Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].O.[CH2:18](OCC)C>CN(C)P(N(C)C)(N(C)C)=O.C[Sn](C)(C)C.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:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: COC(=O)c1ccc(COC(C)=O)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1ccc(COC(C)=O)c(C)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
5.30 g of methyl 4-[(acetyloxy)methyl]-3-bromobenzoate was dissolved in 50 mL of hexamethylphosphoramide, to which 6.6 mL of tetramethyltin and 0.26 g of bis(triphenylphosphine)-palladium(II) dichloride were added at room temperature in a stream of nitrogen, and this solution was stirred for 3 hours at 70° C. The reaction mixture was cooled to room temperature, and was added to a mixture of water and diethyl ether, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 4.17 g of methyl 4-[(acetyloxy)methyl]-3-methylbenzoate as brown oil.
Reaction SMILES: ClC1N=C2NC(=O)C3([C@@H](C4C=CC=C(Cl)C=4F)[C@H](C(N[C@H]4CC[C@H](CO)CC4)=O)[N:12]([C@H:34]([C:43]4[CH:48]=[CH:47][CH:46]=CC=4)[C@@H:35]([OH:42])C4C=CC=CC=4)C43CCC(C)(C)CC4)C2=CC=1.[H][H].C[OH:60]>[C].[Pd]>[NH2:12][C@@H:34]1[CH2:43][CH2:48][C@@H:47]([CH2:46][OH:60])[O:42][CH2:35]1
Reactant: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@H]1CC[C@H](CO)CC1)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2nc(Cl)ccc21
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Product: N[C@@H]1CC[C@@H](CO)OC1
Yield: 100 %

Procedure:
The compound (2.00 g, 7.54 mmol) obtained in Step 2 above was dissolved in methanol (30 ml), 10% palladium carbon (300 mg) was added and the resulting mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The catalyst was removed by filtration through celite and then the filtrate was concentrated under reduced pressure and dried to give 1.13 g (100%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][CH2:9][N:10]([C:13]([SH:15])=[S:14])[CH2:11][CH3:12].C(=S)=S.C(N(CC)CC)C.C(NCC)C>>[CH2:9]([N:10]([CH2:11][CH3:12])[C:13](=[S:14])[S-:15])[CH3:8].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C(=S)S
Agent: CC[NH+](CC)CC
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: S=C=S
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of triethylammonium salt of diethyl dithiocarbamate is as follows: 76 grams (1 mole) carbon disulfide and 101 grams (1 mole) triethylamine are mixed at 10° C. under nitrogen. To the mixture is added in slowly 80.5 grams (1.1 mole) diethylamine drop wise and maintain the temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.[CH3:8]OCCOC.C([Li])CCC.[CH2:19]([N:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[CH:33][C:34](OCC)=O)[N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC>[CH2:33]([C:32]1([C:29]2[N:28]=[CH:27][N:26]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:30]=2[CH3:31])[CH2:8][C:3](=[O:5])[CH2:2][S:1]1)[CH3:34]
Reactant: COCCOC
Reactant: CCOC(=O)C=Cc1ncn(Cc2ccccc2)c1C
Reactant: CCOC(=O)CS
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCC1(c2ncn(Cc3ccccc3)c2C)CC(=O)CS1
Reaction time: 6 h

Procedure:
A solution of ethyl mercaptoacetate (7.45 g., 0.062 mole) in 59 ml. of dry 1,2-dimethoxyethane is cooled to 5° C. and n-butyl lithium (41.3 ml., 0.062 mole) in hexane is added dropwise over 1/2 hour under a nitrogen atmosphere. To this solution is added ethyl 3-(1-benzyl-5-methyl-4-imidazolyl)-2-propenoate (13.0 g., 0.0514 mole) in 50 ml. of 1,2-dimethoxyethane at 10° C. The mixture is stirred at 50°-55° C. for 6 hours and is left at room temperature overnight. The reaction mixture is cooled in ice and is diluted with 300 ml. of ether and filtered. The solid is dissolved in 100 ml. of water and is acidified with dilute hydrochloric acid. The mixture is made basic with sodium bicarbonate and is extracted with a mixture of chloroform and methylene chloride. The combined extracts are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product ethyl 2-[1-benzyl-5-methyl-4-imidazolyl]-4-oxotetrahydrothiophene-5-(and/or 3)-carboxylate is obtained as a brown viscous liquid (12.6 g.).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[C:49]([F:52])([F:51])[F:50]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-4′-fluoro-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-fluoro-3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nc[nH]n1
Reactant: O=C1CCC2(CCCO2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1nnc(NC2CCC3(CCCO3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (0.29 g) and 1-oxaspiro[4.5]decan-8-one (0.64 g) in acetic acid was added sodium cyanoborohydride (1.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:26](=[O:29])(=[O:28])[NH2:27])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH2:38](O)[CH3:39]>>[CH2:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:26](=[O:29])(=[O:28])[NH2:27])[C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:5]([O:7][CH2:38][CH3:39])=[O:6])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(OCc2ccccc2)cc1
Reactant: CCO
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccc(OCc3ccccc3)cc2)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3-amino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid (4 g), benzyl bromide (4.1 g), and ethanol (60 ml) was refluxed for 4 hours. After cooling, the precipitated ethyl 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoate was isolated by filtration and recrystallized from ethanol. The compound was obtained with a melting point of 166°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:32])[C:22]=1O.B(O)(O)O>CN(C=O)C.C(Cl)Cl>[F:32][C:23]1[C:22]2[O:13][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[N:20][C:21]=2[CH:26]=[CH:25][C:24]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccccc34)oc2c1F
Temperature: 0 °C
Yield: 3.7 %

Procedure:
To 1-methylindole-3-carboxylic acid (917 mg, 5.23 mmol) was added methylene chloride (20 ml). Under stirring at 0° C., oxalyl chloride (0.68 ml, 7.85 mmol) and DMF (catalytic amount) were added. After stirring at room temperature for 1.5 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was added with xylene (20 ml). Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.0 mmol) and boric acid (539 mg, 8.72 mmol) were added to the resulting mixture, followed by stirring at 160° C. for 3 days. After the reaction mixture was cooled to room temperature, ice water was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column to collect chloroform/ethyl acetate (10/1) eluate fractions and then, purified by chromatography using a thin layer plate, whereby from chloroform/acetone (10/1) eluate fractions, methyl 7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolylacetate (62 mg, 4%) was obtained as a pale brown solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(OCCCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of diethyl azodicarboxylate (7.3 g; 42 mmol) and tetrahydrofuran (15 ml) was added dropwise at 0° C. to a solution of 4-hydroxybenzonitrile (4.2 g; 35 mmol), 8-chloro-1-octanol (6.9 g; 42 mmol), triphenylphosphine (11.0 g; 42 mmol) and tetrahydrofuran (70 ml) and stirred at room temperature overnight. The reaction mixture was added to water (200 ml) and extracted with ethyl acetate (3×100 ml), dried over magnesium sulphate and filtered. The solvent was then removed in vacuo. The residue was purified by column flash chromatography on silica gel using toluene/ethyl acetate (97:3) as eluent, to give 8.8 g (94%) of p-[(8-chlorooctyl)oxy]benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[CH2:33].CCN(CC)CC>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:8][C:5]1[N:6]=[CH:7][C:2](/[CH:33]=[CH:32]/[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-methylpyridine (5 g, 29.06 mmol) in NMP (60 mL), were added Pd(OAc)2 (0.325 g, 1.45 mmol) and P(o-tol)3 (0.883 g, 2.9 mmol). Subsequently, a solution of tert-butyl acrylate (13.02 g, 101.7 mmol) in Et3N (16.1 mL, 116.2 mmol) was added under N2 to the above mixture and stirred at 90° C. After 16 h, water was added to the reaction mixture and extracted with Et2O (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (SiO2, 100-200 mesh, Et2O/Pet ether 1:9) afforded the title compound. MS: 220 [M+H]+;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[N:14](COC(=O)C(C)(C)C)[CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:27])[NH:14][CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude tert-butyl (2R)-2-{[(7-(benzyloxy)-3-{[(2,2-dimethylpropanoyl)oxy]-methyl}4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (assumed 18 g) was dissolved in 7N ammonia in methanol and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography using 0-10% methanol in DCM as eluent to give a mixture of two products. The mixture was dissolved in DCM, washed with 20% aqueous sodium hydroxide solution (2×) and then dried (MgSO4) and concentrated in vacuo to leave tert-butyl (2R)-2-({[7-(benzyloxy)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate as a beige foam (6.8 g, 48% for the two steps); Mass spectrum MH+ 452.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:37][C:38](=O)[NH:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][N:16]([C:38]([NH:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Nc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CNCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C(=O)Nc2ccccc2N)cc2c1CN(C(=O)Nc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by pyridin-3-yl-carbamic acid 4-nitro-phenyl ester (1.0 eq) and stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: OCc1ccccc1
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C

Procedure:
Using the procedure of Example 3, 12.5 ml of 1 M/l of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 1.35 ml of benzyl alcohol were reacted to obtain 1.77 g of benzyl (1R,trans) 2,2-dimethyl-3[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+47.5°±1.5° (c=1% in chloroform).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.ClCCl>CN(C=O)C.O>[N:1]1([C:10]2[N:15]=[C:14]([N:32]3[CH2:31][C@@H:30]([CH3:29])[O:35][C@@H:34]([CH3:36])[CH2:33]3)[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2nc(N3CCOCC3)nc(-n3cnc4ccccc43)n2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
The obtained 2-(benzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine (320 mg, 1.0 mmol) dissolved in DMF (20 ml) was added with potassium carbonate (430 mg, 3.2 mmol) and cis-2,6-dimethylmorpholine (140 mg, 1.2 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was condensed under reduced pressure and the obtained residue was added with dichloromethane and water and shaken for mixing. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 360 mg (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:22])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:5])=[O:4].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[Si:23]([C:7]1[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:30])[CH3:1])[CH:10]=[C:9]([CH:11]([O:22][C:37](=[O:39])[CH3:38])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=1)([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.750 g, 1.62 mmol) in 8 ml of anhydrous toluene at 0° C., pyridine (0.16 ml, 1.94 mmol) was added followed by acetyl chloride (0.14 ml, 1.94 mmol). The solution was stirred at room temperature for two hours. It was cooled to 0° C. and ice cubes were added. The reaction mixture was partitioned between toluene (5 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and column purified (hexanes:EtOAc; 1:4) to give 0.84 g (100%) of the product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[C@H:32]1[CH2:34][C@H:33]1[CH2:35][OH:36])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[C@H:32]1[CH2:34][C@H:33]1[CH:35]=[O:36])#[N:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CO)c3cc(C#N)ccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of oxalyl chloride (52 μL, 0.60 mmol) in anhydrous dichloromethane (20 ml) was added dimethylsulfoxide (50 μL, 0.70 mmol) dropwise. After stirring 10 min, a solution of cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanemethanol (129 mg, 0.35 mmol) in dichloromethane (5 ml) was added dropwise. After stirring 20 min at −78° C., triethylamine (294 □L, 2.10 mmol) was added dropwise. The reaction was stirred for 5 min at −78° C. and then allowed to warm to room temperature. The reaction was washed with water (2×5 ml), dried with anhydrous magnesium sulfate and the solvent was evaporated to give the crude cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanecarboxaldehyde.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH3:25]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 98 %

Procedure:
4-Phenoxycinnamic acid (4.0 g), conc. sulfuric acid (0.4 ml) and ethanol (40 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(b) to obtain the title compound (4.4 g, 98%) as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)[N:34]=1.[CH2:54]([CH2:58][CH2:59][CH2:60][CH:61]([SiH:63]([CH3:65])[CH3:64])O)CCC>O1CCCC1>[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH2:14][CH2:13][CH2:18][CH:61]([SiH:63]([CH3:64])[CH3:65])[CH2:60][CH2:59][CH2:58][CH3:54])=[CH:51][CH:52]=2)[N:34]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCc1ncc(-c2ccc(O)cc2)nc1F
Reactant: CCCCCCCC(O)[SiH](C)C
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ncc(-c2ccc(OCCCC(CCCC)[SiH](C)C)cc2)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
1.82 ml (11.60 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.04 g (11.60 mmol) of triphenylphosphine in 85 ml of tetrahydrofuran, and this mixture is stirred at 0° C. for 0.5 hour. 2.00 g (7.00 mmol) of 2-fluoro-3-octyl-6-(4-hydroxyphenyl)-pyrazine (prepared as described in Example 4a to 4d) and 2.46 g (11.60 mmol) of 4-butyldimethylsilylbutanol are subsequently added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated, and the residue is purified by chromatography (silica gel/dichloromethane: hexane = 8:2). 1.47 g of 2-fluoro-3-octyl-6-[4-(4-butyldimethylsilylbutyloxy)-phenyl-]pyrazine are obtained. ##STR27##
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CON(C)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH:3]1([CH2:2][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: BrCC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a suspension of Mg (735 mg, 30.5 mmol) in anhydrous THF (20 mL) was added (bromomethyl)cyclohexane (5.4 g, 30.5 mmol) at 10° C. under N2 atmosphere. The resulting mixture was stirred at reflux until all of Mg was consumed. Then the resulting mixture was cooled to ambient temperature and N-methoxy-N-methylbenzamide (1.0 g, 6.1 mmol) was added and the mixture was stirred at 10° C. for 2 hours. The mixture was quenched with aqueous saturated NH4Cl (50 mL). Followed a standard aqueous/EtOAc workup and the residue was purified by column chromatography on silica gel (PE:EtOAc=20:1) to give Intermediate 96 as colorless oil (800 mg, yield 67%).