Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]2[O:9][C:8]([CH2:11][OH:12])([CH3:10])[CH2:7][C:6]=2[CH:13]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:12][CH2:11][C:8]2([CH3:10])[CH2:7][C:6]3[CH:13]=[C:2]([Cl:1])[CH:3]=[C:4]([O:14][CH3:15])[C:5]=3[O:9]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(Cl)cc2c1OC(C)(CO)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc2c1OC(C)(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 76.7 %

Procedure:
Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C18H19ClO5S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8]([C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:6]1[CH:7]=[C:3]([CH2:2][NH:12][C:11]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:8][CH3:9])[N:4]=[CH:5]1
Reactant: CCc1cccc(C)c1N
Reactant: ClCc1cscn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCc1cscn1
Temperature: 100 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
In 200 ml dry dimethylformamide was added 10.2 g 4-chloromethylthiazole, 10.26 g 2-ethyl-6-methylaniline and 10.54 g of potassium carbonate. The mixture was stirred at 100° C. for 3 days and filtered. The filtrate was stripped, dissolved in methylene chloride, washed with water, dried and stripped again. The crude product was chromatographed with methylene chloride through a 200-g silica-gel column to give 7 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Br[Mg][CH3:14].C(OCC)C.[Cl-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[N:4][C:3]=1[C:9]([OH:11])([CH3:14])[CH3:10]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ncc(O)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(3-Chloro-5-hydroxypyridin-2-yl)ethanone (0.075 g, 0.0068 mol) was dissolved in THF (2 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture under nitrogen keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture and was stirred at room temperature for further 3 hours. A saturated aqueous solution of sodium chloride was slowly added to the reaction mixture (10 mL) and then it was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a translucent solid (0.049 g, 4% yield):
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:20]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OCc1ccccc1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of 10.0 g (~36.9 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in a mixture of 700 ml of ethanol and 175 ml of 1M potassium dihydrogen phosphate buffer pH 7.4 was added 14 g (~81 mmol) of benzylbromide. Stirring was continued for 2 h at 25° C. The precipitate was filtered off and washed with ice-cold ethanol to give the title compound (9.9 g; 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:9].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([F:8])=[CH:4][N+:3]=1[O-:9]
Reactant: [O-][n+]1cc(F)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F

Procedure:
Prepared analogously to example 83b from 2-bromo-5-fluoropyridine 1-oxide, conc. sulphuric acid and conc. nitric acid
Reaction SMILES: P12P3P1P23.[OH-].[Na+:6].[PH2:7]([O-:9])=[O:8].[Na+].[P:11]([O-:14])([O-:13])[O-:12].[Na+].[Na+].[Na+].P.[H][H].P.[H][H]>O>[PH2:7]([O-:9])=[O:8].[Na+:6].[P:11](=[O:8])([OH:14])([OH:13])[OH:12]
Reactant: [O-]P([O-])[O-]
Reactant: [H][H]
Agent: O=[PH2][O-]
Agent: P
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)O

Procedure:
Sodium hypophosphite is prepared by reacting tetraphosphorus, P4, with an aqueous solution of sodium hydroxide. This reaction produces a solution of about 50 wt % sodium hypophosphite, about 25 wt % sodium phosphite, and about 25 wt % of a gaseous mixture of phosphine and hydrogen in a 1:1 molar ratio. (Other alkali metal or alkaline earth metal hypophosphites can be made in the same manner.) At the present time, the practice is to burn the phosphine-hydrogen mixture in air followed by scrubbing in water to produce phosphoric acid. However, the resulting phosphoric acid has about the same value as the P4 starting material, so no value is added by these additional steps.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(CBr)cc1
Yield: 33.2 %

Procedure:
Methyl p-tolylacetate (11 g) was dissolved in 250 ml of carbon tetrachloride, followed by addition of 11.7 g of N-bromosuccinimide and 0.15 g of benzoyl peroxide, and refluxed under heating for 2.5 hours. The reaction mixture obtained was cooled, followed by filtration and distillation of the solvent, which was then fractionated at 4 mmHg and 142 to 150 ° C. to produce methyl 4-bromomethylphenylacetate (5.3 g).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:8]3[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]=3[OH:23])[S:13][N:14]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc(C)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(F)cc3)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-Fluoro-phenyl)-4-hydroxy-7-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 360.1 (M−1).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[CH3:29]NC>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CNC
Product: CN(C)C(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
Compound 18 was prepared in a manner similar to that of compound 16 using dimethylamine instead of methylamine, MS 405.12 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[C:24]([NH:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: CC(C)(C)N
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
0.285 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-2-piperazinecarboxylic acid was dissolved in 10 ml of dry tetrahydrofuran and cooled to -15° C. while stirring. There was then added 0.09 g of N-ethylmorpholine followed immediately by 0.107 g of isobutyl chloroformate. The mixture was stirred for 5 minutes and then 0.2 g of tert.butylamine was added dropwise. Stirring was continued overnight, during which time the mixture was allowed to reach room temperature. The solvent was removed by evaporation and there was obtained a buff coloured oil which was partitioned between ethyl acetate and water. The organic phase was washed in sequence with 10% citric acid solution, sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.185 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide as a light brown oil; MS: m/e 420 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29](Cl)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[CH:24]([C:29]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:30])[CH2:23][CH2:22][C:21]2=[O:32]
Reactant: O=C1CCC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 108.3 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 1.0 g of 6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.97 g of the title compound, melting at 275°-278° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13](C)[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc2c3c(n4c2c1CCNCC4)CCC3
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 6-chloro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.33 g, 1.20 mmole) in dichloroethane (80 mL) was added 1-chloroethyl chloroformate (1.2 mL, 10.8 mmole) and the mixture refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (25 mL) and refluxed for another 3 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) provided 0.25 g of the title compound. 46 mg of this was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 188-190° C. MS (ESI) m/z 261 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)=[O:15])[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.CN(C(O[N:39]1N=NC2C=[CH:43][CH:44]=[CH:45][C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.ClCl>O1CCCC1.ClCCl.CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:15])[C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:39]4[CH2:40][CH2:45][CH2:44][CH2:43]4)=[O:22])=[C:18]([C:25]([F:26])([F:28])[F:27])[CH:17]=3)[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC[C@H](NC(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 11 %

Procedure:
Prepared analogously to Example 1g from 4-{N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethyl]aminocarbonyl}-2-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine and pyrrolidine in tetrahydrofuran. Yield: 11%; Rf value: 0.72 (silica gel: dichloromethane/methanol=9:1); C23H22ClF3N4O3 (494.899); mass spectrum: (M+H)+=495/497 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.I[CH2:15][CH3:16].[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:15][CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCI
Reactant: NC(=O)c1c(N)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A solution of 2-aminoindole-3-carboxamide (Reference compound 18-1, 0.40 g, 2.3 mmol) in anhydrous N,N-dimethylformamide (2 mL) and a solution of iodoethane (0.20 mL, 2.5 mmol) in anhydrous N,N-dimethylformamide (2 mL) were successively added to a suspension of sodium hydride (purity 60%, 0.10 g, 2.5 mmol) in anhydrous N,N-dimethylformamide (10 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water (30 mL), and the whole was extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.22 g) as a brown solid (yield 49%).
Reaction SMILES: CN.[Br:3][C:4]1[C:9](F)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[F:14].C[CH2:16][N:17](C(C)C)C(C)C>C1COCC1>[Br:3][C:4]1[C:5]([F:14])=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[CH2:16][NH2:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: CN
Solvent: C1CCOC1
Product: NCc1c([N+](=O)[O-])ccc(F)c1Br
Yield: 91.3 %

Procedure:
Methylamine (2M in THF, 19 mL, 38.1 mmol) was added to a solution of 2-bromo-1,3-difluoro-4-nitrobenzene (4.53 g, 19 mmol) and DIPEA (6.8 mL, 38.1 mmol) in THF (70 mL) and the resultant mixture stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by chromatography eluting with (SiO2 0-80% DCM in cyclohexane) to give title compound as an orange/yellow solid (4.32 g, 91%). LCMS (Method C): RT 3.46 min [M+H]+ 249.0, 251.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:33]([CH3:37])([CH3:38])[C:34](=[O:35])[N:36]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(NCc1ccccc1)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1c(C2=NC(=O)C(C)(C)N2Cc2ccccc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 13 was synthesized from 4a (250 mg, 0.66 mmol) and 5h (189 mg, 0.99 mmol) as a white solid (152 mg, 43%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H), 7.31 (d, 2H), 7.26 (m, 5H), 7.20 (dd, 1H), 7.04 (d, 2H), 7.01 (d, 1H), 5.29 (s, 2H), 2.45 (s, 3H), 1.31 (s, 6H); ESMS m/z: 537.1 (M+1).
Reaction SMILES: NC1C=CC2N=C([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)SC=2C=1.ClC1C2C(=CC(OC)=C(OC)C=2)N=CN=1.C(=O)([O-])O.[Na+]>C(O)CO.[Cl-].[Na+].O>[C:10]([NH2:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Agent: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: OCCO
Product: NC(=O)c1ccccc1

Procedure:
N-[6-6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 30 mg, 0.111 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111 mmol) in ethylene glycol (0.7 mL) to 100° C. for 2 h. Brine (25 mL) and saturated sodium hydrogencarbonate solution (25 mL) were added and the product was extracted with chloroform (3×40 mL). After drying out Na2SO4, the solvent was removed and the residue was purified by pTLC (petroleum ether:dichloromethane:methanol=12:14:3) to yield a yellow solid (19 mg, 41 μmol, 37%). LC/ESI-MS: m/z 458 [M+H]+; m/z=456 [M−H]−; Rt=2.88 min.
Reaction SMILES: C(OC(Cl)=O)C(C)C.[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=O)[CH:13]=[CH:14][C:15]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].CN1CCOCC1.C(N(C(C)C)C(C)C)C.Cl>C1COCC1.CCOC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[C:36](=[O:38])[CH2:35][CH2:34][C:33]2=[O:39])[CH:13]=[CH:14][C:15]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N2C(=O)CCC2=O)cc1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Iso-butylchloroformate (60 μL, 0.46 mmol) was added to a stirred solution of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (200 mg, 0.46 mmol) (disclosed in WO 01/05746) and 4-methylmorpholine (51 μL, 0.46 mmol) in THF (5.0 mL) at −15° C. After 5 min at 0° C. the reaction mixture was cooled to −15° C. and a solution of ethyl diisopropyl amine (65 μL, 0.46 mmol) in THF (5.0 mL) was added. The resulting reaction mixture was kept at 0° C. for 1 h. The reaction mixture was stirred for 16 h at RT and then poured into a mixture of 1 M HCl(aq) and EtOAc. The organic phase was washed with more HCl(aq)(×2). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/EtOAc 1:2 as the eluent to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([NH:11][C:12]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:13]([O:15]C)=[O:14])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([NH:11][C:12]([CH3:20])([CH:17]([CH3:18])[CH3:19])[C:13]([OH:15])=[O:14])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C(=O)NC(C)(C(=O)O)C(C)C)c1ccc(Cl)cc1
Yield: 75.9 %

Procedure:
0.7 g (2.24 mmol) of methyl 2-[2-(4-chlorophenyl)propanoylamino]-2,3-dimethylbutanoate was dissolved in 20 ml of dimethyl sulfoxide. To the solution was dropwise added, at room temperature with stirring, 5 ml (2.87 mmol) of a 23% sodium hydroxide aqueous solution, and a reaction was allowed to take place at room temperature for 1 hour. Part of the reaction mixture was taken by weighing, acidified (pH=2) with diluted hydrochloric acid, and subjected to extraction with ethyl acetate, after which the extract was analyzed by GC. It was confirmed that the total amount of the methyl 2-[2-(4-chlorophenyl)propanoylamino]-2,3-dimethylbutanoate was converted into 2-(4-chlorophenyl)-N-(1-hydroxycarbonyl-1,2-dimethylpropyl)propionamide. 100 ml of water was added and the mixture was allowed to have a pH of 2 with diluted hydrochloric acid. Extraction was made twice using 100 ml of ethyl acetate. The two organic layers were combined, washed with 50 ml of water, and washed with a saturated aqueous sodium chloride solution. The organic layer obtained was concentrated to obtain 0.5 g (1.7 mmol) (yield=75%) of 2-[2-(4-chlorophenyl)propanoylamino]-2,3-dimethylbutanoic acid.
Reaction SMILES: C1(C)CCC(C(C)C)C([Si]([S:31][Si](C2C(C(C)C)CCC(C)C2)(C2C(C(C)C)CCC(C)C2)C2C(C(C)C)CCC(C)C2)(C2C(C(C)C)CCC(C)C2)C2C(C(C)C)CCC(C)C2)C1.C[O-].[Na+].[CH3:67][N:68]([CH3:80])[CH2:69][CH2:70][O:71][C:72]1[CH:79]=[CH:78][CH:77]=[CH:76][C:73]=1[C:74]#[N:75]>CN1CCN(C)C1=O>[CH3:67][N:68]([CH3:80])[CH2:69][CH2:70][O:71][C:72]1[CH:79]=[CH:78][CH:77]=[CH:76][C:73]=1[C:74]([NH2:75])=[S:31]
Reactant: CN(C)CCOc1ccccc1C#N
Reactant: CC1CCC(C(C)C)C([Si](S[Si](C2CC(C)CCC2C(C)C)(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)(C2CC(C)CCC2C(C)C)C2CC(C)CCC2C(C)C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CN(C)CCOc1ccccc1C(N)=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of trimenthylsilyl sulfide (5 g) and sodium methoxide (1.5 g) was added drop by drop to a stirred solution of 2-(2-dimethylamino-ethoxy)-benzonitrile (2.66 g) in 1,3-dimethyl-2-imidazolidinone. The mixture was stirred at room temperature for 24 hours, then extracted with ethyl acetate and the organic layer was washed with water, dried over magnesium sulfate and evaporated. The crude product was used without further purification.