaldehyde (1 g) in methanol (60 ml) in the presence of sodium methylate (1.3 g) under stirring at 45° C. for 7 hours. After cooling, the reaction mixture was acidified with 37% HCl and the precipitate was filtered and washed with methanol and then with water until neutral. Crystallization from chloroform-ethanol gave 1.2 g of 3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 291°-295° C., NMR (CH3COOD) δppm: 3.36 (bs) (4H, C-1 and C-2 protons), 4.09 (s) (3H, --OCH3), 7.09-7.87 (m) (4H, phenyl protons), 8.07 (d) (1H, C-5 proton), 8.41 (bs) (1H, =CH--), 8.76 (dd) (1H, C-6 proton), 9.28 (d) (1H, C-8 proton).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:4]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:21][CH:22]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1

Procedure:
3-Chloro-4-phenyl-1H-pyrrole-2,5-dione (1.55 g, 7.47 mmol) was dissolved in DMF (25 mL) under nitrogen atmosphere and cooled in an ice-bath. tert-Butyl [5-(bromomethyl)pyridin-2-yl]carbamate (2.14 g, 7.46 mmol) was added followed by anhydrous potassium carbonate (1.03 g, 7.47 mmol)and the mixture was stirred for one and a half hours whereafter the cooling-bath was removed. The mixture was stirred for another two hours and then neutralized with 1% HCl. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The extracts were combined, washed with water (100 mL×2), dried with magnesium sulphate, filtered and evaporated. The crude product (3.41 g) was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J=2 Hz, 1H), 7.92-7.89 (m, 3H), 7.83 (bs, 1H), 7.72 (dd, J=9, 2 Hz, 1H), 7.49-7.47 (m, 3H), 4.71 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>CO>[C:1]([N:4]1[C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[CH2:7][N:8]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14]1)(=[O:3])[CH3:2]
Reactant: C=C(C(=O)OC)N(Cc1ccccc1NC(C)=O)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-[(2-acetylamino-benzyl)-(4-methoxybenzenesulfonyl)amino]acrylate (8.40 g, 20.07 mmol) in anhydrous methanol (5 ml) was added anhydrous sodium bicarbonate (2.19 g, 26.09 mmol) and the mixture was stirred at room temperature overnight. Anhydrous sodium bicarbonate (2.2 g) was added and the mixture was stirred for 18 hours, heated to 50° C. for three hours and the solvent removed in vacuo. The residue was dissolved in water and ethyl acetate. The organic layer was separated, washed with saturated sodium chloride and dried with anhydrous sodium sulfate. The solvent was removed in vacuo and the residue dried in vacuo to give 6.64 g of white crystals, m.p. 150-155° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[CH:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1
Product: Nc1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.27) (0.286 g, 0.75 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.234 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.343 g, 97%). MS (ISP) 461.3 [(M+H)+]; mp 194-196° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC/C=C\CCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCC/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\CCCCCC

Procedure:
Compound VI-14 (244 mg, 60.8%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 112 mg, 0.577 mmol) and (Z)-octadec-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.44 mmol).
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: O=C1CCCCCN1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
A mixture of 678 g (6 mols) of caprolactam, 865 g (8 mols) of o-phenylene diamine and 60 g of p-toluene sulphonic acid is melted in a nitrogen atmosphere, 108 g of water distilling off over a period of 6 hours at an internal temperature of 200° to 250°C. The reaction mixture is then subjected to fractional distillation under reduced pressure, giving 1003 g (82.4 % of the theoretical) of 2-(5'-aminopentyl)- benzimidazole with boiling point of 210° to 215°C at 0.05 Torr, and a melting point of 101°C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C>[CH3:17][N:16]1[C:12]([NH:11][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:13][C:14]([CH3:18])=[N:15]1
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1cc(N)n(C)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Temperature: 0 °C
Yield: 44.7 %

Procedure:
A mixture of 2-iodobenzoic acid (14.9 g, 0.06 mol), 5-amino-1,3-dimethylpyrazole (6.7 g, 0.06 mol), DMF (125 ml), Cu(OAc)2 (0,4 g) and K2CO3 (8.28 g, 0.06 mol) was refluxed overnight. The reaction mixture was poured into ice-water (500 ml) and then was acidified with acetic acid to a pH of about 5. The solid which formed was collected by filtration, washed with water (100 ml) and dried. The solid was dissolved in hot CHCl3 (300 ml), filtered, dried over MgSO4 and evaporated to about 20 ml. Hexane (50 ml) was added and then the product was collected by filtration, washed with hexane (30 ml) and dried to afford 6.2 g of N-(1,3-dimethyl-pyrazol-5-yl)anthranilic acid, m.p. 210-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23]NC3C=CC=CC=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](Cl)=[O:38].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:2]3[CH:3]=[C:4]([NH:16][C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][N:33]([CH3:40])[CH3:32])[CH:5]=[CH:6][CH:7]=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Clc1cc(Nc2cc(NNc3ccccc3)ncn2)ccc1OCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
3-{[6-(3-chloro-4-(2-pyridyl) methoxyphenylamino)-pyrimidin-4-ylamino]phenylamine (IR-9) was dissolved in N-methylpyrrolidinone (1.2 mL) and added dropwise over 10 minutes to the ice-cold solution of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride in acetonitrile. The reaction was stirred in an ice bath for 2 hr. To the mixture was added sodium bicarbonate to pH greater than 9. The oil that formed was extracted with EtOAc (3×25 mL). A portion of the material was insoluble and set aside. The organic layer was dried (MgSO4) filtered and evaporated to a dark red oil. Both oils contained substantial amount of product as shown by TLC: SiO2CHCl3:MeOH/NH4OH (8:1) 19:1. The oils were combined and purified by flash column chromatography silica gel (25×300 mm) eluted first with 5% methanol/ammonium hydroxide 8/1 to remove non-polar impurities followed by 10% methanol/ammonium hydroxide 8/1 to elute 59 mg of product. The sample was further purified by a second flash column chromatography silica gel (25×250 mm) eluted with 10% methanol/ammonium hydroxide 8/1 to give the title compound (16.3 mg, 0.03 mmol, 6.4% yield). MS (ES+) 530 (M+): 552, (M+Na); 1H NMR (DMSO-d6, 500 MHz) δ (ppm): 10.04 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.88 (s, 2H), 7.57 (s, 1H), 7.36 (d, 1H, J=7.4 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.9 Hz), 7.18 (m, 2H), 6.74 (m, 1H), 6.30 (d, 1H, J=15 Hz) 6.10 (s, 1H), 5.24 (s, 2H), 3.06 (s, 2H), 2.18 (s, 6H) ppm; HPLC: tR=5.15 min, 97.5% (YMC-Pack ODS-A 4.6×100 mm, 80% water/20% acetonitrile to 5% water/95% acetonitrile over 5.5 min, hold to 9 min.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5])[CH3:2].Cl[CH:21]([O:23]C(Cl)Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:21]=[O:23])[CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A stirred, cooled (ice bath) solution of of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treated with titanium tetrachloride (0.4 mL, 3.26 mmol) followed by . . . ,-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowed to warm to ambient temperature over 2 days, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography to afford the title compound (0.11 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]([CH3:34])([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14][CH2:13][N:12]([S:15]([NH:18][CH2:19][CH2:20]C(OC(C)(C)C)=O)(=[O:17])=[O:16])[CH2:11][CH2:10]1)[CH3:8])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]([CH3:34])([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:10][CH2:11][N:12]([S:15]([NH:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:13][CH2:14]1)[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-N-{1-methyl-1-[1-((tert-butoxycarbony)ethylaminosulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (VI-2, 35 mg, 0.061 mmol) was dissolved in DCM (1.6 mL) and cooled in an ice bath. TFA (0.4 mL) was added dropwise and upon completion of the addition the reaction mixture was stirred in a nice bath for 0.5 h then allowed to warm to roomtemperature and stirred at room temperature for 12 h. The volatile components of the reaction mixture were removed in vacuo then saturated aqueous sodium hydrogen carbonate solution added dropwise. The mixture was extracted three times with EtOAc. The combined organic phase was dried (Na2SO4) and the solvent removed in vacuo to give 2,4-dichloro-N-{1-methyl-1-[1-(ethylaminosulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (VI-3). 1H NMR (CD3OD, 500 MHz), δ 8.62 (d, J=4.1 Hz, 1H), 7.93 (m, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.37 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.66 (s, 2H), 3.48 (m, 2H), 3.00 (q, J=7.0 Hz, 2H), 2.94 (m, 2H), 2.50 (m, 2H), 2.04 (m, 2H), 1.12 (t, J=7.0 Hz, 3H); MS 472 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:21][CH:22]1[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C.C(O)(=O)C>CS(C)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH:22]([OH:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: OC1CNC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC(O)C3)c(F)cc2c1=O

Procedure:
A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.77 g (7.9 mmoles) of 3-hydroxyazetidine hydrochloride, 2.15 g (21.3 mmoles) of triethylamine is heated to 160° C. in 10 ml of dimethyl sulphoxide for 6 hours. The mixture is cooled, diluted with water and acidified with acetic acid. After filtering and recrystallising from dimethylformamide 0.3 g (27%) of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 296°-8° C.