Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[CH3:13][S:14][C:15](SC)=[C:16]([C:19]#[N:20])[C:17]#[N:18].O1CCOCC1.[H-].[Na+]>C(O)(=O)C>[C:17]([C:16]([C:19]#[N:20])=[C:15]([C:2]1[CH:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:6][N:1]=1)[S:14][CH3:13])#[N:18]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CSC(SC)=C(C#N)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccnc(C(SC)=C(C#N)C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a mixture of ethyl 4-pyridylacetate (46.7 g, 0.28 mol), 3,3-bis(methylthio)-2-cyanoacrylonitrile (47.6 g, 0.28 mol) and p-dioxane (300 ml) cooled in an ice bath was added 60% NaH (11.2 g, 0.28 mol) over 30 minutes. The mixture was slowly warmed to room temperature over 2 hours and was stirred at ambient temperature for 4 hours. The mixture was poured into ice-water, acidified with acetic acid and the resulting precipitate was collected by filtration and washed with water. The product was recrystallized from cyclohexane and dried at 70°-75° C. in high vacuum to afford 40.3 g (50%) of ethyl 2-(2,2-dicyano-1-methylthioethenyl)-4-pyridylacetate as orange crystals, m.p. 148°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)phenylamine (7.2 g, 30 mmol, Aldrich) and acetic anhydride (29 mL) was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo to give the title product as a white solid which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 484.0 (M+1).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:27][NH2:28]>C1COCC1.CCO>[CH3:27][NH:28][CH2:6][CH:7]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: CC1(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)CCCCC1
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propyl methanesulfonate in 16 mL of THF, and 10 mL of 33% wt. methylamine in EtOH was heated at 70° C. for 3 h. After cooling to rt, the reaction mixture was evaporated under reduced pressure. The crude benzyl 1-(methylamino)-3-(1-methylcyclohexyl)propan-2-ylcarbamate was used directly in the next step without further purification. MS ESI +ve m/z 319 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CCN(CC)CC.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: C1CSCCN1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSCC1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of thiomorpholine (2.00 mL, 20 mmol) and Et3N (5.0 mL) in CH2Cl2 (60 mL) was added drop wise a solution of 4-nitrobenzoyl chloride (3.71 g, 20 mmol) in CH2Cl2 (50 mL) at 0° C. The reaction was allowed to stir at room temperature for over night and then washed with a saturated NaHCO3 solution (2×75 mL), and water (2×75 mL). The CH2Cl2 layer was dried (Na2SO4) and filtered and concentrated. Finally dried under high vacuum to afford 5.027 g (99%) of the 4-(4-nitrobenzoyl)thiomorpholine. 1H NMR (CDCl3, 300 MHz): δ 8.28 (d, 2H, J=9.0 Hz), 7.54 (d, 2H, J=8.7 Hz), 4.04 (br s, 2H), 3.61 (br s, 2H), 2.75 (br s, 2H), 2.57 (br s, 2H); LCMS (m/z): 253 (MH+).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C:45]([O:47][CH3:48])=[O:46])[C:9]([O:43][CH3:44])=[C:10]([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:42])=[C:19]([CH:41]=2)[O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:22]=2)=[O:14])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]>ClCCl>[C:2]([C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:14])[C:15]2[CH:16]=[CH:17][C:18]([CH3:42])=[C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:22]=3)[CH:41]=2)[C:9]([O:43][CH3:44])=[C:8]([CH:7]=1)[C:45]([O:47][CH3:48])=[O:46])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1OC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCNCC4)c3)c2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 1.4 mL of a 5-6 M isopropanolic hydrochloric acid solution are added to a solution of 270 mg tert-butyl 4-{4-[5-(5-tert-butyl-2-methoxy-3-methoxycarbonyl-phenylcarbamoyl)-2-methyl-phenoxy]-pyridin-2-ylmethyl}-piperazine-1-carboxylate in 6 ml dichloromethane. The solution is stirred overnight at ambient temperature and then diluted with dichloromethane. The solution is washed with saturated aqueous NaHCO3 solution and the aqueous phase is extracted once with dichloromethane. The combined organic phases are dried (Na2SO4), and the solvent is removed completely.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:34](O)[CH2:35][OH:36]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[O:36][CH2:35][CH2:34][O:19]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: OCCO
Reactant: COc1cc(OC)cc(-c2cc(C=O)c([N+](=O)[O-])cc2F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(-c2cc(C3OCCO3)c([N+](=O)[O-])cc2F)c1
Temperature: 130 °C
Yield: 89 %

Procedure:
A mixture of 6-fluoro-3′,5′-dimethoxy-4-nitrobiphenyl-3-carbaldehyde (1.7 g, 5.6 mmol) and 4-toluenesulfonic acid (95.8 mg, 0.6 mmol) in 1,2-ethanediol (4.3 mL) and toluene (60 mL) was heated at 130° C. for 3 hours. After that, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed by water (100 mL*3) and brine (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1 to 5/1) to afford the title compound (1.8 g, 89%) as a yellow solid. MS (ES+) C17H16FNO6 requires: 349, found: 350 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1

Procedure:
Prepared in 37% from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the same procedure as (2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.99 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.30 (s, 1H), 7.24-7.19 (m, 1H), 7.17 (d, J=5.9 Hz, 2H), 5.90 (br. s., 1H), 4.61 (br. s., 1H), 3.83 (br. s., 1H), 3.64 (br. s., 1H), 3.52-3.29 (m, 2H), 3.17-3.08 (m, 1H), 2.68-2.60 (m, 1H), 2.40 (s, 3H), 1.93-1.46 (m, 10H), 1.19 (s, 3H), 1.17 (s, 9H), 1.07 (d, J=6.2 Hz, 3H); LCMS (ESI, M+1): 644.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[C:13]1=[O:22].S(Cl)([Cl:26])(=O)=O>ClC(Cl)=C(Cl)Cl.C1(NC2CCCCC2)CCCCC1>[Cl:26][C:6]1[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:21][CH2:20][CH2:19][CH2:18][C:15]=3[C:16]2=[O:17])=[C:2]([F:1])[CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClC(Cl)=C(Cl)Cl
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 83.1 %

Procedure:
N-(2-Fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl) (2 g) and dicyclohexylamine (0.01 g) were dissolved in tetrachloroethylene (20 ml), and a solution of sulfuryl chloride (1 g) in tetrachloroethylene (5 ml) was added dropwise thereto at 80° C. in 2 hours. After completion of the addition, the resultant mixture was stirred at the same temperature as above for 2 hours, followed by extraction with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 1.85 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (I: R=isopropyl). M.P., 81°-82° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=[CH2:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc2c(Br)ccc(OCc3ccccc3)c2[nH]c1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OCc2ccccc2)c2[nH]c(=O)c(C)cc12
Temperature: 100 °C

Procedure:
Palladium tetrakis(triphenylphosphine) (30 mg) is added to a solution of 8-benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one (239 mg) and tributylvinyltin (203 μL) in toluene (7 mL) at room temperature. The reaction mixture is heated for 2 hours at 100° C., cooled to room temperature, evaporated and the product purified by flash column chromatography on silica gel, eluting with 2% ethyl acetate in dichloromethane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:26]([C:23]1[CH:22]=[N:21][C:20]([N:17]2[CH2:18][CH2:19][CH:14]([O:1][C:2]3[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=3)[CH2:15][CH2:16]2)=[N:25][CH:24]=1)[CH2:27][CH3:28]
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
A stirring suspension of 4-hydroxypyridin-2(1H)-one (5.23 g, 47.1 mmol, Aldrich), 1-(5-propylpyrimidin-2-ylpiperidin-4-yl methanesulfonate (11.7 g, 39.2 mmol), potassium carbonate (12.5 g, 90.0 mmol, EMD) and DMSO (48 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 100% EtOAc and then SiO2, 10% MeOH in CH2Cl2) to yield 5.00 g of desired product as an off-white solid. MS (ESI) 315 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(N(CC)CC)C.O.[C]=O.[C:23]([O:26]CC)(=[O:25])C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:23]([OH:26])=[O:25])=[CH:3][C:4]=1[CH3:12])=[O:7]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)O)cc1C
Temperature: 83 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 4-bromo-2-methylbenzoic acid, methyl ester (22.59 g, 98.6 mmol), triethylamine (32.00 g, 316.2 mmol), palladium(II) acetate (0.56 g, 2.5 mmol), bis(diphenylphosphino)propane (1.04 g, 2.5 mmol) and water (32 mL, 1776.3 mmol) in acetonitrile (80 mL) was pressurized to 40 psi with carbon monoxide and the pressure was released. After six such cycles, the bottle was pressurized again and the contents were stirred at 83° C. for 3 h. The reaction mixture was cooled to room temperature and depressurized. Ethyl acetate (200 mL) was added. The solution was filtered and then extracted with water (2×300 mL). The combined aqueous layers were acidified with 12 M HCl to pH 0. The resulting mixture was extracted with ethyl acetate (2×300 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to give 2-methylbenzene-1,4-dicarboxylic acid 1-methyl ester (16.57 g, 87%) as a white solid, mp 134-136° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(Cl)nc2c1c(-c1ccncc1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.05 g, 0.11 mmol), Pd(PPh3)2Cl2 (0.015 g, 0.022 mmol) and pyridine-4-ylboronic acid (0.03 g, 0.24 mmol) in p-dioxane (0.7 mL) was added a solution of Na2CO3 (0.035 g, 0.33 mmol) in water (0.3 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.02 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:25])[N:24]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:26]([C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH3:25])(=[O:28])=[O:27])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-NI-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2,4-dimethylthiazole-5-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.3 (s, 3H), 2.6 (s, 3H), 5.7 (s, 1H), 5.9 (dt, 1H), 7.1 (q, 1H), 7.2 (d, 1H), 7.3 (m, 1H), 7.4 (d, 1H), 7.4 (s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(#N)C.[CH3:12][C:13]1([CH3:25])[CH2:17][C:16]2[C:18]([CH3:24])=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1>O>[Br:1][C:19]1[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]2[O:14][C:13]([CH3:25])([CH3:12])[CH2:17][C:16]=2[C:18]=1[CH3:24]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
N-bromosuccinimide (12.5 g, 70.0 mmol) was added to a solution of acetonitrile (165 mL) containing 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (11.1 g, 58.3 mmol) synthesized in Reference Example 3 under ice-cooling condition, and the mixture was warmed to room temperature. After stirring for 5 hours, water was added to the reaction solution. The generated precipitate was collected by filtration and washed with a mixture of acetonitrile/water (1/2). The solid was dried to give 13.5 g of the title compound (yield: 86%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:3](=O)[C:2]1=NN.C1N2CCN(CC2)C1.C([OH:27])CCCCC>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][C:2]1=[O:27]
Reactant: NN=C1Nc2ccccc2C1=O
Reactant: CCCCCCO
Agent: C1CN2CCN1CC2
Product: O=C1Cc2ccccc2N1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
14.8 g of isatin (99 mmol, 98.2% purity) were initially charged into a 250 ml three-neck flask and 150 ml of 2-ethylhexanol were added. 6.0 g of hydrazine hydrate (117 mmol; 98% purity) were added with stirring. The reaction mixture was heated to 90° C. for 15 min to form the isatin hydrazone (yellow suspension). The water of reaction was azeotropically removed at 90° C./100 mbar using 1-hexanol. 2.4 g of DABCO (21 mmol, 98%) were then added and the suspension heated to 130° C. for 2.5 h. After the end of the reaction (GC analysis: hydrazone 0.3 area %), 100 ml of 1-hexanol were distilled off (80° C./50 mbar). The remaining solution was cooled to 5° C., the precipitated solid filtered off and dried in a vacuum drying cupboard at 70° C. Altogether, 8.0 g of dry 2-oxindole product (light brown) were obtained which corresponded to an overall yield of 66.5%. Purity: 99.9 area %.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:19]=[CH2:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A 2 L flask was equipped with a mechanical stirrer, a reflux condenser and a stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydroxybenzoate, 960 mL of acetone, 22.50 g (1.625 mol) of anhydrous potassium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the mixture was stirred and refluxed for 14 hours. The mixture was cooled to room temperature, filtered and concentrated to an oil. The residual oil was purified by distillation (97° C. @ 0.03 mm Hg) to afford 53.52 g (86%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH2:13](I)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCI
Product: CCC(=O)Cc1ccc(OC)cc1

Procedure:
Educts: 4-methoxyphenyl acetic acid chloride (70); ethyl iodide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][NH:31][CH2:32]2)([O-:27])=[O:26].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][N:31]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:32]2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 35.7 %

Procedure:
200 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 102 mg of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:11][N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][N:16]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:15][CH2:14]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(I)cc2)CC1
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
A solution of 4-iodo-benzoyl chloride (4.72 g, 17.71 mmol) in DCM (70 mL) at 0° C. was treated with dimethyl-piperidin-4-yl-amine (2.27 g, 17.71 mmol). The resultant suspension was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was diluted with 1M aqueous Na2CO3 solution and the phases separated. The aqueous phase was extracted twice with DCM and the combined organic phase was dried (Na2SO4) and evaporated to afford (4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone as a white solid (6.2 g, 98%). LCMS (Method 3) [M+H]+=359.2, RT=1.82 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([CH:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1>O1CCCC1>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:54][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=4)[N:22]([S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=4)(=[O:35])=[O:34])[CH:21]=3)[C:17]([C:43]#[N:44])=[CH:16][N:15]=2)[CH3:53])=[CH:48][CH:47]=1
Reactant: CC(N)c1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)c4ccc(Cl)nc4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
Diisopropylethylamine (730 μl, 4.2 mmol) was added to a mixture of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (330 mg, 2.1 mmol) and 1-(6-chloropyridin-3-yl)ethanamine (described in the literature: EP 375907 (B1)) (500 mg, 1 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a wax (345 mg, 58% yield).