Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:27]>CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:27])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C#N)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(N)=O)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL round-bottomed flask charged with 2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzonitrile (PREPARATION x83, 52 mg, 0.146 mmol) was added sulfuric acid (1.6 mL, 29.2 mmol). The resulting yellow solution was stirred overnight at room temperature and was subsequently diluted with EtOAc and washed with saturated NaHCO3 to adjust the pH to ˜8. The combined organic layers were dried over MgSO4, filtered, and concentrated to give an orange solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88-3.02 (m, 5 H), 3.09-3.18 (m, 3 H), 3.19-3.28 (m, 2 H), 3.41-3.51 (m, 3 H), 3.59-3.71 (m, 2 H), 3.80-3.91 (m, 3 H), 3.91-4.00 (m, 2 H), 4.19-4.29 (m, 3 H), 4.30-4.58 (m, 2 H), 7.16-7.29 (m, 10 H), 7.37-7.45 (m, 2 H), 7.73-7.82 (m, 2 H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN5O2, 374.1; found 374.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: NCC(F)(F)F
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC(F)(F)F
Yield: 90 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (77 mg, 90%) which was obtained as an off white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:27])=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:18])([CH3:3])[CH3:2]
Reactant: Cc1nc2cnc3ccccc3c2n1NC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A solution of N-isopropyl(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.84 g, 7.66 mmol) dissolved in 50 mL of 1,2-dichloroethane was treated with MCPBA (77% max., 2.36 g, 9.58 mmol). After stirring for 3 h, the reaction mixture was treated with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with saturated 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-isopropyl(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.95 g) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2cccnc2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (120 mg, 0.30 mmol) was dissolved in absolute CH2Cl2 (10 ml), and nicotinaldehyde (65 mg, 0.61 mmol), NaBH(OAc)3 (128 mg, 0.61 mmol) and glacial acetic acid (36 mg, 0.61 mmol) were added. The mixture was stirred at room temperature. After 21 hours, the same amounts of nicotinaldehyde, NaBH(OAc)3 and glacial acetic acid were again added and the mixture was stirred for 3.5 hours. The mixture was then filtered and the organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A yellowish resin was isolated.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[CH:10]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:34][C:33](=[O:35])[NH:32][CH:31]=[C:30]2[C:36](Cl)=[O:37])=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH:18][C:36]([C:30]3[C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH2:34][C:33](=[O:35])[NH:32][CH:31]=3)=[O:37])[CH:16]=2)[CH:11]=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indol-6-ylamine was dissolved in 10 ml dichloromethane and 0.25 ml triethylamine. The solution was cooled to 0° C. and 150 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride in 1.5 ml dichloromethane was added. The resulting mixture was stirred at 0° C. for one hour, then at room temperature for two hours. DMAP (100 mg) was added and the mixture stirred for another hour. The reaction mixture was then partitioned between pH 7 phosphate buffer and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography to give 70 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indol-6-yl}-amide e/z 522 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C>C(O)C>[NH2:20][C:19]1[N:10]([C:4]2[C:3]([F:2])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1c(F)cccc1F
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cnn(-c2c(F)cccc2F)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17](Cl)=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.[S-:22][C:23]#[N:24].[K+]>CC(C)=O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([N:24]=[C:23]=[S:22])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reaction time: 1.5 h

Procedure:
A solution of 56.5 g. (0.172 mol.) of 8-trifluoromethylphenothiazine-1-carboxylic acid chloride in 450 ml. of acetone was added over a 15 minute period to a stirred solution of 25.0 g. (0.257 mol.) of potassium thiocyanate in 200 ml. of acetone. The resulting reddish brown suspension was stirred at 25° for 1.5 hours. The reaction mixture was concentrated under reduced pressure to approximately 300 ml. then diluted with 700 ml. of water. The product was collected by filtration and washed thoroughly with water to give 8-trifluoromethylphenothiazine-1-carboxylic acid isothiocyanate, m.p. 145°-150°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:22])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([O:20][CH3:21])[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH3:22])[CH3:10])=[CH:13][C:14]=3[O:20][CH3:21])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: COc1cc(N(C)C)ccc1C=O
Product: COc1cc(N(C)C)ccc1-c1nc2cc(Br)cnc2[nH]1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-dimethylamino-2-methoxybenzaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1>>[Cl:8][C:7]1[C:2]([NH:12][CH:9]2[CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: NC1CC1
Reactant: Clc1nccnc1Cl
Product: Clc1nccnc1NC1CC1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
2,3-Dichloropyrazine (1.013 ml, 9.73 mmol) and cyclopropylamine (3 ml, 42.8 mmol) were combined in a microwave vial and heated at 130° C. for 30 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 3-chloro-N-cyclopropylpyrazin-2-amine (1.45 g, 8.55 mmol, 88% yield) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[O:24])[NH:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>C1COCC1>[C:10]([CH:9]([NH:23][NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)NNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-phenyl-2-oxobutanoate (2.06 g; 10 mmol) and t-butylcarbazate (1.32 g; 10 mmol) in THF (50 ml) can be warmed at reflux for 8 hours. Solvent can be evaporated and the residue taken up in anhydrous ethanol (25 ml). Sodium cyanoborohydride (0.31 g; 5 mmol) can be added, and the solution stirred for 4 hrs. The residue, after evaporation, can be stirred with EtOAc (50 ml) and hydrochloric acid (0.5 N: 20 ml) for 30 minutes. The aqueous layer can be neutralized by addition of K2CO3 and extracted with EtOAc (3×25 ml). The combined organic portions can be washed with H2O and brine and dried (MgSO4). The residue, upon evaporation, can be purified by chromatography on silica gel, affording N-(1-carboethoxy-3-phenylpropyl)-N'-BOC-hydrazine. An ice-cold solution of the above hydrazine in trifluoroacetic acid can be allowed to stand for 1 hr. Removal of solvent can provide hydrazine (56) as the trifluoroacetic acid salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[C@@H:11]([CH3:13])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C@@H:11]([CH3:13])[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added 1.71 g of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:20][O:21][C:22]2[CH:23]=[C:24]3[N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)[CH:6]=[N:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:28]=[C:26]1[N:25]2[CH2:29][CH2:30][NH:31][C:24]2=[CH:23][C:22]([O:21][CH2:20][C:5]2[CH:6]=[N:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)cnc1Oc1cccc(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((5-cyano-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (120 mg, 0.227 mmol) in DCM (4 mL) and TFA (0.873 mL, 11.3 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CCNc1ccccc1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCNc1ccccc1C(N)=O
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-(3-ethoxycarbonyl-2-propenylamino)benzamide (2.35 g) in methanol (50 ml) was added 10% palladium on carbon (230 mg). The mixture was stirred vigorously under 3 atmospheric pressure of hydrogen. After 2 hours, the catalyst was filtered off, and the solvent was evaporated. The residue was chromatographed on silica gel (40 g). Elution with a mixed solvent of ethyl acetate-hexane (1:1 V/V) gave 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[CH:22]1>>[F:19][C:18]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1cn(C)cn1
Product: Cn1cnc(C(C)(O)C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)c1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-4-yl)but-3-yn-2-ol (WO2009/158011 A1) to give the titled compound as colorless solid (19 mg, 9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([C:23]#[N:24])=[C:4](S(C)=O)[N:3]=1.[CH3:28][NH2:29]>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([C:23]#[N:24])=[C:4]([NH:29][CH3:28])[N:3]=1
Reactant: CN
Reactant: CS(=O)c1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Solvent: CC#N
Product: CNc1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask were added 2-(2-Amino-5-cyano-6-methanesulfinyl-pyrimidin-4-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide (0.2 mmol, 1.0 eq.), methyl amine (2M in THF, 0.3 mmol), and acetonitrile (1 mL). The reaction mixture was stirred at room temperature for overnight. The crude material was purified by column chromatography (18 mg). LC-MS: (ES+) m/z 383 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 8.07(s, 1H), 7.75 (d, 1H), 7.55 (t, 1H), 7.40 (d, 1H), 7.36 (d, 1H), 7.25 (s, 1H), 3.95 (s, 2H), 2.73 (d, 3H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:18]([C:37](OC)=[O:38])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[NH3:41].CO>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)[CH:18]([C:37]([NH2:41])=[O:38])[CH2:17]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: N
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CO
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(N)=O

Procedure:
Methyl 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate hydrochloride (0.3 g) obtained in Example 54 and 13% ammonia/methanol solution (3.5 ml) were heated in a sealed tube at 90° C. for 2 days. The reaction system was cooled, and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.11 g) as a colorless powder.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].[CH2:34]1C2C(=CC=CC=2)CC1CCO.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:34][CH:19]1[CH2:18][CH2:17][N:16]([C@H:27]1[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=1
Reactant: OCCC1Cc2ccccc2C1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC2Cc3ccccc3C2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-indan-2-yl-ethanol and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:20][CH:17]3[CH2:18][CH2:19][O:15][CH2:16]3)[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: NCC1CCOC1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Product: Clc1cc(-c2ccnc(NCC3CCOC3)n2)ccn1

Procedure:
The title compound was prepared from 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) and tetrahydro-3-furanmethanamine (i.e., the product of Step C) in the same fashion as described in Example 9, Step A.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.O.[CH3:26]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:26])=[O:12])=[CH:7]2
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Reactant: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a suspension of 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (8.71 g) in a mixture of methanol (300 mL) and toluene (300 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (12.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. Furthermore 2M trimethylsilyldiazomethane diethyl ether solution (10 mL) was added to the mixture and the mixture was stirred at 0° C. for 1 h, which was repeated three times. And then 2M trimethylsilyldiazomethane diethyl ether solution (5 mL) was added and the mixture was stirred at 0° C. for 30 min, which was repeated two times. To quench the reaction, 1M hydrochloric acid (80 mL) was added to the mixture. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.25 g, 92%) as a purple solid. MS 363 (MH+).