Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](O)=[O:5].[H-].[Na+].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([Cl:24])=[O:5]
Reactant: CCC(C)=CCCC(C)CC=CC(C)=CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(C)=CCCC(C)CC=CC(C)=CC(=O)Cl
Reaction time: 1 h

Procedure:
One gram of 3,7,11-trimethyltrideca-2,4,10-trienoic acid in 30 ml. of benzene and one mol of sodium hydride is stirred about two hours and then a slight excess of oxalyl chloride is added at about 0° and stirred for one hour. The product is worked up by removal of solvent in vacuo and extraction with pentane to yield 3,7,11-trimethyltrideca-2,4,10-trienoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH:14]1([C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 21.2 g (0.12 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 15.0 g (0.10 mole) of cyclohexanecarbonyl chloride in 50 ml of CHCl3. The mixture was allowed to stand at room temperature during 45 minutes and was made basic with 5 g of sodium hydroxide in 50 ml of water. The nonaqueous layer was separated, dried over sodium sulphate and concentrated. The residue was distilled b.p. 150°-56° C. at 0.1-0.2 mmHg to give 21.2 g of 1-cyclohexanecarbonyl-4-benzylpiperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:40])[CH2:18][NH:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=4)[N:22]([C:33](=[O:39])[NH:34]C(C)(C)C)[N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:40])[CH2:18][NH:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=4)[N:22]([C:33](=[O:39])[NH2:34])[N:21]=3)[CH2:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C(=O)NC(C)(C)C)c4ccc(C(F)(F)F)cc34)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C(N)=O)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from de-protection of 4-{3-[2-(1-tert-butylcarbamoyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexanecarboxylic acid ethyl ester (as prepared in Example 88) with TFA using the procedure described in Example 81.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C(C)=CC=CC=1C.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)O)=[O:18])[CH:14]=[CH2:15].[OH-].[Na+]>ClCCl>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)[Cl:3])=[O:18])[CH:14]=[CH2:15]
Reactant: O=S(Cl)Cl
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(Cl)c1cncnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of thionyl chloride (6.05 g) in dichloromethane (70 ml) was added 2,6-lutidine (6.53 g) at 5° C. to 10° C. After the solution was stirred for 30 minutes at the same temperature, the solution of 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl}-1-(pyrimidin-5-yl)methanol (20.0 g) in dichloromethane (100 ml) was slowly dropped thereto below 10° C. After the reaction mixture was stirred for an hour below 10° C., it was stirred at room temperature for 2 hours, then thionyl chloride (6.05 g) and 2,6-lutidine (6.53 g) were added to the reaction mixture. After the reaction mixture was stirred another one hour, thionyl chloride (6.05 g) and 2,6-lutidine (6.53 g) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, then it was poured into ice-water (500 ml) and dichloromethane (400 ml) and adjusted to pH 5.1 with saturated aqueous sodium hydroxide below 15° C. The organic layer was separated and washed with water (400 ml) at pH 4.3 and brine (350 ml). The organic layer was dried over magnesiumsulfate and evaporated. The residue was subjected to column chromatography on silica gel (200 g) [solvent; hexane:ethyl acetate=5:1 to 2:1 to 1:1] to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(pyrimidin-5-yl)-1-chloromethane (9.9 g) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C1C(=O)N([Cl:31])C(=O)C1>CC#N>[Cl:31][C:10]1[C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[C:6]2[C:11]=1[C:2](=[O:1])[NH:3][CH2:4][CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1)C(=O)NCC2
Solvent: CC#N
Product: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of tert-butyl [1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77b, 875 mg, 2.73 mmol) and NCS (401 mg, 3.00 mmol) in MeCN (80 mL) was stirred at 75° C. for 2 hours. After cooling down to room temperature and concentrating under vacuum, the resulting residue was purified by column chromatography (0-100% EtOAc/heptanes) to give tert-butyl [8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77c, 893 mg, 92%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[CH3:20][S:21]([O-:23])=[O:22].[Na+]>CS(C)=O.O>[CH3:20][S:21]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1)(=[O:23])=[O:22]
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Yield: 62.6 %

Procedure:
A solution of (1aR,5aR)-2-(4-bromopyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (80 mg, 0.25 mmol) and sodium methanesulfinate (28 mg, 0.28 mmol) in DMSO (1.5 mL) was stirred overnight at 80° C. The reaction was diluted with H2O, and then extracted with DCM (3×). The combined organics were washed with H2O, dried, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (50 mg). LCMS m/z=320.2 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:39])([CH3:38])[O:6][CH:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][CH2:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:12]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OC(=O)C)C.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:38])[CH3:39])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:11]2=[O:31])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc(N)cc2)c1
Yield: 84.4 %

Procedure:
A reaction is performed with 3.0 g (5.5 mmol) of product 4 in 50 ml ethylacetate and 1.0 g of palladium charcoal 10% for 2 h at 5 bar of a hydrogen atmosphere using an autoclave. The reaction solution is filtrated, evaporated and separated by chromatography on silica gel (methylenehloride/methanol=10/1). 2.4 g (86%) of product 5 is obtained in form of a colourless compound in solid form: C31H40N2O3Si (516.76) MS (ESI+) 517.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:14])[N:7]=1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc(CCl)cs1

Procedure:
In chloroform (10 ml) was dissolved 2-trifluoromethyl-4-hydroxymethylthiazole (1 g), to which was added dropwise thionyl chloride (2.0 ml). The mixture was refluxed for 4 hours. The reaction mixture was cooled and, then, excess volume of thionyl chloride was distilled off under reduced pressure. To the residue was added dichloromethane (30 ml), which was washed with an aqueous solution of sodium hydrogen carbonate (20 ml) and water (20 ml), successively, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was subjected to a silica gel chromatography (2.5×20 cm), eluting with ethyl acetate-hexane (1:3). The desired fraction was concentrated to give 2-trifluoromethyl-4-chloromethyl thiazole (0.66 g) as a pale reddish oily product.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([Cl:21])[C:3]=1[OH:22].[N+]([O-])(O)=[O:24].O>C(O)(=O)C>[Cl:21][C:4]1[C:3](=[O:22])[C:2](=[O:24])[C:7]2[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)c2coc3cc(Cl)c(O)c(Cl)c23)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C(Cl)=C3)cc1
Temperature: 60 °C

Procedure:
To a suspension of compound 10d (100 mg, 0.29 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized (CH2Cl2-pet. ether) to furnish compound SKC-BF-04 (50 mg, 53%) as a red solid. TLC Rf=0.4 (petroleum ether-EtOAc, 7:3); 1H NMR (CDCl3) δ 7.86-7.80 (m, 3H), 7.54 (s, 1H), 6.95 (d, J=9.0 Hz, 2H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]3[CH2:15][CH2:14]3)(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CC1)c1cc(F)c(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1cc(F)c(S(=O)(=O)NC2CC2)cc1F
Reaction time: 16 h
Yield: 19.6 %

Procedure:
According to general procedure B, 4-bromo-N-cyclopropyl-2,5-difluorobenzenesulfonamide (150 mg, 0.5 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.3 mL) was added. Tri-t-butylphosphine (75 μL, 0.026 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropyl-2,5-difluorobenzenesulfonamide (33 mg) HPLC purity 99.0% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C15H13F2N3O2S−H+, 336.06238; found (ESI-FTMS, [M−H]1−), 336.06247
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: NC1CCCCC1
Reactant: O=C1CCC(Oc2ccc3cnccc3c2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: Clc1c(OC2CCC(NC3CCCCC3)CC2)ccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
100 mg (0.36 mmol) 4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexanone (79) were dissolved in 10 ml methanol. After adding 73 mg (0.73 mmol) triethyl amine, 108 mg (1.09 mmol) cyclohexylamine, 218 mg (3.63 mmol) acetic acid and freshly dried molecular sieves, the reaction was stirred at room temperature. After 30 minutes, a solution of 68 mg (1.09 mmol) sodium cyanoborohydride in 2 ml methanol was added and the reaction was kept at room temperature until complete conversion was achieved. For working up, the reaction mixture was filtered and the filtrate was brought to alkaline pH by adding solid NaHCO3. After evaporation of the solvent, the residue was taken up in H2O and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated. Final purification by preparative HPLC gave 69 mg of the desired product as trifluoroacetate, which was dissolved in 2 N HCl and lyophilized, to yield 45 mg of the corresponding HCl-salt. Rt=1.08/1.15 min (Method #1). Detected mass: 359.3/361.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.ClC1N=CN=C([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=O)C=1.C(N(CC)CC)C.CNC1CCCCC1>C1COCC1>[CH:29]1([N:28]([CH3:26])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[O:9])[CH:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: C1CCOC1
Solvent: CNC1CCCCC1
Solvent: CCN(CC)CC
Product: CN(c1cc(C(=O)Nc2ccc(O)cc2)ncn1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (75.0 mg; 0.30 mmol) in THF (4 mL) was treated with triethylamine (42 μl; 0.30 mmol) and N-methylcyclohexylamine (Aldrich, 43 μl; 0.33 mmol). The reaction mixture was stirred for 24 h. The solvents were removed in vacuo, then the crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.3 %

Procedure:
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (0.540 g, 2.5 mmol) in THF (5 mL) was added pivaloyl chloride (0.335 g, 2.79 mmol) and TEA (0.1 mL) and the reaction mixture was stirred for 2-3 h at RT. Excess of solvent was removed under vacuum and the residue was diluted with water, extracted with EtOAC and concentrated to afford 0.500 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 1.31 (t, J=7.5 Hz, 3H), 4.26 (d, J=5.1 Hz, 2H), 4.39 (q, J=6.6 Hz, 2H), 7.33-7.43 (m, 2H), 8.13 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(O)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Br:42])(=O)C.CO>C1(C)C=CC=CC=1>[Br:42][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Br
Reactant: COc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
54.19 g (0.11 mol) of 1,2,3,4-tetraphenyl-5-p-methoxyphenylcyclopenta-1,3-dien-5-ol were suspended in 300 ml of toluene. 74 g (0.6 mol) of acetyl bromide were added dropwise in the course of 20 minutes at room temperature and the reaction batch was then refluxed for 2 hours. Toward the end of the reaction, 2 ml of methanol were also added dropwise. Excess acetyl bromide and toluene were distilled off in vacuo. The remaining oil crystallized after addition of 100 ml of petroleum ether. The orange precipitate was filtered off with suction, rinsed with petroleum ether and dried. The product was used for the further syntheses. Analytically pure orange product was obtained by recrystallization from toluene. (Yield: 54. 32 g (89%); elemental analysis for C36H27OBr: found: C, 77.06%, H, 4.90%. calculated: C, 77.84%, H, 4.90%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Product: O=C(Cl)c1cc(F)c(F)cc1Br
Reaction time: 1 h

Procedure:
Thionyl chloride (70 ml) is added to 2-bromo-4,5-difluorobenzoic acid (39.5 g), and the mixture is allowed to stand at room temperature for one hour and then refluxed for one hour. After completion of the reaction, the excess thionyl chloride is distilled off under reduced pressure. The oily residue is distilled under reduced pressure to give 2-bromo-4,5-difluorobenzoyl chloride (37.8 g) as a pale yellow oily substance, b.p. 121°-123° C. (32 mmHg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([O-])=[O:18])[S:16][C:9]=12.[Li+]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:17]([C:15]2[S:16][C:9]3[C:10](=[N:11][CH:12]=[CH:13][C:8]=3[Cl:7])[CH:14]=2)=[O:18])[CH2:3]1
Reactant: OC1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC(O)C1

Procedure:
This compound was prepared from (+/−)-3-hydroxypyrrolidine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 283/285 (MH+); HPLC Rf: 3.44 min.; HPLC purity 91%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([F:16])[CH:3]=1.CCCCCC.C([Li])CCC.[C:28](=[O:30])=[O:29]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[CH2:15])[CH2:12][CH2:13]2)[CH:5]=[C:4]([F:16])[C:3]=1[C:28]([OH:30])=[O:29]
Reactant: C=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
25 g of 1,3-difluoro-5-(trans-4-vinylcyclohexyl) benzene was dissolved in 100 ml of tetrahydrofuran, and then cooled to a temperature of −70° C. To the solution was then added dropwise 88 ml of a 1.53 mol/l n-hexane solution of n-butyllithium at a rate such that the liquid temperature was kept at −60° C. After 30 minutes of stirring, carbon dioxide was then introduced into the system at a rate such that the liquid temperature was kept at −60° C. When heat generation was terminated, the temperature of the reaction solution was returned to room temperature. To the reaction solution was then added 50 ml of a 10% hydrochloric acid. The reaction solution was then extracted with 250 ml of ethyl acetate. The resulting organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvents were then distilled off to obtain 28.9 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzoic acid.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(Cl)(Cl)Cl.[Cl:11][CH:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>O>[Cl:11][CH:12]([CH3:16])[C:13]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)=[O:14]
Reactant: CC(Cl)C(=O)Cl
Reactant: C1CNOC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)N1CCCO1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of isoxazolidine hydrochloride (11.0 g) and chloroform (200 ml) was added (±)-2-chloropropionyl chloride (13.3 g) under ice-cooling and stirring and then added dropwise triethylamine (22.2 g) under the same conditions. The stirring was continued at room temperature for further one hour, after which an amount of water was added to the reaction mixture to form layers. The organic layer thus separated was washed with 1 N hydrochloric acid and then with a 5% aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-chloropropionyl]isoxazolidine (15.0 g) as a pale yellow oil. Purification of the oil by silica gel column chromatography afforded a colorless oil. nD20 =1.4918.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1(=O)[CH2:18]CCC[CH2:14]1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[C:13]([CH3:18])[CH3:14])[CH2:2][C:1]([OH:10])=[O:9])[CH3:8]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CC(=O)O)=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of of 17.4 g (0.1 mol) diethyl succinate and 9.8 g (0.1 mol) cyclohexanone in 100 ml tert-butanol was added 11.2 g (0.1 mol) potassium tert-butoxide in one portion. The mixture was allowed to stir at room temperature for 30 min. 10 ml of water were added and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 18.5 g (82%) of a thick yellow oil. 1H-NMR: 86% conjugated, 14% deconjugated product.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>CO>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][N:4]2[CH2:3][CH:2]([CH3:13])[NH:1][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:11][N:10]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(N)CNCc1ccc(Cl)nc1
Solvent: CO
Product: CC1CN(Cc2ccc(Cl)nc2)C(=C[N+](=O)[O-])N1
Yield: 73 %

Procedure:
A mixture of 2 g of 2-amino-1-(2-chloro-5-pyridylmethylamino)propane, 1.6 g of 1-nitro-2,2-bis (methylthio)ethylene and 20 ml of methanol was refluxed for 5 hours with stirring. A crystaline product was precipitated after standing at room temperature. The product was filtered with suction, washed with methanol and then dried in vacuum. 1.9 g of 1-(2-chloro-5-pyridylmethyl)-4-methyl-2-(nitromethylene)imidazolidine was obtained in form of light yellow crystals.