Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16](F)[CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[Cl-:36].[CH3:37][N+:38]1[CH2:39][CH2:40][O:41][CH2:42][CH:43]=1>CN(C=O)C>[ClH:36].[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[C:10]([CH:43]3[CH2:42][O:41][CH2:40][CH2:39][N:38]3[CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: [Cl-]
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)c1
Reactant: C[N+]1=CCOCC1
Solvent: CN(C)C=O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C1COCCN1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Intermediate AB (N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea) (200 mg, 0.42 mmol) and 4-methyl-3,6-dihydro-2H-1,4-oxazin-4-ium chloride (69 mg, 0.51 mmol) in DMF (5 mL) is allowed to stir for 1 h at rt. Volatiles are removed in vacuo, and the residue triturated with CH2Cl2, providing the desired compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(NC(C)C)(C)C>C1COCC1.O.[Cu]I>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]#[C:3][CH2:2][CH2:1][C:5]2[CH:16]=[CH:15][C:8]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 200 mg (0.94 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine, 222 mg (0.94 mmol) 2,5-dibromopyridine, 13.2 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium, 3.6 mg (0.02 mmol) CuI and 0.27 mL diisopropylamine in 10 mL THF is heated for 4 h at 40° C. under an argon atmosphere. The reaction mixture is diluted with water, exhaustively extracted with EtOAc, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:23])=[O:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
LiOH (20.29 mg, 0.847 mmol) was added to a stirred solution of methyl 2-[(phenylmethyl)oxy]-5-(1-piperidinylsulfonyl)benzoate (may be prepared as described in Description 68; 330 mg, 0.85 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 220 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6](OS(C)(=O)=O)[CH2:5][N:4]([CH3:13])[C:3]1=[O:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.C(Cl)Cl.C(O)(C)C>[N:15]([CH:6]1[CH2:7][N:2]([CH3:1])[C:3](=[O:14])[N:4]([CH3:13])[CH2:5]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CC(OS(C)(=O)=O)CN(C)C1=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CC(N=[N+]=[N-])CN(C)C1=O
Temperature: 70 °C
Reaction time: 13 h

Procedure:
To a solution of methanesulfonic acid 1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl ester (Step P6) (3.2 g, 14.3 mmol) in DMF (75 mL) at rt was added sodium azide (1.9 g, 28.7 mmol) and the mixture was stirred at 70° C. for 13 h. The mixture was diluted with CH2Cl2/isopropanol 3:1 and extracted with a saturated aqueous NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: [M+H]+ 170.1 (MS 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C.S([Cl:29])(C)(=O)=O>C(Cl)Cl>[Cl:29][CH:12]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cl)c1cc(OC)c(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 7A (280 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.12 mL, 1.5 mmol). After stirring at rt overnight, the reaction was filtered, concentrated and purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 7B (268 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:26][NH:27][S:28](Cl)(=[O:30])=[O:29].[BH4-].[Na+]>N1C=CC=CC=1>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:28](=[O:30])(=[O:29])[N:27]2[CH3:26])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)c(C3OCCO3)c2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)c(C3OCCO3)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 71.9 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-[1,3]dioxolan-2-yl-4-fluoro-phenyl)-methanone 420 (500 mg, 1.48 mmol), N-methylsulfamoyl chloride 213 (574 mg, 4.43 mmol) and NaBH4 (56 mg, 1.48 mmol) in pyridine (10 ml) gave the title compound (442 mg, 72%) after purification by column chromatography with heptane/EtOAc (50:50) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:14]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCC(F)(F)F)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 2,2,2-trifluoro-ethylamine. LC/MS [6.73 min; 440 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:25][CH:26]=1.CS(Cl)(=O)=O.[Br:41][C:42]1[N:46]2[CH:47]=[CH:48][CH:49]=[C:50](O)[C:45]2=[N:44][C:43]=1[CH3:52].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(N(CC)CC)C>[Br:41][C:42]1[N:46]2[CH:47]=[CH:48][CH:49]=[C:50]([O:9][CH2:8][C:7]3[C:2]([Cl:1])=[C:3]([N:11]4[CH:15]=[CH:14][CH:13]=[C:12]4[CH2:16][NH:17][C:18](=[O:35])/[CH:19]=[CH:20]/[C:21]4[CH:22]=[N:23][C:24](/[CH:27]=[CH:28]/[C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:25][CH:26]=4)[CH:4]=[CH:5][C:6]=3[Cl:10])[C:45]2=[N:44][C:43]=1[CH3:52]
Reactant: Cc1nc2c(O)cccn2c1Br
Reactant: O=C(/C=C/c1ccc(/C=C/c2ccncc2)nc1)NCc1cccn1-c1ccc(Cl)c(CO)c1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(/C=C/c5ccncc5)nc4)c3Cl)cccn2c1Br
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 1-(2,4-dichloro-3-hydroxymethylphenyl)-2-[(E)-3-[6-[(E)-2-(pyridin-4-yl)vinyl]pyridin-3-yl]acryloylaminomethyl]pyrrole (70 mg) and triethylamine (28 mg) in N,N-dimethylformamide (1 ml) was added methanesulfonyl chloride (16.7 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture were added 3-bromo-8-hydroxy-2-methylimidazo[1,2-a]-pyridine (31.4 mg) and potassium carbonate (95.7 mg) at ambient temperature, and the mixture was stirred at the same temperature overnight. Water was added thereto, the resulting precipitates were collected by filtration. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[3-(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yloxymethyl)-2,4-dichlorophenyl]-2-[(E)-3-[6-[(E)-2-(pyridin-4-yl)vinyl]-pyridin-3-yl]acryloylaminomethyl]pyrrole (76 mg) as yellow amorphous.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH2:6][S:7][CH3:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)[C@H](CCSC)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A mixture of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid methyl ester (513 mg, 1.44 mmol) in a 1:1 solution of tetrahydrofuran:water (20 mL) was treated with lithium hydroxide monohydrate (120 mg, 2.88 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (438 mg, 89%) as a light amber gum.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][CH2:7][CH2:6][O:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(OCCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOC2(C)CC2)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step (0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) and tetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.1 g, 11.2 mmol) dichloromethane (6 mL) at 0-5° C. The solution was stirred for 3 h at 0-5° C., and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain crude product (100 mg), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].Cl.[NH2:11][OH:12].C([O-])(O)=O.[Na+]>CO>[OH:12][NH:11][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][N:9]=[C:2]([CH3:1])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C#N)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)ccn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 130.4 %

Procedure:
To a solution of 2-methyl-isonicotinonitrile (330 mg, 2.79 mmol) in methanol (12 mL), hydroxylamine hydrochloride (388 mg, 5.59 mmol) and NaHCO3 (469 mg, 5.59 mmol) is added. The mixture is stirred in a sealed vial at 60° C. for 16 h before the solvent is evaporated. The residue is dried to give N-hydroxy-2-methyl-isonicotinamidine (550 mg); LC-MS: tR=0.55 min, [M+1]+=152.25.
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:10]1)=[O:8])(C)(C)C>O1CCOCC1>[CH:7]([OH:8])=[O:6].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[O:14][C@H:11]4[CH2:12][CH2:13][NH:9][CH2:10]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCNC1)C3
Product: O=CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
HCl (2.64 mL) was added to a solution of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g; 2.64 mmol; 1 eq.) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was taken up in DCM, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (48 mg, 4%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.44-7.33 (m, 1H), 7.17-7.09 (m, 1H), 6.91 (td, J=8.4, 2.3 Hz, 1H), 5.14-5.06 (m, 1H), 4.86-4.78 (m, 2H), 4.63-4.42 (m, 2H), 3.35-3.21 (m, 1H), 3.08-2.85 (m, 3H), 2.83 (s, 1.5H), 2.80 (s, 1.5H), 2.61 (s, 1.5H), 2.55 (s, 1.5H), 2.16-1.97 (m, 1H), 1.95-1.83 (m, 1H). HPLC (max plot) 93.3%, Rt 2.67 min. UPLC/MS: (MS+) 430.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[C:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)([OH:29])=[O:28]>O1CCCC1.CCCCCC>[C:12]([C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH2:33][C:32]1[CH:31]=[C:30]([CH:37]=[CH:36][CH:35]=1)[C:27]([OH:29])=[O:28])#[N:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(Cc2cccc(C(=O)O)c2)Sc2ccc(C)cc2)cc1OC
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 85.1 %

Procedure:
To a cold (-78° C.) solution of 1.86 g of 3,4 -dimethoxy-α-[(4-methylphenyl)thio]benzene acetonitrile in 15 mL of tetrahydrofuran is added drop-wise a solution of 2.9 mL of n-butyl lithium (2.2M) in hexane. This solution is stirred at -78° C. for 35 minutes. A solution of 0.67 g of m-carboxybenzyl bromide in 5 mL of anhydrous tetrahydrofuran is added drop-wise, stirred at -78° C. for 40 minutes and then at room temperature for 15 minutes. The mixture is quenched with water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield a yellow oil. This oil is purified by flash chromatography using methylene chloride/methyl alcohol (95:5) to yield 1.15 g of the desired product as a yellow foam.
Reaction SMILES: [C:1]([CH2:3]C(O)=O)#[N:2].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>N1C=CC=CC=1>[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:3][C:1]#[N:2])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of cyanoacetic acid (12.76 g, 150.0 mmol), 4-nitrobenzaldehyde (24.60 g, 162.8 mmol), ammonium acetate (500 mg), toluene (140 mL), and pyridine (75 mL) is refluxed for 64 hours in a flask fitted with a Dean-Stark trap and condenser. After evaporation of the solvents, a solution of the residue in CHCl3 is filtered and washed with H2O. The dried (Na2SO4) organic layer is evaporated, and the bright yellow-orange solid is recrystallized from benzene. The yellow solid 3-(4-nitrophenyl)-acrylonitrile, obtained as a mixture of cis-trans isomers, is suitable for use as an intermediate without further purification.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CC/C=C\CCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC/C=C\CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and cis-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.9 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C1C(=O)N([I:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:17])=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)nc(N)n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 25 °C

Procedure:
10.0 g (70 mmol) 4-Chloro-6-methyl-pyrimidin-2-ylamine in 200 mL acetic acid is cooled to 0° C., 15.7 g (70 mmol) NIS is added and the reaction mixture is stirred at RT until conversion of the starting material is completed (18 h). An aqueous solution of 5% Na2S2O3 and 10% NaHCO3 is added until the mixture decolorizes. The formed precipitate is filtered off, taken up with water and the resulting suspension is stirred at RT for 1 h. The product is filtered off and dried in vacuo at 40° C. Yield: 15.2 g (81%). 1H NMR (CDCl3) δ: 5.2 (s, 2H), 2.6 (s, 3H). TLC (silica, 20% EtOAc in PE): Rf=0.50.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1.O>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CBr)Nc1ccc(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A solution of 2-amino-5-fluorobenzoic acid (15 g, 96.6 mmol) in dry DMF (35 mL) and dioxane (35 mL) was cooled to 0° C. Bromoacetylbromide (8.43 mL, 96.6 mmol) was added dropwise at 0° C. over a 40 min period, and the reaction mixture was left overnight at room temperature. The reaction mixture was cooled to 0° C., and diluted slowly with water (300 mL). The precipitate which formed was collected washed with 5% HBr (50 mL) and water, and dried, to afford 25.43 g (95.1%) of the title compound as a white solid, mp 191.2°-191.8° C.; 1H NMR (acetone-d6) δ 11.60 (s, 1H), 8.71 (dd, J=5.2, J=9.2, 1H), 7.80 (dd, J=3.2, J=9.6, 1H), 7.48-7.43 (m, 1H), 4.18 (s, 2H); 13C NMR (acetone-d6) δ 168.80, 165.71, 158.37 (d, J=241.9), 138.56, 122.78 (d, J=7.8), 122.70, 122.06 (d, J=21.9), 117.98 (d, J=24.0), 30.45; MS (EI, m/z) 277 (M+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]2[CH2:33][O:32]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1>C(O)(C)C.CCO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]([OH:32])[CH2:33][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Reactant: CC(=O)Nc1cc(Cl)ccc1OCC1CO1
Solvent: CC(C)O
Solvent: CCO
Product: CC(=O)Nc1cc(Cl)ccc1OCC(O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Yield: 100.6 %

Procedure:
A solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (480 mg, 2.0 mmol) and N-(5-chloro-2-oxiranylmethoxy-phenyl)-acetamide (490 mg, 2.0 mmol) in isopropanol (i-PrOH) (10 mL) and EtOH (10 mL) were stirred at 80° C. for 17 h, after which the solvent was removed in vacuo. The residue was purified using gradient flash chromatography (CH2Cl2 to MeOH), yielding the desired product as a white solid (960 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)(=[O:23])=[O:22])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]ncc2c1
Yield: 24.3 %

Procedure:
2-Methylsulfonyl-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine and 1.91 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.64 g of 2-methylsulfonyl-N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white solid melting at 245° C. (analysis C14H13N3O4S2 % calculated C, 47.85; H, 3.73; N, 11.96; O, 18.21; S, 18.25. % found C, 47.42; H, 3.72; N, 11.64; S, 17.97).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.O.[C:11]1(C)C(S(O)(=O)=O)=CC=CC=1.C(OC)(OC)OC>CO>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3]1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O=C1CCC(C(=O)O)C1
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)C1CCC(=O)C1

Procedure:
A solution of 193.8 g (1.51 moles) of 3-oxocyclopentane carboxylic acid in 580 ml of methanol, analytical grade, is treated with 1.8 g (9.5 mmoles) of toluene sulphonic acid hydrate with stirring, then 192.4 g (1.81 moles) of trimethyl orthoformate are added in the course of 10 minutes and the mixture is heated to boiling under reflux. This temperature is maintained for 1 hour. The solution is evaporated in vacuo (i.v.), the residue is treated with 200 ml of H2O, 220 ml of toluene and 1.9 ml of concentrated H2SO4 and stirred at room temperature for 1 hour. The phases are separated, the aqueous phase is extracted 3× using 50 ml of toluene each time, the combined organic phases are washed 1× using 90 ml of 2.5% strength LiOH solution and 2× using 50 ml of H2O each time. The organic phase is dried using magnesium sulphate and evaporated in vacuo. The oily residue is fractionally distilled using a water-jet vacuum.