Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl>CS(C)=O>[Cl:20][C:21]1[C:22]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27]
Reactant: CC1(CO)CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (0.301 g, 1.65 mmol) in anhydrous dimethylsulfoxide (3 mL) were added cesium carbonate (1.07 g, 3.30 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.37 g, 1.49 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down to room temperature and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with diethyl ether (2×15 mL). The combined organic layers were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.28 g, 45%). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.67 Hz, 1H), 6.60 (d, J=12.13 Hz, 1H), 3.96-3.89 (m, 4H), 3.72 (s, 1H), 1.98-1.37 (m, 17H), 1.12 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]=[C:12]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16].O>C(Cl)Cl>[C:1]1([S:7]([N:32]2[CH2:31][CH2:30][N:29]([C:12](=[O:11])[CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:34][CH2:33]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
TEA (62.57 mg, 062 mmol) followed by benzenesulphonyl chloride (54.6 mg, 0.31 mmol) were added at to 0° C. to biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product extracted with DCM. The organic layer was separated, washed with 10% HCl solution, saturated NaHCO3 solution and brine, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using 60-120 mesh silica gel and 30% EtOAc in hexane as eluent) to afford 45 mg (31.4% yield) of biphenyl-4-carboxylicacid {2-[4-benzene sulfonyl-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.75%, 1H NMR: (DMSO) δ 8.76 (t, 1H), 7.92 (d, 2H), 7.8-7.6 (m, 9H), 7.54-7.44 (t, 2H), 7.44-7.36 (t, 1H), 4.1 (d, 2H), 3.6 (s, 4H), 3.0-2.86 (d, 4H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:11]>C(O)C>[NH2:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: Cc1ccc(C#N)c(Cl)n1
Solvent: CCO
Product: Cc1ccc(C#N)c(N)n1
Yield: 82 %

Procedure:
2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130° C. for 20 hours. The reaction mixture was concentrated under vacuum and the residue washed with water (2×50 mL) then dried in a vacuum oven for 24 hours to provide the title compound as a light yellow solid (18 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm:2.30 (s, 3H), 6.52 (d, J=7.7 Hz, 1H), 6.78 (s, 2H), 7.73 (d, J=7.7 Hz, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:15]([CH2:27][CH3:28])=[N:16][N:17]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[C:18]=1[C:19]([NH2:21])=[O:20]>C(#N)C>[CH2:25]([O:24][CH2:23][CH2:22][N:17]1[C:18]2[C:19](=[O:20])[NH:21][C:1](=[O:2])[NH:13][C:14]=2[C:15]([CH2:27][CH3:28])=[N:16]1)[CH3:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOCCn1nc(CC)c(N)c1C(N)=O
Solvent: CC#N
Product: CCOCCn1nc(CC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of carbonyldiimidazole (12.3 g, 76.1 mmol) in acetonitrile (123 mL) was warmed to 50° C. The 4-amino-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazole-5-carboxamide prepared in step 3 (13.2 g, 58 mmol) was added to the mixture over a period of one hour and the temperature of the mixture was increased to 75° C. during the addition. The mixture was then cooled and stirred overnight. The mixture was cooled in an ice bath and filtered. The filter cake was rinsed with water and dried to provide 12.8 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:32])([F:31])[C@@H:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:27]5[CH2:28][CH2:29][CH2:30][C@@H:25]([C:24]([F:32])([F:31])[F:23])[CH2:26]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: FC(F)(F)[C@@H]1CCCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](C(F)(F)F)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-3-(trifluoromethyl)piperidine (1.2 equiv) to give 201 (M+1 449.0)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:34]=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][OH:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (300 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 1 hr under a nitrogen atmosphere. Paraformaldehyde (39.6 mg) was added to the reaction mixture, and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (42.5 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][N:26]4C(OC(C)(C)C)=O)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]4)=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]c(C3CCCCN3)cc2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-2-yl)piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 403.2. found 404.4 (M+1)+. Retention time of 0.95 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21](C(C)C)[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5].[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28]>>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:26][CH2:27][CH3:28])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:15])([CH3:16])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5]
Reactant: CC(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that of 2-chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-isopropyl-benzamide with allyltributylstannane replacing isopropenyltributylstannane. Data: LCMS (M/Z): 358 (M+H); 1H NMR (DMSO-d6) δ: 0.91 (t, J=7.3 Hz, 3 H) 1.44 (s, 6 H) 1.61 (sxt, J=7.4 Hz, 2 H) 2.61 (t, J=7.8 Hz, 2 H) 7.28 (d, J=1.0 Hz, 1 H) 7.37 (d, J=8.3 Hz, 1 H) 7.40 (s, 1 H) 7.48 (d, J=7.8 Hz, 1 H) 7.68 (dd, J=8.2, 2.1 Hz, 1 H) 8.06 (d, J=1.0 Hz, 1 H) 9.03 (br. s, 1 H) 10.44 (s, 1 H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.OP(O)(O)=O>O.C1(C)C=CC=CC=1>[OH2:2].[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: OC1CCCC1
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 107.5 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a N2 purged pressure reactor is charged resorcinol (44.0 g, 0.40 mol), cyclopentanol (44 mL, 0.49 mol) and 85% aqueous H3PO4 (55 mL, 0.80 mol). The slurry is heated to 95-120° C. for 6-18 hours. The pink reaction mixture is cooled to ˜70° C. and diluted with water (50 mL) and toluene (200 mL). The layers are allowed to separate at 60±5° C. The bottom orange aqueous layer is cut away. The remaining pink organic layer is extracted with 2×50 mL water at 60±5° C. and then stirred with carbon (5 g) at 60±5° C. for 1-2 hours. The slurry is filtered hot through Supercel, rinsing the cake with hot toluene (50 mL). The orange filtrate is diluted with 5 mL water and allowed to cool to ˜30° C. at which time the product crystallizes. The slurry is cooled to 0-5° C. and the product collected, washed with cold toluene (40 mL) and pulled dry on the funnel to afford 41 g of 4-cyclopentyl resorcinol monohydrate as a white to pale pink solid (≧98% area by HPLC). The material can be recrystallized if desired from hot toluene (5 mL/g) and carbon (10% by weight) filtering through Supercel and/or silica gel to the Form I polymorph of 4-cyclopentyl resorcinol afford as a white solid (≧99.7% by HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
In a 100 mL round bottomed flask was placed 4-(4-chlorophenyl)-5,5-dimethyl-2-pyridin-4-yl-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (240 mg, 0.65 mmol) and 1,2-dichloroethane (10 mL). To the solution were added trifluoroacetic acid (1 mL, 10 mmol) and triethylsilane (1 mL, 6 mmol). The resulting yellow solution was stirred for 16 hr at 90° C. The mixture was allowed to cool to rt then was concentrated under reduced pressure. The residue was diluted with EtOAc, then was washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (24 g RediSep column, gradient 30% EA in hexane to 100% EA in hexane) to give the product (215 mg, 94%) as a colorless syrup: 1H NMR (400 MHz, CDCl3) δ: 8.49 (dd, 2H), 7.31 (dd, 2H), 7.25-7.27 (m, 2H), 7.03 (br d, 2H), 6.84 (s, 1H), 3.67 (s, 1H), 1.77-1.83 (m, 1H), 1.63-1.70 (m, 1H), 1.03 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].O>O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 348 mg) at room temperature, and the mixture was stirred for 30 min. 2,6-Difluorobenzenesulfonyl chloride (1.36 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 1.36 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]1=[O:1]
Reactant: COC(=O)C1CCCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(=O)C1CCCCC(=CN(C)C)C1=O

Procedure:
Methyl 2-oxo-cycloheptanecarboxylate (51 mg, 0.30 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (85 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 226.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21]I.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c(Br)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.0 g (44.2 mmol) of (+/−)-tert-butyl 1-[(3-bromo-4-chlorophenyl)(hydroxy)methyl]cyclopropanecarboxylate were dissolved in 80 ml of DMF, and 4.1 ml (66.6 mmol) of methyl iodide were added at RT. The reaction mixture was cooled to +10° C., and 1.95 g (60% in mineral oil, 48.7 mmol) of sodium hydride were added in several portions. Ten minutes after the addition had ended, the mixture was warmed to RT and stirred at RT for a further 1.5 h. The reaction mixture was then added to water and extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 15.3 g of the target compound (92.2% of theory).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[OH:30][CH:31]([CH3:37])[CH2:32][C:33]([NH:35][NH2:36])=O>C(O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:33]([CH2:32][CH:31]([OH:30])[CH3:37])=[N:35][N:36]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CC(O)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a sealed tube containing ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (300 mg, 0.94 mmol) dissolved in ethanol (15 mL) and triethylamine (0.3 μl, 2.82 mmol) was added a solution of 3-hydroxybutyric acid hydrazide (190 mg, 1.5 mmol) in ethanol. The reaction was sealed and allowed to stir at 70° C. overnight. Solvent was removed and the product was purified via HPLC to yield the title compound. 1H NMR (DMSO-d6) δ 8.7 (s, 1H), 8.1 (m, 3H), 7.75 (d, 1H), 7.4 (t, 2H), ES-MS (m/z) 338 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:12]Br.[OH-].[Na+]>CC(O)=O>[Br:12][C:9]1[C:8]([NH2:11])=[CH:7][CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N)c(Br)n1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 510 mg (2.96 mmol) of 6-methanesulfonylpyridin-3-ylamine in 1.25 mL of AcOH was added a solution of 0.15 mL (2.96 mmol) of bromine in 0.5 mL of AcOH at room temperature dropwise. The resulting slurry was stirred for 1 hour. The reaction was carefully basified to pH=10 with 6 M NaOH. The solution was then extracted with two 150 mL portions of dichloromethane, dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture showed a 3:1 mixture of product:dibromo product by NMR. These two products were separated by silica chromatography (hexanes/EtOAc) to afford 294 mg (40%) of 2-bromo-6-methanesulfonylpyridin-3-ylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].CS(C)=O.Br.[Br:15][C:16]1[CH:17]=[N:18][C:19]([OH:22])=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[N:20]([CH2:7][CH3:8])[CH:21]=1
Reactant: CCI
Reactant: Oc1ncc(Br)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCn1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
With cooling with ice, potassium carbonate (13.2 g, 95.7 mmol) and ethyl iodide (2.84 mL, 35.6 mmol) were added to a dimethyl sulfoxide (130 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (7.0 g, 27.3 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=1/1) to obtain the entitled compound (3.34 g, 60%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1>>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:6]=[N:7][C:2]([C:25]3[CH:26]=[CH:27][S:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)nc1
Reactant: OB(O)c1ccsc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccsc2)nc1

Procedure:
Cross-coupling of 2-(6-chloropyridin-3-yl)-3-cyclopentyl-N-thiazol-2-ylpropionamide (EXAMPLE 1, 100 mg, 297 μmol) with thiophene-3-boronic acid (100 mg, 781 μmol), utilising a procedure similar to that described above for EXAMPLE 2, furnished the title compound: RTA=3.83 min; m/z (ES+)=384.2 [M+H]+.