Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[C:9]#[N:10])=O.Cl.[NH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[F:29])[CH2:15][C:16](OCC)=[O:17]>>[CH3:8][N:7]1[C:3]([CH2:1][N:12]2[CH2:13][CH:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=3[F:29])[CH2:15][C:16]2=[O:17])=[C:4]([C:9]#[N:10])[N:5]=[CH:6]1
Reactant: CCOC(=O)CC(CN)c1cc(F)cc(F)c1F
Reactant: Cn1cnc(C#N)c1C=O
Agent: Cl
Product: Cn1cnc(C#N)c1CN1CC(c2cc(F)cc(F)c2F)CC1=O
Yield: 25.8 %

Procedure:
1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile 127 is prepared according to the method described in 10.1 starting from 5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86 and ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([C:16](=[CH:19]NC1C=CC=CC=1)[C:17]#[N:18])=[O:15]>C(O)C.CCCCCC>[NH2:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:19][C:16]=1[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][CH:29]=[C:11]([Br:10])[CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Solvent: CCO
Solvent: CCCCCC
Product: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
A mixture of 4-fluorophenylhydrazine (4.25 g, 33.7 mmol) and 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (10.0 g, 30.7 mmol) in ethanol (100 ml) was heated at reflux under a nitrogen atmosphere. After 4 h, the reaction mixture was cooled to room temperature, diluted with hexane to give 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (9.7 g) as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:28][CH:27]=[CH2:26])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCBr
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 55 °C
Yield: 105.7 %

Procedure:
A solution of 1,3-di-N-butyl xanthine (10 g, 38 mmol) in anhydrous DMF (80 ml) was treated with K2CO3 (5.2 g, 38 mmol) followed by allyl bromide (3.6 ml, 42 mmol). The mixture was heated at 55° C. under nitrogen for 18 hours. After cooling to rt the mixture was partitioned between water and EtOAc. A few mls of 2M HCl(aq) was added to aid separation. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to afford the title compound as an off-white solid (12.23 g, 106%). m/z 305.3[MH+].
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([N+:13]([O-])=O)[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][CH:4]=1)#[N:2].O>C(OCC)(=O)C.CO.COCCOC.[C].[Pd]>[NH2:13][C:7]1[CH:8]=[CH:9][C:10]([CH3:12])=[C:11]2[C:6]=1[NH:5][CH:4]=[C:3]2[C:1]#[N:2]
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]cc(C#N)c12
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(N)c2[nH]cc(C#N)c12
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
After suspending 400 g (1.99 mol) of the 3-cyano-4-methyl-7-nitro-1H-indole obtained in Example 1A in a mixture of 6 L of ethyl acetate and 6 L of methanol, the suspension was subjected to hydrogenation in the presence of 40 g of 10% palladium-carbon at ordinary temperature, 4 atmospheres. After removing the catalyst by filtration, the filtrate was treated with activated carbon and concentrated to give crude crystals. The crude crystals were dissolved in 6 L of 1,2-dimethoxyethane at an external temperature of 60° C., and then 12 L of water was added dropwise. Upon confirming precipitation of crystals, the mixture was stirred for 1.5 hours while cooling in an ice bath and filtered, and the crystals were washed twice with water (1 L). The crystals were air-dried at 50° C. for 16 hours to give 289 g of the title compound (yield: 84.8%).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.CC(C)([O-])C.[K+].S(OCCC#C)([C:25]1[CH:31]=CC(C)=[CH:27][CH:26]=1)(=O)=O>CN(C)C=O>[CH2:27]([N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15])[CH2:26][C:25]#[CH:31]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCN1C(=O)c2cccc3cccc(c23)C1=O
Reaction time: 1.5 h

Procedure:
A mixture of 6 g (0.03 mol) of 1H-benz[de]isoquinoline-1,3(2H)-dione. 4 g (0.0355 mol) of potassium t-butoxide, 9 g (0.04 mol of 4-tosyloxy-1-butyne [ref. G. Eglinton and M. C. Whiting, J. Chem. Soc. 3650 (1950)] and 150 ml of dimethylformamide was heated on the steam bath with stirring for 1.5 hours. The bulk of the solvent was then removed under reduced pressure and the remaining suspension was filtered. The filtrate was diluted with water and the precipitated product was collected by filtration and dissolved in methylene chloride. The solution was dried and passed over a plug of silica gel using methylene chloride for elution. The fractions containing clean product were combined and evaporated. Crystallization from methylene chloride/ethanol gave the title compound as colorless needles with m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH:24][C:25]([CH2:27][CH3:28])=[O:26])=[NH:23])([CH3:20])[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:23][C:22]([NH:21][CH:18]([CH3:19])[CH3:20])=[N:24][C:25]([CH2:27][CH3:28])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=O)NC(=N)NC(C)C
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C
Temperature: 50 °C
Yield: 24.2 %

Procedure:
Adapted the alternative method for the preparation of 4d as follows: To the solution of the crude dione 15 (0.413 g, 1.429 mmol) in 50 ml of dry CHCl3 was added N-isopropyl-N′-(ethylcarbonyl)guanidine (0.206 g, 1.191 mmol). The reaction mixture was heated at 50° C. for 48 hours. The reaction was quenched with water, extracted with chloroform and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified with a silica gel column using 3% EtOAc/CHCl3 as eluent to yield 4a as a white solid (0.115 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of ethyl {7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21, 42 mg, 0.10 mmol) and LiOH (1 M, 0.146 mL, 0.15 mmol) in THF (2 mL) was stirred at rt for 2 h. Additional LiOH (1 M, 0.070 mL, 0.07 mmol) was added and the mixture was stirred for 2 h. HCl (1 M, 5 mL) was added and the aq. phase was extracted with DCM (3×5 mL). The combined organic layers were dried by passage through a phase separator and concentrated in vacuo providing the title compound (38.0 mg, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:39])[N:15]([C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-])=O)[N:26]=[CH:25][N:24]=1)[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>CC(O)=O.[Fe]>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([N:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:14]([NH:13][C:3]2[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[Cl:12])=[O:39])[CH:28]=1
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3N)ncn2)c1Cl
Temperature: 50 °C
Yield: 65.8 %

Procedure:
A mixture of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-[6-(2-nitro-phenylamino)-pyrimidin-4-yl]-1-pyridin-3-ylmethyl-urea (85 g, 0.149 mmol) and Fe (84 g, 1.5 mmol) in AcOH (5 mL) was heated at 50° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give crude product, which was purified by silica gel column chromatography to afford the title compound (53 mg, yield: 66%). MS (ESI): 540 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:38]1C=CC(C2C(OC)=C(C(CS(C3C=CC=CC=3OC)(=O)=O)=CC=2)C(OC)=O)=[CH:39]1.C(OC(NCCBr)=O)(C)(C)C>>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C:15]1[C:14]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[O:38][CH3:39])(=[O:8])=[O:9])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCBr
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 3-(furan-3-yl)-2-hydroxy-6-(2-methoxybenzenesulphonylmethyl)benzoate (Intermediate 39) and 2-[N-(t-butoxycarbonyl)amino]ethyl bromide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][O:18][C:19]1[C:20](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15])=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][O:18][C:19]1[C:20](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15]
Reactant: CCOC(=O)c1ccccc1OCNC(=O)CCCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OCNC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethylsalicylate (0.58 & 1.41 mmoles) was dissolved in dichloromethane (5 mL) and the solution was cooled in an ice/water bath. Trifluoroacetic acid (5 mL) was added, and the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was evaporated to dryness to give. the product as an oil, which was dried in vacuo over potassium hydroxide pellets to afford 0. 59 g (99% yield) of ethyl (6-aminohexanoyl)aminomethylsalicylate trifluoroacetate.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH2:7][CH:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([C:21]12[CH2:27][CH:24]([CH:25]=[CH:26]1)[CH2:23][CH:22]2[C:28]([O:30]O)=[O:29])C.[CH:32]12[CH2:38][CH:35]([CH:36]=[CH:37]1)[CH2:34][CH:33]2[C:39]([OH:41])=[O:40].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[C:1]([O-:4])(=[O:3])[CH3:2].[CH:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH2:7][CH:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH:21]12[CH2:27][CH:24]([CH:25]=[CH:26]1)[CH2:23][CH:22]2[C:28]([O:30][CH2:33][CH2:39][OH:40])=[O:29].[CH:32]12[CH2:38][CH:35]([CH:36]=[CH:37]1)[CH2:34][CH:33]2[C:39]([OH:41])=[O:40]
Reactant: CCC12C=CC(CC1C(=O)OO)C2
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)OC(=O)C1CC2C=CC1C2
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1C2

Procedure:
2-Maleimidethyl acetate (5) (0.5 to 1 mol), 0.1 to 1 mol of t-butyl 5-norbornene-2-carboxylate (19), 0.05 to 1 mol of 2-hydroxy ethyl-5-norbornene-2- carboxylate (21), and 0.1 to 0.3 mol of 5-norbornene-2-carboxylic acid (20) were dissolved in 200 to 270 g of THF to which was added 0.5 to 20 g of AIBN as a polymerization initiator. The reaction mixture was allowed to react at 60° C. to 75° C. for 4 to 24 hours under a nitrogen atmosphere. The resulting crude resin was precipitated with ethyl ether and dried to obtain poly[2-maleimidethyl acetate/t-butyl 5-norbornene-2-carboxylate/ 2-hydroxyethyl 5-norbornene-2-carboxylate/5-norbornene-2-carboxylic acid] copolymer resin.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=1>O1CCCC1.[Pt]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(OCc2nc3ccccc3s2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Cc1cc(OCc2nc3ccccc3s2)ccc1N
Reaction time: 2 h
Yield: 101.9 %

Procedure:
1.0 g of platinum oxide were added to a solution of 35.0 g of O-(benzothiazol-2-ylmethyl)-3-methyl-4-nitrophenol [prepared as described in step (a) above] in 500 ml of tetrahydrofuran at room temperature and the mixture was vigorously stirred under a hydrogen atmosphere for 2 hours. At the end of this time, the reaction mixture was filtered through Celite™ and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude residue which was washed with diisopropyl ether to give 32.1 g (yield 100%) of the title compound as a solid having a melting point of 110° to 111° C.
Reaction SMILES: [NH2:1][C@:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].Cl[S:12]([OH:15])(=[O:14])=[O:13]>ClCCl>[S:12]([OH:15])([O:4][CH2:3][C@@:2]([NH2:1])([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])(=[O:14])=[O:13]
Reactant: CCCC[C@](N)(CC)CO
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCCC[C@](N)(CC)COS(=O)(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The product (20.0 g) from step (f) was dissolved in dichioromethane (170 ml) and treated with chlorosulfonic acid (26.8 g). The reaction mixture was stirred at room temperature for 17 hours. A major part of the solvent was removed by distillation and the resulting slurry was diluted with acetone, filtered and dried to get a white solid. 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10](Cl)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:8])[CH3:2].[SH2:24].[Na]>>[CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([SH:24])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: S
Agent: [Na]
Product: CCN(CC)CCNC(=O)c1cnc(-c2ccccc2)nc1S
Yield: 63.6 %

Procedure:
Using the procedure in Preparation 34, 6.4 g (0.02 mol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid (2-diethylamino-ethyl)-amide was reacted with 4.8 g (0.066 mol) of sodium hydrogen sulfide to afford 4.2 g of the title compound, mp 178°-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-6-methylpyridine (723 mg, 3.47 mmol) in N,N-dimethylformamide (11.5 ml) was added sodium hydride (mineral oil 55% dispersion) (0.18 g, 4.2 mmol) in portions under ice cooling. After stirring at room temperature for 30 minutes, tert-butyl bromoacetate (0.62 ml, 4.2 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=10:1→5:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.14 g) substantially quantitatively as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](O)[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2([CH3:16])[CH3:15].C(N(CC)CC)C.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(O)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C#C[Si](C)(C)C)c2O1
Yield: 84.2 %

Procedure:
Following General Procedure D and using 6-bromo-8-hydroxy-2,2,4,4-tetramethyl chroman (Intermediate 17, 1.0 g, 3.51 mmol), triethyl amine (5 mL), copper(I)iodide (0.066 g, 0.351 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.246 g, 0.351 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 0.5% ethyl acetate in hexane as the eluent, the title compound (1.08 g, ˜100%) was obtained as a brown oil.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11]>CO>[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[OH:11]
Reactant: Cc1ccc(C(=O)CN(C)Cc2cccc(Br)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(O)CN(C)Cc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Sodium borohydride (646 mg, 17.1 mmol) was added over a period of 10 minutes to an ice-cooled solution of the product from Step A (4.89 g, 15.0 mmol) in methanol (85 mL). The reaction mixture was allowed to warm to room temperature and continued to stir for an additional 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with methylene chloride (3×). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanol (4.58 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 7.40 (d, J=5.8 Hz, 1H), 7.25-7.13 (m, 6H), 4.72 (dd, J=10.0, 3.7 Hz, 1H), 3.86 (br s, 1H), 3.68 (d, J=13.4 Hz, 1H), 3.49 (d, J=13.2 Hz, 1H), 2.62-2.47 (m, 2H), 2.33 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: O.O.C1(S([O-])=O)C=CC=CC=1.[Na+].Cl.C1(C)C=CC=CC=1.C(O)C.[CH:24]([CH:26]1[CH2:31][CH2:30][CH:29]([CH:32]=[CH:33][C@H:34]2[CH2:39][CH2:38][C@H:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]4[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][CH:47]=4)=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)[CH2:28][CH2:27]1)=[CH2:25]>O>[CH:24]([C@H:26]1[CH2:27][CH2:28][C@H:29](/[CH:32]=[CH:33]/[C@H:34]2[CH2:35][CH2:36][C@H:37]([C:40]3[CH:41]=[CH:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH2:38][CH2:39]2)[CH2:30][CH2:31]1)=[CH2:25]
Reactant: C=CC1CCC(C=C[C@H]2CC[C@H](c3ccc(-c4ccc(CCCC)cc4)cc3)CC2)CC1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=C[C@H]1CC[C@H](/C=C/[C@H]2CC[C@H](c3ccc(-c4ccc(CCCC)cc4)cc3)CC2)CC1

Procedure:
A mixture prepared by adding 3.3 g (16.5 mmol) of sodium benzenesulfinate dihydrate, 2.7 ml of 6N hydrochloric acid, and 25 ml of mixed solvent of toluene/ethanol (1/1) to 3.5 g (8.3 mmol) of the crude 4-(trans-4-(2-(4-vinylcyclohexyl)vinyl)cyclohexyl)-4′-butylbiphenyl was refluxed for 95 hours. Water in an amount of 50 ml was added to the reaction mixture, and the mixture was extracted with 100 ml of toluene, washed with water thrice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene/heptane=1/9) to obtain 2.8 g of a crude (E)-4-(trans-4-(2-(trans-4-vinylcyclohexyl)vinyl)cyclohexyl)-4′-butylbiphenyl. This product was recrystallized from a mixed solvent of ethanol/ethyl acetate to obtain 0.7 g of the subjective compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[F-].[K+].C([Si](CC)(CC)[C:22]([F:25])([F:24])[F:23])C>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu]I>[CH3:16][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[C:2]([C:22]([F:25])([F:24])[F:23])[CH:3]=[N:4]1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: COC(=O)c1cc(-c2c(I)cnn2C)cs1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C(F)(F)F)cnn2C)cs1
Temperature: 70 °C
Reaction time: 10 h
Yield: 74 %

Procedure:
To a solution of methyl 4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (470 mg, 1.35 mmol), copper (I) iodide (256 mg, 1.35 mmol) and potassium fluoride (78 mg, 1.35 mmol) in anhydrous DMF/HMPA (2 ml/2 mL) was added triethyl(trifluoromethyl)silane (745 mg, 4.04 mmol). The mixture was heated to 70° C. under N2 in a sealed tube. After 10 h, the reaction was quenched with NH4Cl (sat'd) (2 mL), extracted with ether (5 mL×5) and washed with distilled water (5 mL×5). The combined organic phase was dried over Mg2SO4 and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.29 g, 74%) as a yellow syrup: LC-MS (ES) m/z 291 (M+H)+.