Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17])([OH:6])[CH2:4]Cl.[H-].[Na+]>C(O)(C)(C)C>[Cl:1][CH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[F:17])[CH2:4][O:6]1
Reactant: OC(CCl)(CCl)c1ccc(C(F)(F)F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Fc1cc(C(F)(F)F)ccc1C1(CCl)CO1
Temperature: 100 °C

Procedure:
1,3-Dichloro-2-(2-fluoro-4-trifluoromethylphenyl)-2-propanol (7 g.) was added to a solution of sodium hydride (1.45 g. of 48% dispersion in oil) in tert-butyl alcohol (30 ml.) and heated at 100° C. for 1 hour. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried with anhydrous magnesium sulphate, and the filtered solution was evaporated to dryness to give 2-chloromethyl-2-(2-fluoro-4-trifluoromethylphenyl)oxirane as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=O)[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:20])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:38])=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:38])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2Cc1ccccc1
Product: FC(F)(F)c1nc(Cl)c2c(n1)C(Cc1ccccc1)N(Cc1ccccc1)CC2
Temperature: 150 °C
Yield: 66 %

Procedure:
A mixture of 669 mg (1.68 mmol) of 7,8-dibenzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol and 1.2 mL of phenylphosphonic dichloride was heated in a sealed tube at 150° C. for 2.5 h. The mixture was cooled to ˜100° C., then poured into crushed ice, washing with ethyl acetate. The resultant biphasic mixture was neutralized with solid sodium bicarbonate to ˜pH 8 with vigorous stirring. The ethyl acetate layer was removed. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried, and concentrated to give a red, viscous oil. Purification by Biotage chromatography (silica gel, 5% ethyl acetate/hexane) gave 464 mg (66%) of the title compound as a yellow solid. LC-MS 418.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylene chloride (96 mL) was cooled to 0° C. in an ice bath. Triethylamine (4.9 mL, 35 mmol) was introduced to the solution followed by dropwise addition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with methylene chloride and washed with 0.5 N HCl, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.00 (m, 1H), 6.87 (m, 2H), 2.29 (m, 6H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([F:27])[C:22]=1[O:23][CH2:24][C:25]#[CH:26])[C:11]([N:13]1[CH:19]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:5]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[NH:13][C:11](=[O:12])[C:10]1[CH:20]=[C:21]([F:27])[C:22]([O:23][CH2:24][C:25]#[CH:26])=[C:8]([F:7])[CH:9]=1)#[N:6]
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C#N)cc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
At room temperature, 99 mg of trimethylsilyl cyanide was added dropwise to a mixture of 12 ml of tetrahydrofuran and 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and, further, tetrabutylammonium fluoride (0.05 ml of 1M tetrahydrofuran solution) was added. The resulting mixture was heated with stirring at 40° C. for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.24 g of N-(2-cyanocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 80 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:16]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:17])=[O:5]
Reactant: O=C=NC1CC1
Reactant: NNC(=O)c1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccccc1Cl)NC1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 10.0 g (58.6 mmol) of 2-chlorobenzoic acid hydrazide is placed in 50 ml tetrahydrofuran. 4.87 g (58.6 mmol) of cyclopropyl isocyanate, dissolved in 50 ml tetrahydrofuran, are added dropwise at 50° C., and the mixture further stirred overnight at 50° C. The resulting precipitate is filtered off after cooling to room temperature and then washed with diethyl ether. 13.9 g (93% of theory) of the target compound are thus obtained.
Reaction SMILES: C(N1CCC2(CC3C=C([Cl:22])C=CC=3O2)CC1)C1C=CC=CC=1.Cl.C([N:31]1[CH2:36][CH2:35][C:34]2([CH2:40][C:39]3[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:38]=3[O:37]2)[CH2:33][CH2:32]1)C1C=CC=CC=1>>[ClH:22].[Cl:45][C:42]1[CH:43]=[CH:44][C:38]2[O:37][C:34]3([CH2:33][CH2:32][NH:31][CH2:36][CH2:35]3)[CH2:40][C:39]=2[CH:41]=1
Reactant: Clc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: Cl
Product: Clc1ccc2c(c1)CC1(CCNCC1)O2

Procedure:
A sample of 2,3-dihydro-1'-benzyl-5-chlorospiro[benzofuran-2,4'-piperidine], free base of Example 6, is treated in a manner consistent with the procedure of Example 9 to provide the product 2,3-dihydro-5-chlorospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 217°-218° C. This product is obtained after three recrystallizations, two from ethyl alcohol and then one from an ethyl alcohol-ether mixture.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:29])CC.C(=O)(O)[O-].[Na+].C(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[F:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNCC(F)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
159 mg of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine (0.5 mmol, described in example S43) in 5 ml DCM was cooled to 2° C. and treated with 0.2 ml of DAST (1.5 mmol) for 2 min. After 2 h stirring at 0° C. followed by 1 h at rt, the reaction mixture was again cooled down to 0° C. and treated with 5 ml saturated aqueous sodium bicarbonate. The reaction mixture was stirred until CO2 evolution stopped, then the organic phase was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was Purified by silicagel chromatography (40 g silica gel; heptane/EtOAc 2:1) leading to 27 mg of a light yellow semi-solid (17%). M(ISP) 320.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([NH2:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:15]([S:22](Cl)(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:12][S:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])([CH3:11])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(N)(C#N)COc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C#N)(COc1ccc(Cl)cc1)NS(=O)(=O)Cc1ccccc1

Procedure:
suspension of 1-(4-chloro-phenoxy)-propan-2-one (3.7 g, 20 mmol), ammonium chloride (1.6 g, 29.2 mmol) and sodium cyanide (1.15 g, 23.3 mmol) in a solution of aqueous ammonia (100 ml, 28%) is stirred vigorously at room temperature for 20 hours. The aqueous phase is extracted repeatedly with ethyl acetate. The collected organic extracts are dried and the solvent is evaporated under reduced pressure to give the 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile as a solid. c) A solution of 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile (0.5 g, 2.4 mmol) and benzylsulfonyl chloride (0.5 g, 2.6 mmol) in pyridine (5 ml) is heated at +80° C. with stirring in the presence of DMAP (0.02 g) for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate and the product is purified by flash chromatography (eluent: ethyl acetate/hexanes 1:3) to give the 2-(4-chlorophenoxy-methyl)-2-benzylsulfonylamino-propionitrile in form of a colorless solid, m.p. 120-121° C.
Reaction SMILES: S(C)C.[C:4]1([S:10]([N:13]2[C:23]3[C:24]4[C:15]([CH2:16][NH:17][C:18](=O)[C:19]=4[CH:20]=[CH:21][CH:22]=3)=[CH:14]2)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[C:4]1([S:10]([N:13]2[C:23]3[C:24]4[C:15]([CH2:16][NH:17][CH2:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)=[CH:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCc2cn(S(=O)(=O)c3ccccc3)c3cccc1c23
Solvent: C1CCOC1
Solvent: CSC
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNC2
Reaction time: 5 h

Procedure:
SMe2 (205 μL, 2.2 mmol) was added dropwise over 5 min. to a refluxing mixture of 1-(phenylsulfonyl)-3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-one, Intermediate 2, (225 mg, 0.72 mmol) in dry THF (10 mL) with continuous reflux for 2.5 h. Additional two portions BH3:SMe2 (100 μL×2) were added (2.5 h reflux between the additions). Reflux was continued for 5 h after the last addition, then room temperature over night. The reaction was quenched by addition of HCl in MeOH (1.25 M, 4 mL) and reflux 1 h. The solvent was evaporated and the crude mixture was extracted with DCM (×2) and sat. Na2CO3(aq). The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (3-5% MeOH in DCM) which gave 66 mg of the title compound as a beige solid. MS m/z 299 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[CH:52]=[CH:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: C=Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC1(CCO)OCCc2c1[nH]c1c(C=Cc3ccccc3)cc(C(C)C)cc21
Temperature: 90 °C

Procedure:
The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(dibenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90° C. (oil bath) overnight. It is quenched with water and extracted with ethyl acetate. Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6](N)=[C:5]([O:11][CH3:12])[CH:4]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:24]#[N:25].[C-]#N.[Na+]>Cl.O.C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:24]#[N:25])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1cc(Br)cc(C)c1N
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(C)c1C#N
Temperature: 0 °C
Yield: 53.4 %

Procedure:
(4-Bromo-2-methoxy-6-methyl-phenyl)-amine hydrobromide (5.0 g, 23.2 mmol) is suspended in concentrated hydrochloric acid (5.5 ml) and ice (20 g) followed by the drop wise addition of a solution of sodium nitrite (1.63 g, 23.6 mmol) in water (5.5 ml) at 0° C. The resulting mixture is stirred at 0° C. for 30 min and neutralized with aqueous sodium carbonate. This mixture is then added with vigorous stirring at 0° C. to a suspension prepared by mixing copper(I) cyanide (2.6 g, 28.9 mmol) in water (11 ml) with a solution of sodium cyanide (3.6 g, 73.6 mmol) in water (5.5 ml) at 0° C. To the mixture is added toluene (45 ml) and stirred at 0° C. for 1 h, at RT for 2 h and at 50° C. for 1 h. The reaction mixture is cooled and the toluene layer is separated. The organic layer is washed with water (2×40 ml), dried over sodium sulfate and evaporated to get the crude product which is purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to obtain 4-bromo-2-methoxy-6-methyl-benzonitrile (2.8 g, 12.4 mmol, 53%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:5][C:6]=1[C@H:7]([O:10]C(=O)[C@H](OC)C1C=CC=CC=1)[CH2:8][CH3:9].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[S:5][C:6]=1[C@H:7]([OH:10])[CH2:8][CH3:9]
Reactant: CC[C@@H](OC(=O)[C@H](OC)c1ccccc1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC[C@@H](O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 3.74 g of (−)-(R)-methoxy-phenyl-acetic acid (R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propyl ester in 19 mL of tetrahydrofuran and 19 mL of ethanol at 0° C. was dropwise added 24.5 mL of a molar solution of sodium hydroxide in 20.4 mL of water. The resulting mixture was stirred at 0° C. for 15 minutes then 24.5 mL of a 5N solution of hydrochloric acid in 20.4 mL of water was added. After removal of the organic solvents under vacuum, the mixture was extracted with ethyl acetate, filtered through a silicone treated paper filter and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane 90/ethyl acetate 10) to give 2.09 g of (+)-(R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.O.NN>C1COCC1.CCO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(5-nitro-1-benzofuran-7-yl)piperazine-1-carboxylate* (1 g, 2.9 mmol) was dissolved in THF/EtOH (1:4). An excess of Raney-Ni (slurry in ethanol) was added followed by hydrazine-hydrate (0.58 g, 11.5 mmol). The reaction mixture was stirred at room temperature overnight. Filtration and evaporation afforded 1.19 g of the title product that was used in the next step without further purification. HPLC purity 93%, RT=1.71 min (System A; 10-97% MeCN over 3 min). *Previously described in WO 2002100822.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29]CC=C)=[O:28])=[CH:5][CH:4]=1)#[N:2].N1CCOCC1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl 4-(4-cyanophenyl)-2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydro-3-pyridinecarboxylate (Example 46) (1.00 g, 2.27 mmol) and tetrakis(triphenylphosphin)-palladium(0) (68 mg, 0.059 mmol) in tetrahydrofuran (50 ml) is slowly added morpholine (3.36 g, 38.6 mmol). After stirring at room temperature for 1 h, the reaction mixture is quenched with water (50 ml). The basic solution (pH ca. 10) is neutralised with 1 N hydrochloric acid, and the aqueous phase is extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water, dried, and the solvent is removed in vacuo to yield pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(=O)([O-])[O-]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:18][C:19]2[CH:24]=[N:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11](=[O:15])[C:10]=1[Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc(OCc2ccccc2)c1Br
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccccc2)ccn1Cc1ccc(F)nc1

Procedure:
A mixture of 4-(benzyloxy)-3-bromopyridin-2(1H)-one (0.2 g, 0.00076 mol), 5-bromomethyl-2-fluoropyridine (0.25 g, 0.0013 mol) and pot. Carbonate (0.15 g, 0.0011 mol) in DMF (3.0 ml) was stirred at room temperature for 16 h under argon atmosphere. DMF was distilled in vacuo and the residue was partitioned between water (15 ml) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. 1H NMR (CD3OD/400 MHz) δ 8.22 (m, 1H, 2.4 Hz), 7.92 (m, 1H), 7.82 (d, 1H, J=7.6 Hz), 7.44-7.31 (m 5H), 7.03 (m, 1H) 6.49 (d, 1H, J=7.6 Hz), 5.29 (s, 2H), and 5.20 (s, 2H); 19F NMR (CD3OD/400 MHz)6-72.30 (d, J=6.0 Hz) and −115 (m); ES-HRMS m/z 389.0295 (M+H C18H15N2O2FBr, requires 389.0309).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([Mg]Cl)([CH3:11])[CH3:10].C(N(CC)CC)C.II>COCCOC.O1CCCC1>[Cl:8][C:5]1[N:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: CC(C)[Mg]Cl
Reactant: Fc1cnc(Cl)nc1
Agent: II
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)c1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 5-fluoro-2-chloropyrimidine (5.00 g, 37.7 mmol) in 1,2-dimethoxyethane (25 mL) is treated with a solution of 2 M isopropyl magnesium chloride in tetrahydrofuran (28.3 mL, 56.6 mmol) while keeping the temperature below 15° C. The resulting solution is stirred for one hour under nitrogen and then cooled to 0° C. and treated drop wise with a solution of triethylamine (5.76 mL, 37.7 mmol) in tetrahydrofuran (5 mL). A solution of iodine (9.58 g, 37.7 mmol) in tetrahydrofuran (20 mL) is added. The reaction is quenched with water and saturated sodium bicarbonate and saturated sodium bisulfate are added. The mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel with a 30 minute gradient, dichloromethane/hexanes (5 to 100%) to give the title compound (2.55 g, 39%). GC/MS (m/e): 174.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cn1ncc2cc(CN)ccc21
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Product: Cc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-methylbenzene-1-sulfonyl chloride and (1-methyl-1H-indazol-5-yl)methanamine.
Reaction SMILES: CS(C(CCCC(OC(=O)C)CCCCC)CCCCCCC(OC)=O)(=O)=O.[CH3:29][S:30]([CH:33]([CH2:44][C:45]#[C:46][CH:47]([O:55]C(=O)C)[C:48]([CH3:54])([CH3:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]C)=[O:41])(=[O:32])=[O:31]>>[CH3:29][S:30]([CH:33]([CH2:44][C:45]#[C:46][CH:47]([OH:55])[C:48]([CH3:54])([CH3:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])(=[O:31])=[O:32]
Reactant: CCCCC(C)(C)C(C#CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCC(C)(C)C(O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 3, Step E, except that methyl 8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent amount of methyl 8-methylsulfonyl-12-acetoxy-13,13-dimethyl-10-heptadecynoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12](C)[CH3:13]>CCO>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)C
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 40 °C
Yield: 89.6 %

Procedure:
A mechanically stirred mixture of 2-chloro-5-nitropyridine (56.25 g, 0.355 mol) and absolute EtOH (960 ml), under nitrogen was treated, during 15 minutes with 25% aqueous trimethylamine (217 g). The mixture warmed to 40° C. and a thick yellow precipitate formed; it was warmed to 80° C. during 1 hour, cooled to ambient temperature and filtered. The solid was washed with cold 20% H2O-EtOH and dried to give 53.2 g of the titled product, m.p. 151°-152° C.