Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9](\[CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)/[CH2:10][NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.[OH-].[Li+]>O1CCCC1.O>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][CH2:10]/[C:9](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:8]/[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12
Yield: 99.7 %

Procedure:
(Z)-Methyl-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)-methyl)oct-6-enoate (278 mg, 0.63 mmol) obtained in Example (3-1-1) was dissolved in tetrahydrofuran (2.52 ml) in a 25 ml vessel and stirred. To the resulting mixture, a solution of lithium hydroxide monohydrate (LiOH.H2O) (79 mg, 1.89 mmol, 3 eq.) dissolved in water (0.63 ml) was added and stirred at room temperature for 12 hrs. After the completion of reaction, the aqueous layer was washed with ethyl ester and acidified (pH 4) with 6N hydrochloric acid. The resultant was distilled under reduced pressure and extracted with ethyl acetate twice. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography to obtain 268 mg of the title compound as pale yellow foam (100%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.N1C=CC=CC=1.[Na].N1C=CC=CC=1.O>O>[OH:9][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]#[CH:8]
Reactant: c1ccc2occc2c1
Agent: [Na]
Solvent: c1ccncc1
Solvent: O
Product: C#Cc1ccccc1O
Temperature: 25 °C
Yield: 62 %

Procedure:
A 500 ml., three-necked, round-bottomed flask equipped with a thermometer, magnetic stirring bar, reflux condenser, and means for providing a nitrogen atmosphere was charged with a solution of 2,3-benzofuran, 19.0 g. (0.161 mole) in 190 ml. (186 g., 2.35 mole) of pyridine. The reaction system was purged with nitrogen and kept under nitrogen atmosphere throughout the course of reaction. Then freshly cut sodium metal, 11.3 g. (0.490 mole), was added, and the mixture was stirred magnetically and heated with a silicon-oil bath at 190° (reaction mixture temperature 117°) for 4 hours. After cooling to room temperature, the black reaction mixture was treated by successive dropwise addition of 100 ml. of pyridine, 50 ml. of 50% (v/v) pyridine-water, and 100 ml. of water. The resulting red-brown reaction mixture was extracted with 400 ml. of ether. The pyridine-water layer was acidified with excess (750 ml.) of 6 N HCl solution, while the reaction temperature was kept between 20°-30° with an ice-water bath. The acidified mixture was extracted with four 300 ml.-portions of ether. The combined ethereal extracts were washed with 200 ml of 6 N HCl solution and three 200 ml.-portions of water, dried over MgSO4 and concentrated to give 15.3 g. of yellow-brown oil, which was further purified by distillation via a 5" Vigreux column giving rise to 11.7 g. (62% yield) of colorless product, bp12mm 72°-73°.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)=[CH:8][CH:7]=3)[C:12](=[O:25])[CH:13]=2)=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 45 mg (0.13 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-4-ylmethoxy)-1H-pyridin-2-one (example 10.1a) in 3.0 mL DCM is added at RT 56 μL (0.40 mmol) triethylamine and subsequently 21 μL (0.27 mmol) methanesulfonyl chloride. The reaction mixture is stirred 1 h at RT. Additional 56 μL triethylamine (0.40 mmol) and subsequently 21 μL (0.27 mmol) methanesulfonyl chloride are added at RT and the reaction mixture is stirred for additional 1.5 h. Then 22 μL (0.27 mmol) pyrrolidine is added. The mixture is stirred overnight at RT, diluted with 50 mL DCM and is washed four times with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via chromatography (silica gel; DCM/MeOH/NH4OH 9:1:0.1 to 8:2:0.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:18]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1cc(Br)ccc1Sc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1Sc1ccccc1

Procedure:
478 g of 3-bromo-6-(phenylthio)-benzoic acid in 1.5 litres of methanol and 200 ml of concentrated sulphuric acid are heated under reflux for 8 hours. The solution is concentrated under reduced pressure, treated with water and extracted with water. The organic solution is washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained methyl 3-bromo-6-(phenylthio)-benzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl-].[Cl-].[Cl-].[Al+3].[C:14]1(=[O:24])[O:19][C:17](=[O:18])[C@H:16]2[CH2:20][CH:21]=[CH:22][CH2:23][C@@H:15]12>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[C:14]([C@H:15]1[CH2:23][CH:22]=[CH:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:24]
Reactant: COc1ccccc1Cl
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1Cl

Procedure:
0.5 mole of 2-chloroanisole was added slowly to a suspension of 0.5 mole aluminiumtrichloride in 1 l of dichloromethane at 0° C. After complete addition, cis-1,2,3,6-tetrahydrophthalic anhydride was added to the solution. After 8 hours of reflux the solution was poured into ice-cold water. The precipitate was filtered off, washed with water and diethyl ether and dried. M.p. 183-1 85° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 49.0 mg (53%) of the title compound as a colorless solid.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.Cl.[C:28](Cl)(Cl)=[S:29].C>O>[Na+:1].[Na+:1].[Na+:1].[N:4]([C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]2)=[C:28]=[S:29]
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1cc(N=C=S)c2c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 129.8 %

Procedure:
To a solution of 78.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt in 500 ml of water is added 17.0 ml of concentrated hydrochloric acid. The solution is cooled to room temperature and 29 g of thiophosgene is added with vigorous stirring. Stirring is continued for 2.5 hours at room temperature. The mixture is treated with activated charcoal, filtered through diatomaceous earth and evacuated by water pump to remove excess thiophosgene. The filtrate is neutralized with 5N sodium hydroxide and evaporated in vacuo to 250 ml. The solution is allowed to crystallize at room temperature, then in an ice bath. The mixture is filtered and the precipitate is washed with ice water, acetone and ether to give a yellow powder. The power is recrystallized from 110 ml of water by warming, then cooling and seeding. The product is collected after standing and the resulting filtrate is concentrated and recrystallized as above. The products are combined and dried by conventional means to yield 36.9 g of 8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Br:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][C@H:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[Br:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: O=CCC1Cc2ccc(Br)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)Cn1ccc2c1-c1cc(Br)ccc1C2
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.37 g of (R)-1-amino-2-propanol in 10 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 4:1). 1.19 g (52%) of (R)-1-(7-bromo-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=1[O:19][CH3:18])#[N:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1I
Temperature: 60 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (5.60 g, 0.0145 mol) and 2,4-dimethoxybenzylamine (3.51 mL, 0.0234 mol) were combined in tetrahydrofuran (100 mL) and stirred at 60° C. for three days. The reaction was concentrated in vacuo, diluted with dichloromethane and hexanes and the resultant precipitate was filtered to yield the title compound (5.56, 81%) as a yellow solid. LCMS: (FA) ES+, 473. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (s, 1H) 7.10 (d, 1H, J=8.57 Hz), 6.60-6.50 (m, 2H), 4.30 (s, 2H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.26-1.21 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH2:5]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Reactant: CN1Cc2cc(I)ccc2N(C)C1=O
Product: C[C@H]1C[C@@](O)(c2csc(Sc3ccc4c(c3)CN(C)C(=O)N4C)c2)CCO1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)thien-4-yl]tetrahydropyran in 74% yield as a gum;
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:22]([CH3:23])[C:21]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH:33][CH2:34][CH3:35])[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]([CH2:39][C:40](Cl)=[O:41])[CH3:38]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:22]([CH3:23])[C:21]3[CH2:20][CH2:19][N:18]([C:40](=[O:41])[CH2:39][N:37]([CH3:38])[CH3:36])[CH2:17][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH:33][CH2:34][CH3:35])[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCNC3)N2C)C(=O)N1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCN(C(=O)CN(C)C)C3)N2C)C(=O)N1Cc1ccccc1

Procedure:
To the product of Example 183 in CHCl3 was added N,N-dimethylaminoacetyl chloride and TEA. After 4 h the product mixture was concentrated and chromatographed (silica gel, 0-40% EtOAc/Hex) to yield the title compound. 1H-NMR (CDCl3): δ 7.39-7.44 (2H, m), 7.33 (2H, m), 7.23-7.30 (2H m), 7.19 (1H, br s), 6.47 (1H, d), 5.15 (2H, s), 4.61 (1H, br s), 4.51 (1H, br s), 4.27 (1H, m), 3.92 (2H, m), 3.64 (3H, br s), 3.22 (1H, br s), 3.16 (1H, br s), 2.99 (2H, m), 2.63 (1H, br s), 2.56 (1H, br s), 2.31 (3H, s), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 588 (MH+).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13][CH2:12]3)[O:3]1.Cl>C1COCC1.O>[CH2:22]([O:21][C:19]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]([OH:5])[OH:3])[CH:10]=2)[CH2:15]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)OC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2cc(B(O)O)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a stirring solution of benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.991 g, 2.52 mmol, 1.00 eq) in THF (10 ml) and H2O (2.5 ml) was added NaIO4 (1.62 g, 7.56 mmol, 3.00 eq). The resulting suspension was stirred at 25° C. for 30 min and then treated with 3M HCl (1.68 ml, 5.04 mmol, 2.0 eq). The mixture was stirred for 2.5 h. The supernatant was decanted away from the solids, rinsing forward with THF. The combined organic phases were washed with brine (2×), dried (MgSO4) and concentrated in vacuo to give crude 2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.640 g, 82% yield) as a foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 7.68-7.58 (m, 2H), 7.45-7.29 (m, 6H), 7.17 (m, 1H), 5.13 (s, 2H), 4.62-4.56 (brm, 2H), 3.65 (brs, 2H), 2.86 (t, 2H, J=5.60 Hz); MS (ESI) m/z: 312.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C([O:27][C:28](=O)[CH2:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31])(C)(C)C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:28](=[O:27])[CH2:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: CC(C)(C)OC(=O)CC(=O)C1CC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192e) was reacted with 3-cyclopropyl-3-oxo-propionic acid tert-butyl ester (CAS Reg. No. 134302-07-1) to give the title compound as brown oil. MS (ESI): m/z=448.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: FC1(F)CCNCC1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
A suspension of 1-bromo-4-(3-bromopropoxy)benzene (1.85 g, 6.29 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.34 mmol) and potassium carbonate (2.17 g, 15.7 mmol) in acetonitrile (100 mL) was heated to 60° C. overnight, then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. The layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3) afforded the title compound as a clear oil (1.07 g, 50%). LCMS m/z 334.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.08 (m, 6H) 2.47-2.64 (m, 6H) 3.99 (t, J=6.34 Hz, 2H) 6.75-6.81 (m, 2H) 7.34-7.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(C2=CC3CCC(C2)N3)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Fc1ccc(C2CC3CCC(C2)N3)cc1
Yield: 89.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene (10 g) was dissolved in glacial acetic acid (150 ml). Platinum oxide (0.5 g) was added followed by treatment with hydrogen gas at 3 atm of pressure in a conventional Parr apparatus. Filtration and removal of solvent in vacuo left a viscous oil. Water was added and the mixture made alkaline (pH>9) with aqeous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo gave 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]-octane (9 g) as an oil. The title compound 24 was obtained from 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]octane and 4-(1,2-benzisoxazol-3-yl)-1-butyl methanesulfonate (prepared as described in EXAMPLE 19) by the method described in EXAMPLE 2. The oxalate salt crystallized from acetone by addition of oxalic acid. Yield. 1.1 g, mp: 169-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[SH:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:25][CH2:24][CH:23]([S:39][C:35]2[N:34]([CH3:33])[CH:38]=[N:37][N:36]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: Cn1cnnc1S
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(Sc2nncn2C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (92 mg, 0.2 mmol, 1.0 eq.), 4-methyl-4H-[1,2,4]triazole-3-thiol (46 mg, 0.4 mmol, 2.0 eq.), triphenylphosphine (105 mg, 0.4 mmol, 2.0 eq.), DIAD (77 μL, 0.4 mmol, 2.0 eq.) and triethyl amine (42 μL, 0.3 mmol, 1.5 eq.) were weighed into a round-bottomed flask containing THF (2.0 mL). The solution was purged with N2 and stirred at room temperature for 12 h. The solution was concentrated to an oil and then purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (63 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]3[CH:24]=[CH:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[CH:20]([S:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:19]=3[CH:35]=1)[CH:6]=[CH:5]2.[OH-].[Na+:37]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]3[CH:24]=[CH:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[CH:20]([S:29][CH2:30][CH2:31][C:32]([O-:34])=[O:33])[C:19]=3[CH:35]=1)[CH:6]=[CH:5]2.[Na+:37]
Reactant: O=C(O)CCSC1c2ccccc2C=Cc2ccc(/C=C/c3ccc4cc(F)c(F)cc4n3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])CCSC1c2ccccc2C=Cc2ccc(/C=C/c3ccc4cc(F)c(F)cc4n3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[3-[(E)-2-(6,7-difluoroquinolin-2-yl)ethenyl]-5H-dibenzo[a,d]cyclohepten-5-yl]thio}propionic acid obtained in Example 4(a) was dissolved as such in a mixed solution of 10 ml of tetrahydrofuran and 20 ml of methanol, 0.35 ml (0.35 mmol) of an aqueous 1N sodium hydroxide solution was added to the solution and the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>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>[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: Nc1ncccc1Br
Reactant: CCC(C)c1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: CCC(C)c1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of sodium carbonate (412 mg), tetrakis(triphenylphosphine)palladium(0) (112 mg), 4-(1-methylpropyl)phenylboronic acid (450 mg) and 3-bromopyridin-2-amine (336 mg) in 1,2-dimethoxyethane (15 mL) and water (3 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (392 mg) as a pale-yellow solid.