Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1.C(O)(=O)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([NH:5][S:6]([CH2:9][C:20]([C:19]1[CH:24]=[CH:25][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)NS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CC(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Under inert gas, 1.00 g of N-tert-butylmethanesulfonamide were initially charged in 20 ml of THF and then, at a temperature of −78° C., 9.00 ml of a 1.6 N butyllithium solution in hexane were added dropwise. After stirring with ice cooling for 5 minutes, the mixture was cooled again to −78° C., and a solution, likewise cooled to −78° C., of 1.33 ml of methyl 4-fluorobenzoate in 10 ml of THF was added dropwise. The mixture was allowed to come to room temperature and stirred for 1 hour. The reaction solution was admixed with 0.82 ml of acetic acid, diluted with 50 ml of ethyl acetate, and washed with 40 ml of saturated aqueous sodium hydrogencarbonate solution and 40 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (662 mg) with a molecular weight of 273.3 g/mol (C12H16FNO3S).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].O.[CH3:16][O:17][CH2:18][CH:19]1[O:23][CH:22]([C:24]([CH2:26][S:27][C@H:28]2[NH:31][C:30](=[O:32])[C@H:29]2[NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:25])[CH2:21][CH2:20]1.C(N(CC)CC)C>ClC(Cl)C.C(Cl)(Cl)Cl>[OH:3][CH:2]([N:31]1[C@H:28]([S:27][CH2:26][C:24]([CH:22]2[CH2:21][CH2:20][CH:19]([CH2:18][O:17][CH3:16])[O:23]2)=[O:25])[C@H:29]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:30]1=[O:32])[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C=O)cc1
Reactant: COCC1CCC(C(=O)CS[C@H]2NC(=O)[C@H]2NC(=O)COc2ccccc2)O1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: COCC1CCC(C(=O)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C(O)C(=O)OCc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxybenzyl glyoxylate (1.82g) in dichloroethane (30ml) was heated at reflux using a Dean and Stark water separator for 1h. The solution was then cooled to room temperature and then (3R,4R)-4-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-ylcarbonylmethylthio]-3-phenoxyacetamidoazetidin-2-one (2.94g) in dichloroethane (20ml) was added followed by triethylamine (0.1ml). The mixture was stirred at room temperature for 1h and then the solvents were removed on a rotary evaporator. The product was isolated as a mixture of isomers (3.23g) by column chromatography of the residue (silica gel, ethyl acetate as eluent); vmax (CHCl3) 3411, 1780, 1745 and 1691cm-1.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[N:1]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 849 mg (4.00 mmol) diethyl pyrazole-3,5-dicarboxylate and 1.02 g (4.00 mmol) 2-bromo-1-(4-tert-butyl-phenyl)-ethanone in 4 ml acetone is treated with 663 mg (4.80 mmol) potassium carbonate. The resulting suspension is stirred overnight at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated to give 1-[2-(4-tert-butyl-phenyl)-2-oxoethyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester as light yellow foam; HPLC/MS 2.77 (A), [M+H] 387.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=[O:14])[CH2:12][CH3:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing 9.5 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, 50 ml of dimethylformamide and 8 ml of dimethylformamide dimethyl acetal was stirred at room temperature overnight and then concentrated to dryness on a rotary evaporator. The residue was refluxed with isopropyl alcohol; the insoluble yellow solid was collected, washed with isopropyl alcohol and dried at 90° C. to yield 2.8 g of 1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, m.p. 278°-280° C. with decomposition. The mother liquor was treated with decolorizing charcoal, filtered and concentrated to about 150 ml and allowed to stand at room temperature. The product that separated was collected, washed with isopropyl alcohol and dried to yield another 1.8 g of product, m.p. 270° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([CH2:30][OH:31])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:31][CH2:30][C:23]12[CH2:22][CH:21]3[CH2:29][CH:25]([CH2:26][CH:27]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:11]=3)[CH2:28]1)[CH2:24]2
Reactant: O=C(O)c1cccc(OCCc2ccccn2)c1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCCc2ccccn2)c1

Procedure:
Prepared from 3-(2-pyridin-2-yl-ethoxy)-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 8.88 (t, 1H), 8.28 (q, 1H), 7.84 (d, 1H), 7.75 (q, 1H), 7.32 (q, 2H), 7.23-7.29 (m, 1H), 6.93-7.04 (m, 1H), 6.44-6.51 (m, 1H), 4.44 (q, 2H), 4.14-4.22 (m, 1H), 3.61 (q, 2H), 3.27 (s, 1H), 2.10-2.24 (m, 2H), 1.98-2.09 (m, 2H), 1.55-1.94 (m, 8H), 1.45-1.54 (m, 1H), 1.40 (d, 1H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17](I)=[C:18]([C@@H:20]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:21])[N:19]=2)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:18]([C@@H:20]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:21])[N:19]=2)[CH:16]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1I
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added phenylboronic acid (0.104 g, 0.852 mmol), (S)-benzyl 1-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)ethylcarbamate (0.250 g, 0.568 mmol), sodium carbonate (0.181 g, 1.74 mmol), and 1,1′-bis(diphenyl-phosphino)ferrocene palladium (II) chloride, 1:1 complex with DCM (0.023 g, 0.028 mmol) in dioxane (3.44 mL) and water (0.34 mL). The suspension was stirred at 110° C. under microwave irradiation for 2 h. Purification by MPLC (eluted with a gradient of 0-6% MeOH in DCM) afforded (S)-benzyl 1-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)ethylcarbamate as a brown oil. LC-MS (ESI) m/z 390.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:22].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1

Procedure:
The product from Example 87A was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. Then the reaction mixture was concentrated, partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and concentrated to yield the title compound. MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([O:34]C(C)(C)C)=[O:33])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45]>Cl.O1CCOCC1>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=4)[C:32]([OH:34])=[O:33])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45]
Reactant: CC1C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccccc2)c2ccccc21
Yield: 13.2 %

Procedure:
A solution of tert-butyl 3-((8-(3-(3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (100 mg, 0.164 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 16 h. The mixture was concentrated and dried in vacuo to afford the hydrogen chloride salt of the title compound as a white powder (12 mg, 14%); 1H NMR (400 MHz, DMSO-d6): δ 1.34 (d, 3H, J=7.6 Hz); 1.63 (d, 2H, J=12.8 Hz); 1.79 (t, 2H, J=6.8 Hz); 2.49 (bs, 2H); 2.56 (bs, 2H); 2.67-2.77 (m, 4H); 3.45-3.51 (m, 1H); 3.7-3.75 (m, 2H); 4.59 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.2 and 7.6 Hz); 6.86 (d, 2H, J=8.4 Hz); 7.01 (t, 1H, J=7.2 and 7.6 Hz); 7.10 (d, 1H, J=8 Hz); 7.19-7.25 (m, 3H); 7.31 (d, 1H, J=7.2 Hz); 7.48-7.52 (m, 2H); 7.86-7.88 (m, 1H); 13.01 (bs, 1H); MS for C33H36N4O4 m/z 553.11 (M+H)+.
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: CC[O-]
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(C)(C)C)cc23)CC1
Yield: 34.6 %

Procedure:
Beginning with 2.00 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride ethanolate and 1.78 gm (14.4 mMol) trimethylacetyl chloride, 0.623 gm (34.6%) of the title compound were recovered as an off-white powder.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:23]1([C:26](Cl)=O)[CH2:25][CH2:24]1.[Cl-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O.CCOCC.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:23]1([CH2:26][N:18]2[CH2:19][CH2:20][CH:21]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][C:12]=3[OH:22])[CH2:17]2)[CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)(C)c1ccc(C2=CCCN(CC3CC3)C2)c(O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 596 mg. (1.98 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 2.25 ml. of toluene and 4.5 ml. of pyridine is added 180 μl (3.96 mmoles) of cyclopropanecarboxylic acid chloride in 2.25 ml. of toluene. The reaction mixture is stirred for one hour at 25° C. and for 0.5 hour at 80° C. Another 180 μl (3.96 mmoles) portion of cyclopropanecarboxylic acid chloride is added and the heating at 80° C. continued for 2 hours. The reaction mixture is cooled and added to 300 ml. of saturated sodium chloride. The quenched mixture is extracted with two 75 ml. portions of dichloromethane. The extract is washed once with 50 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield an oil. A solution of this oil in 100 ml. of ether is added dropwise to a mixture of 3.0 g. (78.9 mmoles) of lithium aluminum hydride in 150 ml. of ether. The reaction mixture is refluxed for 17 hours, cooled in ice and decomposed by the addition of 3 ml. of water, 3 ml. of 15% sodium hydroxide and 9 ml. more of water. After stirring for 30 minutes at 25° C. the quenched reaction mixture is filtered and the filtrate evaporated to a solid. Recrystallization from dichloromethane and pentane gives 296 mg. (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:13]2[N:12]=[C:11]3[C:16]([C:17](=[O:18])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]4[N:10]3[CH:22]=[CH:23][N:24]=4)=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1c2cnc(Nc3ccc(Br)cc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (250.0 mg, 0.695 mmol) and 4-bromoaniline (191 mg, 1.112 mmol) was heated at 90° C. for 1 hour. While warm, the residue was treated with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was triturated with a small amount of ethyl acetate. The solids were filtered, washed with ethyl acetate/hexane, and oven-dried to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14])#[N:2].[S:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>O1CCCC1>[F:11][CH:10]([F:12])[O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:13]([N:19]2[CH2:20][CH2:21][S:17][CH2:18]2)(=[O:15])=[O:14])[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(OC(F)F)cccc1S(=O)(=O)Cl
Reactant: C1CSCN1
Solvent: C1CCOC1
Product: N#Cc1c(OC(F)F)cccc1S(=O)(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
54 mg of 2-cyano-3-difluoromethoxy-benzenesulfonyl chloride in 10 ml of tetrahydrofuran are treated with 32 I of thiazolidine and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo. Purification by HPLC affords 35 mg of 2-difluoromethoxy-6-(thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH2:21][NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC1CN(C(=O)OC(C)(C)C)C1(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)C1(CCNCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the residue (95.0 g) obtained in (7) in tetrahydrofuran (300 ml) was added benzylamine (34 ml) at room temperature, and the mixture was stirred for 2 hours. The mixture was cooled to 0° C. Then, thereto was added sodium triacetoxyborohydride (83.3 g), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water (300 ml), and the mixture was extracted with n-hexane/ethyl acetate (1/3, 600 ml). The separated organic layer was washed with water (300 ml) and saturated aqueous sodium chloride solution (200 ml), and then extracted with 5% aqueous citric acid solution (300 ml, 200 ml) twice and 10% aqueous citric acid solution (250 ml×3) 3 times. The combined aqueous layer was basified by 4M aqueous sodium hydroxide solution to pH 10 and extracted with chloroform (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (46.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=3)[O:13][CH:14]=2)=[O:9])[C:4]([N:27]2[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]2=[O:33])=[N:3]1>CCCCCC.C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][C:23]([F:25])([F:26])[F:24])[CH:16]=3)[O:13][CH:14]=2)=[O:9])[C:4]([N:27]2[CH2:31][CH2:30][C@H:29]([CH3:32])[C:28]2=[O:33])=[N:3]1
Reactant: CC1CCN(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1=O
Solvent: CCO
Solvent: CCCCCC
Product: C[C@H]1CCN(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1=O
Yield: 46 %

Procedure:
Racemic N-(1-methyl-3-(3-methyl-2-oxopyrrolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide (399 mg) was resolved by HPLC (column: CHIRALPAK IA (trade name), 50 mmID×500 mL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=500/500), and the compound (186.7 mg) having a shorter retention time was recrystallized from THF/diisopropyl ether to give the title compound (183.7 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
to a suspension of 7-bromoheptanoic acid (1.7 g, 8.13 mmol) obtained above in CH2Cl2 (30 mL) were added oxalylchloride (2.13 mL, 24.39 mmol) and a catalytic amount of DMF. The mixture was stirred overnight at room temperature. The solvent was removed by evaporation in vacuo to give 1.84 g (100%) of the 7-bromoheptanoyl chloride as a yellow solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10].C(O)(C)C>O>[CH2:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]([CH3:10])[CH3:8]
Reactant: Cc1ccccc1
Reactant: C=CC
Solvent: O
Solvent: CC(C)O
Product: CC(C)Cc1ccccc1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
A 1-L Parr autoclave provided with a high shear turbine-type impeller was charged with 4.3g of NaK (an alloy having a K content of 78% by weight) and 428g of toluene. The mixture was heated to 160° C. under normal agitation, i.e., an agitator tip speed of 1.5 m/sec.; and the agitator tip speed was then increased to 5.7 m/sec. The mixture was agitated at this speed for 15 minutes, after which the temperature was increased to 190° C. Then 160 g of propene was fed over a period of 30 minutes while the temperature was maintained below 200° C. with cooling and the pressure below 2.8 MPa by regulating the propene feed rate. The autoclave was kept at 190° C. for one hour, and agitation was then slowed to normal. The NaK was deactivated by the addition of 12 g of isopropanol and 142 g of water. Analysis of the organic phase by gas chromatography showed that the reaction resulted in conversion to isobutylbenzene at the rate of 0.975 mol/hr. This compares with a conversion rate of only about 0.75 mol/hr. when diatomaceous earth- or potassium carbonate-supported NaK is employed as the catalyst and normal agitation conditions are maintained throughout the reaction.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][S:4]([OH:7])(=[O:6])=[O:5].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>>[CH2:10]([O:9][CH2:8][C@H:2]([NH:1][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H](COCc1ccccc1)CS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(N[C@@H](COCc1ccccc1)CS(=O)(=O)O)OCc1ccccc1

Procedure:
(S)-3-Benzyloxy-2-benzyloxycarbonylamino-propane-1-sulfonic acid was prepared by an analogous procedure as described in example 26 iv) starting from 1.76 g (7.19 mmol) (S)-2-amino-3-benzyloxy-propane-1-sulfonic acid and 1.16 ml (1.1 equiv.) benzyl chloroformate. Final purification by preparative RP-HPLC CH3CN/H2O gradient+0.1% TFA) gave pure (S)-3-benzyloxy-2-benzyloxycarbonylamino-propane-1-sulfonic acid as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[N:20]=[CH:19][CH:18]=2)[CH:12]=1>C(Cl)(Cl)Cl>[Br:1][C:25]1[CH:24]=[N:23][N:22]2[C:17]([C:13]3[CH:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[CH:16]=[CH:15][CH:14]=3)=[CH:18][CH:19]=[N:20][C:21]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1

Procedure:
A 3.75 g. portion of N-bromosuccinimide is added to a solution of 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of chloroform producing an exothermic reaction. The mixture is refluxed on a steam bath for 15 minutes and then treated as described in Example 14, giving the desired product, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)CCCCCCCCCCCCCCC.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56]CC2)CCCCC1>O1CCCC1>[CH3:1][N:50]([C:51]1[CH:56]=[CH:57][CH:58]=[CH:53][N:52]=1)[CH3:44]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 364 mg of radicicol, 384 mg of palmitic acid, 15 ml of dry tetrahydrofuran, 309 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 62 mg of the title compound were obtained.