Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]2)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>O1CCCC1.[Pt]=O>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC#Cc1ccc2cc(C(=O)OC)ccc2c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCCCCCCc1ccc2cc(C(=O)OC)ccc2c1
Yield: 96.2 %

Procedure:
A mixture of Methyl 6-(1-heptynyl)naphthalene-2-carboxylate (4.51 g) and platinum oxide (0.4 g) in tetrahydrofuran was stirred under 3.5 atm pressure of hydrogen for 5 hours. The catalyst was filtered off and the filtlate was evaporated to give Methyl 6-heptylnaphthalene-2-carboxylate (4.40 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=2)=[CH:27][CH:26]=1)[CH2:17][CH3:18].[C:38](O)(=[O:46])[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34]([O:37][C:38](=[O:46])[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH3:45])=[CH:33][N:32]=2)=[CH:27][CH:26]=1)[CH2:17][CH3:18]
Reactant: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCC/C=C\CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC/C=C\CC(=O)Oc1cnc(-c2ccc(CCCCCOCCC)cc2)nc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
0.8 g of N,N'-dicyclohexylcarbodiimide was added within 5 minutes while stirring to a solution of 1.0 g of 2-[4-(5[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine, 0.4 g of (Z)-3-octenoic acid and 0.05 g of 4-(dimethylamino)pyridine in 30 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered and the filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) and two-fold recrystallization of the thin-layer chromatographically pure fractions gave 1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-{[(Z)-3-octenoyl]oxy}pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22]O)=[N:20][CH:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22][NH:39][CH:36]5[CH2:38][CH2:37]5)=[N:20][CH:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2cccc(-n3ncnc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1
Reactant: NC1CC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ncnc3CNC3CC3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 7-chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 63) (218 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF as described in Example 47. Obtained as an off-white solid (135 mg, 57%).
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.Cl[Si](C)(C)C.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26](Cl)[CH:27](C)C)=[O:24].[C:31]12([C:41]([OH:43])=[O:42])[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2>C(Cl)(Cl)Cl>[C:31]12([C:41]([O:43][CH2:27][CH2:26][O:25][C:23]([NH:7][C:3]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]3)=[O:24])=[O:42])[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: NC1(C(=O)O)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)O)CC1)OCCOC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 6.4 %

Procedure:
Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and admantane carboxylic acid (3.5 g, 19.7 mmol) provided 0.220 g (6.4% yield) of the title compound (22) as a white solid after aqueous work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.81 (q, 1H), 5.62 (s, 0.2H), 5.38 (s, 0.8H), 2.09 (m, 4H), 1.93 (m, 6H), 1.72 (m, 6H), 1.61 (s, 2H), 1.52 (d, 3H), 1.37 (br s, 2H). MS (ESI) m/z 374.01 (M+H)+, M−H=350.04 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].O.NN.[OH-].[K+].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(=O)C(=O)O)cc1F
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(CC(=O)O)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
2-(3-Fluoro-4-(methylthio)phenyl)-2-oxoacetic acid (4.5 g, crude) was added to hydrazine hydrate (5.1 mL, 5 eq) at −50° C. The contents were heated to 80° C., KOH (2.7 g, 2.3 eq) was added and the overall reaction mixture was stirred for 12 h at 100° C. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.8). On completion of the reaction, to the contents was added water and ethyl acetate and the layers were separated. The aqueous layer was acidified with diluted HCl at 0-5° C., the precipitate was filtered and dried to yield 2-(3-fluoro-4-(methylthio)phenyl)acetic acid as a white colored solid (3 g, 71%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[C:19]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[C:19]([CH:29]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:18]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: COc1ccc2nc(C=Cc3ccccn3)nc(Cl)c2c1
Reactant: N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CNC(=O)C(F)(F)F)CC3)c2c1

Procedure:
A solution of 140 mg of cis-4-trifluoroacetylaminomethylcyclohexylamine in 15 mL of toluene was combined with 180 mg of 4-chloro-6-methoxy-2-[2-(2-pyridyl)ethenyl]quinazoline, 500 mg of triethylamine and 20 mg of 4-dimethylaminopyridine, and heated under reflux for 15 hours. After the reaction solution was distilled off, the residue was combined with water, and extracted with chloroform. After drying over magnesium sulfate and concentrating, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 140 mg of the desirable compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1.Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:27][O:26][CH3:25])[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON
Reactant: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ncc(Cl)cc1Cl)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To 1.00 g of N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]phthalimide in 10 ml of ethanol, 2.39 g of methoxyamine hydrochloride and 3.40 g of pyridine were added and refluxed with heating for 18 hours with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of 1N aqueous hydrochloric acid and extracted with ethyl acetate (40 ml×2). The resulting organic layers were combined, washed with 30 ml of 1N aqueous hydrochloric acid and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.81 g of the desired product as a colorless resinous substance.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH3:35])=[CH:20][N:21]2[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CC#N>[CH3:35][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[CH:1]=[CH2:2])[N:21]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:20]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2cccc(Br)c12
Solvent: CC#N
Product: C=Cc1cccc2c1c(C)cn2S(=O)(=O)c1ccccc1
Yield: 204.7 %

Procedure:
Tributyl(vinyl)stannane (0.400 mL, 1.37 mmol) and Pd(PPh3)2OAc2 (51 mg, 0.069 mmol) were added to 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole (240 mg, 0.69 mmol; Intermediate 29) in dry MeCN (4 mL). The reaction mixture was irradiated with micro-waves at 180° C. for 720 s. The mixture was combined with earlier batches of this intermediate (followed this experimental and starting with 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole, 50 and 310 mg; Intermediate 29), filtered and concentrated. Purification was performed by flash chromatography (30% hexane in DCM). This afforded the product (420 mg, 82%) as a white solid. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:3]2[S:2][C:6]3[CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:5]=3[N:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: I
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1ccc(F)cc1
Yield: 35.2 %

Procedure:
Acylation of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 4-fluorobenzoyl chloride (0.116 mL; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 35 mg of 4-Fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide 3. EI-HRMS m/e calcd for C17H11FN2OS 310.0576, found 310.0577.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Ca+2].[OH-].[C:14]([CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19])(=O)[CH3:15]>O.C(O)C>[CH3:6][O:7][C:8]1[NH:9][C:18](=[O:19])[C:17]([CH2:22][CH2:21][OH:20])=[C:14]([CH3:15])[N:10]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g, 0.11 mol) followed by a solution of 2-acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C[O:23][C:24]1[CH:33]=[C:32]2[C:27](CCC[CH:31]2[NH2:34])=CC=1.[CH2:35]([N:38]([CH2:52][CH2:53][CH3:54])[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([CH2:50]C)[CH:49]=1)C(O)=O)=[O:40])[CH2:36][CH3:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[C:43]1[CH:47]=[C:48]([CH3:50])[CH:49]=[C:41]([C:39]([N:38]([CH2:35][CH2:36][CH3:37])[CH2:52][CH2:53][CH3:54])=[O:40])[CH:42]=1)[C@H:11]([OH:12])[CH2:13][NH:34][CH2:31][CH:32]1[CH2:33][CH2:24][O:23][CH2:27]1
Reactant: COc1ccc2c(c1)C(N)CCC2
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCC2CCOC2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3), (tetrahydro-3-furanylmethyl)amine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+546.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1>CN(C=O)C>[CH3:17][C:18]([OH:19])([CH3:21])[CH2:20][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C

Procedure:
Sodium hydride (58.74 mg, 0.002448 mol) was added to solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500.0 mg, 0.002577 mol) in DMF (5 mL) at room temperature. After gas evolution ceased, 2,2-dimethyl-oxirane, (0.46 mL, 0.0052 mol) was added. The mixture was heated to 100° C. for 1 hour. The material was extracted with EtOAc, and washed with water (3×). The organic layer was concentrated in vacuo to afford the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=1.04 (s, 6H), 1.25 (s, 12H), 4.03 (s, 2H), 4.68 (s, 1H), 7.56 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:40][C@@:6]2([OH:8])[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32].[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@]1(O)OC(=O)c1ccc([N+](=O)[O-])cc1
Product: CC1CCC(C(C)C)C(O)C1
Reaction time: 15 h

Procedure:
After L-menthol (300 mg, 1.92 mmol), triphenylphosphine (605 mg, 2.30 mmol), 4-nitrobenzoic acid (387 mg, 2.30 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.21 ml, 2.30 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 15 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (1S,2S,5R)-1-(4-nitrobenzoyloxy)-2-isopropyl-5-methyl cyclohexanol as a white solid substance (423 mg, yield: 72%/L-menthol).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+:4].C(Cl)(=O)C1C=CC=CC=1.[Cl:14][C:15]1[CH:16]=[C:17](NC2C=CC=CC=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1.O>CC(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:3][C:2]([NH2:4])=[S:1])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: N#C[S-]
Reactant: [NH4+]
Reactant: Clc1cc(Cl)cc(Nc2ccccc2)c1
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 87.5 %

Procedure:
To a mixture of 4 liters of acetone and 110 g (1.5 moles) of ammonium thiocyanate are added dropwise 173 g (1.23 moles) of benzoyl chloride. The reaction mixture is then heated for a further 15 minutes. Next, 200 g (1.23 moles) of 3,5-dichlorophenyl aniline dissolved in 200 ml of acetone are added. The mixture is then heated for a further 30 minutes, cooled and poured into 4 liters of water. The precipitate is collected and rinsed with 1 liter of water. The crystals are mixed with 2 liters of water containing 50 g of sodium hydroxide. The mixture is heated for 30 minutes and then cooled. The precipitate is collected to give 238 g (88%) of N-[3,5-dichlorophenyl]thiourea, m.p. 180° C.
Reaction SMILES: O=[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[NH:3]1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C(C)C)(C)C>>[Cl:25][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Into a round bottom flask was added methyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.21 g, 0.70 mmol) dissolved in phosphoryl chloride (3.0 mL, 32.2 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.6 mmol). The reaction mixture was heated to 120° C. and stirred overnight. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.17 g, 77%). LC-MS: (FA) ES+ 315.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45])[CH3:36].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:24]([NH:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([O:37][CH2:35][CH3:36])=[O:46])=[O:26])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 52.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (100 mg) was added, and the admixture was refluxed with heat for 2 minutes. Ethyl-2-aminobenzoate (84 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 2 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 86 mg of the title compound (yield: 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1COCC1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]4[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCCCC4Cc4ccccc4)cc3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.55 mmol) and 2-benzylcyclohexanone (0.156 g, 0.83 mmol) were combined in toluene and stirred at 110° C. for 1 hour. After cooling to room temperature, THF was added, followed by sodium cyanoborohydride (0.086 g, 1.37 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was adsorbed onto silica gel and purified by silica gel chromatography to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27]O)[CH2:21][O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>C1COCC1>[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:52]3[C:51](=[O:53])[C:50]4=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]4[C:48]3=[O:58])[CH2:21][O:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCCC1COC(c2ccccc2)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1COC(c2ccccc2)O1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A solution of diethyl azodicarboxylate (8.6 g, 49.4 mmol) in 40 mL of THF was slowly added to a cold (ice bath) solution of 17 (10.0 g, 45.0 mmol), triphenylphosphine (13.0 g, 49.5 mmol) and phthalimide (7.3 g, 49.7 mmol) in 60 mL of THF. After being kept at ambient temperature overnight, the solution was concentrated and the residue was triturated with ether (˜150 mL) to precipitate triphenylphosphine oxide which was then removed by filtration. The filtrate was concentrated to give an oily residue which was chromatographed on silica eluting with 33% ethyl acetate in hexane. Concentration of the pure product fractions followed by drying under vacuum afforded 14.6 g (92%) of the desired product as a semi-solid (a mixture of diastereomers): 1H NMR (CDCl3, 300 MHz, ppm) 7.85 (m, 2H), 7.71 (m, 2H), 7.46 (m, 2H), 7.36 (m, 3H), 5.90 (s, 0.4H), 5.78 (s, 0.6H), 4.3-4.0 (m, 2H), 3.68 (m, 3H), 1.9-1.3 (m, 61H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[C:5]([OH:7])=[O:6].C[O:16][C:17]([C:19]1[N:20]=[CH:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:23]=2)=O.C1CCN2[C:40](=[N:41]CCC2)CC1>CC(N(C)C)=O>[C:40]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:2][CH2:3][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([OH:7])=[O:6])=[O:16])[N:20]=1)#[N:41]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: C1CCC2=NCCCN2CC1
Reactant: NCC(C(=O)O)c1ccccc1F
Agent: Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NCC(C(=O)O)c2ccccc2F)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 150 °C

Procedure:
A mixture of HCl salt of 3-amino-2-(2-fluoro-phenyl)-propionic acid (82 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg) and DBU (0.112 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product (40 mg). LC-MS ESI+: 472 (M+1)+.