Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C:25]([F:27])=[CH:26][C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1cc(C(=O)O)c(Cl)cc1F
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)cccc12
Yield: 8.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-5-(pivalamidomethyl)benzoic acid (Intermediate-63, 159 mg, 0.56 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (5 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.69-8.66 (d, J=7.2 Hz, 1H), 8.47 (s, 1H), 8.16-8.11 (m, 2H), 7.62-7.57 (m, 2H), 7.52-7.45 (m, 2H), 4.31-4.29 (d, J=5.7 Hz, 2H), 1.53 (s, 9H), 1.10 (s, 9H); MS [M+H]+: 486.45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:17][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCN1CCCC1
Yield: 0.1 %

Procedure:
Following preparation as described in PCT application WO 2002/101146, 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (59 mg, 0.25 mol) was stirred overnight in DMF (2 mL) containing with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (65 mg, 0.25 mol), EDC (96 mg, 0.50 mol), HOBT (77 mg, 0.50 mol) and NaHCO3 (116 mg, 1.37 mol). After dilution of the reaction with 40 mL of EtOAc, the organic layer was washed with H2O (10 mL×2) and brine. The organic layer was dried over Na2SO4, and cone, in vacuum to a brown oil. The oil was purified by flash column chromatography (silica gel, CH3OH in CH2Cl2, 0-10% gradient) to yield 109 mg (99%) of the title compound as a colorless oil. MS (ESI) 440 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH:1]1([CH2:4][C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Stir cyclopropaneacetic acid (30 g, 300 mmol) in dichloromethane (1 L) and treat with 1,1′-carbonyldiimidazole (52.5 g, 324 mmol) slowly. Stir for 2 hrs at room temperature and treat with N,O-dimethylhydroxylamine hydrochloride (30 g, 308 mmol), neat, in one portion; stir overnight. Pour mixture into water and extract twice with dichloromethane. Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate, filter, and evaporate to provide the title compound (38 g, 89%). 1H NMR (CDCl3) δ 3.66 (s, 3H), 3.18 (s, 3H), 2.35 (d, J=8.0 Hz, 2H), 1.08 (m, 1H), 0.54 (m, 2H), 0.16 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH:9]([C:44]([F:47])([F:46])[F:45])[CH2:10][C:11]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:12]=1[CH2:13][NH:14][C:15](=[O:38])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:37])[C@H:22]([NH:29]C(OC(C)(C)C)=O)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[NH2:29][C@H:22]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][CH2:13][C:12]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:11]=1[CH2:10][CH:9]([NH2:8])[C:44]([F:46])([F:47])[F:45])=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)(F)F)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)C1CCCCC1)C(F)(F)F

Procedure:
TFA (2.5 mL) was added to a stirred solution of N-[2-(2-amino-3,3,3-trifluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.282 g, 0.48 mmol) in CH2Cl2 (5 mL) and after 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a foam; MS m/z=489.6.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH:14](Cl)(Cl)Cl>O>[CH3:1][N:2]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1)[CH3:14]
Reactant: CNCc1nc(CSCCN)cs1
Reactant: ClC(Cl)Cl
Solvent: O
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: C[C@H:2]1[C@:19](O)([C:20](CO)=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:29])[CH2:6]3)[CH2:3]1.I(O)(=O)(=O)=[O:31]>CO.O>[F:29][C@@H:7]1[C:8]2[C@:14]([CH3:28])([CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C@:15]2([F:27])[C@H:5]([C@H:4]3[C@@:18]([CH2:17][C@@H:16]2[OH:26])([CH3:25])[C@@H:19]([C:20]([OH:21])=[O:31])[CH2:2][CH2:3]3)[CH2:6]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](C[C@H](F)C4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reaction time: 3 h

Procedure:
6α-Fluoro-dexamethasone (2 g) dissolved in methanol (100 ml) was treated with stirring overnight at room temperature with 1.5 g periodic acid in water (25 ml). The mixture was evaporated to small bulk in a rotary evaporator at 50° C. and refrigerated for 3 hours. The acid was collected by filtration and washed 3 times with small volumes of water.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[OH2:17].C(=O)([O-])[OH:19].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:15][CH:16]=1)(=[O:19])=[O:17]
Reactant: O
Reactant: O=C([O-])O
Reactant: CSc1ccc(OC2CCC(=O)CC2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(OC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 50 ml of methylene chloride was dissolved 2.50 g of 4-[4-(methylthio)phenoxy]-1-cyclohexanone. After adding 5.48 g of m-chloroperbenzic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into water, pH was adjusted to 8.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed successively with aqueous solution of sodium thiosulfate, water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Recrystallization of the residue from ethanol gave 2.05 g of 4-[4-(methylsulfonyl)phenoxy]-1-cyclohexanone as a colorless crystalline product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)c1

Procedure:
The title compound was prepared from 4-methyl-2-thiopheneboronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.00 (d, 1H), 7.25 (m, 3H), 7.10 (s, 1H), 6.95 (s, 1H), 6.94 (dd, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 2.39 (s, 3H), 2.18 (s, 3H); RP18-HPLC RT: 6.41 minutes; API MS: 376 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].N1C=CC=CC=1.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30]([C:37](=[O:53])[NH:38][C:39]1[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:42]=[C:41]([S:49]([OH:52])(=[O:51])=[O:50])[CH:40]=1)=[C:31]2[OH:36].CN(C)C(=O)C>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([S:15]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30]([C:37](=[O:53])[NH:38][C:39]2[CH:44]=[C:43]([S:45]([OH:48])(=[O:47])=[O:46])[CH:42]=[C:41]([S:49]([OH:52])(=[O:51])=[O:50])[CH:40]=2)=[C:31]3[OH:36])(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)([OH:2])=[O:4]
Reactant: Nc1cccc2c(O)c(C(=O)Nc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c3)ccc12
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Solvent: CCO
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(C(=O)O)cc(S(=O)(=O)Nc2cccc3c(O)c(C(=O)Nc4cc(S(=O)(=O)O)cc(S(=O)(=O)O)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.8 %

Procedure:
3,5-Dimethoxycarbonylbenzenesulfonyl chloride (1.9 grams) and 2 ml of pyridine were added to 2.7 grams of 5-amino-2-(3,5-disulfophenylcarbamoyl)-1-naphthol and 27 ml of N,N-dimethylacetamide. The mixture was stirred for 1 hour at room temperature and then 50 ml of ethyl alcohol were added, and the crystals which precipitated out were recovered by filtration. 30 ml of methyl alcohol, 2 grams of sodium hydroxide and 10 ml of water were added to the crystals and, after boiling under reflux for 1 hour, 5 grams of 5-(3,5-dicarboxyphenylsulfonamido)-2-(3,5-disulfophenylcarbamoyl)-1-naphthol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.55 mmol) (from Example 13, Step A, supra) and NH4Cl (0.24 g, 4.43 mmol) in a mixture of MeOH, H2O and CHCl3 (50 mL, 2:1:12) was added Zn powder (0.72 g, 11 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired N4-(4-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as a pale yellow gum. (Yield 0.16 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:30][CH:31]2[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[O:15])[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: CN1CCSc2c(C(=O)O)cc(Cl)cc21
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCSc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21

Procedure:
To a solution of 1.8 g of 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.05 g of triethylamine, and then added 0.891 g of pivaloyl chloride dropwise with stirring at -10° C. to -5° C. followed by stirring the mixture at the same temperature for 30 minutes. To the resultant mixture was added a solution of 1.12 g of 3-aminoquinuclidine in 15 ml of ethyl acetate at -10° to -5° C. and then stirred at room temperature for an hour. After the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated, the crystalline residue thus obtained was recrystallized from ethyl acetate to give 6-chloro-4-methyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzothiazine-8-carboxamide as yellow crystals. Melting point: 195°-196° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[C:54]([O:55][CH2:56][CH:57]([F:59])[F:58])=[CH:53][C:37]3[N:38]([CH3:52])[C:39]([NH:41][C:42]4[C:47]([Cl:48])=[CH:46][CH:45]=[C:44]([CH2:49][NH2:50])[C:43]=4[Cl:51])=[N:40][C:36]=3[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30].CCN(C(C)C)C(C)C.[F:69][C:70]([CH3:75])([CH3:74])[C:71](O)=[O:72]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[C:54]([O:55][CH2:56][CH:57]([F:58])[F:59])=[CH:53][C:37]3[N:38]([CH3:52])[C:39]([NH:41][C:42]4[C:47]([Cl:48])=[CH:46][CH:45]=[C:44]([CH2:49][NH:50][C:71](=[O:72])[C:70]([F:69])([CH3:75])[CH3:74])[C:43]=4[Cl:51])=[N:40][C:36]=3[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(F)C(=O)O
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Reaction time: 72 h

Procedure:
TBTU (1.0 mL of a 0.11 M solution in DMF) was added to a mixture of N-(3-chloro-4-fluoro-phenyl)-2-(2,6-dichloro-3-aminomethyl-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (1.0 mL of a 0.10 M solution in DMF), DIPEA (52 μl, 0.3 mmol) and 2-fluoro-2-methylpropionic acid (1.0 mL of a 0.13 M solution in DMF) and it was stirred for 3 d and the mixture was purified by prep. HPLC.
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:10][O:11][CH:20]([C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(CO)CO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC1COC(c2ccc(C#N)cc2)OC1
Yield: 72.9 %

Procedure:
In a 500-ml egg-plant type flask were put 32.3 g of 2-octyl-1,3-propanediol, 22.5 g of p-cyanobenzaldehyde, 0.11 g of p-toluenesulfonic acid monohydrate and 300 ml of benzene, and the mixture was heated. The generated water was removed by azeotropy with benzene. Then, benzene was distilled away, and the residue was neutralized with aqueous saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the extract was washed with water and then dried over anhydrous sodium sulfate. Dichloromethane was distilled away to give a solid which was then recrystallized from isooctane to give 37.7 g of colorless crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:5]1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2n1C
Reaction time: 23 h
Yield: 92.9 %

Procedure:
A 3-liter 3-necked roundbottom flask equipped with overhead stirring was charged with N,1-dimethyl-1H-indole-2-carboxamide (23.45 g, 124.58 mmole) and anhydrous THF (170 mL). The solution was stirred while a solution of LiAlH4 in THF (1.0 M, 250 mL, 250 mmole) was added via syringe. Gas was evolved during the addition of the first 50 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (9.5 mL), 15% NaOH (9.5 mL), and H2O (28.5 mL). The mixture was stirred for 15 min, then was filtered through Celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% conc. NH4OH). The title compound (20.17 g, 93%) was obtained as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 1 H), 7.02-7.35 (m, 3 H), 6.38 (s, 1 H), 3.88 (s, 2 H), 3.75 (s, 3 H), 2.49 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].C(I)C.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1([CH2:19][CH3:20])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCI
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 1-tert-butoxycarbonylisonipecotic acid ethyl ester (576 mg) in THF (15 ml) was added a solution of lithium diisopropyl-amide (290 mg) in THF (10 ml) in a stream of argon gas at −78° C., and the reaction mixture was stirred at the same temperature for 1 hour. Ethyl iodide (0.36 ml) was added to the above solution at −78° C., and the mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (585 mg, yield 92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:14](=[O:15])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: C1CCOC1
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (750 mg, 3.26 mmol; Example 1, Step H), TEA (1.4 mL, 9.78 mmol), and Ac2O (0.7 mL, 6.85 mmol) were placed in THF (15 mL) and stirred for 30 minutes. The reaction mixture was filtered, and the solid was dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (595 mg, 67% yield), which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[CH:15]=3)=[N:11][C:10]=2[CH:22]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:1](=[O:3])[CH3:2])=[C:16]([CH3:21])[CH:15]=3)=[N:11][C:10]=2[CH:22]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2nc3cc(F)ccc3s2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc3cc(F)ccc3s2)cc1C
Reaction time: 0.5 h

Procedure:
Acetyl Chloride (0.09g, 1.55 mmol) was added to a solution of 5-fluoro2-(4′-amino-3′-methylphenyl)benzothiazole (0.2 g, 0.78 mmol) in chloroform (5 ml) containing triethylamine (86 mg, 0.85 mmol). The resulting solution was stirred for 30 min, then poured into water (20 ml). The organic layer was removed, dried (Na2SO4) and evaporated. Recrystallisation from ethanol gave a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:25][CH2:26][CH2:27][OH:28].C(S(C1C=C(C2[C:47]3C4C=C(C)C=NC=4[NH:50][C:46]=3[C:45]([O:56]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[NH2:50][C@@H:46]([CH3:47])[C:45]([O:28][CH2:27][CH2:26][CH2:25][O:24][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=2)=[C:12]2[C:7]=1[NH:6][C:5]1[N:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]2=1)=[O:56]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCOC(=O)[C@H](C)N)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 225 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H) 8.12 (s, 1H) 8.08 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=7.84 Hz, 1H) 7.69 (s, 1H) 7.21 (d, J=8.32 Hz, 1H) 7.16 (d, J=8.32 Hz, 1H) 4.65 (m, 2H) 4.42 (t, J=6.08 Hz, 2H) 4.14 (q, J=7.32 Hz, 1H) 3.36 (q, J=7.6 Hz, 2H) 2.39 (m, 2H) 1.55 (d, J=7.32 Hz, 3H) 1.33 (t, J=7.6 Hz, 3H). [M+H] calc'd for C25H27ClN3O5S, 516; found, 516.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:21]1[CH2:26][CH2:25][N:24]([C:12]2[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:19])[F:20])[C:4]([F:7])([F:5])[F:6])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:23][CH2:22]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=[N+]([O-])c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2[N+](=O)[O-])CC1

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-fluoro-3-nitrophenyl)propan-2-ol and tert-butyl piperazine-1-carboxylate were used for a similar reaction and treatment as Example 6-b), and the title compound was obtained as a yellow oil.