Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[CH3:35][C:36]1[S:40][CH:39]=[N:38][CH:37]=1>C1(C)C=CC=CC=1.CCOCC>[Br-:1].[C:10]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)[C:5]1[CH:4]=[C:3]([CH2:2][N+:38]2[CH:37]=[C:36]([CH3:35])[S:40][CH:39]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CBr)c2)cc1
Reactant: Cc1cncs1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A mixture of 3 g of N-[3-(bromomethyl)phenyl]-N-[[4-(tetradecyloxy)phenyl]methyl]acetamide and 2.24 g of 5-methylthiazole in 40 ml of toluene is refluxed for 4 hours, cooled and diluted with 60 ml of ether and allowed to stand at room temperature overnight. The solid is collected by centrifugation and washed three times with ether then vacuum dried to give 3.1 g of the desired product as a white powder, m.p. 130°-134° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1([C:26]#[N:27])[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([CH3:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1.C(OCC)(=O)C>ClCCl.CCCCCCC>[C:26]([C:6]1([NH:5][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([CH3:25])[CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)#[N:27]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(N)(C#N)CC2)cc1C
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
Acetyl chloride (0.106 g, 1.356 mmol) in dichloromethane (1 ml) was added to room temperature solution of N-(4-amino-4-cyanocyclohexyl)-4-ethoxy-3-methylbenzenesulfonamide (Intermediate 124, 0.366 g, 1.085 mmol) in dichloromethane (9 ml) and the reaction was stirred 18 hours. The reaction was diluted with dichloromethane and rinsed with two volumes of saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered, and concentrated to yield 464 mg of a crude film. TLC (50% ethyl acetate in heptane) indicated a major spot Rf=0.07 by UV. The crude product was chromatographed on Biotage 25S by TLC generated gradient to yield N-(1-cyano-4-(4-ethoxy-3-methylphenylsulfonamido)cyclohexyl)-acetamide (320 mg, 0.843 mmol) as a colorless solid. Carbon-13 NMR displayed a characteristic signature for nitrile at 119.1 ppm along with a signal at 110.7 ppm for the aromatic carbon ortho to aryl ether; in addition the peaks at 169.7 ppm and 160.97 ppm represent the amide and ipso-carbon of the aryl ether (no assignment implied). LCMS [M+H]=380.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[O:15])=[CH:9][C:8]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CC(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 62B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[C:1]1([C:7]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a stirred solution of (1-phenyl-cyclohexyl)-methanol (251) (43.0 g, 225.97 mmol) in dichloromethane (250.0 mL) was added Et3N (63.0 mL, 451.9 mmol), followed by drop-wise addition of mesyl chloride (21.0 mL, 271.16 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was then washed with water and brine and dried over sodium sulfate and concentrated under reduced pressure to get a crude product. It was purified by normal silica gel column chromatography (using 5% ethyl acetate in hexane) to get methanesulfonic acid 1-phenyl-cyclohexylmethyl ester (252) (49.3 g, 81.0%) as a white solid.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16])[CH3:13]>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ncc2scc(Br)c2n1
Product: CCOC(=O)c1ccc(-c2csc3cnc(Cl)nc23)cc1
Yield: 71.6 %

Procedure:
Ethyl 4-(2-chlorothieno[3,2-d]pyrimidin-7-yl)benzoate (185 mg, 72% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) and 4-(ethoxycarbonyl)phenylboronic acid (157 mg, 0.81 mmol).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:28])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1F
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general proedure in Sheme 5, beginning with 4-(2,6-difluoro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (d, 1H), 7.98 (d, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 7.31 (t, 2H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H); LC/MS m/z 514 (M−H)−, 516 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:12])[CH2:6]2.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:5]1[CH2:6][C:7]2[C:3]([CH:4]=1)=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([CH3:11])=[CH:9][CH:8]=2
Reactant: CC1=Cc2c(ccc(C)c2Br)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(ccc(C)c2-c2ccccc2)C1

Procedure:
4-Bromo-2,5-dimethylindene (9.0 g, 40 mmol), prepared as described under I.(b) above, and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 300 ml of diethyl ether (Et2O). Phenylmagnesium bromide, 3.0 M in Et2O, (13.5 ml, 40 mmol) was added under vigorous stirring and the reaction stirred overnight at reflux. The resultant reaction was slowly quenched with H2O to neutralize unreacted Grignard reagent, subsequently treated with 100 ml of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The resultant organic layer was dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield is 1.3 g (15%).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 10,11-dihydro-5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer) for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A. and B., 10,11-dihydro-5-(3-methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer) is obtained as a yellow oil. The product is converted to the hydrochloride that melts at 275.5°-276.5° C. (sintered, 274.5° C.) after recrystallization from methanol-ether mixtures.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.O[N:26]1C2C=CC=CC=2N=[N:27]1.[CH:35]([N:38]([CH2:42][CH3:43])[CH:39](C)C)(C)[CH3:36].Cl.CN(C)CCCN=C=NCC.CN1CCNCC1>CN(C=O)C.C1COCC1>[CH3:39][N:38]1[CH2:42][CH2:43][N:26]([NH:27][C:15](=[O:17])[CH2:14][O:13][C:7]2[N:6]=[C:5]3[S:4][C:3]([C:18](=[O:23])[NH:19][CH:20]4[CH2:22][CH2:21]4)=[C:2]([NH2:1])[C:10]3=[C:9]([CH3:11])[C:8]=2[Cl:12])[CH2:36][CH2:35]1
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)c(OCC(=O)NN2CCN(C)CC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.4 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.200 g, 0.562 mmol) in a 1:1 mixture of THF:DMF (1.5 ml each) are added 1-hydroxybenzotriazole hydrate (0.099 g, 0.731 mmol), N,N-diisopropylethylamine (0.109 g, 0.843 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.162 g, 0.843 mmol), and N-methylpiperazine (0.169 g, 1.69 mmol). The resulting solution is stirred at room temperature for 24 hours, then at 50° C. for 24 hours. The reaction is cooled to room temperature and quenched by the addition of water. The mixture is partitioned between water and EtOAc (40 ml each), and the layers are shaken and separated. The aqueous layer is acidified to pH 3 with 1 N HCl and then extracted with EtOAc (40 ml). The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (100% EtOAc) to give the title compound as a yellow solid (0.080 g, 33%). Mass (m/z): 438.2 (M++1), 436.2 (M+−1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[N:19]=[C:20]4[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[N:7][N:8]2[CH2:11][C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4nccn4C)c4cc(Cl)ccc34)nc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 106 %

Procedure:
2-(6-Chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (106 mg, 183 μmol) was dissolved in dichloroethane (10 mL). To this mixture was added trifluoroacetic acid (2.09 g, 1.41 mL, 18.3 mmol) and the mixture was heated to 80° C. After 15 h, the mixture was concentrated in vacuo. The residue was dissolved in 60:20:1 dichloromethane:methanol:ammonium hydroxide (10 mL). After 2 h the mixture was concentrated in vacuo, then purified by chromatography (silica, Analogix 40 g, 0-5% methanol in dichloromethane, over 15 min) to give 2-(6-chloro-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 194 μmol, 106%) as a yellow powder. MS (M+H)+=449; 1H NMR (CDCl3) δ: 11.90-12.06 (m, 1H), 8.97-9.07 (m, 1H), 8.27-8.35 (m, 1H), 8.11-8.17 (m, 1H), 7.95-8.05 (m, 1H), 7.72-7.82 (m, 1H), 7.05-7.13 (m, 1H), 6.94-7.03 (m, 1H), 6.81-6.92 (m, 1H), 5.69-5.83 (m, 2H), 4.17-4.38 (m, 1H), 3.72 (s, 3H), 1.24 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][C:35]1[CH:43]=[C:42]2[C:38]([CH2:39][CH2:40][CH:41]2[NH2:44])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:44][CH:41]2[C:42]3[C:38](=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:43]=3)[CH2:39][CH2:40]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(N)CC2
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(NC(=O)C1COCCN1c1nc(Cl)ncc1Br)CC2

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 500 mg, 1.550 mmol), EDC (446 mg, 2.325 mmol), HOBt (356 mg, 2.325 mmol), 6-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (464 mg, 2.325 mmol) and triethylamine (0.324 mL, 2.325 mmol) in DMF (10 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.94 (m, 1H), 2.30-2.47 (m, 1H), 2.62-2.93 (m, 2H), 3.48-3.65 (m, 2H), 3.70 (d, J=4.80 Hz, 3H), 3.87-3.96 (m, 1H), 4.24-4.43 (m, 2H), 4.89-5.01 (m, 1H), 5.26-5.41 (m, 1H), 6.70-6.82 (m, 2H), 7.08-7.18 (m, 1H), 8.45 (s, 2H). ESI-MS m/z [M+H]+ calc'd for C19H20BrClN4O3, 467.04. found 467.3.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].C[O:9][C:10]1[C:15]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[CH:18][CH:17]=2)=[N:14][N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:12](=[O:37])[CH:11]=1.O>CC#N>[OH:37][C:12]1[N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[N:14]=[C:15]([C:16]2[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=[CH:18][CH:17]=2)[C:10](=[O:9])[CH:11]=1
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1cc(O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Chlorotrimethylsilane (0.46 mL, 3.6 mmol) was added to a solution of sodium iodide (0.55 g, 0.73 mmol) in MeCN (20 mL) at room temperature. After stirring for 30 min, 5-methoxy-6-(1-phenyl-1H-pyrazol-5-yl)-2-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (0.30 g, 0.73 mmol) was added to the resulting suspension. The mixture was stirred at room temperature for 1 h, and then refluxed for 3 h. After cooling to room temperature, the mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with diisopropyl ether/hexane and recrystallized from AcOEt/hexane to give the title compound (0.21 g, 73% yield) as white crystals: mp 241-243° C.; NMR (300 MHz, DMSO-d6): δ ppm 6.16 (1H, s), 6.88 (1H, d, J=1.9 Hz), 7.36-7.42 (3H, m), 7.45-7.54 (4H, m), 7.59 (1H, t, J=7.9 Hz), 7.70 (1H, d, J=7.9 Hz), 7.82 (1H, d, J=1.9 Hz), 12.23 (1H, brs). LC-MS (ESI) m/z 399 [M+H]+. Anal. Calcd for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.35; H, 3.37; N, 14.10.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:15]([F:32])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH:33]O>C1COCC1.C[Re](=O)(=O)=O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]4[CH:31]=[CH:30][N+:29]([O-:33])=[CH:28][CH:27]=4)=[CH:23][CH:24]=3)[C:15]([F:32])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1cccc(Nc2ncc(F)c(Nc3ccc(Cc4ccncc4)cc3)n2)c1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(Nc2ncc(F)c(Nc3ccc(Cc4cc[n+]([O-])cc4)cc3)n2)c1
Reaction time: 24 h

Procedure:
A mixture of N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamine (50 mg) and methyltrioxorhenium (VII) (5 mg) in THF (15 mL) was treated with 30% aq. H2O2 (23 μL). After 24 h stirring, 30% aq. H2O2 (23 μL) was added and stirred for 24 h. The reaction mixture was filtered through Celite, washed the bed with methanol and concentrated. The residue was purified by HPLC yielded 10 mg of desired product. 1H NMR (DMSO d6, 300 MHz): δ 9.47 (s, 1H), 9.35 (s, 1H), 8.10 (m, 4H), 7.92 (m, 1H), 7.73 (d, 2H, J=8.4 Hz), 7.32-7.18 (m, 8H), 3.91 (s, 2H); LCMS (m/z): 467 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12]O)[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=O)OCCCl)([O-:3])=[O:2].[C:21](=O)([O-])[O-:22].[Na+].[Na+].[OH2:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:21][OH:22])[O:10][CH:11]([OH:27])[CH3:12])([O-:3])=[O:2]
Reactant: O=C(Nc1ccc(OCCO)cc1[N+](=O)[O-])OCCCl
Reactant: O=C([O-])[O-]
Reactant: O
Agent: [Na+]
Product: CC(O)Oc1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
0.1 mol (30.45 g) of β-chloroethyl 2-nitro-4-(β-hydroxyethoxy)-phenylcarbamate is introduced into 62 ml of water. 10 ml of 10N sodium carbonate solution are added gradually in the course of a few minutes, whilst stirring. The temperature rises to about 60° C. The temperature of the reaction medium is then raised to 70° C. and 22 ml of 10N sodium carbonate solution are then added, whilst stirring. Stirring is continued for 15 minutes at 70° C. After cooling, the desired product is filtered off; after washing with water, drying and recrystallisation from methanol, it melts at 82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[N:17][NH2:18])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[N:17][NH:18][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NN
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 2.0 g. (7.57 millimoles) of ethyl-9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 20 ml. of anhydrous chlorform 1.6 ml. (11.35 millimoles) of triethylamine and 1.3 ml. (11.35 millimoles) of benzoyl chloride are added. The mixture is heated to boiling for 2 hours, whereupon it is cooled to room temperature and thoroughly admixed with 20 ml. of water. The organic phase is separated and the aqueous layer is extracted with 10 ml. of chloroform. The united organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from methanol. Thus 1.5 g. (53.8%) of ethyl-9-(benzoyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are obtained. Mp.: 209°-210° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31](OC)=[O:32])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.[CH3:38][NH2:39]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]3[CH:37]=[CH:36][CH:35]=[C:30]([C:31](=[O:32])[NH:39][CH3:38])[CH:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CN
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(=O)OC)c3)cnc2c1
Product: CNC(=O)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCOC)ccn45)cccc32)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a vial was added methyl 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate (Example 93; 0.026 g, 0.0521 mmol) followed by methylamine (0.972 mL, 7.81 mmol, 33% in EtOH) and the mixture was sealed and heated to 50° C. with stirring for 8 hours. Additional methyl amine (0.972 mL, 7.81 mmol) was added and the mixture was stirred at 50° C. overnight. The mixture was cooled to ambient temperature and purified directly by preparative TLC (10% MeOH/CH2Cl2), providing 0.014 g (54%) of the product as a tan powder. MS (ES+APCI) m/z=499 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH:15]2[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]2[O:13][CH2:12]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH:15]3[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]3[O:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: NC1COC2C(OCCO)COC12
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCCOC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a suspension of 2,4,5-trichloropyrimidine (0.71 g, 3.88 mmol) in EtOH (20 mL) were added 2-((6-aminohexahydrofuro[3,2-b]furan-3-yl)oxy)ethanol (crude product) and N,N-diethylethanamine (1.10 mL, 7.89 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as brown liquid (0.21 g, 16%, for three steps).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.C([N:15](CC1C=CC(OC)=CC=1)C)C1C=CC(OC)=CC=1.[C:26]1([CH:32]=[CH:33]B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[NH2:15][CH:2](/[CH:33]=[CH:32]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:1]([OH:5])=[O:4]
Reactant: COc1ccc(CN(C)Cc2ccc(OC)cc2)cc1
Reactant: OB(O)C=Cc1ccccc1
Reactant: O=CC(=O)O
Solvent: Cc1ccccc1
Product: NC(/C=C/c1ccccc1)C(=O)O
Reaction time: 0.02 h
Yield: 202.2 %

Procedure:
To a stirred solution of glyoxylic acid (110 mg, 1.2 mmol) in toluene (12 mL) was added di-(p-anisyl)-methylamine (291 mg, 1.2 mmol) in one portion. After 1 min, 2-phenylethenyl boronic acid (177 mg, 1.2 mmol) was added and the reaction mixture was stirred vigorously for 12 hours. The precipitated product was isolated by filtration, washed with dichloromethane (15 mL), toluene (10 mL) and dried under vacuum to give the expected product (430 mg, 89% yield). 1H-NMR (360 MHz, CD3OH) d 6.8-7.5 (m, 13H), 6.60 (d, J=15.5 Hz, 1H), 6.25 (dd, J=15.5 Hz, 9.5 Hz, 1H), 5.49 (s, 1H), 4.00 (d, J=9.5 Hz, 1H), 3.75 (s, 6H), 2.3 (s, 1H).