Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=[O:8]>C(Cl)Cl.C1COCC1.[Pt]>[NH2:10][C:5]1[CH:4]=[C:3]([F:13])[C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1cc(F)c(Br)cc1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Pt/C (10%, 1.5 g, 0.77 mmol) in DCM (200 mL) and THF (50 mL) was added 5-bromo-4-fluoro-2-nitrobenzaldehyde (9.0 g, 36.3 mmol). The mixture was purged with H2 gas, and was stirred under an atmosphere of H2 gas at ambient temperature for 24 h. The reaction mixture was filtered through celite rinsing with DCM. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane to afford 2-amino-5-bromo-4-fluorobenzaldehyde.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1C=CC=CC=1.ClC1[N:36]=[C:35]([Cl:37])[CH:34]=[C:33]([CH3:38])[N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:35]1[N:36]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[N:32]=[C:33]([CH3:38])[CH:34]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: Cc1cc(Cl)nc(-n2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2=O)n1

Procedure:
4-{3-[1-(6-Chloro-4-methyl-pyrimidin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,4-dichloro-6-methylprimidine for the iodobenzene in Step 3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(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)C=CC=CC=1>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:16]2[CH:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(Cc2cccc(-c3ccc(C(=O)O)cc3)c2)CC1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
98 mg 4-Carboxybenzeneboronic acid, 159 mg 1-(3-Bromo-benzyl)-4-methyl-piperazine, 410 mg potassium carbonate, and 69 mg tetrakis-triphenylphosphino-palladium were stirred under an argon atmosphere in a mixture of 1 ml dioxane and 1 ml water at 85 C for 16 hrs. The mixture was cooled to RT, diluted with 100 ml water and filtered. The filtrate was carefully treated with conc. HCl until the product precipitated. Filtration and drying of the residue yielded 190 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)[CH3:23])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[CH2:31](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:31][N:11]([C:12]3[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1)[CH3:23]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(Cl)cc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(-n2cnc3cc(Cl)c(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
3-Chloro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N6-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 39, 0.5 g) was dissolved into ethanol (20 mL) with Pd—C (150 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.12 g desired product. MS (electrospray): 416 (M+1) for C19H19ClFN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H) 8.30 (s, 1H) 7.90 (d, 1H) 7.50 (m 2H) 6.70 (d, 1H) 6.00 (s, 1H) 5.40 (m, 1H) 4.60 (m, 1H) 1.60 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=O)[CH:7]=[CH:6]2.Cl.[NH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21].C([O-])(=O)C.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH:14]1[NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21]1)[CH3:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2cc([C@H](C)C3N[C@H](C(=O)O)CS3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of (2S)-2-(6-methoxy-2-napthyl)-propanal (8.2 g; 38.3 mmoles) in acetone (50 ml) is added dropwise to a solution of (R)-cysteine hydrochloride (5.94 g; 37.6 mmoles) and of potassium acetate (3.69 g; 37.6 mmoles) in 100 ml of water and acetone (1:1 v/v) kept under stirring at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:10])=[N:4][C:5](Cl)=[N:6][C:7]=1Cl.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[NH2:10][C:3]1[C:2]([CH3:1])=[C:7]([O:12][CH3:11])[N:6]=[C:5]([O:15][CH3:14])[N:4]=1
Reactant: Cc1c(N)nc(Cl)nc1Cl
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(N)c(C)c(OC)n1
Yield: 60 %

Procedure:
A mixture of 10.7 g (0.06 mol) of 5-methyl-4-amino-2,6-dichloropyrimidine, 100 ml of methanol and 22 g of 30% sodium methylate (0.122 mol) is allowed to react at 120° C. for 20 hours in an autoclave. After cooling, the grey reaction mixture is concentrated in vacuo; the residue is taken up in 70 ml of water, stirred and then filtered. The residue is washed with water, dried and recrystallised from carbon tetrachloride. There remain after drying 6.1 g of 4-amino-5-methyl-2,6-dimethoxypyrimidine as white crystals, which melt at 60° C. (yield=60% of theory).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:12]=2)[CH2:2]1.[CH3:19]CN(C(C)C)C(C)C.[C:28]1([CH2:34][CH2:35][CH:36]=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[C:28]1([CH2:34][CH2:35][CH2:36][N:1]2[CH2:5][CH2:4][CH2:19][C@@H:3]([NH:6][C:7]3[N:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:12]=3)[CH2:2]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=CCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCCN(CCCc3ccccc3)C2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate (335 mg) in dichloromethane (5 mL) was added DIEA (870 uL), 3-phenylpropanal (157 ul), and sodium triacetoxyborohydride (424 mg), and the reaction mixture was stirred at ambient temperature for 2 hours. To the resultant was added saturated aq.NaHCO3, which was stirred for 30 min. The mixture was extracted with dichloromethane. The organic phase was washed with brine and dried over MgSO4, filtered, and evaporated in vacuo. The residue was crystallized from acetone and IPE to give methyl (2E)-3-[5-[{(3R)-1-(3-phenylpropyl)-3-piperidinyl}amino]-2-pyrazinyl]acrylate (183 mg) as a pale yellow crystal. The filtrate was evaporated and the residue was column chromatographed on silica gel (hexane:AcOEt=25:75) to give 84 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2nc(C)c(C)c(N3CCc4ccccc4C3C)n2)cc1
Product: Cl
Yield: 27.3 %

Procedure:
After p-toluidine(0.45 g, 4.20 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.80 g, 2.78 mmol) and dimethylformamide(5 ml), 0.30 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: ClC1C=CC=CC=1C[O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])NC1SC(SCC(C)(C)C(O)=O)=CN=1.Br[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[C:45]([F:48])([F:47])[F:46].C([O:51][C:52](=[O:63])[C:53]([S:56][C:57]1[S:61][C:60]([NH2:62])=[N:59][CH:58]=1)([CH3:55])[CH3:54])C>>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:5][CH2:6][CH2:7][N:8]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:9](=[O:24])[NH:62][C:60]2[S:61][C:57]([S:56][C:53]([CH3:54])([CH3:55])[C:52]([OH:51])=[O:63])=[CH:58][N:59]=2)=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:40]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccc(F)cc2C(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-4-fluoro-2-trifluoromethyl-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13](Cl)=[O:14])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)C1C=CC=CC=1>>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14]
Reactant: O=C(Cl)N1CC=C(c2ccccc2)CC1
Reactant: O=C(NCCCCO)c1ccccc1
Product: O=C(NCCCCO)N1CC=C(c2ccccc2)CC1

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid (4-hydroxybutyl)amide (62B) is prepared from 62A as described for 1D. The product is obtained in almost quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (110 mg, 0.40 mMol) in ethanol (6 mL) was added SnCl2.2H2O (448 mg, 2.0 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution and continually refluxed for another 3 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with cold ethanol (2×1 mL) to give 61 mg (62%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 43 mg of pure title compound as bright yellow needles, mp>350° C. (dec.), changed color from 320° C. IR (KBr, cm-1): 3468; 3389; 3057; 1695; 1636; 1596; 1397. NMR (1H, DMSO-d6): δ5.935 (s, 2H); 6.595 (s, 1H); 11.317 (s, 1H); 11.868 (s, 1H). Purity >98.95% by HPLC. HRMS: calcd for C8H5N3O2Br2 (M+) m/z: 244.9757; found 244.9740. Potency relative to DCK: 323%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]1[C:30]([C:31]([O-])=[O:32])=[N:29][N:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].C1(N=C=NC2CCCCC2)CCCCC1.Cl>N1C=CC=CC=1>[CH2:19]([N:26]1[C:30]([C:31]([NH:11][C:10]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:32])=[N:29][N:28]=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C)cc(N)c1OCc1ccccc1
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
A mixture of 2-benzyloxy-3-methoxy-5-methylaniline (2.6 g), potassium 1-benzyl-1H-tetrazole-5-carboxylate (2.5 g) and dicyclohexylcarbodiimide (2.1 g) in dry pyridine (100 ml) was stirred at room temperature overnight. The mixture was then poured into a mixture of ice (250 g) and concentrated hydrochloric acid (100 ml), and the mixture was allowed to stand for 1 hour. The precipitate was filtered off and recrystallised from ethanol to give 1-benzyl-2'-benzyloxy-3'-methoxy-5'-methyl-1H-tetrazole-5-carboxanilide (0.16 g), m.p. 181°-183° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[NH:16][CH:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20](O)[CH3:21]>>[C:6]1([CH:12]2[NH:16][CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: O=C(O)C1CCC(c2ccccc2)N1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCC(c2ccccc2)N1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Ethyl (2RS,5SR)-5-phenylprolinate may be obtained as follows: 0.5 cm3 of concentrated sulphuric acid is added dropwise to a solution of 5.5 g of (2RS,5SR)-5-phenylproline in 50 cm3 of ethanol. The reaction mixture is then stirred at a temperature in the vicinity of 80° C. for five hours, then cooled to a temperature in the vicinity of 20° C. and concentrated under reduced pressure. The residue is taken up in 50 cm3 of water, brought to a pH in the vicinity of 9 by a normal aqueous sodium hydroxide solution and extracted with 3 times 100 cm3 of ethyl acetate. The combined organic extracts are washed with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is subjected to chromatography on silica [eluent cyclohexane/ethyl acetate (90/10 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 2.16 g of ethyl (2RS,5SR)-5-phenylprolinate are thus obtained in the form of an oil, used as it is in subsequent syntheses.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[O:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2o1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(F)cc3o2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzoxazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzoxazole.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][C:67]([C:70]#[N:71])=[CH:68][CH:69]=1>>[C:70]([C:67]1[N:66]=[CH:65][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)#[N:71]
Reactant: N#Cc1ccc(N)cn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.37 g, 2.9 mmol), diphenylphosphinic chloride (0.27 g, 1.1 mmol), then reacted with 3-amino-6-cyanopyridine (Aldrich) (0.1 g, 0.9 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-cyano-pyridin-3-yl)-amide as a yellow solid (Yield 0.12 g, 38%).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:20])=[C:4]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)[C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[S:8].C(=O)([O-])[O-].[K+].[K+].CS>CN(C=O)C>[CH3:13][C:5]1[C:4]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[C:3]([CH3:20])[CH:2]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[S:8]
Reactant: CCOC(=S)c1cc(Cl)c(C)c(-c2cc(C)no2)c1C
Agent: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=S)c1ccc(C)c(-c2cc(C)no2)c1C
Temperature: 25 °C
Reaction time: 23 h
Yield: 65.3 %

Procedure:
0.50 g of the obtained ethyl 5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate and 1.06 g of potassium carbonate were added to 15 ml of DMF, and further a solution of 0.36 g of methyl mercaptan dissolved in 5 ml of DMF was dropped at room temperature. The resulting solution was stirred at room temperature for 23 hours. The same procedure as that in Example 1 was repeated to give 0.29 g of the title compound as white crystals. 0.08 g of ethyl 5-chloro-2-methyl-3-(3-methylisoxazol-5-yl)-4-methylthiobenzoate was recovered.
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[OH:19][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH:8]=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.9 g, 10.0 mol) in dichloromethane (40 ml) was added dropwise to a stirred solution of (S)-pyrrolidin-2-yl-methanol (1.0 g, 10.0 mmol) and triethylamine (2.8 ml, 20.0 mmol) in dichloromethane 60 ml. The reaction mixture was stirred for 10 minutes at ambient temperature and then allowed to stand for 3 h at ambient temperature. The reaction mixture was washed with 1M NaOH (30 ml) and 2M HCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.76 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1). 1.28 g (49% of theory) of (3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-((S)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone was obtained in form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[C:23](N1C=CN=C1)(=[O:25])[CH3:24].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CC(=O)n1ccnc1
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At RT 60 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile and 30 mg (0.3 mmol) of N-acetylimidazole are stirred in 0.5 ml of DMF for 1 hour. Water is slowly added dropwise, the mixture becomes slightly turbid and the crude product crystallizes out. The product is filtered off with suction, washed with water and dried under reduced pressure. This gives 53 mg of yellow crystals. The crystals are dissolved in 1 ml of a 1:1 mixture of CH2Cl2/CH3OH, and a few drops of concentrated ammonia are added (removal of diacetylated byproduct). The mixture is stirred at RT for 5 hours. The product crystallizes out when the reaction solution is concentrated. The product is filtered off with suction and washed with methanol.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined example 83. Yield 4.67 g (47%); off white powder; mp 203° C.; MS: 418.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:7]([O:9][P:10]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8]
Reactant: BrCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCBr)OCC

Procedure:
In another method, 1,4-dibromobutane is heated with triethylphosphite to give diethyl-4-bromobutylphosphonate, for example, as described by Eberhard and Westheimer, 1965. The resultant bromide is then reacted with, for example, biphenyl-4-carboxylic acid in dimethylformamide, in the presence of potassium carbonate. Again, the phosphate ester groups, e.g., ethyl groups, are removed e.g., with trimethylsilylbromide or left in place. An example of such a method is illustrated in the following scheme.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:12]=O.[ClH:14].[CH3:15][NH:16][CH3:17]>C(O)(=O)C>[ClH:14].[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7]([CH2:15][N:16]([CH3:12])[CH3:17])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: CNC
Reactant: C=O
Reactant: C=CCOC1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: C=CCOC1CCC(=O)C(CN(C)C)C1
Yield: 77 %

Procedure:
15.5 g of compound (12) (100 mmole), 1.5 g (50 mmole) paraformaldehyde and 4.1 g (50 mmole) dimethylamine hydrochloride were stirred for 25 minutes in 30 ml acetic acid in a bath at 105° C. The acetic acid was distilled off under vacuum, and the residue was dissolved in 110 ml 2-butanone. Compound (13) was obtained in a yield of 77% theoretical, melting point 125° C.-127° C.