Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:27][C:26]([O:25][CH3:24])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ncnc3nc[nH]c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21
Reaction time: 0.25 h

Procedure:
6-Benzyloxypurine (4.18 g; 18.5 mmol) was added to a suspension of potassium carbonate (3.1 g; 22.4 mmol) in DMF (100 ml). After 15 min., bromoacetic acid methyl ester (1.93 ml; 20.4 mmol) was added. The reaction was monitored by TLC in butanokacetic acidiwater 4:1:1. Upon completion, the reaction mixture was partitioned between water (600 ml) and ethyl acetate (600 ml). The organic phase was dried over magnesium sulfate and evaporated to a volume of ˜10 ml and precipitated with pet. ether. The two products were separated by column chromatography using ethyl acetate as the solvent. The products were precipitated in pet. ether. Yield: 2.36 g (43%). Melting point: 111.5-115° C. UV λmax=250 nm (9-alkylated); λmax=260 nm (7-alkylated). 1H-NMR (DMSO-d6): 8.60 (1H, s); 8.43 (1H, s); 7.6-7.35 (5H, m); 5.69 (2H, s); 5.26 (2H, s); 3.75 (3H, s).
Reaction SMILES: [F:1][C:2]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)([F:4])[F:3].Cl.[CH3:12][O:13][NH:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:12][O:13][N:14]([CH3:15])[C:8]([C:5]1([C:2]([F:4])([F:3])[F:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CNOC
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
Trifluoromethyl cyclopropane carboxylic acid (500 mg, 3.24 mmol) was added to a freshly prepared solution of Weinreb amine (3.90 mmol) prepared by treating N-methoxymethanamine HCl salt with EtN-iPr2 (3.90 mmol) in CH2Cl2 at −40° C. and stirring for 5 min. DCC (801 mg, 3.90 mmol) in 5.0 mL of DCM was then added slowly over 3 min while cooling the solution at 0° C. The reaction mixture was stirred at RT for 48 h. It was then filtered through a plug of silica gel washing with Et2O. The volatiles were removed and the residue was purified on an ISCO 12 g column (20-70% EtOAc:Hexanes) to yield N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (456 mg, 71% yield) as a clear colorless oil. A reference for this procedure could be found in: J. Org. Chem. 2005, 70, pages 5721-5724.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[NH:4][CH:3]=1.S(Cl)(Cl)=O.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[OH:18][C:19]1[CH:20]=[C:21]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:11]([CH:9]3[CH2:8][CH2:7][C:6]4[N:2]=[CH:3][NH:4][C:5]=4[CH2:10]3)=[O:13])[CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: Oc1cccc(C2CNc3ccccc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(C1CCc2nc[nH]c2C1)N1CC(c2cccc(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
A mixture of 1.99 g of hydrochloride (racemic form) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid, 0.15 ml of dimethyl formamide and 20 ml of thionyl chloride was refluxed for three hours. The resultant reaction solution was distilled to dryness under a reduced pressure. The residue consequently formed was added to a solution of 2.07 g of (+)-3-(3-hydroxyphenyl)indoline in 75 ml of tetrahydrofuran. This reaction solution was stirred at room temperature for 12 hours, then weakly alkalinized by addition of the saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then distilled. The residue was refined by silica gel column chromatography to obtain 2.00 g of 5-[{3-(3-hydroxyphenyl)indolin-1-ylcarbonyl}]-4,5,6,7-tetrahydrobenzimidazole (56.8%) as an epimer mixture.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH:4]3[CH2:5][CH:1]([C:6](=[O:7])[C:8]=2[CH:13]=1)[CH:2]=[CH:3]3
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)C2CC=CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C1C=CC2C1
Temperature: 120 °C
Yield: 95.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(cyclopent-3-enecarbonyl)-4-methoxy-phenyl ester (19.09 g, 54.5 mmol) was dissolved in DMF (100 mL) under a N2 atmosphere and treated with dilsopropylethylamine (10.6 g, 82.0 mmol), potassium acetate (1.07 g, 11.0 mmol) and 1,3-bis(diphenylphosphino)propane (2.25 g, 5.46 mmol). This mbdure was stirred and degassed (3 vacuum/N2 purge cycles) then treated with palladium acetate (0.49 g, 2.18 mmol). After stirring 20 min. the mixture was warmed to 120° C. for 18 hours, cooled and poured into brine (300 mL). The resulting mixture was extracted with ElOAc (4×100 mL) and the combined organic layer was washed with a sat. aq. NaHCO3 soin. (100 mL), H2O (100 mL) brine (100 mL), dried (MgSO4), filtered, concentrated and chromatographed on silica gel to provide an oil (10.4 g, 95%). (elute w/7%OAc/hexanes). 1H NMR (CDCl3) δ 7.41 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.88 (dd, J=8.0,2.8 Hz, 1H), 6.72 (dd, J=5.2,3.0 Hz, 1H), 6.06 (dd, J=5.2,3.2 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J=4.3,3.2 Hz, 1H), 3.44 (dd, J=5.0,3.4 Hz, 1H), 2.65 (AB m, 1H), 2.56 (br AB d, J=10.5 Hz, 1H). 13C NMR (CDCl3) 196.11, 158.87, 145.90, 140.34, 130.295, 129.94, 128.14, 119.42, 111.90, 55.61, 55.48, 49.08, 45.97. GCMS m/e 200 (M+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>CO>[CH2:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/Cc1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C/CC1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
A solution of 300 mg (2.17 mmols) of potassium carbonate and 3 ml of water was added to a solution of 705 mg (2.17 mmols) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxyquinoline, 10 ml of water and 50 ml of methanol and stirred at room temperature for 10 minutes. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, followed by addition of 50 ml of chloroform, washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C 200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 550 mg (yield 90%) of 2-(trans-2-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: C(O[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=[CH:7][C:8]#[N:9])C.[ClH:12]>C(O)(=O)C>[Cl:12][C:8]1[CH:7]=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:9]=1
Reactant: Cl
Reactant: CCOC=C(C#N)C=CC#N
Solvent: CC(=O)O
Product: N#Cc1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
A solution of 30 g of ethoxymethylene-glutacononitrile in 300 ml of glacial acetic acid was cooled to 0° C. and saturated with HCl gas. The mixture was allowed to rise to room temperature and left to stand overnight. It was concentrated and the residue was stirred together with 70 ml of water and neutralized with NaHCO3 solution. After being filtered off and recrystallized from ethanol, 2-chloro-5-cyanopyridine was obtained in 73.5% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([O-])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:21]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([Cl:21])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Yield: 88.5 %

Procedure:
Sixty grams of potassium 4-chloro-3,5-dinitro-o-toluenesulfonate, 70 grams of phosphorus pentachloride and 120 ml of phosphorus oxychloride are mixed and refluxed for 3 hours. The mixture is filtered to remove some insoluble solid. The filtrate is carefully poured into water at 20° C. to 30° C. The precipitated solid is collected and dissolved in 500 ml. of benzene. The benzene solution is washed with water and then dried over MgSO4. After removing the magnesium sulfate, the benzene is concentrated to 100 ml. and 400 ml. of hexane added. The precipitated solid is collected and recrystallized from 300 ml. hexane and 100 ml. of benzene to yield 50 grams of solid with melting point 105° C. to 107° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.CCN(CC)CC.[CH:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=O)([CH3:29])[CH3:28].CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:32][C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)c1ccccc1C(=O)Cl
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Cc2ccccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL), sodium cyanoborohydride (0.50 g, 8.1 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2) to provide a solid (0.118 g, 124°-126° C.). 1H NMR (400 MHz, DMSO-d6) δ10.855 (bs, 1H), 7.395-7.306 (m, 5H), 7.115 (dd, 1H, J=1 Hz, J=7.5 Hz), 6.991 (t, 1H, J=7 Hz), 6.622 (td, 1H, J=1 Hz, J=7 Hz), 6.123 (d, 1H, J=7 Hz), 3.422 (s, 2H), 3.210-3.102 (m, 3H), 1.975-1.871 (m, 2H), 1.437-1.371 (m, 1H), 1.142-1.084 (m, 7H), 0.938-0.807 (m, 1H), 0.791-0.766 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:7])[OH:6].C(=O)(O)[O-].[Na+].[C:17]([O:22][CH:23]([O:25][C:26](OC1CC(=O)NC1=O)=[O:27])[CH3:24])(=[O:21])[CH:18]([CH3:20])[CH3:19]>O.C(#N)C.C(OC(=O)C)C>[C:17]([O:22][CH:23]([O:25][C:26]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[OH:7])=[O:27])[CH3:24])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CCCCP(=O)(O)CCCN
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCP(=O)(O)CCCNC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropyl(n-butyl)phosphinic acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) was added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethylacetate (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 μL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (31) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 6.78 (q, J=8 Hz, 1H), 3.49 (s, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.51-2.55 (m, 1H), 1.80-1.84 (m, 2H), 1.65-1.75 (m, 3H), 1.55-1.58 (m, 2H), 1.39-1.48 (m, 4H), 1.17 (d, J=8.4 Hz, 9H), 0.93 (t, J=7.2 Hz, 3H). Phosphorus (162 MHz, CDCl3) δ0.31. MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].C(N(CC1C=NC=CC=1)C(NC)=S)C1C=CC=CC=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CCO>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH:38][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:33][CH:32]=1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Reactant: NCc1ccc(Cl)nc1
Agent: CNC(=S)N(Cc1ccccc1)Cc1cccnc1
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The 1-dimethylamino-1-methylthio-2-nitroethylene (1.0 g) prepared in (1) and 1.0 g of 6-chloro-3-pyridylmethylamine were refluxed in 30 ml of EtOH for 2 hours. The EtOH was then distilled off and the residue was subjected to silica gel column chromatography using CHCl3 -MeOH (10:1) as an eluent. The crystals obtained were recrystallized from EtOH to recover 0.82 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:5]([O:7]C)=[O:6].[Li+].[OH-].O.CC(O)=O>C1COCC1.O.CO>[CH3:14][N:2]([CH3:1])[CH2:3][CH:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CN(C)C)c1ccsc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC(C(=O)O)c1ccsc1
Reaction time: 12 h

Procedure:
To methyl 3-(dimethylamino)-2-(thiophen-3-yl)propanoate (E42) in THF/H2O/MeOH was added LiOH*H2O, and the solution was stirred for 12 hours. AcOH was added and the solvents were evaporated. Column chromatography (SiO2, 10-15% 2M NH3— MeOH/EtOH) gave pure 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43).
Reaction SMILES: [OH-].[K+].[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([O:18]C)=[O:17])=[O:8])([CH3:5])[CH3:4]>O.C(O)C>[CH:3]([NH:6][C:7]([C:9]1[S:13][N:12]=[C:11]([CH2:14][CH3:15])[C:10]=1[C:16]([OH:18])=[O:17])=[O:8])([CH3:4])[CH3:5]
Reactant: CCc1nsc(C(=O)NC(C)C)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1nsc(C(=O)NC(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2.8 g of KOH in 30 ml of water are added to 11 g of the ester from Example 5 in 50 ml of ethanol, and the mixture is stirred overnight at room temperature. It is diluted with 150 ml of water and extracted with ether, and the aqueous phase is acidified with concentrated hydrochloric acid. Extraction by shaking with dichloromethane and evaporation give 10 g of 5-isopropylaminocarbonyl-3-ethylisothiazole-4-carboxylic acid of melting point 138°-140° C. (compound 3006).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Fc1cccc(-c2nc3cc(Br)ccn3n2)c1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 102.4 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.42 mmol) and tert-butyl carbamate (481 mg, 4.11 mmol) as starting materials. The reaction affords 2-(3-fluoro-phenyl)-[[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (1.15 g, 102%) as light yellow foam. MS: m/z=329.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[O:18])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)NC1CC1
Yield: 77 %

Procedure:
The process was carried out according to Example 59, starting with 3 g of the compound of Example 37, 2.4 g of carbonyldiimidazole and 1.1 g of cyclopropylamine. product was recrystallized from ethanol to obtain 2.6 g of the desired product, m.p. 170°-172°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11])=[C:2]=[S:3].[OH-].[NH4+:13]>>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][NH:1][C:2]([NH2:13])=[S:3]
Reactant: CN1CCCC1CCN=C=S
Reactant: [NH4+]
Agent: [OH-]
Product: CN1CCCC1CCNC(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 2-(2-isothiocyanatoethyl)-1-methylpyrrolidine and concentrated ammonium hydroxide (3 mL) were heated at 100° C. for 30 minutes. Additional ammonium hydroxide (1 mL) was added and heating was continued for an additional 30 minutes. The reaction mixture was allowed to cool to room temperature and then it was lyophilized to give [2-(1-methylpyrrolidin-2-yl)ethyl]thiourea as a very viscous colorless oil.
Reaction SMILES: [C:1](/[C:3](=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)/[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]COC)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].Cl.CO>>[C:1](/[C:3](=[CH:21]\[C:22]1[NH:26][CH:25]=[CH:24][N:23]=1)/[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccc(OCOC)cc1
Agent: Cl
Solvent: CO
Product: CCCC(NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
(E)-2-cyano-3-(1H-imidazol-2-yl)-N-(1-(4-(methoxymethoxy)phenyl)butyl)acrylamide (14.8 mg, 0.041 mmol) was dissolved into HCl/MeOH (1.25 M, 2 mL). This solution was stirred at room temperature for 18 hours. TLC showed a single product. The mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The separated organic layer was washed with sat. brine and dried with sodium sulfate and concentrated to give a light amber solid (9 mg) as crude product. The crude material was recrystallized from ethyl acetate/hexanes to afford the titled compound as a light yellow solid (6 mg) in 46% yield. 1H NMR (500 MHz, CDCl3/CD3OD) δ 7.84 (m, 1H), 7.28 (m, 1H), 7.18 (s, 1H), 6.99 (d, J=6.8, 2H), 6.82 (d, J=7.8, 2H), 3.73 (m, 2H), 1.53 (m, 2H), 1.30 (m, 2H), 0.88 (t, J=7.1, 3H). Mass spec ES+, m/z=311.1 (m+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[Cu][C:24]#[N:25]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:24]#[N:25])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(C#N)ccc23)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
3-(6-Bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.19 g, 0.5 mmol) and copper(I) cyanide (0.090 g, 1.0 mmol) were combined in DMSO (10 mL) in a sealed reaction vessel and stirred at 130° C. for overnight. The resulting mixture was cooled to room temperature, and subjected to standard aqueous workup. The crude residue was purified by silica gel chromatography (10-100% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21]C)=[CH:16][N:15]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].Br[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]#[N:41]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[C:40]#[N:41])[C:17]([OH:21])=[CH:16][N:15]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Reactant: N#Cc1cnccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
50 mg of 4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-5-ol (1-11-1, 0.149 mmol, 1. eq.) were dissolved in 3 ml of N,N-dimethylformamide. 103 mg of potassium carbonate (0.746 mmol, 5 eq.) and 32.8 mg of 4-bromopyridine-3-carbonitrile (0.179 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 100° C. bath temperature for 18 hours. After cooling at room temperature the mixture was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC and preparative TLC to yield 4.21 mg (0.01 mmol, 6.1%) of the analytically pure target compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].O1CCOCC1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)#[N:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 90 °C
Yield: 81.7 %

Procedure:
To a 500 mL RBF containing ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (17.20 g, 44.65 mmol, prepared as in WO 2009154741) was added anhydrous 1,4-dioxane (172.0 mL, 2204 mmol). To the resulting suspension was added morpholine (8.177 mL, 93.77 mmol). A reflux condenser was attached and the pink/orange heterogeneous suspension was heated to bath temp 90° C. and allowed to stir. Shortly after heating began, reaction mixture became a cherry red, homogenous solution. Reaction was stirred for 16 hours at 90° C. The reaction was then cooled to room temperature and diluted with water (100 mL). Mixture was filtered, and the solid was dried for in vacuo at 40° C. for 5 days to afford ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (14.3 grams, 82% yield). LCMS: (FA) ES+ 393; 1H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1, 2H), 3.78-3.70 (m, 4H), 3.63-3.57 (m, 4H), 1.26 (t, J=7.1, 3H).