Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:18])=[O:6])C.[Cl:19][CH2:20][C:21]#[N:22].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:19][CH2:20][C:21]1[NH:22][C:5](=[O:6])[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][S:9][C:8]=2[N:18]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N#CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94 g, 0.02 mol) and chloroacetonitrile (1.4 ml, 0.022 mol) in anhydrous 1,4-dioxane (60 ml) for about 4 hours. A thick suspension formed initially which slowly dissolved. The mixture was stirred at ambient temperature for 18 hours before being poured into water (250 ml) and basified (pH 8) by the addition of sodium hydrogen carbonate. The supernatant was then decanted to leave a gummy solid which was triturated with aqueous ethanol to give 2-chloromethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid (3.70 g), which was used without further purification.
Reaction SMILES: CP(C)C.O1CCCC1.[CH2:10]([O:12][C:13]([C@:15]1([N:37]=[N+]=[N-])[C@H:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:14])[CH3:11].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)C>[CH2:10]([O:12][C:13]([C@:15]1([NH2:37])[C@H:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:14])[CH3:11]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](SCc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: CP(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
7.7 mL of a solution of 1M trimethylphosphine/tetrahydrofuran was added to 3.35 g of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 100 mL of tetrahydrofuran and 10 mL of water, and the mixture was stirred for 1 hour at room temperature. The mixture was diluted with 200 mL of diethyl ether, and after 50 mL of a saturated aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was stirred for 1.5 hours at room temperature. After separation, the organic layers were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with chloroform, and then silica gel (Wako gel C200 (made by Wako Pharmaceutical Industries Ltd.)) was added thereto. The mixture was concentrated under reduced pressure, left to stand for 18 hours at room temperature, and then purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=2:1), thereby yielding 2.78 g of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: N1([C:6]([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=3)=[CH:10][CH:9]=2)=[O:7])C=CN=C1.O.[BH4-].[Na+]>O1CCCC1>[OH:7][CH2:6][C:8]1[S:12][C:11]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(C(=O)n3ccnc3)s2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CO)s2)cs1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A solution of N-(4-{2-[5-(1H-imidazol-1-ylcarbonyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (220.0 mg, 0.635 mmol) in anhydrous tetrahydrofuran (17.6 ml) was cooled to 0° C., and water (4.4 ml) and sodium borohydride (240.2 mg, 6.350 mmol) were added. After stirring at 0° C. for 1.5 hr, the reaction mixture was concentrated to about 2 ml, and saturated aqueous ammonium chloride (20 ml) was added dropwise. This was extracted 3 times with ethyl acetate, and the combined organic layer was washed with aqueous ammonium chloride and saturated brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=2:1) to give N-(4-{2-[5-(hydroxymethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (157.1 mg, 0.556 mmol, yield 87.6%) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:27]
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) were successively added dropwise at 0° C. in a nitrogen atmosphere and stirred at room temperature for 24 h. Water was added to the reaction mixture, which was distilled under reduced pressure; thereafter, ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=1:1) to give 213 mg of the titled compound (yield, 87%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(Cl)(Cl)(Cl)Cl>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Reaction time: 48 h
Yield: 83.7 %

Procedure:
In 200 ml of carbon tetrachloride, 19.1 g (0.100 mol) of 4-cyano-2,3,5,6-tetrafluorophenol and 13.0 g (0.125 mol) of methacrylic acid chloride were dissolved. To the resultant solution was added 20 g of molecular sieve 3 Å in diameter. The resultant mixture was refluxed as agitated for 48 hours. The reaction mixture so produced was cooled and then filtered to separate the molecular sieve. The filtrate was dried with magnesium sulfate and then evaporated to dryness with a rotary evaporator. Consequently, there was obtained 21.7 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (yield 83.8% based on 4-cyano-2,3,5,6-tetrafluorophenol, purity 96.5%).
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[H][H]>[Pt].CO>[OH2:7].[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC=Cc2ccc(F)cc2)C[C@H]1OC
Agent: [Pt]
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCc2ccc(F)cc2)C[C@H]1OC
Product: O
Yield: 81 %

Procedure:
A mixture of 3.12 parts of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)-3-butenyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 2.54 parts (81%) of cis-4-amino-5-chloro-N-[1-[4-(4-fluorophenyl)butyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate; mp. 132.7° C. (compound 237).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].CC(O)CC.[OH-].[Na+:26]>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:26]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)O
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O

Procedure:
A solution of amorphous ibandronic acid (4.5 g) in water (20 ml) and 1 N aqueous sodium hydroxide (14 ml) was stirred at room temperature to obtain a pH of 3.5. The solution was added dropwise into 2-butanol (100 ml) while stirring. The obtained precipitate was stirred at room temperature for 16 hours. The precipitate was isolated by vacuum filtration, washed with 2-butanol (2×20 ml), and dried in a vacuum oven at 50° C. for 24 hours to obtain 4.4 g of ibandronate sodium crystal form Q2.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:17]1([O:16][C:10]2[CH:15]=[CH:14][C:13]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Cc1cnc(N)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.922 g) was added to a suspension of 3-bromo-5-methylpyrazin-2-amine (5 g), 4-(cyclohexyloxy)phenylboronic acid (7.61 g) and sodium carbonate decahydrate (15.2 g) in DME (200 mL) and water (40 mL) and the mixture was stirred at 80° C. under nitrogen overnight. The insoluble material was removed by filtration (eluted with EtOAc), and silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.5 g) as a pale orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13]>C(N(CC)CC)C.O.[Cu]I.Cl[Pd]Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:13][C:12]#[C:11][OH:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(CC#CO)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A suspension of 3 g (15.1 mmol) of 2-acetyl-6-bromopyridine, 0.89 g (15.9 mmol) of propargyl alcohol, 0.078 g of CuI, 300 mg of PdCl2 (P (Ph)3)2 in 60 ml of triethylamine was stirred under nitrogen at room temperature for 6 h. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2×), brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was purified by MPLC (silica gel 60, hexane/ethyl acetate, 1:1) to afford 1.3 g (50%) of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine, as a solid product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@H]1CN>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@H:23]2[CH2:32][NH2:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: NC[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2CN)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanamine. MS (m/e): 400.4 (MH+).
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@H:12]2[O:16][C@@:15](C(=O)COC3C=CC=CC=3)([N:17]3[C:31]4[N:30]=[C:24]([NH:25]C(C)(C)C)[NH:23][C:21](=[O:22])[C:20]=4[N:19]=[CH:18]3)[CH2:14][C@@H:13]2[OH:42])=O)=CC=1)([O-])=O.ClCCl.C(#N)C.C(N(P(N(C(C)C)C(C)C)OCCC#N)C(C)C)(C)C.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C>ClCCl>[C@@H:15]1([N:17]2[C:31]3[N:30]=[C:24]([NH2:25])[NH:23][C:21](=[O:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:12]([CH2:11][OH:10])[C@@H:13]([OH:42])[CH2:14]1
Reactant: CC(C)(C)Nc1nc2c(ncn2[C@@]2(C(=O)COc3ccccc3)C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1
Agent: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reaction time: 2 h

Procedure:
5′-O-p-nitrobenzoyl-2-N-t-butylphenoxyacetyldeoxyguanosine (1 eq) is dried in a dichloromethane/acetonitrile mixture and reacted with 1.2 eq of bisdiisopropylaminocyanoethoxyphosphine and 0.5 eq of diisopropylammoniumtetrazolide in anhydrous dichloromethane. After reacting for 2 hours, the reaction mixture is diluted and washed successively with 0.5 M sodium bicarbonate and saturated sodium chloride. The organic phase is evaporated to dryness. After redissolution in chloroform and precipitation in hexane, the product is dried under vacuum and stored under argon. This amidite is soluble in acetonitrile, a solvent in which oligonucleotide syntheses are conventionally carried out.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)([OH:14])[CH2:9][NH:10][CH2:11][CH2:12]O)=[CH:4][CH:3]=1.OS(O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[O:14][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Reaction time: 20 h
Yield: 43.2 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol (701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H2SO4 (0.1 mL, 1.9 mmol). After 20 hours, another portion of H2SO4 (1.0 mL, 19 mmol) was added and the mixture stirred for a further 2 hours. The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate and brine then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2), eluting with 0.5% triethylamine in ethyl acetate to afford the title compound (290 mg, 43%); LCMS (PS-A2) Rt 2.40 min [M+H]+ 400.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]>>[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.54) (158 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 80%). MS (ISN) 571.0 [(M−H)−]; mp 153° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[O:11][CH:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][N:43]([CH2:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([NH2:57])[CH2:53][CH2:52]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([NH:57][C@H:54]3[CH2:53][CH2:52][C@H:51]([CH2:50][N:43]([CH3:42])[CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:56][CH2:55]3)=[O:17])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2coc(/C=C/C(=O)O)c2)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2coc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[4-(4-methylphenyl) furan-2-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (133 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (189 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (295 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (0.3 g) and triethylamine (0.18 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 4 days. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:3→1:2) and to recrystallization (ethyl acetate/hexane) to obtain (trans, E)-3-[4-(4-methylphenyl)furan-2-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 74) (137 mg) as light yellow crystals.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[O:19]=[C:20]1[NH:24][C:23]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:22]=2[O:21]1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:27]=[CH:28][C:22]4[O:21][C:20](=[O:19])[NH:24][C:23]=4[CH:25]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: O=c1[nH]c2cc(B(O)O)ccc2o1
Product: O=c1[nH]c2cc(C=C3c4ccccc4CCc4cc(Cl)ccc43)ccc2o1

Procedure:
Following procedures essentially as described in Example 219 and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.630 mmol) and 2-oxo-2,3-dihydro-benzooxazole-5-boronic acid (134 mg, 0.750 mmol), provides the title compound. Purify by UV-guided semi-prep reverse-phase HPLC to obtain 14 mg (6%) of the Z-isomer (Example 222(a)) of title compound as a white solid (MS (ES) 391 (M+NH4), 372 (M−H); HPLC shows 94% purity) and 5 mg (2%) of the E-isomer (Example 222(b)) of the title compound as a white solid. MS (ES) 391 (M+NH4), 372 (M−H); HPLC shows 96% purity.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])[CH:9]=2)[N:4]1[CH:23]=[O:24].C(N(S(F)(F)[F:31])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:31][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])[CH:9]=2)[N:4]1[CH:23]=[O:24]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO)N3C=O)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CF)N3C=O)C(=O)O1
Temperature: -70 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
A stirred mixture of the product from Step 11 (0.085 g, 0.255 mmol)) and CH2Cl2 (10 ml), under nitrogen is cooled to −70° C. and treated, dropwise stirring 2 min, with a solution of (diethylamino)sulfur trifluoride (0.07 ml, 0.53 mmol) in CH2Cl2 (1 ml). The mixture is allowed to warm to ambient temperature slowly during 3 h. Additional CH2Cl2 (10 ml) is added and the mixture is kept at ambient temperature for 20 h, cooled to −70° C. and treated with 0.07 ml of additional DAST. It is kept at −70° C. for 1 h and at ambient temperature for 4 h, mixed with ice cold, saturated NaHCO3 and extracted with EtOAc. The extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 3.5% MeOH—CH2Cl2 gave 0.036 g of the titled product: HRMS (FAB) calcd for C16H18FN3O4+H 336.1359, found 336.1351; 1H NMR [300 MHz, (CD3)2SO] δ1.81 (s, 3H), 2.85, 3.00 (m, m, 1H), 3.38 (m, 3H), 3.71 (m, 1H), 4.06 (m, 1H), 4.30-4.88 (m, 4H), 7.30 (m, 1H), 7.43, 7.87 (d, d, 1H), 7.50 (m, 1H), 8.23 (t, 1H), 8.45, 9.00 (s, s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C:16](=[O:25])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCOCC.[ClH:33]>CO.C(Cl)Cl.CCOCC>[ClH:33].[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C@H:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C@H:16]([OH:25])[CH2:15]3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O[C@@H]1C[C@@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (2.1 mmol) of (±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 40 mL of MeOH and 0.35 g of NaBH4 were added portionwise. The reaction mixture was stirred 2 h at room temperature, the MeOH removed in vacuo, then the residue was taken up in 1N NaOH and extracted with CH2Cl2. The organic phase was dried and the solvent was removed in vacuo. The crude product was purified by chromatography, eluting with CH2Cl2 and then with a mixture CH2Cl2/MeOH 100:3 respectively, yielding 100 mg of trans isomer which was dissolved in a mixture CH2Cl2/Et2O: The solution was brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with hot acetone, filtered and dried, yielding 90 mg of the title compound. m.p.>250° C.