Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:12][O:13]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Fc1ccc2c(c1)OCCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1cc2c(cc1F)OCCO2

Procedure:
7-Fluoro-2,3-dihydrobenzo[1,4]dioxine-6-carboxaldehyde was prepared from 6-fluoro-2,3-dihydrobenzo[1,4]dioxine [V. Daukas et al Chemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl ether and titanium tetrachloride: LC-MS (ES) m/e 155 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2CO)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 5-chloro-N-methyl-N-(p-toluenesulfonyl)anthranilic acid (5.20 g (15.3 mmol)) in chloroform (20.0 ml), thionyl chloride (2.00 g (27.4 mmol)) was added with stirring at room temperature. The resulting mixture was heated at 50° C. for 2 hours with stirring and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (20.0 ml) and added dropwise to a solution of sodium borohydride (90%, 1.30 g (30.9 mmol) in water (20.0 ml) under cooling with ice. After one hour's stirring at room temperature, water (100.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.40 g (88%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1])[CH2:21][CH:20]=[CH2:19]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
To an acetonitrile (40 mL) solution of 2-chloro-4-nitrophenol (2.60 g; 15.0 mmol) and potassium carbonate (2.74 g; 19.8 mmol), 4-bromo-1-butene (2.81 g; 20.4 mmol) was added, and the mixture was refluxed and then reacted overnight. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-3-chloronitrobenzene (1 h) (2.32 g, 68% of yield, a light yellow solid, melting point of from 39 to 40° C.) represented by the following formula.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:24]CC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of CeliteTM. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1 -butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL ) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL ) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL ) was treated with 1.0M BH3-THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d,J=7.8, 1H), 7.42 (t,J=7.8, 1H), 7.31 (d,J=7.8, 1H), 7.02 (t,J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9 H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>ClCCl>[CH3:1][N:2]1[C:6]([C:7]([Cl:29])=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.0 g (12.8 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid are suspended in 50 ml of dichloromethane. 0.02 ml of N,N-dimethylformamide and 3.54 ml (38.4 mmol) of oxalyl chloride are then added in succession. The reaction mixture is then stirred first at room temperature for 30 minutes and then under reflux for 30 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride formed is used for the subsequent synthesis step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(c2cc(F)cc(F)c2)C(C)(C)C)C1

Procedure:
A mixture of 720 mg (2.14 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate and 600 mg of palladium on activated carbon (10%) in 6 mL of ethyl acetate and 5 mL of MeOH was pressurized to 50 psi with hydrogen gas at room temperature for 72 h. The solution was filtered through CELITE and the filtrate was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 0.88 (s, 9H), 1.43 (s, 9H), 2.69 (d, J=11 Hz, 1H), 3.09-3.18 (m, 2H), 3.71 (t, J=8.2 Hz, 1H), 3.81(m, 1H), 4.12 (t, J=8.5 Hz, 1H), 6.49 (br, 1H), 6.69 (m, 2);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[Si:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][C:2]=1[Cl:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: NC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(N)=O)cc1Cl
Yield: 77.4 %

Procedure:
A solution of 2-(3-chloro-4-hydroxy-phenyl)-acetamide (100 mg), imidazole (184 mg), and tert-butyldimethylsilyl chloride (163 mg) was stirred for 2 h in 5 mL of dimethylformamide. The solution was diluted with 50 mL of ethyl acetate and washed with 50 mL of sodium carbonate. The ethyl acetate was evaporated to afford 125 mg of 2-[4-(tert-butyldimethylsilanyloxy)-3-chlorophenyl]acetamide.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Yield: 51.4 %

Procedure:
A mixture of 5.51 g (0.25 mole) of 2,6-di-tertiary-butyl-p-benzoquinone, 4.54 g (0.027 mole) of 3-(4-aminophenyl)propionic acid, 50 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate was heated on a steam cone under a slow stream of nitrogen for two hours. The resulting solid was triturated with hexane, collected, rinsed with hexane and recrystallized from a mixture of ethyl acetate and hexane to give 5.1 g yellow 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, m.p. 165°-167° C. Analysis: Calculated for C23H29NO3 : %C, 75.2; %H, 8.0; %N, 3.8; Found %C, 74.8; %H, 7.9; %N, 3.7.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[F:30].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][C:3]=1[F:30]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Yield: 70.9 %

Procedure:
1,1-Dimethylethyl N-((7-chloro-6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (79 mg, 180 μmol) was reacted with TFA (2 mL) at ambient temperature for 30 minutes. The resulting mixture was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (49 mg) as an off-white solid. MS m/e=384 (M+H)+. Calculated for C17H15NO6 383.06.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([F:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1F
Reaction time: 7 h
Yield: 101.6 %

Procedure:
Ethyl 2-fluoro-5-nitrobenzoate (0.63 g) was dissolved in ethanol (10 ml), and 10% Pd-C (0.064 g) was added to the solution. The mixture was subjected to catalytic reduction at room temperature for 7 hr. The reaction solution was filtered through Celite, and was washed with ethanol. The solvent was then removed by distillation under the reduced pressure to give 0.55 g (100%) of ethyl 5-amino-2-fluorobenzoate.
Reaction SMILES: C([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=3[CH3:27])=[N:14][C:13]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:13]2[N:14]=[C:15]([O:17][C:18]3[C:19]([CH3:27])=[CH:20][C:21]([C:22]#[N:23])=[CH:24][C:25]=3[CH3:26])[C:16]3[NH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 160 °C
Yield: 26.3 %

Procedure:
To a suspension of 4-(5-benzyl-2-(4-cyanophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (240 mg, 0.51 mmol) in 1,2-dichlorobenzene (20 mL) was added AlCl3 (681 mg, 5.1 mmol). The reaction mixture was heated at 160° C. for 1.5 h, during which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC TLC eluting with Hexanes:Ethyl acetate (2.5:1) and produced the product as a pink solid (51 mg, 26%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>C1COCC1>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[OH:19])=[CH:14][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a stirred solution of 2-bromothiophene (10 g, 61.34 mmol) in dry THF (42 mL) was added n-butyl lithium (42.0 mL, 67.48 mmol) dropwise at −78° C. and the mixture was stirred at same temperature for 30 min. Then a solution of isonicotinaldehyde (6.56 g, 61.34 mmol) in dry THF (30 mL) was added dropwise and continued stirring at −78° C. for another 2 h. The reaction mixture was quenched with NH4Cl solution (10 mL), diluted with water (200 mL) and extracted with diethyl ether (2×200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was triturated with mixture of hexane and diethyl ether to get the desired compound as an off-white solid (4 g, 34%); 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J=4.9 Hz, 1.5 Hz, 2H), 7.45-7.38 (m, 3H), 6.97-6.93 (m, 2H), 6.45 (d, J=4.4 Hz, 1H), 5.97 (d, J=4.4 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(C(C)C)CC)(C)C.I.[NH2:26][C:27]1[C:28]([C:35]([NH:37][C:38](=[NH:41])SC)=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1>C(O)C>[NH2:26][C:27]1[C:28]([C:35]([N:37]=[C:38]([NH2:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 12-aminododecanoic acid (1) (0.096 g, 0.45 mmol) and diisopropylethylamine (0.39 mL, 2.23 mmol) in absolute ethanol (5 mL) was stirred at 70° C. for 30 min. 1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (191 mg, 0.49 mmol) was added in one portion and heating at 70° C. was continued for a further 16 hours. After this time, the reaction was cooled to room and the resulting yellow precipitate collected by filtration and washed with ethanol (2×2 mL). Further purification by Biotage silica gel column chromatography using a gradient of 3% to 20% of 10% concentrated aqueous ammonium hydroxide in methanol to dichloromethane afforded acid 2 (96 mg, 50%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 4H), 2.18 (t, 2H), 3.15 (t, 2H), 6.92 (m, 3H). m/z (ESI) 428 [C18H30ClN7O3+H]+. mp 194-196° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17][CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19](/[CH:24](CO)[CH2:25][OH:26])=[CH:20]\[CH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[O:26][CH2:25][C@H:24](/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH3:23])[CH2:18][O:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC/C=C/C(CO)CO
Reactant: COC=C1CCC(c2ccc(C#N)c(F)c2)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 1 h

Procedure:
A mixture of 0.98 g of 2-fluoro-4-[4-(methoxymethylidene)cyclohexyl]benzonitrile (U.S. Pat. No. 4,784,471), 0.70 g of 2-(1E-pentenyl)-1,3-propanediol, 45 ml of toluene, 2 ml of water and 10 drops of 10 percent sulphuric acid was stirred at about 85° C. for 75 minutes, then heated to boiling for 1 hour, whereby moist solvent distilled off and was replaced by fresh toluene. The reaction mixture was treated with 12 drops of triethylamine and, after cooling, washed three times with 15 ml of water, dried over sodium sulphate, filtered and concentrated. Chromatography of the residue (1.86 g) on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization from 8 ml of hexane each time gave 0.65 g of pure 2-fluoro-4-[trans-4-[trans-5-(1E-pentenyl)-1,3-dioxan-2-yl]cyclohexyl]benzonitrile, m.p. (C-N) 91.2° C., cl.p. (N-I) 192.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=O)C.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1nnc(S)o1
Product: CN(C)C(=O)c1nnc(S)o1

Procedure:
This product (m.p. 185°-187° C.) was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with dimethylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>C(#N)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:19]([N:17]2[CH2:18][C@H:14]([O:13][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:15][C@H:16]2[C:32]([OH:34])=[O:33])=[O:20])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
608 μl of chlorotrimethylsilane and 670 μl of triethylamine, whilst ice-cooling, were added to a solution of 620 mg of trans-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 20 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium chloride. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 648 mg of trans-1-(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline as a powder. The whole of this was dissolved in 14 ml of dry acetonitrile, and then 330 mg of N,N'-carbonyldiimidazole were added. The mixture thus obtained was stirred at room temperature for 1 hour. At the end of this time, a solution of 630 mg of 1-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]piperazine in 2 ml of dry acetonitrile was added to the reaction mixture, and the resulting mixture was stirred overnight an room temperature and then at 40° C. for a further 1 hour. The reaction mixture was then mixed with 14 ml of 1N aqueous hydrochloric acid and stirred at room temperature for 1 hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was made slightly alkaline by the addition of an aqueous solution of sodium hydrogencarbonate; it was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 589 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(i) above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:11]=3[CH:10]2O)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH:10]1[CH:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:11]1=2
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc2c(c1)C(O)C(Cc1ccc(F)cc1)CC2
Product: Cc1cnc2c(c1)C(Cl)C(Cc1ccc(F)cc1)CC2
Reaction time: 3 h

Procedure:
5,6,7,8-Tetrahydro-6-((4-fluorophenyl)methyl-5-hydroxy-3-methylquinoline (2.4 g prepared according to Example 13) was dissolved in thionyl chloride (15 ml) and left to stir for 3 hours. The solvent was evaporated the residue diluted with water. The aqueous solution was basified with solid K2CO3 and extracted into ethyl acetate. The organic solution was dried (Na2SO4) and evaporated to give 5,6,7,8-tetrahydro-5-chloro-6-(4-fluorophenyl)methyl-3-methylquinoline (2.13 g). This was dissolved in THF (20 ml) and L-Selectride (1M solution in THF, 20 ml) was added. The reaction mixture was left to stir for 20 hours and acetic acid (5 ml) was added. The solvent was evaporated under reduced pressure and the residue dissolved in 2N HCI. The acidic solution was washed with ethyl acetate and basified with solid K2CO3. The basic solution was extracted into ethyl acetate, dried (MgSO4), evaporated and the residue dissolved in methanol and ethereal hydrogen chloride added. The solvent was evaporated under reduced pressure and the methanol was replaced and evaporated three times. The residue was recrystallised from EPA/ethyl acetate to give the title compound as the monohydrochloride salt (1.12 g), mp=168°-169° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[CH:3](OC)OC.[Cl:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.O>[Cl:16][C:17]1[C:18]2[N:19]([C:2]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=3)=[CH:3][N:23]=2)[CH:20]=[CH:21][N:22]=1
Reactant: COC(OC)C(Br)c1ccnc(SC)n1
Reactant: Nc1nccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CSc1nccc(-c2cnc3c(Cl)nccn23)n1

Procedure:
The mixture of 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (from Example 43 supra) (7.5 g, 25.6 mmol), 3-chloropyrazin-2-amine (3.96 g, 30.7 mmol) and p-toluenesulfonic acid (1.594 g, 9.22 mmol) in the mix solvent of acetonitrile/water (120 mL:6 mL) was heated at reflux for 6 hours. The reaction mixture was concentrated and purified by chromatography (dichloromethane:methanol, 20:1) to give 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine as a white solid. (Yield 2.3 g, 32.4%). LC-MS: [M+H]+ 278.