Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.[CH3:26][C:27]1([CH3:37])[NH:31][CH2:30][C:29](=[O:32])[N:28]1[CH2:33][C:34]([NH2:36])=[O:35]>CN(C)C=O>[CH3:26][C:27]1([CH3:37])[N:31]([C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:30][C:29](=[O:32])[N:28]1[CH2:33][C:34]([NH2:36])=[O:35]
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Reactant: O=C(O)CN1CCCC1=O
Agent: CCCCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (1.45 g) and triethylamine (1.45 ml) in dimethylformamide (7 ml) was treated dropwise while stirring with butyl chloroformate (1.3 ml). After stirring at 0° C. for 45 minutes, 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (1.75 g) was added at once and stirring was prolonged at room temperature overnight. After evaporation under reduced pressure, the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 1:1. The selected fractions were collected and evaporated, the residue was taken up with ethyl acetate and the resulting solid was crystallized from ethanol, to give the title compound as a white powder, m.p. 225°-227° C., (decomp.).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.O.CC(C)=O>O>[ClH:1].[N:20]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CNCC(CCCN2CCCC2)C1
Solvent: O
Solvent: CC(C)=O
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCCN3CCCC3)C2)c2ccccc21
Yield: 56 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[3-(1-pyrrolidinyl)propyl]piperidine in a yield of 56% of theory. Colourless crystals, m.p. >260° C. (from water/acetone), water solubility: about 0.3%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9]C)=[O:8].CO.O.[Li+].[OH-]>C1COCC1>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1COCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1COCCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of 4-([4-2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester (0.1 g, 0.28 mmol) in 2.4 mL of THF:methanol:water [4:1:1] was cooled in an ice bath and 2N LiOH (0.3 mL, 0.59 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with ether and filtered. The solid was dissolved in water, neutralized with 1N HCl to pH˜3 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.06 g of 4-[4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid. Yield˜69.8%. mp 40-42° C. Electrospray Mass Spec 338.1(M−H)−.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:18][NH2:19]>>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Product: CNC(=NCCSCc1cnccn1)NC#N

Procedure:
Reaction of this isothiourea with methylamine by the procedure of Example 3(c)(ii) gives the title compound.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.[OH-].[K+]>O1CCCC1.C(O)C.O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.8 %

Procedure:
Ethyl 7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.56 g) was dissolved in a mixture of tetrahydrofuran (10 mL) and ethanol (15 mL). A solution of potassium hydroxide (85%, 0.8 g) in water (10 mL) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature and stirred for 13 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (14 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (0.93 g, 81%) as a pale orange solid. MS 349 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2=[CH:20][CH:21]=[CH:22][C:23]3=[CH:24][CH:25]=[CH:26][C:7](=[C:8]23)[NH:6][C:5]1=[O:27].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl>CS(C)=O>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][N:6]1[C:5](=[O:27])[C@@H:4]([OH:3])[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2=[CH:20][CH:21]=[CH:22][C:23]3=[CH:24][CH:25]=[CH:26][C:7]1=[C:8]23
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)NC(=O)[C@H]2O)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 0.415 g of sodium hydride (58% dispersion in mineral oil) in 50 mL dimethyl sulfoxide (dried over CaH2) was stirred under nitrogen at 70° (bath temperature) for 1 hour then allowed to cool to room temperature. To this mixture 2.8 g of (±)-trans-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one was added then stirred at room temperature for 30 minutes. After the dropwise addition of 1.2 g of 2-dimethylaminoethyl chloride in 10 mL dimethyl sulfoxide, the mixture was heated at 50° for 30 minutes, then poured on 50 mL of ice-water. The aqueous solution was extracted with ethyl acetate (3×40 mL). The combined extracts were washed with brine (40 mL) and dried (magnesium sulfate). Removal of the solvent gave 3.1 g (92%) of crude (±)-trans-2,3-dihydro-5[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5 -thiazocin-4(5H)-one. For analysis a sample of this compound was crystallized from ethyl acetate, mp 157°-158°.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinic acid (D100) (70 mg, 0.22 mmol), methyl 4-(1-aminocyclopropyl)benzoate (D7) (50.31 mg, 0.22 mmol) and N,N-Diisopropylethylamine (0.115 ml, 0.66 mmol) in dimethylformamide (5 ml) was stirred at room temperature for 1 h. (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (137.9 mg, 0.265 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether (3×15 ml). The combined organic layers were washed with brine (2×10 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by Biotage column (10 g) eluting with a mixture dichloromethane/ethylacetate from 100/0 to 90/10. Collected fractions, after solvent evaporation, afforded the title compound (D144) (66 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccs4)c2)c1=O)CCCC3
Yield: 20 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 2-thiophenesulfonyl chloride (27 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 9 mg, yield 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][S:41](=[O:44])(=[O:43])[NH2:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[NH3:46]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:46])[NH:40][S:41](=[O:43])(=[O:44])[NH2:42])[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Reactant: N
Solvent: C1CCOC1
Product: N=C(NS(N)(=O)=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-sulfamoyl-1-piperidinecarboximidate (Formula 6.0) (prepared as described in Example 5above) (0.089 g, 0.1 mmoles) was dissolved in anhydrous THF (1 ml). A saturated solution of ammonia in anhydrous THF (4 ml) was added and the mixture was stirred in a sealed reaction vessel at 25° C. for 19 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2%-6% methanol in dichloromethane as the eluant to give the title compound (Formula 7.0) (0.0667 g, 84%), ESIMS: m/z 638.0 (MH+).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH2:25]([Li])[CH:26]([CH3:28])[CH3:27]>O1CCCC1>[CH3:4][C:2]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:6])([CH3:1])[CH3:3]
Reactant: [Li]CC(C)C
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R,E)-2-methyl-N-((4′-(trifluoromethyl) biphenyl-4-yl)methylene)propane-2-sulfinamide (25.0 g, 70.7 mmol) and tetrahydrofuran (140 mL) and cooled down to −78° C. To this solution was added isobutyllithium (1.6M in heptane; 50.8 mL) dropwise over 20 minutes. The reaction was allowed to stir at −78° C. for 30 minutes. LC-MS analysis showed complete conversion of the starting material and the formation of two product diastereomers (4.6:1). The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1-10% ethyl acetate/dichloromethane) allowed isolation of the major isomer (the less polar isomer), (R)-2-methyl-N-((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 74.2%) as a colorless gum. 1H NMR (400 MHz, CDCl3, δ): 0.91 (d, 3H) 0.96 (d, J=6.44 Hz, 3H) 1.24 (s, 9H) 1.49-1.59 (m, 1H) 1.63-1.72 (m, 1H) 1.84-1.94 (m, 1H) 3.38 (br. s., 1H) 4.46 (dd, J=8.19, 6.83 Hz, 1H) 7.43-7.46 (m, 2H) 7.56-7.60 (m, 2H) 7.68-7.70 (m, 4H). MS (M+1): 412.3.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.C([N:18]([CH2:27][CH3:28])[C:19]([C:21]1[CH:25]=[CH:24][O:23][C:22]=1[CH3:26])=[O:20])C.[CH3:29][N:30]([CH3:35])[CH2:31]CC#N.Cl>O1CCCC1.CC(C)=O>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:28][C:27]1[NH:18][C:19](=[O:20])[C:21]2[CH:25]=[CH:24][O:23][C:22]=2[CH:26]=1
Reactant: CN(C)CCC#N
Reactant: CCN(CC)C(=O)c1ccoc1C
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCc1cc2occc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (5.1 ml, 30.4 mmole) in dry tetrahydrofuran (60 ml), cooled at -78° C. (dryice/acetone) under an argon atmosphere, was added dropwise n-butyllithium (17.3 ml, 27.6 mmole). After the addition the reaction was warmed to -10° C. (ice/acetone). To this solution was added N,N-diethyl-2-methylfuran-3-carboxamide (5.0 g, 27.6 mmole) in tetrahydrofuran (15 ml). After stirring this mixture for 1.0 hour, 3-(dimethylamino)propionitrile (3.27 ml, 29.0 mmole) was added dropwise. The reaction was allowed to warm overnight. The reaction was poured into ice/water and acidified to a pH 3.25 with hydrochloric acid. The mixture was then extracted with diethyl ether (3×150 ml). The pH of the aqueous layer was adjusted to 13.0 using sodium hydroxide solution (40%) and this solution was extracted exhaustively using methylene chloride (10×150 ml). The combined extracts were washed with water (2×50 ml), brine (2×100 ml) and dried (MgSO4). After solvent evaporation 8.25 g of an oil was obtained. This was purified by flash chromatography using 15% methanol/chloroform as the eluting solvent to give analytically pure product (4.65 g, 82% yield), mp: 97.5°-98.0° C. Some starting amide (1.05 g) was recovered from the initial diethyl ether extracts.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.CO[C:22]([C:24]1[S:25][C:26]([CH:29]([CH2:32]O)[CH2:30][CH3:31])=[CH:27][CH:28]=1)=[O:23].Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:22]([C:24]1[S:25][C:26]([CH:29]([CH2:32][O:8][C:6]2[CH:5]=[C:4]([CH3:9])[C:3]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:30][CH3:31])=[CH:27][CH:28]=1)=[O:23]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: CCC(CO)c1ccc(C(=O)OC)s1
Reactant: COC(=O)CCN
Agent: Cl
Product: CCC(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 94 using 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol and 5-(1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid methyl ester in Step A and 3-amino-propionic acid methyl ester hydrochloride salt in Step C as the starting materials to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.225 g) as a white solid. MS (ES): 532.3 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak AD-H 4.6×150 mm; eluent: 20:80 IPA/supercritical CO2; flow rate: 5 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.049 g, >99% ee) and Isomer 2 (0.049 g, 96.8% ee).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[I:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(I)c1
Yield: 21.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (8.5 g), 3-iodoaniline (12.5 g) and potassium carbonate (9.0 g) in 1,4-dioxane (100 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-iodophenylamino)-3-nitropyridine (3.88 g) as an orange solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: -5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of L-hydroxyproline methyl ester hydrochloride (the compound obtained in Reference Example 1-1); 24.37 g, 134 mmol) and triethylamine (41.2 ml, 295 mmol) in methylene chloride (240 ml) was stirred at room temperature for 10 minutes, cooled to -5° C., treated dropwise with a solution of allyl chloroformate (14.9 ml, 140 mmol) in methylene chloride (30 ml). The reaction mixture was stirred at -5° C. for 1 hour, and washed twice with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford the title compound (30.8 g, 100% yield) as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]([NH:10][C:11]([NH2:13])=[S:12])=[CH:8][C:7]([CH3:14])=[N:6]1.[CH3:16][I:17]>C(O)C>[IH:17].[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]([NH:10][C:11](=[NH:13])[S:12][CH3:16])=[CH:8][C:7]([CH3:14])=[N:6]1
Reactant: Cc1cc(NC(N)=S)n(CCC(C)C)n1
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1cc(C)nn1CCC(C)C
Product: I

Procedure:
[1-(3-methylbutyl)-3-methyl-5-pyrazolyl]thiourea (23.0 g.) was dissolved in 250 ml. ethanol and 15.62 g. methyl iodide and refluxed for 4 hours. The ethanol was concentrated in vacuum and ether added to get 29.3 g. product, mp 128°-131° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[N:11][C:6]2[O:7][CH2:8][CH2:9][NH:10][C:5]=2[CH:4]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C.O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([N:10]2[CH2:9][CH2:8][O:7][C:6]3[N:11]=[CH:12][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][C:5]2=3)=[O:20])[CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: FC(F)(F)c1cnc2c(c1)NCCO2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C(F)(F)F)cc32)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In a 5 ml flask, 7-trifluoromethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (27 mg, 0.23 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (65 mg, 0.20 mmol) were dissolved in dichloromethane (0.6 ml), and then triethylamine (0.55 ml, 0.33 mmol) was added thereto dropwise at 0□. After stirring for 4 hours at room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:100. The fractions containing the product were collected and evaporated to obtain white solid (64 mg, 98%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]([CH2:15][C:16]([OH:18])=O)[CH2:8]1)(=[O:4])=[O:3].C([N:26]1[CH:30]=CN=C1)(N1C=CN=C1)=O.Cl.CN(C)O.[C:36](=O)(O)[O-:37].[Na+]>O.C(OCC)(=O)C>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]([CH2:15][C:16]([N:26]([O:37][CH3:36])[CH3:30])=[O:18])[CH2:8]1)(=[O:3])=[O:4]
Reactant: CC1(C)O[C@H](COS(C)(=O)=O)C[C@H](CC(=O)O)O1
Reactant: O=C([O-])O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](COS(C)(=O)=O)OC(C)(C)O1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
Ethyl acetate (50.0 mL) was added to [(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid (10.0 g) prepared in Preparation 8. The reaction mixture was cooled to 0˜5° C. and then 1,1′-carbonyldiimidazole (7.6 g) was slowly added thereto. The temperature of the reaction mixture was raised to 20˜30° C. The reaction mixture was stirred for 3 hours. Dimethylhydroxyamine hydrochloride (5.6 g) and sodium bicarbonate (3.2 g) were added to the reaction mixture, which was then stirred for over 3 hours while maintaining the temperature of 20˜25° C. Water (40.0 mL) was added to the reaction mixture under stirring. The separated organic layer was concentrated under reduced pressure to obtain 2-[(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (10.0 g, yield 87%).
Reaction SMILES: [Zn:1](OC(C)=O)[O:2][C:3]([CH3:5])=[O:4].O.O>CO>[C:3]([O-:4])(=[O:2])[CH3:5].[Zn+2:1].[C:3]([O-:4])(=[O:2])[CH3:5]
Reactant: CC(=O)O[Zn]OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)[O-]
Product: [Zn+2]

Procedure:
946 mL of MeOH was added to Zn(OAc)2.2H2O (93.09 g) to form zinc acetate solution. 41.99 g of KOH was added to 350 ml of MeOH to form a KOH solution. The KOH solution was then mixed with the Zn(OAc)2 solution under vigorous stirring to form the reaction solution. The reaction temperature was maintained at 60° C. 4.69 g Tetraethyl orthosilicate (TEOS) was dissolved in 25 ml of distilled water. 30 seconds after the KOH solution was mixed with the Zn(OAc)2 solution, the TEOS solution was added to the reaction solution. 60 seconds after the KOH solution was mixed with the Zn(OAc)2 solution, 40.8 ml distilled water was added to the reaction solution. 16.81 g KH570 was dissolved in 25 ml of distilled water. 15 minutes and 30 seconds after the KOH solution was mixed with the Zn(OAc)2 solution, the KH570 solution was added to the reaction solution. The resulting solution was continued to age at 60° C. for 45 minutes.