Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30][C:31]([NH:33][C:34]2[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=2)=[O:32])[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:40][C:37]1[N:38]=[CH:39][C:34]([NH:33][C:31]([NH:30][C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][CH2:12]2)=[O:32])=[N:35][CH:36]=1
Reactant: [H][H]
Reactant: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)Nc2cnc(C)cn2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C

Procedure:
A stirred suspension of the crude 3-{4-Methyl-2-[3-(5-methyl-pyrazin-2-yl)-ureido]-phenoxymethyl}-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (6.6 mg, 12 μmol) was heated in 5 mL EtOAc on a heat gun until in solution. The clear solution was cooled to rt and treated with triethylamine (3.4 μL, 24 μmol) followed by Pearlman's catalyst (20% palladium hydroxide on carbon, 9 mg). The mixture was put through a vacuum/purge cycle three times with hydrogen gas and then held under 1 atmosphere hydrogen pressure for 1 hour. The reaction was filtered through GF/F filter paper with EtOAc and concentrated to a white solid which corresponds to the desired product (4.7 mg, 100%). 1H-NMR (400 MHz, CDCl3/CD3OD) δ8.23 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.04(t, 1H), 6.97 (d, 1H, 6.81 (m, 2H), 6.67 (t, 1H), 6.58 (d, 1H, 4.04 (m, 2H), 3.57 (d, 1H, 3.26 (t, 1H), 2.92 (ddd, 2H), 2.64 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H) LRMS (APCI, Positive) m/e 404.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2ccccn2)cn1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nc2)nc1

Procedure:
To a solution of 6′-chloro-[2,3′]bipyridinyl (0.275 g, 1.440 mmol) in acetonitrile (10 mL) was added piperazine (0.310 g, 3.600 mmol) and the mixture was stirred at reflux for 32 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated NaHCO3 solution (10 mL). Organic layer was separated, dried over MgSO4 and filtered. The filtrate was use in the next step without isolation of the product.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=NC=1)(=[O:4])=[O:3].[N:13]1C=CN=C[C:14]=1CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:14][N:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCc1cncnc1
Reactant: OCc1cnccn1
Product: CS(=O)(=O)OCc1cnccn1

Procedure:
Pyrazin-2-ylmethyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using pyrazin-2-ylmethanol instead of pyrimidin-5-ylmethanol. LCMS-ESI+ (m/z): [M+H]+ calc'd for C6H8N2O3S: 189.03; found: 189.01.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:32])=[C:12]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2)(=O)C.O.C(OCC)(=O)C>O1CCOCC1>[OH:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:32])=[C:12]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)=[O:31])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1cc(C(=O)c2c(C)c(OCCOC(C)=O)c3ccccn23)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(C)c(OCCO)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
1.52 ml of 1 N sodium hydroxide are added to 420 mg (1.02 mmol) of 2-{[3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]oxy}ethyl acetate, a compound of Example 79, dissolved in 6 ml of dioxane, and the medium is stirred at room temperature for 6 hours. The reaction medium is poured over water and ethyl acetate. The organic phase is separated after settling out, washed with water, dried over sodium sulphate and concentrated under reduced pressure. 340 mg of an orange-coloured powder are obtained, which powder is used without further purification in the subsequent nitro reduction step.
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.C([Cl:17])(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:17][CH2:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1=CSCCl
Yield: 87.9 %

Procedure:
1.0 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 10 ml of methylene chloride, and 470 mg of acetyl chloride was added dropwise. The mixture was subjected to reaction at room temperature for 12 hours, and then 50 ml of 5% sodium hydrogen carbonate was added thereto. The mixture was extracted twice with 50 ml of chloroform, and the organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, whereby 960 mg of 2,2,5,5-tetramethylcyclopentylidenemethyl chloromethyl sulfide was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccc(Br)cn2n1
Product: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((AS), 5.0 g; 23.47 mmol; 1.0 eq.) and benzoyl chloride (6.57 g; 46.9 mmol; 2.0 eq.) as a white powder (6.5 g, 87%). HPLC, Rt: 2.49 min. (purity 97.1%). LC/MS, M+(ESI): 317.0, M−(ESI): 316.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2
Product: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(OC)c(OC)c2)c2ccccc21
Yield: 42.5 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.0 g, 3.05 mmol) prepared in Reference Example 1 and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl)oxy]pentanoate (487 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (760 mg, yield: 42%) as a colorless oil. (cis:trans=1:1.2)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:21])=[C:4]([CH3:22])[N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: COc1nc(Cl)nc(C)c1COc1cc(C(C)C)ccc1C
Reactant: Cc1cccc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc(-c2c(C)cccc2C)nc(C)c1COc1cc(C(C)C)ccc1C
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture containing 2-chloro-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (˜3.91 mmol), 2,6-dimethylphenylboronic acid (1.17 g, 7.82 mmol), 15.6 mL of 1 M aqueous sodium carbonate and dioxane (56 mL) is degassed by bubbling with argon for 20 min. To this mixture is added Pd(PPh3)4 (226 mg, 0.05 mol %). The resulting yellow mixture is heated at 90° C. under nitrogen with magnetic stirring for 24 h. Another 50 mg of Pd(PPh3)4 is added and heating is continued for another 18 h until the reaction is complete by LC/MS analysis. The reaction mixture is allowed to cool to ambient temperature and partitioned between EtOAc (200 mL) and water (70 mL). The organic layer is separated, extracted with water (70 mL×2), brine (70 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a yellow oil. Purification by chromatography on silica gel (5-50% EtOAc/Hexanes) provides the title compound as a colorless solid. LC-MS found 391.4 (MH+), rt=1.93 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=O.ClC(Cl)(Cl)C(Cl)=O.C(OCC)(=O)C.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:14])([F:15])[C:11]#[N:13]
Reactant: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70.7 %

Procedure:
In 5 ml of pyridine was dissolved 150 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy4(1H-1,2,4triazol-1-yl)butanamide. To the solution was added 100 mg of trichloroacetyl chloride at 0°-5C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. Then, the reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.O>C(O)(=O)C>[Cl:4][C:9]1[C:10](=[O:15])[NH:11][C:12](=[O:14])[NH:13][C:8]=1[CH2:7][Cl:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Sulfuryl chloride (120 ml) was added dropwise to a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml) over 20 minutes at room temperature, and the mixture was stirred for an additional 3 hours at room temperature. The resultant solution was poured into iced water (500 ml), and then precipitated crystals were collected through filtration, to there by obtain 182.3 g of 5-chloro-6-chloromethyluracil (92% yield).
Reaction SMILES: FC(F)(F)C([N:5]([CH:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)[CH2:6][C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=O.[OH-].[Na+]>CO>[C:12]1([C:10]2[N:11]=[C:7]([CH2:6][NH:5][CH:24]3[C:32]4[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[O:8][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 81.4 %

Procedure:
To a solution of 1-[N-trifluoroacetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.29 g) of methanol (2 ml) was added 1N NaOH aqueous solution (2 ml). The mixture was refluxed for 1 day and the solvent was removed in vacuo. The residue was extracted with ethyl acetate, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.19 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cccc(N)c1F
Agent: [Na+]
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1F
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 250 mg of 2-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 208 mg of N-(2-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:11][CH2:10][C:9]([O:12][C:17](=[O:18])[NH:16][CH2:15][CH2:14][Cl:13])=[N:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCONC(=O)CCl
Reactant: O=C=NCCCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCCCCCON=C(CCl)OC(=O)NCCCl
Temperature: 25 °C

Procedure:
N-Hexyloxychloroacetamide (19 grams; 0.1 mole), benzene (100 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. β-Chloroethylisocyanate (12.6 grams; 0.12 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-β-chloroethylcarbamoyloxy)-2-hexyloxyiminoethane.
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[C:17]([OH:19])=O)=[CH:10][CH:9]=1.CCN(CC)CC.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[C:17]([N:27]=[N+:28]=[N-:29])=[O:19])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Ethyl chloroformate (1.9 mL) was added to a solution of (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (Intermediate C, 4 g, 0.0165 mol) and Et3N (2.51 mL, 0.0199 mol) in acetone (60 mL) at −20° C., stirred at same temperature for 1 h, then a solution of NaN3 (1.3 g, 0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt. After completion of reaction, checked by TLC, the solvent was evaporated and crude residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (4 g). The crude residue is carried to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:13])[CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1
Reactant: Nc1nc(O)cc(CCl)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)cc(CCl)n1
Reaction time: 0.17 h

Procedure:
47.9 Parts of 2-amino-4-chloromethyl-6-hydroxypyrimidine was added portionwise to 410 parts of phosphorus oxychloride with stirring. The mixture was placed in an oil bath at 130° C. and stirred until all the solid had dissolved and then for a further 10 minutes. The solution was cooled and the excess of phosphorus oxychloride was removed in vacuo. The residual viscous oil was poured onto 300 parts of ice with stirring and the pH of the resulting mixture was adjusted to pH 8 by the portionwise addition of solid sodium bicarbonate. The mixture was extracted four times with diethyl ether. The ether extracts were combined, dried over anhydrous magnesium sulphate and evaporated to give a pale-yellow solid. Recrystallisation from carbon tetrachloride gave pure 2-amino-4-chloro-6-chloromethylpyrimidine m.p. 126°-128° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27].C(=O)(O)[O-].[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].COCCOC>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (39 g, 97.2 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (31 g, 107 mmol), and sodium bicarbonate (32.6 g, 389 mmol) were combined in 3:1 DME:H2O (500 mL), and the mixture was purged with N2 for 15 minutes. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (2.13 g, 2.91 mmol) was added, and the reaction was purged with N2 for an additional 10 minutes and then stirred at 90° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc/hexane gradient) to give the title compound.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[C:11]([O:44][CH3:45])=[C:12]([S:18]([NH:21][C@H:22]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH:33]2[C:39]([O:41]CC)=[O:40])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][CH3:8].[OH-].[Na+]>C(O)C.O>[CH2:5]([O:9][C:10]1[C:11]([O:44][CH3:45])=[C:12]([S:18]([NH:21][C@H:22]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH:33]2[C:39]([OH:41])=[O:40])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1c(OC)ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(C)CC2C(=O)OCC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1c(OC)ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(C)CC2C(=O)O)c1OC
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 5.8 g of ethyl 1-[N2 -(3-butoxy-2,4-dimethoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 80 ml of ethanol and 40 ml of water was added 10 ml of 2N NaOH aqueous solution at room temperature and stirring was continued overnight at room temperature. At the end of this period, the reaction solvent was distilled off under reduced pressure at a temperature below 30° C. The residue was dissolved in a small amount of water and then neutralized with 2N NCl to precipitate a white gummy substance. The aqueous solution was separated by decantation and the white precipitate was dissolved in 200 ml of chloroform, washed with 30 ml of water and then dried over anhydrous sodium sulfate. Upon evaporation of solvent, there was obtained 4.0 g (79%) of 1-[N2 -(3-butoxy2,4-dimethoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid in the form of an amorphous solid.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CO[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)=[O:14]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([O:10][C:13]([CH:15]1[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:22])[CH2:19][CH2:20]1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: CC(C)CCCCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)CCCCCCOC(=O)C1CCC(C(=O)OCCCCCCC(C)C)CC1
Temperature: 185 °C

Procedure:
Isononyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 1.7%, trans 98.3%, Eastman, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(isononyl)cyclohexane-1,4-dicarboxylate (cis 3%, trans 97%) was obtained with a purity of 99.7% in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([S:6]([C:9]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:10]=1[CH2:11][N:12](C)[C:13](=O)OCC1C=CC=CC=1)(=[O:8])=[O:7])[CH3:5]>CO.[Pd]>[CH3:1][O:2][CH2:3][C@@H:4]([S:6]([C:9]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:10]=1[CH2:11][NH:12][CH3:13])(=[O:7])=[O:8])[CH3:5]
Reactant: COC[C@H](C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc(N)ccc1S(=O)(=O)[C@@H](C)COC
Reaction time: 7.5 h
Yield: 99.5 %

Procedure:
To a suspension of 6D (327 mg, 0.749 mmol) in MeOH (10 mL), was added 10% Pd—C (40 mg, 0.038 mmol). The mixture was evacuated and flushed with H2 (3×), then was stirred under an atmosphere of H2 for 7.5 h. The reaction mixture was filtered and concentrated to give 6E (203 mg, 99% yield) as a colorless semisolid. MS (ESI) m/z: 273.2 [M+1]+. 1H NMR (400 MHz, methanol-d4) δ ppm 7.58 (d, J=8.78 Hz, 1H) 6.69 (d, J=2.51 Hz, 1H) 6.64 (dd, J=8.66, 2.38 Hz, 1H) 3.78-3.89 (m, 2H) 3.59-3.67 (m, 1H) 3.44-3.55 (m, 2H) 3.21 (s, 3H) 2.37 (s, 3H) 1.28 (d, J=6.78 Hz, 3H).