Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>O1CCCC1>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 50 °C
Yield: 85.5 %

Procedure:
A stirred mixture of methyl 1-(biphenyl-4-ylcarbonyl)piperidine-4-carboxylate (0.10 g, 0.31 mmol), sodium hydroxide (25 mg, 0.62 mmol), water (4 mL) and tetrahydrofuran (1 mL) is heated at 50° C. for 3 h. Solvents are removed under reduced pressure giving a residue. The residue is redissolved 1M aqueous HCl (4 mL) and extracted with EtOAc (3×4 mL). The organic layers are combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give 82 mg (93%) of 1-(biphenyl-4-ylcarbonyl)piperidine-4-carboxylic acid. m/z=310 [M++H].
Reaction SMILES: [CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:5][CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(C=CC(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(CCC(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Yield: 97.8 %

Procedure:
Using a Parr hydrogenation apparatus, 0.23 gram (0.0005 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-2-pentene was hydrogenated in 50 ml of ethanol in the presence of 10% palladium on charcoal. Upon completion of the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, yielding 0.2 gram of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)pentane. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[F:2][C:3]1[C:4](=[S:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([CH2:12][S:10][C:4]1[C:3]([F:2])=[CH:8][NH:7][C:6](=[O:9])[N:5]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSc1nc(=O)[nH]cc1F
Yield: 29 %

Procedure:
A solution of the sodium salt of 5-fluoro-4-thiouracil (0.0195 mol) and ethyl chloroacetate (0.0195 mol) in ethanol (50 ml) was heated under reflux for 2 hr. The solvent was removed at reduced pressure triturated with cold water and the residue recrystallised from water; yield 29%; m.p. 156° C. (Found: C, 41.38; H, 4.12. Calc for C8H9FN2O3S: C, 41.38; H, 3.90).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].[Li+].[OH-]>CN1C(=O)CCC1.C(Cl)Cl.O.N1C=CC=CC=1>[Cl:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Reactant: CCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
DCM (2 mL) and pyridine (1 mL) were added to (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.3 g, 0.820 mmol; Example 91, Step A) in NMP (2 mL), and then propionyl chloride (0.228 g, 2.46 mmol) was added. The reaction was then stirred for 1 hour at room temperature, and then 3M aqueous LiOH (3 mL) was added. The reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the organic fraction was dried, filtered and concentrated. Purification of the crude product by reverse phase HPLC (5-95% ACN in water) gave the product (R)-tert-butyl 1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.220 g, 63.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[N:18][OH:19]
Reactant: NO
Reactant: COc1ccccc1C(=O)c1sccc1Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=NO)c1sccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 20g of (3-bromothien-2-yl) (2-methoxyphenyl)methanone in 200 g of pyridine containing 10 g of hydroxylamine hydrochloride was heated at 100° for 10 minutes and thereafter allowed to cool. After standing at room temperature for 16 hours, the solution was poured onto 600 g of ice water and the organics were extracted into ether. The combined ether solution was washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum left a solid residue which was recrystallized from ether/hexane to give prisms, m.p. 129°-130° C.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[N:10]=1)(=O)=O.[NH3:19]>>[F:18][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CS(=O)(=O)c1nncc(-c2cc(F)cc(F)c2)n1
Reactant: N
Product: Nc1nncc(-c2cc(F)cc(F)c2)n1
Yield: 74 %

Procedure:
5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine (18 g, 74%) was prepared from 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31.0 g, 115.0 mmol) and ammonia gas according to the general procedure of Preparation 2.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
Sodium hydride (60 wt%, 0.20 g) was added to dimethyl sulfoxide (15 ml), and the mixture was stirred at room temperature for 10 min. 4-Amino-3-nitrophenol (0.77 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinazoline (1.12 g) was added thereto, and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a 1 N aqueous sodium hydroxide solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give the title compound (1.10 g, yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]([CH3:14])[CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[OH:16][CH:17]([C:25]1[CH:34]=[CH:33][C:28]2[C:29](=[O:32])[O:30][CH2:31][C:27]=2[C:26]=1[CH3:35])[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl>[OH:16][CH:17]([C:25]1[CH:34]=[CH:33][C:28]2[C:29](=[O:32])[O:30][CH2:31][C:27]=2[C:26]=1[CH3:35])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:12][CH:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[CH3:14])[CH2:21][CH2:20]1
Reactant: COc1cc(C(C)C=O)ccc1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(C)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile (0.020 g, 0.106 mmol) were added dichloromethane (15 mL) and 5-[1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [(0.037 g, 0.116 mmol), in dichloromethane (2 mL), and triethylamine (0.029 mL, 0.211 mmol)], and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.112 g, 0.529 mmol) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with water (5 mL), and the organics were extracted with EtOAc (2×40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and dried (MgSO4). Filtration followed by concentration afforded an oily residue, which was purified via mass-directed reverse-phase HPLC followed by evaporation and drying of the pure fraction obtained which then converted to HCl salt by triturating in 1M HCl in diethyl ether (0.50 mL, 2 h). Evaporation and dried under vacuum provided 4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-2-(methyloxy)benzonitrile.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1OC(C2CC2)=NC1NC=O
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]OC[CH2:41]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH:25]([CH2:41][CH2:40][CH3:44])[C:26]([O:28][CH3:29])=[O:27]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.260 g; 0.62 mmol), LHMDS 1N in THF (0.7 mL; 0.7 mmol), 1-iodopropane (0.127 mL; 1.3 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.233 g (83%) of the title compound as a yellow oil.
Reaction SMILES: COC1C=C(C(CC)C(C2C=CC=CC=2)=O)C=CC=1.[C:20]1([C:26](=[O:44])[CH:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:26]([OH:44])[CH:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(CCC(C(=O)c2ccccc2)c2ccccc2)c1
Agent: CCC(C(=O)c1ccccc1)c1cccc(OC)c1
Product: COc1cccc(CCC(c2ccccc2)C(O)c2ccccc2)c1

Procedure:
Using the procedure of step A of Example 3, but replacing 1-(p-hydroxyphenyl)-4-(m-methoxyphenyl-2-phenyl-1-butanone by 1,2-diphenyl-4-(m-methoxyphenyl)-1 -butanone there is obtained 1,2-diphenyl-4-(m-methoxyphenyl)-1-butanol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.36 g) in dichloromethane (6 mL) were added triethylamine (0.2 mL) and methanesulfonyl chloride (0.05 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3-ethyl acetate) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonylamino)propoxy]phenyl}methyl)-1H-pyrazole (255 mg). This material was dissolved in methanol (6 mL). To the solution was added sodium methoxide (28% methanol solution, 0.11 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.16 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B([O-])OC(C(C)(C)C)C)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[S:3][C:4]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=2)=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)sc1C#Cc1ccc(F)cc1
Reactant: CC(OB([O-])c1cnc(N)nc1)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(-c2cnc(N)nc2)sc1C#Cc1ccc(F)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
705 mg (2.00 mmol) of tert-butyl N-{2-chloro-5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}carbamate are dissolved in a mixture of 4 ml of DMF, 2 ml of water and 8 ml of DME together with 663 mg (3.00 mmol) of pinacolyl 2-amino-pyrimidine-5-boronate, and 829 mg (6.00 mmol) of potassium carbonate and 81 mg (0.10 mmol) of Pd(dppf)2Cl2.CH2Cl2 are introduced. Argon is subsequently passed through the reaction mixture for 10 min, the vessel is sealed and heated at 85° C. for 44 h. After cooling, the reaction mixture is extracted twice with saturated NaCl solution, and the aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/2; 1% of triethylamine), giving 205 mg (0.49 mmol, 25%) of tert-butyl N-[2-(2-aminopyrimidin-5-yl)-5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl]carbamate as yellow solid; m.p. 201-203;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([O:11]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:10].Cl.C([O-])(O)=O.[Na+]>C(#N)C.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)c1ccc(F)cn1
Yield: 15.2 %

Procedure:
1 g (5.68 mmol) 2-bromo-5-fluoropyridine, 160 mg dichlorobis(triphenylphosphine) palladium and 170 mg CuI were suspended in baked flasks under protective gas in 30 ml acetonitrile, 6.09 g (16.87 mmol) (1-ethoxyvinyl)-tributylstannane were added, the mixture was heated 8 hours at reflux, 200 ml 1.5 n HCl were subsequently added and reflux was continued for an additional hour. For workup the mixture was neutralized with saturated NaHCO3 solution, was extracted 3× with ethyl acetate, the combined organic phases were washed with saturated NaCl solution and were dried with MgSO4. After filtration 30 ml saturated KF solution were added, the mixture was filtered over Celite and evaporation-concentrated. Purification by chromatography on silica gel (dichloromethane/methanol 0-3%) yielded 120 mg 1-(5-fluoropyridine-2-yl)ethanone as an oil, which was directly reacted further.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C@@H:18]1[CH2:24][CH2:23][C@H:22]2[C@H:20]([O:21]2)[CH2:19]1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Si:16]([O:17][C@@H:18]1[CH2:24][CH2:23][C@H:22]([OH:21])[C@@H:20]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:26])[CH3:25]
Reactant: Cn1cccn1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2O[C@@H]2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Yield: 68.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (500 mg, 6.09 mmol), n-butyl lithium (2.69 M solution in hexane, 2.37 mL, 6.37 mmol), tert-butyl(dimethyl)[(1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-yloxy]silane (J. Pharm. Pharmacol., 49, 835-842, 1997; 1.32 g, 5.78 mmol) and THF (30 mL), to yield the title compound (1.23 g, 69%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCC=O
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (3.14 g, 15 mmol) in methylene chloride (50 ml) under a nitrogen atmosphere were added valeraldehyde (2.0 ml, 18.75 mmol) and acetic acid (5.18 ml, 90 mmol). The mixture was stirred for 5 minutes followed by addition of sodium triacetoxyborohydride (6.36 g, 30 mmol). The reaction was stirred for 30 minutes, diluted with methylene chloride (50 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and, dried (MgSO4). The solvent was evaporated in vacuo to give 4.19 g of product (100%) that used without further purification. 1H NMR (DMSO-d6) d 7.31 (t, J=7.9 Hz, 1H), 6.81-6.75 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (bs, 2H), 1.68-1.60 (m, 2H), 1.45-1.32 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([CH:13]([OH:15])[CH3:14])[CH:4]=1>ClCCl.[O-2].[Mn+2]>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: COc1cc(C(C)O)cc2c1OCCO2
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(C)=O)cc2c1OCCO2
Yield: 94.5 %

Procedure:
In a round-bottomed flask, 0.65 g (3.1 mmol) of the alcohol 11 was dissolved in dichloromethane. To this solution was added an excess of manganese oxide. The suspension was heated to reflux overnight. The mixture was cooled and filtered through Celite. The filtrate was evaporated in vacuo to afford 0.61 g (85%) of 12 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[C:15]1([C:12]2[N:11]=[N:10][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=4)=[S:30])=[CH:7][CH:6]=3)=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(Sc2ccc(-c3ccccc3)nn2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc(-c4ccccc4)nn3)cc2)ccc1Cl
Yield: 69.1 %

Procedure:
3-(4-aminophenylthio)-6-phenylpyridazine (7.0 mmoles, 2.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (7.0 mmoles, 1.66 g) were reacted according to procedure C to yield of the title compound 2.5 g, 69%. Mass Spec (FD) 516. Calculated for C24H16ClF3 N4O2S2 : C, 55.76; H, 3.12; N, 10.84. Found: C, 55.98 H, 3.19; N, 10.78.
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH:32]1(O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:13][CH:12]=3)[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cn2c(=Nc3ccc(O)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC4CCCC4)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Reaction time: 16 h

Procedure:
To the title compound of Example 20, Step A (0.03 mmol, 14 mg) in CH2Cl2 (0.6 mL) was added cyclopentanol (0.08 mmol, 7 μL), DIAD (0.06 mmol, 12 μL) and Ph3P (0.06 mmol, 16 mg). The reaction mixture was allowed to stand at ambient temperature for 16 h, then purified by chromatography on silica eluting with 10% and 25% EtOAc in hexanes to afford the product as a white solid. LC-MS (ESI, Method B): 2.12 min, m/z 524.2 (M+1).