Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].CS(O[Na])=O>CN(C=O)C.O.CCOC(C)=O>[F:32][C:33]1[CH:41]=[CH:40][C:36]([CH:37]([O:39][C:2]2[N:7]=[C:6]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:3]=2)[CH3:38])=[CH:35][CH:34]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Agent: CS(=O)O[Na]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(OC(C)c4ccc(F)cc4)n3)cccc2s1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (465 mg, 1.0 mmol, Example 7(d)), 4-fluoro-α-methylbenzyl-alcohol (140 mg, 1 mmol, Aldrich), K2CO3 (207 mg, 1.5 mmol) and 85% MeSO2Na (30 mg, 0.25 mmol, Aldrich) in DMF (50 mL) was heated at 120° C. with stirring for 5 h. The reaction mixture was allowed to reach room temperature and was diluted with water (50 mL), and exacted with EtOAc (2×50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue purified by silica gel column chromatography (20% EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 569 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[NH2:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1>CO>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=4)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:33][CH:34]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c3CCCC4)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A slurry of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (1.66 g, 8.18 mmol) and 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) in 14 mL 2-BuOH was heated in a sealed pressure vessel to 110° C. The reaction became a thick mass that eventually became a stirring suspension over about 30 min. After 4 h, the reaction was cooled to ambient temperature, and the material was partitioned between 2N NaOH and EtOAc. The aqueous layer was extracted once with EtOAc. The organic layers were dried over anhyd. sodium sulfate, filtered, and concentrated to yield a brown solid. This solid was dissolved in MeOH/MC and adsorbed onto 10 g silica gel, dried, and purified by chromatography (0-100% EtOAc/DCM) to give 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine as an off-white solid. MS m/z=460 [M+H]+. Calc'd for C24H22ClN7O: 459.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[O:7][CH2:6]2.BrN1C(=[O:21])CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:9]=1[C:8]([OH:7])=[O:14])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C=O)c(C(=O)O)cc1OC
Yield: 59.4 %

Procedure:
A mixture of 5,6-dimethoxy-3H-isobenzofuran-1-one (10 g, 51.5 mmoles), obtained as described in example 1, under N2 in CCl4 (250 ml), N-bromo-succinimide (13.88 g, 77.25 mmoles) and benzoyl peroxide (320 mg, 1.23 mmoles) was kept under reflux for 2 hours, then cooled, filtered and washed with a 10% Na2SO3 solution (200 ml), then with water, anhydrified and brought to dryness. The residue was taken up with 5% HCl (100 ml) and kept under reflux for 4 hours, then the solution was cooled, basified with NaOH, washed with ethyl acetate and slowly re-acidified to give a precipitate which was filtered, washed with water, dried on P2O5 under vacuum to give 6.43 g of the title compound (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][N:27]([CH3:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([N:27]([CH3:26])[CH3:37])=[CH:36][CH:35]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (13.8 mg, 0.052 mmol) in CHCl3 (2 mL) was treated with Et3N (0.021 mL, 0.15 mmol), 4-(dimethylamino)benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was washed with 2 N aqueous NaOH solution (2 mL×2) and brine (2 mL), and dried by filtration through a PTFE membrane using CH2Cl2 (3 mL). Concentration afforded the desired material (compound No. 952) (24.9 mg, quant): The purity was determined by RPLC/MS (91%); ESI/MS m/e 415.0 (M++H, C22H27ClN4O2).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:39])[N:21]([CH3:38])[C@@H:22]([C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:38])[C@@H:22]([C:30](=[O:37])[NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:39]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 101.8 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl) carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.12 g, 1.97 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated solution of aqueous sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added until a clear solution was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethanelmethanol/25% aqueous ammonia 100:10:1 as eluent, to give 946 mg of (2R)-2-methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl) carbamoyl)ethyl)propionamide.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:11][C:12]1[C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:9][C:4]1[C:3]([F:10])=[C:2]([C:13]2[C:14]([C:15]#[N:16])=[CH:17][CH:18]=[CH:19][C:12]=2[F:11])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2c(F)cccc2C#N)OC1(C)C
Reactant: Nc1ccc(F)c(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Temperature: 50 °C
Yield: 67.3 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (0.6451 g, 3.10 mmol) and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.915 g, 3.70 mmol) and potassium fluoride (0.5953 g, 10.2 mmol) in tetrahydrofuran (8 ml) was degassed with nitrogen for 15 min before adding tris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 0.0621 mmol) and tri-tert-butylphosphine (1.24 ml of a 0.1 M solution in 1,4-dioxane, 0.124 mmol). The mixture was degassed for a further 5 min, then heated at 50° C. for 18 h under nitrogen. After cooling to ambient temperature, the mixture was partitioned between water (50 ml) and ethyl acetate (40 ml). The organic layer was washed with saturated aqueous NaCl (20 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, 30% EtOAc/isohexane) to afford 0.5180 g (67%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 3.70 (2H, br s), 6.84–6.92 (2H, m), 7.44 (1H, t, J 8.4), 7.53 (1H, td, J 8.2, 5.1), 7.61 (1H, d, J 7.3).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[CH3:33][C:34]1[CH:50]=[CH:49][C:37]([C:38]([NH:40][C:41]2[C:42]([C:46](O)=O)=[N:43][NH:44][CH:45]=2)=[O:39])=[CH:36][CH:35]=1.[CH3:51][C:52]1[CH:53]=[C:54]([NH2:60])[C:55]([NH2:59])=[CH:56][C:57]=1[CH3:58]>>[CH3:51][C:52]1[C:57]([CH3:58])=[CH:56][C:55]2[NH:59][C:46]([C:42]3[C:41]([NH:40][C:38](=[O:39])[C:37]4[CH:49]=[CH:50][C:34]([CH3:33])=[CH:35][CH:36]=4)=[CH:45][NH:44][N:43]=3)=[N:60][C:54]=2[CH:53]=1
Reactant: Cc1ccc(C(=O)Nc2c[nH]nc2C(=O)O)cc1
Reactant: Cc1cc(N)c(N)cc1C
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: Cc1ccc(C(=O)Nc2c[nH]nc2-c2nc3cc(C)c(C)cc3[nH]2)cc1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide, however using 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid and 4,5-dimethylbenzene-1,2-diamine to give N-[3-(5,6-dimethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide (32 mg) as a white solid. (LC/MS: Rt 3.42, [M+H]+ 346.26).
Reaction SMILES: C(C1C=C(F)C(N[C@@H](C(C)(C)C)CS(N)(=O)=O)=NC=1C1C2C(=NC=C(F)C=2)NC=1)#[N:2].[F:31][C:32]1[C:33]([NH:58][C@@H:59]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:60][S:61]([OH:64])(=[O:63])=[O:62])=C[C:35]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([F:47])[CH:45]=3)[N:40](S(C3C=CC(C)=CC=3)(=O)=O)[CH:39]=2)=[N:36][CH:37]=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[F:31][C:32]1[C:33]([NH:58][C@@H:59]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:60][S:61]([OH:64])(=[O:63])=[O:62])=[N:2][C:35]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([F:47])[CH:45]=3)[NH:40][CH:39]=2)=[N:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CS(N)(=O)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Sulfonic acid, 11, was synthesized in a manner similar to compound 30, using compound 57a: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4](C1C(=O)CCCC1=O)=[O:5].[Cl:22]C1C=C(S(C)(=O)=O)C=CC=1C(O)=O.S(Cl)(Cl)=O.C1(=O)CCCC(=O)C1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.N1C=NC=N1>[Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=C1CCCC(=O)C1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
2-(2-Chloro-4-methanesulphonylbenzoyl)-1,3-cyclohexanedione from the acid chloride. 2-Chloro-4-methanesulphonylbenzoyl chloride (5 g) was prepared by the reaction of 2-chloro-4-methanesulphonylbenzoic acid with thionyl chloride. The acid chloride was dissolved in acetonitrile (40 ml). A mixture of 1,3-cyclohexanedione (2.24 g), potassium carbonate (6.9 g) and acetonitrile (40 ml) was stirred at room temperature for 4 hours. To this solution was added the acid chloride solution over 10 min and allowed to stir 1 hour. 1,2,4-Triazole (0.07 g) was then added and the mixture allowed to stir 16 hours at room temperature. The solvent was removed and the residue was dissolved in water and acidified. The product was extracted into dichloromethane and the solvent was dried then evaporated to give the desired product in 83.6% yield.
Reaction SMILES: Br[C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(OC)=CC=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:2]2[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: COc1cccc(N)c1Br
Agent: COc1cccc2nc(S)sc12
Product: COc1cccc2nc(Cl)sc12
Temperature: 120 °C

Procedure:
The title compound was prepared from 2-bromo-3-methoxyaniline via 2-mercapto-7-methoxy-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 120° C. for 10 h.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(CCl)c1cccc(F)c1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound. ES-MS m/e (%): 517.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=1.C([O-])(=O)C.[Na+].[Br-:19].[K+].BrBr>CO>[Br:19][C:9]1[N:6]2[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:1])[F:13])=[N:4][C:5]2=[N:11][CH:10]=1
Reactant: [Br-]
Reactant: FC(F)(F)c1ccn2ccnc2n1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)c1ccn2c(Br)cnc2n1

Procedure:
7-Trifluoromethylimidazo[1,2-α]pyrimidine (20. g, 10.7 mmol) and sodium acetate (1.1 mg, 13.4 mmol) were dissolved in methanol (30 ml) which had been saturated with potassium bromide and this mixture was cooled to −10° C. before dropwise addition of bromine (1.86 mg, 11.7 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1M sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was treated with water (100 ml) and saturated sodium hydrogencarbonate solution (100 ml) and extracted with ethyl acetate (3×100 ml). The organics were combined then washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to give an off-white solid. This solid was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) to give 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.98 g) as a white solid: δH (400 MHz, CDCl3) 7.35 (1H, d, J 7), 8.02 (1H, s), 8.62 (1H, d, J 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:27][CH3:28])[C:23]([F:24])([F:25])[F:26])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A mixture of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (475 mg, 1.14 mmol), potassium carbonate (174 mg, 1.26 mmol) and methyl iodide (242 mg, 1.71 mmol) in N,N-dimethylformamide (3.0 mL) was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.2 mg, 0.114 mmol, 10%).
Reaction SMILES: Br[C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:2]=1[NH:21][CH:18]1[CH2:20][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: NC1CC1
Reactant: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-N-tert-butyl-3-nitrobenzamide (460 mg, 1.52 mmol) and cyclopropanamine (350 μL, 4.55 mmol) in THF (10 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAC:DCM (1:1) as eluent to give N-tert-butyl-2-(cyclopropylamino)-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 8.26 (1H, br), 8.09 (1H, dd, J=8.0, 4.0 Hz), 7.57 (1H, d, J=8.0 Hz), 6.72 (1H, t, J=8.0 Hz), 5.81 (1H, br), 2.98-2.92 (1H, m), 1.49 (9H, s), 0.82-0.76 (2H, m), 0.58-0.52 (2H, m); LC-MS (ESI) m/z 278.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1cccnc1
Product: COc1ccc2c(Nc3cccnc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-3-ylamine to give 6-Methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-3-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:26][C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Yield: 38.4 %

Procedure:
The product of Example 320C (400 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL) was reacted with tert-butyl bromoacetate (0.555 mL, 3.76 mmol), potassium carbonate (1.225 g, 3.76 mmol) and tetrabutylammonium iodide (catalytic) at 25° C. for overnight. The reaction mixture was diluted with water and adjusted to pH 7 with glacial acetic acid. The reaction was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with a gradient of 3:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to give the title compound (195 mg, 38%).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:4]1[CH2:3][CH2:2][N:6]2[C:5]=1[CH2:9][S:8][C:7]2=[O:10]
Reactant: O=C1N=C(NCCO)CS1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1SCC2=NCCN12
Temperature: 40 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)amino]-1,3-thiazol-2(5H)-one (641 mg) and triphenylphosphine (1570 mg) in THF (10 mL) was added 1.9M diisopropyl azodicarboxylate toluene solution (3.16 mL) at room temperature. The reaction mixture was stirred overnight at 40° C. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (260 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[C:4](OC)=[O:5].C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.C(OCC)(=O)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:22])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: CCc1ccc(C(=O)c2cc(Br)c(C(=O)OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-chloro-4-(4-ethylbenzoyl)benzoate (7.64 g, 20 mmol) in 2,2,2-trifluoroacetic acid (38 mL) was added to triethylsilane (5.88 mL, 40 mmol) under argon. After it was stirred for 10 min at room temperature, trifluoromethanesulfonic acid (0.1 mL) was added. The reaction temperature was raised from 26° C. to reflux. After stirring for 2 hours, TLC (petroleum ether:ethyl acetate=6:1, Rf=0.7) showed the reaction was complete. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed 2× with H2O, 2× with NaHCO3, and 2× with brine, dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as a white solid. Yield: 7.2 g (100%). 1H NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 7.10 (s, H), 7.07 (s, 1H), 4.05 (s, 2H), 3.92 (s, 3H), 2.63 (q, J=7.8 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H).