Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9][N:8]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.O.[CH3:54][N:55](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.[Pd+2]>[C:54]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:1]=1[C@H:7]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:8]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:9][CH2:10]2)#[N:55]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2[C@@H]1c1ccccc1
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [C-]#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2[C@@H]1c1ccccc1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
Tert-butyl (1S)-1-phenyl-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.75 g) was dissolved in N,N-dimethylacetamide (40 mL). To the reaction mixture were added zinc (537 mg), zinc cyanide (1.15 g), trifluoroacetic palladium (II) (682 mg), and biphenyl-2-yl(di-tert-butyl)phosphine (1.22 g). The temperature was increased from room temperature to 95° C. over 45 minutes and then the mixture was stirred at 95° C. for 18 hours. Water was added to the mixture which was then filtered through celite. Thereafter, the mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (EtOAc:hexane) to obtain tert-butyl (1S)-8-cyano-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (796 mg).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(C)=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1ccc(CCl)cc1
Agent: Cc1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.7 %

Procedure:
The title compound (0.013 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.74 g) using 4-methylbenzyl chloride (0.45 g) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 5.21 (s, 2H), 2.83-2.67 (m, 4H), 2.75-2.72 (m, 2H), 2.69-2.67 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([CH2:8][CH:9](Cl)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][S:4]1>C(=O)([O-])[O-].[Na+].[Na+]>[C:10]1([CH:9]2[CH2:8][N:7]3[C:3]([S:4][CH2:5][CH2:6]3)=[N:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N=C1SCCN1CC(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(C2CN3CCSC3=N2)cc1

Procedure:
Method A ##STR90## 2-Imino-3-(2'-chloro-2'-phenylethyl)thiazolidine hydrochloride (27.7 g) was heated for 1 hour on a steam-bath with 200 ml of 2N sodium carbonate solution. During this time an oil formed. On cooling this solidified. It was separated and recrystallised from 20% aq. ethanol to yield the desired compound. The hydrochloride was obtained by dissolving the base in ethanol and saturating the solution with dry HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH3:29][C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:45]=[CH:44][C:43]3[CH2:42][CH2:41][CH2:40][NH:39][C:38]=3[N:37]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(CNc2ncnc(N3CCC(c4ccc5c(n4)NCCC5)CC3)c2C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 109 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane 50-50, ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21]C=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.C([N:25](CC)CC)C.S1C=CN=C1S(Cl)(=O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][N:25]=2)(=[O:16])=[O:17])[CH2:12][CH2:11][NH:10]1
Reactant: CCN(CC)CC
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: O=S(=O)(Cl)c1nccs1
Solvent: ClCCl
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2nccs2)CCN1
Temperature: 0 °C
Yield: 121.2 %

Procedure:
A 50-mL round-bottomed flask was cooled to 0° C. and charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine (100 mg, 0.5 mmol, Example 82, Step 2), CH2Cl2 (5 mL) and triethylamine (0.07 mL, 0.5 mmol). Thiazole-2-sulfonyl chloride (92 mg, 0.5 mmol, Bioorg. Med. Chem., 2006, 14, 6628) was added and after 10 min the reaction was concentrated and acidified with 4 N HCl in dioxane (5 mL). The HCl salt was collected after filtration and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% (2M NH3 in MeOH) in CH2Cl2) to give (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg).
Reaction SMILES: [C:1]([CH:8]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:31][CH3:32])=[CH:12][C:11]=1[CH2:33][CH2:34][CH3:35])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:8]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:31][CH3:32])=[CH:12][C:11]=1[CH2:33][CH2:34][CH3:35])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of 21.4 mg (0.038 mmol) of the product of Step P in CH2Cl2 (1 mL) was added TFA (0.4 mL, 5.19 mmol) at rt. The solution was stirred at rt for 2 hours. The crude mixture was directly purified by flash chromatography eluted with CHCl3 /MeOH/NH4OH (100:10:1) to give 11 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].C(O)(=O)C.N1CCCCC1>ClCCl.C1CCCCC1.C(OCC)(=O)C>[C:15]([C:14]([C:13](=[O:18])[CH3:12])=[CH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])(=[O:17])[CH3:16]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: CC(=O)CC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)C(=Cc1ccc(C#N)cc1F)C(C)=O
Yield: 83.3 %

Procedure:
120 mg (0.805 mmol) of 3-fluoro-4-formylbenzonitrile, 80.6 mg (0.805 mmol) of 2,4-pentanedione, 72.5 mg (1.21 mmol) of acetic acid and 14 mg (0.16 mmol) of piperidine are dissolved in 8 ml of dichloromethane and heated under reflux with an inverse water trap overnight. The mixture shows complete conversion (TLC check, mobile phase: cyclohexane/ethyl acetate 5:1). The mixture is diluted with dichloromethane, washed with water and saturated sodium chloride solution and dried with sodium sulfate. The solvent is removed in a rotary evaporator. 155 mg (83.3% of theory) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-fluorobenzonitrile are obtained and are reacted without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 54.4 %

Procedure:
Using the general method of Example 145, except that the reaction was run at ambient temperature, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.2 mmol) was reacted with phenyl isocyanate (0.35 mL, 3.2 mmol) to provide 0.75 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as white needles, m.p. 185-187° C. Analysis: Calculated for C25H30N6O.H2O: % C, 66.94; % H, 7.19; % N, 18.74. Found: % C, 67.31; % H, 7.20; % N, 18.70.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:10][CH3:9])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-chloropyrimidine (10 g, 52 mmol) and sodium methoxide (8.42 g, 156 mmol) were taken in methanol (50 mL) and stirred at room temperature overnight. Reaction mixture was concentrated followed by the addition of water. The resulting mixture was extracted with ethyl acetate and dried over MgSO4. The titled compound was obtained after concentration (8.07 g, 82.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]=[C:34]=[S:35])[CH2:27][CH2:26]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:34]([NH:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:16]2[N:15]([CH2:14][C:10]3[O:9][CH:13]=[CH:12][CH:11]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:26][CH2:27]1)=[S:35]
Reactant: S=C=NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Yield: 87 %

Procedure:
A mixture of 5.4 parts of 3,4-pyridinediamine, 16 parts of 1-(2-furanylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (87%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea (intermediate 133).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH2:6][N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:8]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.[CH2:24]([O:26][P:27]([CH2:32]P(=O)(OCC)OCC)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:25]>>[CH2:24]([O:26][P:27]([CH:32]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH2:6][N:7]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH:8]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1)([O:28][CH2:29][CH3:30])=[O:31])[CH3:25]
Reactant: CCOC(=O)C1C2CCC(=O)CC2CCN1C(=O)OC(C)(C)C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Product: CCOC(=O)C1C2CCC(=CP(=O)(OCC)OCC)CC2CCN1C(=O)OC(C)(C)C
Yield: 91 %

Procedure:
Following the preparation of Example 3A above, 2.0 g of ethyl decahydro-6-oxo-2-t-butoxycarbonyl-1-isoquinoline carboxylate were treated with 2.6 g of methylene diphosphonic acid tetraethyl ester to provide 2.57 g of the desired subtitled intermediate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Product: COC(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.78 min; [M+H]+=252.9.
Reaction SMILES: [C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@H:35]([C:38]([O:40]CC6C=CC=CC=6)=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 80 %

Procedure:
To a solution of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate in THF (1.5 mL) and MeOH (0.5 mL) was added 1N lithium hydroxide (0.115 mL, 0.115 mmol). The reaction was stirred at 75° C. After 3 h the reaction mixture was concentrated and the crude material was dissolved in THF (2 mL)/H2O (150 μL) and purified by reverse phase prep-HPLC using prep-HPLC method 15 and dried under vacuum to give (S)-4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (21 mg, 0.023 mmol, 80% yield) as a white solid. LC/MS: m/e 659.5 (M+H)+, 34.14 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 5.33 (br. s., 1H), 5.17 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.70 (br. s., 1H), 4.52 (s, 1H), 4.03 (d, J=8.6 Hz, 1H), 3.75 (br. s., 1H), 3.72 (d, J=8.6 Hz, 1H), 3.18-3.09 (m, 2H), 3.09-2.92 (m, 4H), 2.79-2.64 (m, 2H), 2.53-2.42 (m, 1H), 2.31-2.23 (m, 2H), 2.16 (br. s., 2H), 2.04-1.93 (m, 8H), 1.81-1.73 (m, 2H), 1.72 (s, 3H), 1.69-1.63 (m, 1H), 1.61-1.33 (m, 12H), 1.30 (dd, J=12.2, 3.4 Hz, 1H), 1.24 (br. s., 1H), 1.20-1.14 (m, 1H), 1.12-1.09 (m, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 11.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (38 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (7 mg, 12%). MS m/e 491.19 (M+H+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].O.Cl.[C:15](=[NH:23])([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[O:10]=[C:8]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=2)[N:22]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:23]1
Reactant: N#Cc1ccc(F)c(C(=O)O)c1
Reactant: N=C(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A stirring solution of 5-cyano-2-fluorobenzoic acid (2.02 g, 12.2 mmol) and benzimidamide hydrochloride monohydrate (2.14 g, 12.2 mmol) in DMF (15 mL) was treated with DIEA (5.34 mL, 30.6 mmol) and HATU (4.65 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 30 min then heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and water (200 mL) was added. A precipitate formed which was isolated by filtration and dried under vacuum to afford 1.66 g (54%) of 4-oxo-2-phenyl-3,4-dihydroquinazoline-6-carbonitrile INT-87 as a light powdery white solid. LCMS-ESI (m/z) calculated for C15H9N3O: 247; found 248 [M+H]+, tR=1.70 min (Method 10).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[N:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[O:26][C:20](=[O:21])[NH:19]2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cncc(Br)c2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(5-bromopyridin-3-yl)-2-hydroxy-2-(3-methoxyphenyl)ethylcarbamate (3.76 g, 4.44 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 40 mL) and stirred at room temperature for 1 h. The reaction was concentrated, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (40 mL), cooled to 0° C., and treated with carbonyldiimidazole (1.46 g, 9.00 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. The reaction was re-cooled to 0° C., and treated with an additional portion of carbonyldiimidazole (500 mg) and stirred at room temperature for 1 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was purified by column chromatography (25%-->50% EtOAc/Hex) to give 660 mg (21%). 1H-NMR (CDCl3, 500 MHz) δ 8.69 (d, J=2.1, 1H), 8.39 (d, J=2.1, 1H), 7.92 (dd, J=2.1, 1.8, 1H), 7.34 (dd, J=7.9, 7.9, 1H), 6.95 (dd, J=8.6, 1.8, 1H), 6.77-6.91 (m, 3H), 5.22 (d, J=7.6, 1H), 4.82 (d, J=7.6, 1H), 3.82 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.3, 158.9, 151.7, 146.4, 137.8, 136.7, 136.0, 130.5, 121.6, 118.1, 115.2, 111.4, 85.6, 62.2, 55.5. Mass spec.: 349.12 (MH)+.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([N:19]1[CH2:32][CH2:31][CH2:30][C@H:20]1[C:21]([NH:23][C@H:24]([P:26](=[O:29])([OH:28])[OH:27])[CH3:25])=[O:22])=O)C1C=CC=CC=1.Br.C1OC1C>C(O)(=O)C.CO>[NH:19]1[CH2:32][CH2:31][CH2:30][C@H:20]1[C:21]([NH:23][C@H:24]([P:26](=[O:27])([OH:28])[OH:29])[CH3:25])=[O:22]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)P(=O)(O)O
Agent: Br
Agent: CC1CO1
Solvent: CC(=O)O
Solvent: CO
Solvent: NCc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.3 of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-prolyl)amino] -ethylphosphonic acid were added to a stirred solution (45%) of hydrogen bromide in glacial acetic acid and washed in with 2.5 ml of glacial acetic acid. The mixture was stirred at room temperature for 6 hours and then 75ml of ether were added while stirring. The supernatant was decanted and the residue was again treated with 75ml of ether. The granular solid obtained was dissolved in 30ml of methanol and the solution treated with a solution of 5ml of propylene oxide in 10ml of methanol. After standing for several hours, the precipitate was filtered off, washed with methanol and ether and dried. Crystallization from water/ethanol gave 0.39 g of (1R)-1-(L-prolylamino)-ethylphosphonic acid of melting point 291°-293° C (decomposition); [α]D20 = - 92.3°(c = 0.5% in water).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([SH:16])[C:13]([Cl:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([S:16][CH2:27][C:26]#[CH:25])[C:13]([Cl:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: C#CCBr
Reactant: CSc1c(Cl)c(-c2cc(S)c(Cl)cc2F)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCSc1cc(-c2nn(C)c(SC)c2Cl)c(F)cc1Cl
Yield: 80.4 %

Procedure:
A mixture of 4-chloro-3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-5-methylthio-1H-pyrazole (0.60 g, 1.86 mmoles), 30 ml acetone, a K2CO3 powder (2.04 mmoles), and propargyl bromide (2.23 mmoles), was subjected to reaction under reflux for 2 hours. Then the resulting solution was filtered to remove acetone-insoluble matter and the filtrate was concentrated and purified by silica gel column chromatography, giving crystals (0.54 g) of the title compound, m.p. 93-96° C., yield 80.5%.