Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]([CH3:16])([CH3:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:13]1([CH3:16])[C:12]2[CH:11]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[CH:8][C:7]=2[C:6]2[C:14]1=[CH:2][CH:3]=[CH:4][CH:5]=2
Reactant: CC1(C)c2ccccc2-c2cccc(Br)c21
Reactant: Nc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccccc3)cc21

Procedure:
50 g of bromo-9,9-dimethyl-9H-fluorene (183 mmol), 20 ml of aniline (220 mmol), 1.5 g of DPPF (2.7 mmol), 0.5 g of palladium(II)acetate and 45 g of sodium tert-butoxide (486 mmol) are heated at the boil in 1.5 l of toluene under a protective atmosphere for 18 h. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water and dried over Na2SO4 and evaporated in a rotary evaporator. The residue which remains is recrystallised from heptane/ethyl acetate. The yield is 31.2 g (110 mmol, 52%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:8])[C:3]=1[N+:16]([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:16][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2F)c1N
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-2-fluorophenylmethanone of Example VIa (6.2 g, 25 mmoles) in tetrahydrofuran (THF) (25 ml) was added to a mixture of SnCl2.2H2O (22.4 g, 100 mmoles) in concentrated hydrochloric acid (40 ml) and THF (20 ml) with ice-bath cooling over 1 hour. After warming to room temperature, the reaction mixture was poured into cold 10% sodium hydroxide (500 ml) with stirring and extracted with ethyl acetate. The extracts were washed with dilute sodium chloride and dried (sodium sulfate). Concentration gave an oil which was flash chromatographed (20% ethyl acetate:hexane) to yield 2.4 g (44%) of an oil that solidified.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([N:23]([CH2:31][C:32](OCC)=[O:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH2:31][CH2:32][OH:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[O:22])=[CH:37][CH:38]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1)c1ccccc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(CCO)c3ccccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-ethoxycarbonylmethyl-N-(2-methylphenyl)benzamide (100 mg) in ethanol (5 ml) was added sodium borohydride (37 mg) at 0° C. and the mixture was stirred for 2 hours at ambient temperature. Since the reaction was not completed and it was so slow, sodium borohydride (220 mg) was added to the mixture at 0° C. and stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Filtering and the removal of solvents afforded 4-(4′-methylbiphenyl-2-carboxamido)-N-(2-hydroxyethyl)-N-(2-methylphenyl)benzamide (70 mg) as a colorless prisms.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Li])[CH2:6][CH2:7][CH3:8].[O:10]=[C:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:5]([C:11]1([OH:10])[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:15][CH2:16]1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, anhydrous cerium chloride (4.63 g) was added to anhydrous tetrahydrofuran (50 ml), and the mixture was stirred at room temperature for 2 hours. After the suspension was cooled to −78° C., 1.6 M butyl lithium in hexane (6.40 ml) was added to the suspension and then the mixture was stirred for 1 hour. A solution of t-butyl 4-oxocyclohexylcarbamate (2.36 g) in anhydrous tetrahydrofuran (50 ml) was added to the reaction mixture over 10 minutes, and the mixture was gradually warmed to about 25° C. and then stirred overnight. After a saturated aqueous ammonium chloride was added to the reaction mixture, the mixture was filtrated through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: chloroform/methanol=100/1) to give 2.53 g of t-butyl 4-butyl-4-hydroxycyclohexylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16]([O:18]CC)=O)=[O:5].[CH3:26][NH:27][CH3:28]>CO>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][N:14]=[C:15]([NH2:21])[C:16](=[O:18])[N:27]([CH3:28])[CH3:26])=[O:5]
Reactant: CNC
Reactant: CCOC(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CO
Product: CN(C)C(=O)C(N)=NNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-ethoxycarbonylmethylene)hydrazine (24.9 g) in methanol (300 ml), excess of gaseous dimethylamine is introduced at room temperature, and the reaction mixture is allowed to stand overnight. After evaporating the solvent under reduced pressure, the residue is recrystallized from ethanol to give 1-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-(1-amino-1-dimethylcarbamoylmethylene)hydrazine (21.3 g) as reddish orange crystals melting at 150 to 151° C. The yield is 85.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12]C)=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)ccc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a suspension of 5-chloro-2-methoxy-benzenesulfonamide (0.52 g, 2.33 mmol) in dichloromethane (25 mL) at −78° C. was added boron tribromide (1M solution in dichloromethane, 3.5 mL, 3.5 mmol). The reaction was stirred at −78° C. for 30 minutes and then warmed to ambient temperature and stirred overnight. The reaction was quenched with water (0.30 mL) and the precipitate formed was removed by filtration. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel to give the title compound (0.32 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O-:10])(=[O:9])=[O:8].[Na+].O.C(#N)C.[F:16]F>O1CCCC1>[F:16][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O-:10])(=[O:9])=[O:8]
Reactant: FF
Reactant: O=S(=O)([O-])c1ccccn1
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)([O-])c1cccc[n+]1F
Yield: 38 %

Procedure:
Sodium 2-pyridinesulfonate (1 mmol) was added to 2.2 ml of a solvent mixture containing water and acetonitrile (1:10). A gas mixture containing fluorine gas and nitrogen gas (1:9) was then introduced into the resultant mixture at -25° C. and at a flow rate of 30 ml/min. The amount of the fluorine introduced was 9 mmol. After the reaction, 20 ml of tetrahydrofuran was added to the reaction solution, and the separated precipitate was filtered off. The thus-formed precipitate was extracted with acetonitrile, and the solvent was then removed by distillation to provide 68 mg (38 percent) of N-fluoropyridinium-2-sulfonate. The spectral data of the product was the same as that obtained in Example 1.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]2=[O:27])([O-:16])=[O:15].FC1C=C2C(=CC=1)NC(=O)C2=O>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]1[C:21](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:20]2=[O:27])([O-:16])=[O:15]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc([N+](=O)[O-])ccc2-n2c1nc1ccccc1c2=O
Yield: 18 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-nitroisatin for 5-fluoroisatin gave the title compound in 18% yield: mp 302.2°-303° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (d, 1H) 8.77 (d, 1H) 8.66-8.74 (m, 1H) 8.46-8.52 (m, 1H) 8.09 (d, 1H) 7.88-7.98 (m, 1H) 7.72-7.80 (m, 1H); MS (M+H)+ 293.
Reaction SMILES: C[Si](C)(C)Br.[Cl:6][C:7]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:8]=1[O:9][CH:10]([P:19](=[O:26])([O:23]CC)[O:20]CC)[P:11](=[O:18])([O:15]CC)[O:12]CC>C(Cl)Cl>[Cl:6][C:7]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:8]=1[O:9][CH:10]([P:11](=[O:12])([OH:15])[OH:18])[P:19](=[O:20])([OH:26])[OH:23]
Reactant: CCOP(=O)(OCC)C(Oc1ccc(Cl)cc1Cl)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(Oc1ccc(Cl)cc1Cl)P(=O)(O)O
Reaction time: 3 h

Procedure:
Trimethyl bromosilane (17.3 ml) was added to a stirred solution of tetraethyl (2,4-dichlorophenoxymethylene)-bisphosphonate (5.0 g) in methylene chloride (18 ml). After 3 hours at room temperature, the mixture was evaporated in vacuo, and residual trimethyl bromosilane was removed by repeated evaporation with methylene chloride. The residue was stirred overnight in ethanol and evaporated in vacuo. Crystallization from ether gave the title compound as colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH2:12]=O>C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Brc1ccc2c(c1)CNCC2
Solvent: O=CO
Product: CN1CCc2ccc(Br)cc2C1
Temperature: 150 °C
Yield: 75.3 %

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.7 mmol) in formic acid (20 mL) was added formalin (1.2 mL, 15 mmol). The solution was heated to 150° C. for 5 min under microwave irradiation. The solvent was removed in vacuo and the residue was dissolved into ethyl acetate (100 mL), washed with sat. sodium bicarbonate (2×10 mL), brine (10 mL) and dried over MgSO4. Removal of the solvent gave the title compound as a white solid (800 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.11 (s, 2H), 3.37-3.34 (m, 2H), 3.27-3.24 (m, 2H) 2.95 (s, 3H); MS ESI 225.9, 227.9 [M+H]+, calcd for [C10H12BrN+H]+ 226.0, 228.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].CC(O)=O>ClC(Cl)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCC(=O)CC
Reactant: Nc1cc(Br)cnc1N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCC(CC)Nc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
To a solution of 2,3-diamino-5-bromopyridine (10.0 g, 53.2 mmol, 1.0 equiv) and 3-pentanone (6.18 mL, 58.5 mmol, 1.1 equiv) in dichloroethane (150 mL) was added AcOH (3.0 mL, 53.2 mmol, 1.0 equiv) followed by NaHB(OAc)3 (16.9 g, 79.8 mmol, 1.5 equiv), added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-bromo-N3-(pentan-3-yl)pyridine-2,3-diamine as an off white solid (2.0 g, 14%). m/z=240.1 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.CC[N+](C)(C)C.[Li]CCCC.[Sn](Cl)(C)(C)C.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].[F-].[K+]>CCOCC.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28]
Reactant: Cn1cccc1
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](C)(C)C
Agent: C[Sn](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cn1cccc1-c1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
EX-602A) To solution of N-methylpyrrole (0.97 mL, 11 mmol) in Et2O (20 mL) was added neat TMEA (1.5 mL, 10 mmol) and 1.6 M n-BuLi in hexanes (6.3 mL, 10 mmol). The solution was heated to reflux under N2 for 1 h and then cooled to −78° C. A 1.0 M solution of Me3SnCl in THF was added over 15 min, and the resulting solution stirred for 30 min at −78° C. After warning to room temperature, 3-bromo-benzaldehyde (0.70 mL, 6.0 mmol), Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) and dioxane (10 mL) were added. The slurry was heated to reflux for 18 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 15 min. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.45 g (24%) of the desired 3-(1-methyl-1H-pyrrol-2-yl)benzaldehyde product as a yellow oil. MS: m/z=186.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12]C)=[N:7]2.C([O-])(O)=O.[Na+]>Cl.O>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2
Reactant: COc1ccc2c(N)cccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cccc2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 50.4 %

Procedure:
1.45 g (8.3 mmol) of 5-amino-2-methoxyquinoline is refluxed in 29 ml of 6N HCl for 4.5 hours. It is allowed to cool to room temperature, diluted with water, made basic with NaHCO3, extracted with ethyl acetate, the combined organic extracts are dried (Na2SO4) and concentrated by evaporation. Purification of the residue by chromatography on silica gel with hexane-ethyl acetate yields 670 mg of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[OH:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Clc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2sccc2Cl)CC1

Procedure:
From 3-chlorothiophene (612 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) by procedure D. Yield: 420 mg (27%). Yellow solid. MS (m/z): 332.2 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:24])[C:13]2[CH2:14][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C1C=C(O)C2C(C)[C:39]3CCC(C)C[C:44]=3[O:45]C=2C=1)C(C)CCCCC>>[C:44]([O:24][C:12]1[C:13]2[CH2:14][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=[C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=1)(=[O:45])[CH3:39]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCCC1)C2
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCCC1)C2

Procedure:
When an equivalent amount of 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxyxanthene is substituted in the procedure of Example 16 for 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene, 1-acetoxy-3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydroxanthene is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[F:30][C:31]1[CH:65]=[CH:64][C:34]([C:35](/[N:37]=[C:38]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:36])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:35](/[N:37]=[C:38]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:4][C:3]=3[N:17]\2[C@H:18]2[CH2:19][CH2:20][C@@H:21]([C:24](=[O:25])[NH:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23]2)=[O:36])=[CH:64][CH:65]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(OCCN4CCCCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. The product was isolated as an off-white solid (96 mg, 15% yield). M/Z calc'd for C31H40FN5O3: 549.68. found 550 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.O1CCCC1.[NH3:26].O>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:26])=[O:9]
Reactant: O=C(O)c1sccc1Br
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1sccc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
3-Bromothiophene-2-carboxylic acid (63.61 g, 307.2 mmol) was weighed into a 1 L round bottom flask equipped with reflux condenser and the flask was purged with argon. To this flask was added toluene (636.1 mL, 5972 mmol) and thionyl chloride (44.82 mL, 614.4 mmol) at room temperature, and the resulting mixture was stirred for 3 h at 100° C. The reaction mixture was evaporated and the residue was azeotroped with toluene (2×100 mL). The resulting residue was dissolved in tetrahydrofuran (954.1 mL, 11760 mmol) then 10 M ammonia in water (170 mL, 2500 mmol) was added slowly into the solution. The mixture was stirred for 5 h at room temperature. Thin-layer chromatography showed complete reaction. The reaction mixture was rotovaped to remove THF and the solid residue in water was filtered through a glass frit funnel then washed with water and dried under vacuum to give 3-bromothiophene-2-carboxamide as a white solid (33.26 g, 52.5%). LCMS: (FA) ES+ 206.0, 208.0
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 36.6 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 33(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.59 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.42 g, 39%) was obtained as a colorless solid.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:17][CH2:18][CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[C:11]1([C:9]2[S:17][CH2:18][CH2:19][O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: c1ccc(C2=C(c3ccccc3)SCCO2)cc1

Procedure:
Benzoin (106 g, 0.5 mole), 2-mercaptoethanol (43 g, 0.55 mole), and p-toluenesulfonic acid (pTSA) (5 g) are charged into a 2-liter 3-neck flask. n-Butanol (1200 mL) is added and the mixture stirred with a mechanical stirrer. The reaction is heated to reflux and the distillate passed through a vacuum-jacketed column (18 in by 3/4 in) packed with porcelain saddles. A Dean-Stark trap is placed at the top of the column to assist in the separation of the aqueous layer from the butanol/water azeotrope. After water ceases to separate, distillate is slowly removed until the vapor temperature at the top of the column reaches 117°-118°, the boiling point of dry n-butanol. The reaction mixture is cooled and seeded, and the crystalline product separated by filtration. The filtrate is returned to the reactor along with further amounts of benzoin, 2-mercaptoethanol, and pTSA as specified above. Sufficient n-butanol is added to make up for that removed in the prior reaction. When the procedure is repeated five times, the overall isolated yield of 2,3 -dihydro-5,6-diphenyl-1,4-oxathiin is 76% of theoretical.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([Cl:24])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 79, 210 mg, 0.73 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 421 μL, 0.84 mmol) which produced gas evolution and it was then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 1.5 mL and then enough methylene chloride was added to bring the total volume to 6 mL. This resulted in a roughly 0.12 M solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride which was used crude without purification.