Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 3,6-dichloropyridazine (1.49 g, 10 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1.04 g, 5 mmol), K2CO3 (1.38 g, 10 mmol), and Pd(PPh3)4 (289 mg, 0.25 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (9 mL/2 mL) was added and the resulting mixture was heated at 100° C. for 5 h. The resulting mixture was poured into EtOAc/H2O (30 mL/30 mL). The organic layer was washed with brine (30 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CO
Product: COC(=O)c1ccc(CN(C)C)cc1
Reaction time: 0.42 h
Yield: 99 %

Procedure:
Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a saturated solution of dimethylamine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between 1N NaOH and ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), filtered, and concentrated to provide the title compound as a colorless liquid (1.67 g, 99%). 1H NMR (250 MHz, CDCl3) δ 8.00 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H), 3.47 (d, 2H), 2.25 (s, 6H).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[NH2:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([CH3:28])[C:19]2=[O:36])=[C:15]([O:39][CH3:40])[CH:14]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH2:17][C:16]1[CH:37]=[CH:38][C:13]([N:12]3[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:14][C:15]=1[O:39][CH3:40])[C:19](=[O:36])[C:20]2([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH3:28]
Reactant: BrCCCCBr
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(N2CCCC2)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 115 °C

Procedure:
0.4 g of sodium bicarbonate powder and 0.14 ml of 1,4-dibromobutane are added to 0.5 g of the compound of Example 48 in 50 ml of hexamethyl-phosphoramide. The reaction mixture is heated at 115° C. for 10 hours. The reaction mixture is hydrolysed at room temperature and extracted with ethyl acetate. The organic phase is washed several times with water and dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. The oil obtained is treated with hydrochloric acid in diethyl ether; M.p.=198° C. (HCl.0.4H2O).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.Cl[C:17]1N=CN=C(NC2CC2)[C:18]=1N>C(#N)C>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH:15]3[CH2:18][CH2:17]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)ncnc1NC1CC1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Solvent: CC#N
Product: COc1nc2c(Cl)ncnc2n(C2CC2)c1=O

Procedure:
4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one was prepared in the same manner as 4-chloro-8-methyl-6-methoxypteridin-7(8H)-one. The reaction of 6-Chloro-N4-cyclopropyl-pyrimidine-4,5-diamine (3.00 g, 16.2 mmol), methyl 2,2,2-trimethocyacetate (3.73 g, 22.7 mmol), 1-camphorsulfonic acid (0.754 g, 3.25 mmol) in acetonitrile (30 mL) at 80° C. for 16 hours gave 3.045 g of 4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one as a tan colored solid. 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 4.01 (s, 3H), 2.95 (m, 1H), 1.16 (m, 2H), 0.86 (m, 2H). MS (EI) C10H9ClN4O2: 253 (MH+).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](#[N:25])/[CH:21]=[CH:22]/[C:23]#[N:24]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:16]3)=[C:22]([C:23]#[N:24])[C:21]=2[C:20]#[N:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#C/C=C/C#N
Reactant: CCC[C@H]1CC[C@H](C=CC=CC2CCCCC2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc(C3CCCCC3)c(C#N)c2C#N)CC1

Procedure:
Using 1-cyclohexyl-4-(trans-4'-n-propylcyclohexyl)-1,3-butadiene and fumaronitrile, 3-cyclohexyl-6-(trans-4'-n-propylcyclohexyl)phthalonitrile was obtained by the same method as in Example 1. It was a monotropic nematic liquid crystal having m.p. of 102.5° C. and cl.p. of 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1C(=O)CCC1CSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CC1(C(=O)OC)C(=O)CCC1CSc1ccccc1
Yield: 64.2 %

Procedure:
In accordance with the process of Example 22, 2-oxo-5-phenylthiomethylcyclopentanoic acid methyl ester (792 mg; 3 m mol), ethyl bromoacetate (501 mg; 3 m mol) and potassium carbonate (415 mg; 3 m mol) were used to obtain 674 mg of 1-ethoxycarbonylmethyl-2-oxo-5-phenylthiomethyl-cyclopentanecarboxylic acid methyl ester as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([N:25]([CH2:36][CH3:37])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:24]>O1CCCC1>[CH2:36]([N:25]([CH2:23][CH3:24])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:4](=[O:5])[C:3]([OH:7])([CH3:8])[C:2]([F:10])([F:9])[F:1])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:37]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of α-trifluoromethyl lactic acid (0.37 g) in dry tetrahydrofuran (10 ml) at 22° C. was added carbonyldiimidazole (0.38 g) in one portion. The mixture was stirred for 30 minutes, then treated with 4-(N,N-diethylaminosulfonyl)aniline (0.53 g) and stirred at 22° C. for 1 hour followed by heating at reflux for 18 hours. After cooling to 22° C., the mixture was concentrated to an oil which was purified by chromatography (9:1 CH2Cl2 : diethyl ether) and crystallization from hexane to produce the title compound as a colourless crystalline solid (0.15 g); mp 115°-130° C.; MS: m/z=341(M+1); NMR (250 MHz, CDCl3): 1.12 (t,6), 1.78 (s,3), 3.22 (s,4), 3.73 (s,1), 7.67-7.79 (m,4), 8.62(broad s,1). Analysis for C14H19F3N2O4S: Calculated: C, 45.64; H, 5.19; N, 7.61; Found: C, 45.74; H, 5.22; N, 7.66.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>[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.O1CCCC1>[OH:1][CH2:2][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C#C[Si](C)(C)C)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl [(1S)-2-hydroxy-1-(3-iodobenzyl)ethyl]carbamate (1.0 g, 2.6 mmol), copper(I) iodide (0.020 g, 0.11 mmol), bis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.11 mmol), tetrahydrofuran (7 mL), and triethylamine (0.41 mL, 2.9 mmol) were combined. The reaction mixture was stirred under N2 for 5 min. (Trimethylsilyl)acetylene (1.1 mL, 8.0 mmol) was then added. The reaction mixture was stirred at 65° C. for 1 h, then evaporated under vacuum. The residue was purified by combi-flash chromatography to give 0.84 g (91% yield) of the desired product as light brown solid. LC-MS found: 248.0 (M−Boc+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5]2.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[O:29][CH2:28][C:27]([CH:34]=O)=[CH:26]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[O:29][CH2:28][C:27]([CH:34]1[O:16][CH2:15][CH:12]([C:11]3[CH:10]=[C:9]4[C:4]([CH2:5][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:7][O:8]4)=[CH:3][C:2]=3[F:1])[CH2:13][O:14]1)=[CH:26]2
Reactant: CCCCCC1COc2cc(C(CO)CO)c(F)cc2C1
Reactant: O=CC1=Cc2cc(F)cc(F)c2OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC1COc2cc(C3COC(C4=Cc5cc(F)cc(F)c5OC4)OC3)c(F)cc2C1

Procedure:
1.30 g (4.39 mmol) of 2-(6-fluoro-3-pentylchroman-7-yl)propane-1,3-diol and 900 mg (4.59 mmol) of 6,8-difluoro-2H-chromene-3-carbaldehyde are dissolved in 50 ml of dichloromethane and heated under reflux on a water separator for 5 h in the presence of 50 mg of p-toluenesulfonic acid. The solution is subsequently washed with sat. sodium hydrogencarbonate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is recrystallised from heptane/toluene, giving 6,8-difluoro-3-[5-(6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]-2H-chromene (trans:cis=80:20) as a colourless solid.
Reaction SMILES: CC1C2C(=CC=CC=2[N+]([O-])=O)NC=1.[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[NH:17][CH:16]=1>C(O)C.[Pd]>[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Agent: Cc1c[nH]c2cccc([N+](=O)[O-])c12
Solvent: CCO
Product: Cc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (3 g, 17 mol) and 10% Pd—C (0.5 g) in ethanol (30 mL) was stirred overnight under H2 (1 atm) at room temperature. Pd—C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 3-methyl-1H-indol-6-ylamine (B-7) (0.6 g, 24%). 1H NMR (CDCl3) δ 7.59 (br s, 1 H), 7.34 (d, J=8.0 Hz, 1 H), 6.77 (s, 1H), 6.64 (s, 1 H), 6.57 (m, 1 H), 3.57 (br s, 2 H), 2.28 (s, 3H); ESI-MS 147.2 m/z (MH+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C.[Na+].[Cl-]>[Si:13]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
To a solution of (S)-(−)-ethyl lactate (20 mL, 191.06 mmol) in DMF (191 mL) was added tert-butyldimethyl silyl chloride (39.6 g, 262.59 mmol) and imidazole (41.6 g, 612.72 mmol). After stirring at room temperature for 20 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (600 mL) and extracted with petroleum ether (3×400 mL). The organic layer was washed with a cold 3% HCl solution (200 mL) and a saturated aqueous NaCl solution (200 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (700 g) with petroleum ether (2 L), followed by 3% ethyl acetate in petroleum ether (4 L). The 3% ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 36.57 g of (S)-(−)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (82% yield). 1H NMR (CDCl3): δ 4.23 (q, 1H, J=6.8 Hz, H2, —CH—), 4.11 (q, 2H, J=7.2 Hz, —CH2—), 1.32 (d, 3H, J=6.8 Hz, H3, —CH3), 1.21 (t, 3H, J=7.2 Hz, —CH3), 0.83 (s, 9H, Si—(CH3)3), 0.03 (s, 3H, Si—CH3), 0.00 (s, 3H, Si—CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH2:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].C(OC1(OCC)CCCO1)C>O.C(O)C.C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:13]2[CH:16]=[CH:15][CH:14]=[CH:19]2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(N)c(C)c(N)c1
Agent: CC(=O)[O-]
Agent: CCOC1(OCC)CCCO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)c(C)c(-n2cccc2)c1

Procedure:
A mixture of 18 g. of methyl 3,5-diamino-4-methylbenzoate, 0.7 g. of p-toluenesulfonic acid, 8.2 g. of sodium acetate, 32 g. of diethoxytetrahydrofuran, 10 ml of glacial acetic acid, 100 ml. of ethanol and 100 ml. of water was boiled at reflux for 3 hours. The alcohol was removed in vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with ethyl acetate and recrystallization from high-boiling petroleum ether, there was obtained methyl 3-amino-4-methyl-5-(pyrrol-1-yl)benzoate, having a melting point of 112° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)C.[CH2:17]([O:24]C(CO)CO)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH:16]1[CH2:1][O:3][CH:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[O:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCOC(COc1cccc(Cl)c1)OCC
Product: Clc1cccc(OCC2OCC(OCc3ccccc3)CO2)c1

Procedure:
Using the procedure of Example 47, (3-chlorophenoxy)acetaldehyde diethyl acetal and 2-benzyloxy-1,3-propanediol were reacted to give 5-benzyloxy-2-(3-chlorophenoxymethyl)-1,3-dioxane, nD25 1.5587. The ir spectrum was consistent with the assigned structure. The nmr spectrum indicated 40% cis isomer and 60% trans isomer.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]=2[CH2:24][O:25][CH2:26][CH3:27])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:31])=O.C(N(CC)CC)C.O>O1CCCC1>[Cl:31][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:11][C:10]=1[CH2:24][O:25][CH2:26][CH3:27]
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (1.8 g) in tetrahydrofuran (30 mL) were added oxalyl chloride (0.6 mL) and triethylamine (1.0 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.9 g, 100%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([O:23][C:24]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:37]#[CH:38])[CH:34]=2)[C:29]([CH3:45])([CH3:44])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.O.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.[Cu]I>[C:19]([O:23][C:24]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:37]#[C:38][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH:34]=2)[C:29]([CH3:44])([CH3:45])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CC(CCCCC)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C#Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
A mixture of 0.043 g of methyl 4-iodobenzoate, 0.093 mL of triethylamine, 4.6 mg of Pd(Ph3P)2Cl2 and 2.5 mg of copper (I) iodide in 2 ml of DMF was degassed and treated with a solution of 4,4-dimethyl-7-(1-pentyl-prop-2-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.049 g, 0.13 mmole) in 1 mL of DMF. The reaction mixture was stirred at room temperature for 18 hours, diluted with 10 mL of water and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of 1N HCl, 10 mL of water and 10 ml of brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 0.035 g of 7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6].[I-].[Na+].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][C:10]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:14][C:13]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12][N:11]1[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCCl)(c2ccccc2)S1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Temperature: 90 °C
Reaction time: 4 h
Yield: 119.8 %

Procedure:
The optically active N-[5-(3-chloropropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.50 g, 2.90 mmol) obtained in Step 1 mentioned above, sodium iodide (8.69 g, 58.0 mmol) and sodium azide (1.89 g, 29.0 mmol) were suspended in DMF (20 mL), and the suspension was stirred at 90° C. for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give optically active N-[5-(3-azidopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.82 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([Cl:27])=[N:12][C:13]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:27].[CH3:9][C:10]1[C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12][C:13]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(N2CCc3ccsc3C2C)nc(Cl)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccsc3C2C)nc(Nc2ccc(F)cc2)c1C
Product: Cl
Yield: 26.5 %

Procedure:
After 4-fluoroaniline(0.3 ml, 3 mmol) was added to a mixture solution of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-4-chloropyrimidine (0.4 g, 1.4 mmol) and dimethylformamide(10 ml), 0.15 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccc(F)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (83.4 mg, 86%) as a solid. MS: 294 (M+H).