Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH:8]=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>C1C=CC=CC=1>[Cl-:1].[O:7]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[CH:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCCCCl
Solvent: c1ccccc1
Product: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
A solution containing 20 parts of (5-chloropentanoylmethylene)triphenylphosphorane in 200 parts of benzene is heated at the reflux temperature for about 16 hours. Cooling of this solution results in crystallization of a product which is isolated by filtration to afford [(tetrahydro-2H-pyran-2-ylidene)methyl]triphenylphosphonium chloride. This product is characterized by 60-MHz nuclear magnetic resonance peaks in CDCl3 (deuterated chloroform) at about 107 cps (multiplet), 170 cps (multiplet), 228 cps (multiplet) and 329 cps (doublet, J≃ 18 cps) in addition to the aromatic protons. This compound melts at about 215°-221° C. and is represented by the following structure: ##STR8##
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OC(=O)[N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)(C)(C)C.[H-].[Na+].C(OCC)C>CN(C)C=O.O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]#[N:15])[CH2:29][CH2:28][NH:24][CH2:25][CH2:26]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Temperature: 70 °C

Procedure:
To a solution of (3,5-bis-trifluoromethylphenyl)-acetonitrile (25 mmol; 6.33 g) and bis-(2-chloroethyl)-carbamic acid tert-butyl ester (28 mmol; 6.73 g) in N,N-dimethylformamide (50 mL) under Argon was added sodium hydride (75 mmol; 1.90 g) in small portions over a 30 min period. When the addition was complete, the resulting mixture was heated at 70° C. for 1 hour, then stirred for 2½ days at room temperature. Diethyl ether (250 mL) was added, followed by water (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and evaporated. The resulting residue was dissolved in a 4N hydrochloric acid solution (20 mL) and the mixture was stirred for 1 hour at room temperature. The resulting mixture was evaporated and triturated with diethyl ether (50 mL). The solid was separated via centrifugation and purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with a 1N sodium hydroxide solution (20 mL). The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in diethyl ether, and a 1N HCl solution in diethyl ether (10 mL) was added dropwise. A white precipitate formed that was separated via centrifugation and dried under vacuum to yield 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carbonitrile as a hydrochloride salt. MS (ESI) m/z 323.1 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (84 mg, 47%). 1H NMR (CDCl3): 9.80 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 6.26-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.08 (s, 1H), 2.99 (s, 1H), 1.96-1.89 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.47-1.41 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li+].CC([N-]C(C)C)C.[CH:19](N1CCCCC1)=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([C:5]([F:9])=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)c(F)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 1-bromo-2,4,5-trifluoro benzene (25 g, 0.12 mol) in THF (200 mL) at -78° C. was added LDA (80 mL, 1.5 M) dropwise. The mixture was stirred at -78° C. for 1 hour, then N-formylpiperidine (16 g, 0.144 mol) was added in one portion and stirring continued for 2 hours. An additional 15 g of N-for ylpiperidine was then added every 0.5 hour in 5 g portions. The reaction was quenched with 3N HCl (pH 3) at -78° C. The reaction was warmed to 0° C. and partitioned between zO and ether. The ether layer was dried and concentrated and the residue was distilled to provide 13 g (45%) of the desired aldehyde; bp 63°-65° C. (0.2 mm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8](N)[S:9][CH:10]=1)[CH3:2].[Cl:13][CH2:14][C:15](Cl)=[O:16].O.C[N:20](C)C(=O)C>>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH:20][C:15](=[O:16])[CH2:14][Cl:13])[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: O
Product: CCOC(=O)C(NC(=O)CCl)c1cscn1
Yield: 92 %

Procedure:
To a solution of 9.3 g of 2-amino-4-thiazolyl acetic acid ethyl ester in 50 ml of N,N-dimethylacetamide is added under ice-cooling 7.91 g of chloroacetyl chloride with stirring. The mixture is stirred for one hour at room temperature, to which is added 300 ml of water. Then the resulting crystals are collected by filtration. The crystals are washed with water and ether in this order, followed by drying over phosphorus pentachloride to yield 12.1 g (92%) of 2-chloroacetamido-4-thiazolyl-acetic acid ethyl ester, m.p. 145°-146° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27]#[N:28])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: N#C/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.9 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (10.25 g, 43 mmol) in CH2Cl2 (55 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylnitrile (5.70 g, 29 mmol) and trifluoroacetic acid (0.22 mL, 3 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2) afforded the title compound (7.0 g, 73%) as a colorless oil. ES-MS m/e: 332.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].C1(C)C=CC=CC=1>C(N(CC)CC)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a suspension of 5.000 g of methyl 3-hydroxybenzoate, 6.955 g of 4-nitrophenyl chloroformate, and 100 mL of toluene was added 4.81 mL of triethylamine at room temperature, followed by stirring overnight. The insolubles were removed by filtration, and as solvent was removed by distillation under reduced pressure to obtain 5.948 g of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a pale yellow solid. To a mixture of 100 mg of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate, 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, and 4 ml of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate as a pale yellow oily compound.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CCOCC>CCOC(C)=O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 44.3 %

Procedure:
Following the procedure described for Preparation 13(A), 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (5.0 g, 18.1 mmol) was alkylated with tert-butyl bromoacetate (2.94 mL, 19.9 mmol). Trituration with Et2O (100 mL), hexanes (30 mL) and EtOAc (10 mL) provided 3.13 g of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester. 1H NMR (CD3OD) δ 7.68 (d, 1H), 7.60-7.51 (m, 4H), 7.43 (m, 2H), 7.23 (t, 1H), 6.99 (d, 1H), 4.86 (d, 1H), 4.44 (d, 1H), 3.99 (d, 1H), 3.83 (d, 1H), 1.36 (s, 9H); MS 391.4 (M+1), 389.3 (M−1).
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]1[CH:19]2[CH2:20][CH:21]([OH:23])[CH2:22][CH:16]1[CH2:17][CH2:18]2>>[ClH:13].[C:1]1([C:7]2([C:11]([O:23][CH:21]3[CH2:22][C@H:16]4[N:15]([CH3:14])[C@H:19]([CH2:18][CH2:17]4)[CH2:20]3)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Product: CN1[C@@H]2CC[C@H]1CC(OC(=O)C1(c3ccccc3)CCC1)C2
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarbonyl chloride with tropine at 80° C. for 22 h. The yield was 0.5 g (28%); mp 181-183° C.; 1H NMR (D2O) δ 1.78 (q, 2H), 1.96 (m, 1H), 2.04 (d, 2H), 2.13 (m, 3H), 2.38 (m, 2H), 2.64 (m, 2H), 2.77 (s, 3H), 2.87 (m, 2H), 3.82 (m, 2H), 5.07 (t, 1H), 7.42 (m, 1H), 7.47 (m, 2H), 7.52 (m, 2H). Anal. (C19H25NO2.HCl) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:21]([OH:22])=[N:20][C:11]2[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CN1CCCC1=O.C(OCC)(=O)C>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:13]2[N:14]=[CH:15][C:10]3[CH:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:21]([OH:22])=[N:20][C:11]=3[N:12]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc3cc(-c4ccccc4Cl)c(O)nc3n2)CC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a solution of sulfone 2 (1.27 g, 3.78 mmol) in 15 mL of 1-methyl-2-pyrrolidinone was added trans-1,4-diaminocyclohexane (3.75 g, 32.8 mmol). The reaction mixture was stirred at 65° C. for 1.5 hours, cooled, and diluted with 80 mL of ethyl acetate. The resulting suspension was filtered and washed several times with ethyl acetate and methanol. The solid was dried to yield 1.31 g (94%) of 2-(trans-4-aminocyclohexylamino)-6-(2-chlorophenyl)-pyrido[2,3-d]pyrimidin-7-ol as an off-white powder (mass spec. M+H+=370). The free base was taken up in ethyl acetate and treated with a 1 M solution of HCl/Et2O to form the dihydrochloride salt of the title compound as a white powder with a melting point of >300° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C@:9]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH3:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:32][C:30]1[N:31]=[C:26]([CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C@:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)([OH:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: Cc1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccc(CN2CCC(NC(=O)[C@](O)(c3ccccc3)[C@@H]3CCC(F)(F)C3)CC2)n1
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 17 mg of (2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide in 2 ml of tetrahydrofuran, 3 μl of acetic acid, 12 mg of 6-methylpyridine-2-carbaldehyde and 21 mg of sodium triacetoxyborohydride were added sequentially at room temperature, and stirred overnight at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck) chloroform/methanol=10/1) to provide 9 mg of the title compound as a solid substance.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2([Cl:18])C=O)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].O>C(O)C>[C:27]([C:29](=[CH:21][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]=1[Cl:18])[C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28]
Reactant: O=CC1(Cl)Cc2ccccc2N1Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
To 608 mg of 1-(4-chlorobenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (9a). Yield 650 mg of (9a). M.p. 179°-80° C. (sample recryst. from EtOH).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])[C:4]([OH:13])=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[C:18](=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CO>[CH3:18][O:10][C:9](=[O:11])[C@H:8]([CH2:7][C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[OH:13])[NH:12][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C([O-])[O-]
Reactant: NC(Cc1ccccc1O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1O)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
9.5 g (52.4 mmol) of o-tyrosine (2-hydroxyphenylalanine, Heraeus) is suspended in 48 ml of methanol, cooled in an ice bath and mixed drop by drop with 7.6 ml (105 mmol) of thionyl chloride. After one hour, the batch is heated to reflux temperature and stirred for three hours. Then, it is allowed to stir overnight at room temperature. It is evaporated to dryness, the residue is taken up in methanol, concentrated by evaporation and the process is repeated twice. It is taken up in 50 ml of water, adjusted to pH 8.5 with 1.5 molar sodium carbonate solution and 22.1 ml (63 mmol) of benzyl chloroformate is added under pH control. It is stirred for four hours at room temperature, the organic phase is separated, it is washed with water and dried on sodium sulfate. After the concentration by evaporation, the residue is chromatographed on silica gel (methylene chloride/ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH2:27][CH2:28][OH:29])=[N:3][CH:4]=1
Reactant: NCCO
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: OCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 56 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (180 mg, 0.43 mmol) obtained in Example 54 and 2-aminoethanol (300 μl) was stirred at 120° C. for 64 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (106 mg, 56%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.[CH3:12][NH:13][CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:13]([CH3:14])[CH3:12])[CH2:6][CH2:5]2
Reactant: ClC1CCc2cc(Br)ccc21
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)C1CCc2cc(Br)ccc21
Temperature: 90 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-1-chloro-indane (542 mg, 2.35 mmol) in toluene (9 ml) was added dimethylamine (3 ml) and resulting mixture was heated at 90° C. for 1.5 hr. The reaction mixture is concentrated under reduced pressure to yield the title compound (300 mg, 53%). 1H NMR (CDCl3): 2.06 (m, 2H), 2.24 (s, 6H), 2.81-2.93 (m, 2H), 4.27 (t, 1H), 7.22 (d, 1H), 7.33 (d 1H), 7.36 (s, 1H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH2:34]1[C:37]2([CH2:40][NH:39][CH2:38]2)[CH2:36][O:35]1.C(=O)([O-])[O-].[K+].[K+].CC#N>C(Cl)Cl>[F:31][C:28]([F:29])([F:30])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][N:39]2[CH2:40][C:37]3([CH2:36][O:35][CH2:34]3)[CH2:38]2)=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: C1NCC12COC2
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC3(COC3)C2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 31.9 %

Procedure:
A 10-mL microwave vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.140 g, 0.265 mmol, Intermediate B), 2-oxa-6-azaspiro[3.3]heptane (0.026 g, 0.265 mmol. ASW MedChem, Inc. New Brunswick, N.J.), potassium carbonate (0.040 g, 0.291 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 100° C. for 1 h. The mixture was diluted with 5 mL of CH2Cl2, filtered, and the filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (20-100% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.045 g) as a mixture of two isomers:
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19]1([CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]([Mg]Br)[CH:20]=1.Cl.O>C1COCC1.C(OCC)(=O)C>[C:19]1([CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]([C:4](=[O:17])[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:20]=1
Reactant: CON(C)C(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc([Mg]Br)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)CCc2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 82.1 %

Procedure:
To a solution of 0.4 g (1.5 mmol) N-Methoxy-N-methyl-3-(4-trifluoromethyl-phenyl)-propionamide in 7 mL THF under argon at 0° C., was added dropwise 3.062 ml (3.1 mmol) m-Tolylmagnesiumbromid (1M in THF). The reaction mixture was stirred for 15 minutes at 0° C. and at RT for 50 minutes, cooled to 0° C. and acidified with 1N HCl to pH 1-2. Water and ethyl acetate were added and the water phase was extracted twice with ethyl acetate. The organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified with flash column chromatography on silica gel eluting with a gradient formed from heptane and ethylacetate to provide 0.36 g (81%) of title compound as colorless oil. MS (m/e): 293.0 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[CH:6]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[C:6]=1[Br:26]
Reactant: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2Cl2 (7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 413) and concentrated. The dried product showed about 14% of di-bromonated product by analytical HPLC. The compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water (30 minute gradient) at a 100 mL/min flow rate to afford (after lyophilization) the salt of the desired compound. The salt was diluted in ethyl acetate and washed with NaHCO3. The organic extracts were dried over anhydrous Na2SO4 and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid. 1H-NMR (d6-DMSO, 400 MHz) δ7.94 (d, 1H, J=7.2 Hz), 7.29 (m, 10H), 6.48 (s, 1H), 5.12 (s, 2H), 3.33 (s, 3H); ES-HRMS m/z 413.0495 (M+H calculated for C20H18O3Br requires 413.0496).