Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1I>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1nccc(Cl)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nccc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 4-chloro-3-iodopyridin-2-amine (146 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (111 mg) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[O:31]1[CH:32]=[CH:33][C:29]([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:24]=2)=[O:28])=[CH:30]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)cc1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3 -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.19 min, MH+428. NMR: δH [2H6]-DMSO 10.38, (1H, s), 10.00, (1H, s), 9.19, (1H, s), 8.38, (2H, m), 7.83, (1H, s), 7.80, (1H, s), 7.76, (1H, s), 7.73-7.69, (3H, m), 7.32, (1H, s), 7.01, (1H, s), 6.96, (2H, d), 3.76, (3H, s), 2.34, (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.50 g) MS (Q1) 284 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10](O)[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17].[N:18]1[CH:23]=CC=C[CH:19]=1.S(Cl)(Cl)=O.CNC>C(#N)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10]([N:18]([CH3:23])[CH3:19])[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: c1ccncc1
Reactant: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Agent: CNC
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)c(=O)c(O)c(C(N(C)C)C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (618 mg, 2.3 mmol) was mixed with pyridine (276 μL, 3.4 mmol) in acetonitrile (10 mL) at room temperature. Thionyl chloride (249 μL, 3.41 mmol) was added dropwise. After being stirred at room temperature for 30 minutes, the reaction mixture was concentrated by rotary evaporation. The residue was dried under vacuum and then mixed with ethanol (20 mL) under ice-water bath. An ethanolic dimethylamine (5.6 M, 4.06 mL, 22.8 mmol) solution was added at about 5° C. and the mixture was stirred for 20 minutes. The reaction mixture was concentrated by rotary evaporation. The residue was mixed with water (10 mL) and the pH of the solution was adjusted to 5.5. The precipitated solid was collected by suction filtration, and washed with water, then triturated with ether/hexanes to give 3-chloro-6-[1-(dimethylamino)-2,2,2-trifluoroethyl]-5-hydroxy-1,2-dimethylpyridin-4(1H)-one (380 mg) as an off-white solid. Yield=56%; 1H NMR (CDCl3, 90 MHz) δ (ppm): 4.88 (q, J=8.6 Hz, 1H), 4.08 (s, 3H), 2.65-2.81 (m, 3H) and 2.39 (s, 6H); MS m/z 299 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:12]=1)[C:5]#[N:6].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:26][C:8]1[CH:7]=[C:4]([C:5]2[NH:29][N:28]=[N:27][N:6]=2)[CH:3]=[C:2]([Cl:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)c(Oc2ccc(O)c(C(=O)N3CCCCC3)c2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C(c1cc(Oc2c(Cl)cc(-c3nnn[nH]3)cc2Cl)ccc1O)N1CCCCC1

Procedure:
{5-[2,6-Dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-piperidin-1-yl-methanone was prepared from 3,5-dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-benzonitrile according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (2.0 equiv) and ammonium chloride (2.0 equiv) were used initially, and the reaction mixture was heated to reflux for 2 hours, after which additional sodium azide (2.0 equiv) was added, and the reaction was heated to reflux for 20 hours. After the reaction had been acidified and the crude product collected by filtration, then purified by preparative TLC (methanol:water:dichloromethane 20:3:77) to afford the title product of Example 3. MS (APCI+) Calc.: 433.0, Found: 434.1 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Cl:12])=[CH:8][CH:7]=1.O>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Cl:12])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(CCCl)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CCCl)ccc1O
Reaction time: 3.5 h
Yield: 55 %

Procedure:
A solution of concentrated nitric acid (1.8 ml) in acetic acid (4 ml) was added to a stirred solution of 4-hydroxyphenethyl chloride (4.5 g) in acetic acid (25 ml), keeping the temperature below 15°. The mixture was then stirred at 10° for 3.5 hours, poured into water, and extracted into ethyl acetate. The organic extract was washed with 5% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (50 g) using hexane plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless solid (3.2 g, 55%), m.p. 53°-55°.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)(=O)=O.[C-:36]#[N:37].[Na+]>CS(C)=O.C(Cl)Cl>[C:36]([CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)#[N:37]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (525 mg, 1.00 mmol, 1.00 equiv) in DMSO (20 mL) was added NaCN (294 mg, 6.00 mmol, 6.00 equiv) and the resulting solution was stirred for 2 h at 70° C. under nitrogen. After cooling, the mixture was diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield 380 mg (83%) of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:10]1[N:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ccc(Oc2ccc(Cl)nc2)cc1

Procedure:
A solution of 22 g of 3-(p-chlorophenoxy)pyridine N-oxide in 500 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed 30 minutes, cooled and concentrated at reduced pressure. The resulting oil is dissolved in 400 ml of dichloromethane, washed with 40 ml ice cold concentrated ammonium hydroxide and the dichloromethane solution is dried over anhydrous MgSO4. The mixture is filtered, concentrated under reduced pressure and distilled to yield the mixture of desired chlorinated pyridines; bp 103°-105° C./0.1 mm. The oil is dissolved in 100 ml of toluene and chromatographed over 400 g of silica gel in toluene to yield in the first eluate, 6-chloro-3-(p-chlorophenoxy)pyridine. Continued elution with toluene yields 2-chloro 3-(p-chlorophenoxy)pyridine. Finally, elution with toluene-methanol (50:50) yields 4-chloro-3-(p-chlorophenoxy)pyridine.
Reaction SMILES: C([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][C:11](Br)=[C:6]2[CH:5]=[C:4]1[C:13]([OH:15])=[O:14])C.[CH2:16]([N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[C:20]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][C:6]=23)[C:20]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:19]1)[CH3:17]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CCn1c(C(=O)O)cc2c(Br)ccnc21
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 6 with ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided title compound. ESMS [M+H]+: 378.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH2:63])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1>CN(C=O)C>[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH:63][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methoxycarbonyl)benzoic acid (18 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol), and diisopropylethylamine (39 mg) in DMF was stirred at RT for 5 min. A syn and anti mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (31.5 mg, 0.1 mmol) in DMF was added and stirred at RT. DMF was evaporated and the residue was purified by PTLC using 10% methanol in DCM as eluent to afford the syn and anti isomers of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate. ESI: m/z 478.2 [[M+1+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
4-(4-Methoxyphenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(4-methoxyphenoxy)phenyl]carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH3:7].C([Li])CCC.[S:23](Cl)([Cl:26])(=[O:25])=[O:24]>C1COCC1>[C:11]([O:10][C:8]([N:5]([CH2:6][CH3:7])[C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([S:23]([Cl:26])(=[O:25])=[O:24])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)c1cccc(S(=O)(=O)Cl)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
3-Bromo-N-tert-butoxycarbonyl-N-ethylaniline (3.0 mmol) was dissolved in freshly distilled THF (25 ml) under a N2 atmosphere. The solution was chilled to −78° C. and butyl lithium (1.8 ml, 2.0 M solution in cyclohexane, 3.6 mmol) was added. After 35 minutes, sulfuryl chloride (0.30 ml, 3.6 mmol) was added over ˜2 minutes. The reaction was stirred for 5 minutes at −78° C. then was allowed to warm to room temperature. After 30 minutes at room temperature the reaction was cooled to −78° C. and quenched with a saturated ammonium chloride solution. The THF was removed by evaporation and the resulting residue was and partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O and brine before being dried with Na2SO4. The solvent was removed in vacuo to give 900 mg of crude product. HPLC showed the material to be ˜80% pure and it was used as is. LC/MS (ES): 320.1 (M+1).
Reaction SMILES: [S:1]([CH2:5][CH2:6][N:7]=[C:8]=[S:9])([OH:4])(=[O:3])=[O:2].[Na:10].CO.[C:13]([N:16]([CH3:18])[NH2:17])(=[O:15])[CH3:14]>O>[C:13]([N:16]([CH3:18])[NH:17][C:8]([NH:7][CH2:6][CH2:5][S:1]([OH:4])(=[O:3])=[O:2])=[S:9])(=[O:15])[CH3:14].[Na:10]
Reactant: CC(=O)N(C)N
Reactant: O=S(=O)(O)CCN=C=S
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(=O)N(C)NC(=S)NCCS(=O)(=O)O
Yield: 66 %

Procedure:
175.3 g of sodium sulfoethylisothiocyanate was added to a solution obtained by adding 600 ml of methyl alcohol and 300 ml of water to 114.2 g of 1-acetyl-1-methylhydrazine. The system was then heated under reflux for 4 hours. After the reaction, the reaction solution was dried under reduced pressure. The resulting solid matter was then recrystallized from 1 l of methyl alcohol to obtain 169.4 g (yield: 66.0%) of the desired compound. m.p. 255°-256° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH2:35]>C1COCC1.CCOC(C)=O>[CH3:34][NH:35][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: CN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 65.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available methylamine (2 M in THF, 2.05 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 65%) as a white solid. MS (ISP) 484.2 [(M+H)+]; mp 176° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:23]([O:30][CH3:31])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-])=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:31][O:30][C:23](=[O:29])/[CH:24]=[CH:25]/[C:26]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[O:27]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCCN)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/C(=O)NCCCC[C@@H](C(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirring mixture of (S)-tert-butyl 6-amino-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (800 mg, 2.31 mmol), monomethyl fumarate (361 mg, 2.77 mmol), DIEA (1.1 mL, 6.93 mmol) in 10 mL acetonitrile was added HATU (1.14 g, 3.00 mmol) in one portion at 0° C. under an inert atmosphere of argon. The resulting reaction mixture was stirred at room temperature tor 2 h and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc (50 mL) and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S,E)-tert-butyl 6-(4-methoxy-4-oxobut-2-enamido)-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (900 mg, 85%).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[PH:10](=[O:13])([OH:12])[OH:11].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=O)[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]>C(O)C>[PH:10](=[O:11])([OH:13])[OH:12].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=[N:2][OH:3])[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]
Reactant: CCC(C)(CC)C(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NO
Agent: Cl
Agent: O=[PH](O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(C)(CC)C(=NO)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
Hydroxylamine hydrochloride (0.29 g), then pyridine (7.7 ml), was added under nitrogen to a stirred solution of diethyl 3-oxo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 42) in ethanol (20 ml). The mixture was stirred at room temperature for three hours, then evaporated under reduced pressure. The residue was treated with water, basified to pH 8 with 1M sodium hydroxide solution, and extracted with chloroform. The organic layers were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-oximino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.90 g, m.p. 190°-192° C.), probably as a single geometric isomer of unknown configuration. NMR (CDCl3): δ1.2(6H,t), 1.95-2.1(2H,m), 3.05(2H,m), 3.95(4H,m), 7.1-7.3(15H,m), 8.0(1H,s), 9.1(1H,br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[N:20]1([CH2:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([CH2:25][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH:27]=3)[N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: NC(=O)c1cc(Br)ccc1Nc1nc(Cl)ncc1Cl
Product: NC(=O)c1cc(Br)ccc1Nc1nc(Nc2cccc(CN3CCCC3)c2)ncc1Cl

Procedure:
5-Bromo-2-[(5-chloro-2-{[3-(1-pyrrolidinylmethyl)phenyl]amino}-4-pyrimidinyl)amino]benzamide was prepared by contacting 5-bromo-2-[(2,5-dichloro-4-pyrimidinyl)amino]benzamide (Intermediate 37) with 3-pyrrolidinylmethylaniline following a procedure substantially as described for the preparation of Example 1. Mass (M+H)+ 501, 503, 505
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:16][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])([C:12]([F:13])([F:14])[F:15])[C:8]([F:11])([F:10])[F:9])=[O:28]
Reactant: Cc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccccc1C)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 21 g (0.081 mol) of 2-tolylhexafluoro-2-propanol and 8.2 g (0.08 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 40 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.02 g of hydroquinone monomethyl ether. 19.6 g (73 percent of theory) of 2-tolylhexafluoro-2-propyl α-fluoroacrylate having a boiling point of 58° to 60° C. (under 0.27 mbar) were obtained.