Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH:11]([CH3:13])[CH3:12])=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:15][O:16][NH2:17].C(O)C>C(OCC)(=O)C>[CH3:15][O:16][N:17]=[C:4]([CH2:3][C:2](=[O:1])[CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)C=C(O)C(C)C
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)C(C)C)=NOC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of 5.0 g of ethyl 4-hydroxy-5-methyl-2-oxo-3-hexenoate, 2.46 g of O-methylhydroxylamine hydrochloride and 10 ml of ethanol was stirred at room temperature for 6 hours. After ethyl acetate was poured into the reaction mixture, the organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.32 g of ethyl 2-methoxyimino-5-methyl-4-oxohexanoate of the formula:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[Br:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Br:9][C:10]1[CH:11]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:13]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: CC(=O)O
Product: OCc1nc2ncc(Br)cn2n1
Temperature: 60 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (6.29 g, 33.12 mmol) in acetic acid (25 ml) was added bromomalonaldehyde (5 g, 33.12 mmol). The mixture was heated at 60° C. for 5 hours, and then cooled to room temperature. The light yellow solid was formed. After the solid were removed by filtration followed by drying in vacuum oven provides the light yellow solid as desired product, the filtrate was concentrate by rotary evaporation to give yellow oil. The crude oil was purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light yellow solid (combine total 6.5 g, 86% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 4.65 (d, J=5.46 Hz, 2H) 5.50-5.67 (m, 1H) 8.94 (d, J=2.45 Hz, 1H) 9.83 (d, J=2.26 Hz, 1H). MS: (APCI) 230 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12](O)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O)(=O)C.[O:26]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]1=2>O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:32]1[CH:33]=[CH:34][C:27]2[O:26][CH2:30][CH2:29][C:28]=2[CH:31]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Reactant: c1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
N-Benzyloxycarbonyl-α-hydroxyglycine (10.4 g., 0.046 mole) was added to a stirred mixture of concentrated sulfuric acid (4 ml.) and glacial acetic acid (36 ml.) at 0°-5° C. followed, after five minutes, by the dropwise addition of 2,3-dihydrobenzo(b)furan (5.8 g., 0.048 mole). The reaction mixture was stirred at ambient temperature overnight and the resulting pale mauve emulsion poured into stirred ice and water to afford a gum, which was induced to solidify. The crude product was collected, washed with water, dried in vacuo, and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to provide Dl-α-benzyloxycarbonylamino-2,3-dihydro-5-benzo(b)furanyl acetic acid (5.3 g.), m.p. 121°-123° C. Recrystallization of a sample raised the m.p. to 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[N:24][C:25]([O:29]C)=[C:26]([CH3:28])[CH:27]=4)[C:19]([CH3:31])=[CH:18][CH:17]=3)=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Si](I)(C)(C)C>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]4[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][CH:23]=4)[N:21]=3)=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)cc1Cl
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4c[nH]c(=O)c(C)c4)n3)CC2)cc1Cl
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (44 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (57.2 μL, 0.40 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN in water). ESI-MS m/z calc. 423.1. found 424.3 (M+1)+. Retention time 1.52 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Br:10])=[CH:4][C:3]=1[O:11][CH3:12].C([Li])CCC.CN([CH:21]=[O:22])C>CCOCC>[Br:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([CH:21]=[O:22])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)c(OC)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C=O)c(OC)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 1,4-dibromo-2,5-dimethoxybenzene (7.00 g, 23.65 mmol) in 100 mL ether was cooled to −78° C. and was treated with n-butyllithium (10.41 ml, 26.0 mmol). After stirring for 10 minutes, the reaction mixture was quenched with DMF (3.66 ml, 47.3 mmol), and the cooling bath was removed. After stirring for an additional hour, LC/MS showed mostly product, so the reaction mixture was washed with 1N citric acid solution, the organics dried over MgSO4 and concentrated. The crude product was carried forward in step two without purification. (M+H)+=245.1.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[S:25](=[O:28])(=[O:27])[NH2:26]>CCOCC>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([S:7][CH2:6][C@@H:2]([CH3:1])[C:3]([OH:5])=[O:4])=[O:21])=[CH:18][C:17]=1[S:25](=[O:27])(=[O:28])[NH2:26]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: C[C@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3 g of 2(S)-methyl-3-mercaptopropionic acid is added to a mixture of 3.5 g of potassium carbonate, 60 ml of water and 30 ml of ether with stirring atroom temperature under a nitrogen atmosphere whereupon 6.3 g of 4-chloro-3-sulfamoylbenzoyl chloride is added, and the resulting mixture is stirred at room temperature for 5.5 hours. The aqueous layer is then collected and made acidic with dilute hydrochloric acid, and the separatedoil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl ether is added to the residual oil. The crystals thus obtained are recrystallized from a mixture of ethyl acetate and hexane to give 3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionic acid as white crystalline powder, melting at 152°-153° C. (sinteringat 145° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1>>[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][N:19]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 42 %

Procedure:
The title compound was prepared from 2,2-Dimethyl-propionyl chloride and the amine of example 12, in 42% yield, using the procedure described in example 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 91.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and p-methoxyaniline (70 mg, 0.57 mmol) to give 179 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.86 (s, 1H), 7.46 (d, 2H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.16 (d, 1H, J=2 Hz), 6.88 (d, 2H, J=9 Hz), 5.15~5.25 (m, 1H), 3.72 (s, 3H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.50~2.64 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.78~1.94 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: NC(=O)CCCCCl
Agent: Cl
Product: CC1=C2CCN(CCCCC(N)=O)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 5-chlorovaleric acid amide are reacted in accordance with the process described in Example 1. Reaction period 19 hours at 60°. The hydrochloride of the title compound has a M.P. of 194°-196° from ethanol.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(#N)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:acetonitrile (40:60 v/v, 12.33 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetonitrile (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1 hour to obtain a pH of 4.05. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2×20 ml), and dried in a vacuum oven at 50° C. for 20 hours to obtain 3.9 g of ibandronate sodium crystal form Q5. Form Q5 can exhibit a weight loss of about 5% to about 11% in TGA.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.[H-].[Na+]>O1CCCC1>[CH2:1]([C:8]1[C:13]([O:14][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[C:10]([I:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(I)nc1Cc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)nc1Cc1ccccc1

Procedure:
12 g of 2-benzyl-3-hydroxy-6-iodopyridine was dissolved in 50 ml of tetrahydrofuran, followed by adding 3.8 ml of chloromethyl methyl ether. 2 g of 60% oily sodium hydride was added little by little thereto to under stirring under ice-cooling. After adding sodium hydride, the cooling medium was removed and the mixture was stirred at room temperature for 2.5 hours. Then, ice water was added thereto little by little under cooling, followed by extracting with ethyl acetate. The organic phase was further washed brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane as an eluent for separation and purification, to give 13 g of the target compound.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C[O-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>CO.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:16]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: SC1=NCCS1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic sodium methylate solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 litre of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C@H:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C@H:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: C[C@H](CCCC(=O)OC(C)(C)C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CCCC(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
1,1-dimethylethyl(5R)-5-[(2,5-dichlorophenyl)-[(4-chlorophenyl)sulfonyl]-amino]hexanoate (700 g, 1.40 mmol) was treated with a 50% solution of trifluoroacetic acid in dichloromethane (20 mL). After 3 h the reaction was diluted with dichloromethane then washed with water, brine and dried over MgSO4. Concentration under reduced pressure afforded (5R)-5-[(2,5-dichlorophenyl][(4-chlorophenyl)sulfonyl]-amino]hexanoic acid in quantitiative yield. MS (ESI), (M−H−) 450. IR-2975,1706,1466,1348.
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:5]4[CH2:6][CH2:7][O:8][CH2:9][C:4]=34)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1[nH]nc2c1COCC2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1COCC2
Yield: 65.7 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylic acid (0.168 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was triturated twice with acetonitrile. Yield 65.7%. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 2.70 (t, 2H), 3.72-3.80 (m, 2H), 4.23-4.46 (m, 3H), 4.56-4.68 (m, 2H), 6.94 (d, 1H), 7.82 (d, 1H), 7.97-8.00 (m, 2H), 8.07-8.09 (m, 1H), 8.21 (d, 1H). 12.98 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[CH3:37][C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (156 mg, 0.4 mmol) and 5-Bromo-2-methyl-benzenesulfonamide (example B.18) (124 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (22 mg, 10%). MS (ISP) 525.3[(M+H)+]; mp 255-267° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](S(C2C=CC(C)=CC=2)(=O)=O)[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[S:41][C:42]([C:45]([NH2:47])=[O:46])=[CH:43][N:44]=1.ClC1SC(C(N)=O)=CN=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:40]2[S:41][C:42]([C:45]([NH2:47])=[O:46])=[CH:43][N:44]=2)=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Reactant: NC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)c1cnc(Cl)s1
Product: CC(C)(C)Nc1nnc(-c2ccc3[nH]cc(-c4ncc(C(N)=O)s4)c3c2)o1
Yield: 52 %

Procedure:
The title compound (49 mg, 52% yield) as a yellow crystalline solid was prepared similar to that described in Example 275, using N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (131 mg, 0.244 mmol), 106 mg of the 1:1 mixture of 2-bromothiazole-5-carboxamide and 2-chlorothiazole-5-carboxamide, and Pd(PPh3)4 (Strem Chemicals, 14 mg) as the starting materials and reagent. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br.), 8.63 (1H, s), 8.38 (s, 1H), 8.28 (1H, s), 8.14 (1H, br.), 7.75 (1H, d, J=8.80 Hz), 7.66 (2H, m), 7.53 (1H, br.), 1.40 (9H, s). MS (ESI, pos. ion) m/z: 383.0 (M+H)+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cccc(F)c4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 66.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino)ethyl)anilino]-N-(3-fluorobenzyl)-1-piperidinecarboxamide (0.174 g, 0.225 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][C:4]1[C:8]([Zr+2:10][C:11]2([CH3:20])[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]2[CH3:19])([CH3:9])[C:7]([CH3:21])=[C:6]([CH3:22])[C:5]=1[CH3:23].[C:24]([OH:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:24]([O-:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[C:24]([O-:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[CH3:16][C:15]1[C:11]([Zr+2:10][C:8]2([CH3:9])[C:7]([CH3:21])=[C:6]([CH3:22])[C:5]([CH3:23])=[C:4]2[CH3:3])([CH3:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14]=1[CH3:17]
Reactant: CC(C)(C)C(=O)O
Agent: CC1=C(C)C(C)([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)[O-]

Procedure:
To a solution of bis(pentamethylcyclopentadienyl)zirconium dichloride (0.865 g, 2.001 mmol) and pivalic acid (0.685 g, 6.710 mmol) in toluene (30 ml) at 40° C. was added triethylamine (0.726 g, 7.174 mmol) with stirring. A white precipitate formed immediately which was removed by filtration. The title compound was isolated as an off-white powder in 90% by evaporating the solvent and excess pivalic acid under vacuum at 65° C. The title compound such prepared exhibited purity above 98% based on NMR results. 1H NMR (toluene d8) δ1.83 (s, 30H), 1.30 (s, 18H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)c2)n1
Yield: 97.7 %

Procedure:
A mixture of 6-methyl-2′-(3-nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example 306) (6.6 g, 15.15 mmol) in THF-MeOH 1:1 (300 mL) and 10% palladium on carbon (10 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was triturated with diethyl ether and dried in HV to give the title compound as a light brown solid (6.0 g, 97%). MS (ISP) 406.3 [(M+H)+]; mp 162° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH:11]([OH:14])[C:12]#[N:13].CO.[ClH:17].[O:18]1CCOC[CH2:19]1>C(OCC)C>[ClH:17].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH:11]([OH:14])[C:12](=[NH:13])[O:18][CH3:19]
Reactant: C1COCCO1
Reactant: COc1cc(C(O)C#N)c(F)cc1F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=N)C(O)c1cc(OC)c(F)cc1F
Temperature: 4 °C
Reaction time: 24 h

Procedure:
To 98B (427 mg, 2.1 mmol) in anhydrous diethyl ether (10 mL) at 0° C. was added MeOH (0.87 mL, 10 eq.) and 4.0 N HCl in dioxane (4.2 mL, 16.8 mmol). The mixture was stirred at 4° C. for 24 h. Solvent was removed to give methyl 2-(2,4-difluoro-5-methoxyphenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (8.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated to give product 98C (493 mg, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.41 (d, J=4.83 Hz, 1H) 3.72 (s, 3H) 3.80 (s, 3H) 5.32 (d, J=4.83 Hz, 1H) 6.78-6.84 (m, 1H) 6.90 (dd, J=9.01, 6.81 Hz, 1H).