Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3](OCC)=[O:4].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=1)[NH:15][C:16]([NH:18][O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[S:17]>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([N:15]2[C:3](=[O:4])[C:2](=[O:8])[N:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]2=[S:17])[CH:26]=1
Reactant: CCOC(=O)CONC(=S)Nc1cc(Cl)ccc1C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CON1C(=O)C(=O)N(c2cc(Cl)ccc2C)C1=S
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
Ethyl chlorooxoacetate (11.1 mL; 0.1 mol) was added dropwise to the solution of ethyl 2-({[(5-chloro-2-methylanilino) carbothioyl]amino}oxy)acetate (15.1 g; 0.05 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was stirred in ether for 15 minutes and the solids were filtered. The solids were washed with fresh ether and dried to give 13.1 g of ethyl 2-{[3-(5-chloro-2-methylphenyl)-4,5-dioxo-2-thioxo-1-imidazolidinyl]oxy}acetate as a solid, m.p. 157–159° C. Mass spectrum; FAB (M+H)+ m/z 357. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50 (d, 1H), 7.42 (m, 2H), 4.90 (q, 2H), 4.20 (q, 2H), 2.17 (s, 3H), and 1.24 ppm (t, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(5-bromopentoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:10]([N:12]1[C@@H:20]([C:21]#[C:22][Si](C)(C)C)[CH2:19][CH2:18][C@H:13]1[C:14]([O:16]C)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:10]([N:12]1[C@@H:20]([C:21]#[CH:22])[CH2:19][CH2:18][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-((trimethylsilyl)ethynyl)-L-prolinate (1.65 g, 3.66 mmol) in MeOH (10 mL) and H2O (10 mL) at room temperature was added LiOH.H2O (0.23 g, 5.49 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜4 by adding 4% KHSO4 dropwise. The clear solution was extracted with ethyl acetate (3×) and the combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/e 365 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl>C(Cl)Cl>[CH2:18]([O:17][C:15]([N:13]1[CH2:12][CH2:11][S:10][C:9]1=[S:8])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SC1=NCCS1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCSC1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12.9 ml of triethylamine cooled to 0° to 5° C. were added to 10 g of mercapto-thiazoline in solution in 200 ml of methylene chloride, then 12 ml of benzyl chloroformate in solution in 60 ml of methylene chloride were added dropwise. After stirring for 3 hours at ambient temperature, the mixture was poured into an iced solution of N hydrochloric acid and the aqueous phase was extracted with methylene chloride. The organic phase was dried and concentrated to dryness and the residue was chromatographed on silica (eluant: hexane-ethyl acetate 7-3) to obtain 17.9 g of the expected product melting at 72° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9].[F:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH:30]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH3:12])=[O:9])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: O=CCOc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2CCOc2ccc(F)cc2)cc1
Yield: 70.4 %

Procedure:
Stir a mixture of methyl 4-[(1S)-1-[[(2R)-piperidine-2-carbonyl]amino]ethyl]benzoate hydrochloride (650 mg, 1.99 mmol) and 2-(4-fluorophenoxy)acetaldehyde (337 mg, 2.19 mmol) in DCE (9.9 mL) at room temperature for 30 min. Add acetic acid (0.113 mL, 1.99 mmol) and sodium triacetoxyborohydride (590 mg, 2.78 mmol) and stir at room temperature for three days. Quench the reaction with saturated aqueous NaHCO3 (25 mL) and extract the aqueous layer with EtOAc (2×25 mL). Wash the combined organic layers with saturated aqueous NaCl (25 mL), then dry the organic phase over MgSO4, filter, and concentrate under reduced pressure. Subject the resulting oil to flash chromatography on silica gel, eluting with a gradient of 0% to 100% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to provide the title compound as a white solid (600 mg, 70% yield). Mass spectrum (m/z) 429 (M+H)+, 451 (M+Na)+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[H-].[Na+]>O1CCOCC1>[Br:7][C:8]1[CH:9]=[N:10][C:11]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cnc(OC2CCCC2)nc1
Temperature: 0 °C

Procedure:
36.3 μL (0.40 mmol) cyclopentanol and 38.7 mg (0.20 mmol) 5-bromo-2-chloro-pyrimidine are added to 1.5 mL dioxane and cooled down to 0° C. Then the reaction mixture is charged with 24.0 mg NaH. After removing of the cooling bath the reaction mixture is stirred at r.t. over night. The reaction is quenched by the addition of water. The solvent is removed under vacuo and the residue is dissolved in DCM, washed with water and dried with MgSO4. The solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[CH3:25]S(Cl)(=O)=O.[N:30]1[C:35](C)=CC=C[C:31]=1C>CN(C=O)C>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([N:1]=[CH:31][N:30]([CH3:35])[CH3:25])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C)n1
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)C=Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (example 59)(15 mg, 0.045 mmol), methanesulfonyl chloride (7.4 mg, 0.065 mmol), 2,6-lutidine (7.4 mg, 0.068 mmol), and DMF (0.1 mL) was stirred at 25° C. for 2 hrs. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-70% CH3CN in 0.1% TFA/H2O over 20 mins to give 15 mg (68%) the title cpd as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.52 (s, 1H), 7.68 (dd, 1H), 7.48 (m, 4H), 7.32 (m, 2H), 6.96 (d, 1H), 6.80 (s, 1H), 3.25 (s, 3H), 3.12 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C21H17ClN4O2 392.1, found 393.1 (M+H).
Reaction SMILES: [Zn:1].[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[OH-].[NH4+].C(=O)=O.[C:12](=[S:14])=[S:13]>O>[CH2:2]([N:4]([CH2:5][CH3:6])[C:12](=[S:13])[S-:14])[CH3:3].[Zn+2:1].[CH2:2]([N:4]([CH2:5][CH3:6])[C:12](=[S:13])[S-:14])[CH3:3]
Reactant: CCNCC
Reactant: [Zn]
Reactant: S=C=S
Agent: O=C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)C(=S)[S-]
Product: [Zn+2]
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
The sequence of addition of the zinc compound and carbon disulfide is changed to conform to the method of Example 1 of U.S. Pat. No. 6,534,675, and zinc diethyldithiocarbamate (ZDEC-C) is prepared. Add 73 grams of diethylamine to 150 grams of water with temperature controlled at 25° C., then add 900 grams of solution with 3.4% ammonium hydroxide and 1% carbon dioxide which prevents the premature precipitation of the zinc content. Further add 346 grams of zinc ammonia complex solution A as in Example 1 containing 9.56% zinc to the solution and 1.7 grams of emulsifier Tanemul 1203. Lower the solution temperature to 15° C., add 78.5 grams of carbon disulfide slowly into the mixture under heavy agitation over 1 hour while keeping the temperature at or below 20° C. Yellowish white precipitates appear with the addition, and vapor comes out from the mixture. Continue the agitation for 3 hours, then heat the solution gradually to 40° C. Boil the solution, continue agitation for another 2 hours, then vacuum filter the precipitates. The filtrate has a pH of 8.45, and is substantially free of zinc and ammonia. The filtration is finished in 5 minutes. Wash the solid at the filter with 500 ml of 80° C. distilled water four times. Then dry the precipitate at 110° C. for 2 hours to obtain 172 grams of zinc diethyldithiocarbamate with 0.1% moisture content. We call this sample ZDEC-C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[CH2:10]([NH:13][C:7]1[C:2]([NH2:1])=[C:3]([Cl:9])[N:4]=[CH:5][N:6]=1)[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCO
Product: C=CCNc1ncnc(Cl)c1N
Temperature: 80 °C

Procedure:
A mixture of 5-amino-4,6-dichloro pyrimidine (3.0 g, 0.018 mol) and allyl amine (1.5 ml, 0.020 mol) was taken in ethanol (30 ml) and heated at 80° C. for 16 hrs. Solvent was removed to get crude product which was further purified by column chromatography to get pure N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine as off white solid (2.30 g, 68%).
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]([C:26]#[N:27])([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)#[N:6]>O>[C:5]([C:7]([C:26]#[N:27])([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1)#[N:6]
Reactant: N#CC(C#N)(CCC1CCC2(CC1)OCCO2)CCC(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: N#CC(C#N)(CCC1CCC(=O)CC1)CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 20 mL of a 50% aqueous acetic acid solution, 1.85 g of 8-(3,3-dicyano-6,6,6-trifluorohexyl)-1,4-dioxaspiro[4.5]decane was added, followed by stirring at 50° C. for 8 hours under a nitrogen atmosphere. To the reaction mixture was added 100 mL of water, followed by extraction twice with 100 mL of ethyl acetate. The combined organic layer was washed sequentially with 100 mL of a saturated aqueous sodium hydrogen carbonate solution and 100 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.37 g of 4-(3,3-dicyano-6,6,6-trifluorohexyl)cyclohexanone represented by the following formula:
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:6][CH2:5]2.[Li+].CCC[CH2-].[CH3:25][C:26]([N:30]1[CH2:40][CH2:39][C:33]2([C:37](=[O:38])[NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31]1)([CH3:29])[CH:27]=[O:28]>O1CCCC1>[Si:12]([O:11][CH:7]1[C:8]2[C:4](=[C:3]([CH3:19])[C:2]([CH:27]([OH:28])[C:26]([N:30]3[CH2:40][CH2:39][C:33]4([C:37](=[O:38])[NH:36][CH2:35][CH2:34]4)[CH2:32][CH2:31]3)([CH3:29])[CH3:25])=[CH:10][CH:9]=2)[CH2:5][O:6]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Cc1c(Br)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C=O)N1CCC2(CCNC2=O)CC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)(C)N2CCC3(CCNC3=O)CC2)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of ((5-bromo-4-methyl-1,3-dihydroisobenzofuran-1-yl)oxy)(tert-butyl)dimethylsilan (3.9 g, 11.36 mmol) in tetrahydrofuran (50 ml) at −78° C. was added N-butyllithium (5.00 ml, 12.50 mmol). After 15 min, 2-methyl-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propanal (0.892 g, 3.98 mmol) was added in one portion. The resulting solution was stirred at −78° C. for 3.5 h before being quenched by addition of methanol (6 mL) and saturated sodium bicarbonate (100 mL). The mixture was extracted with 30% isopropanol/methylene chloride (3×100 mL). The combined organic phase was dried over sodium sulfate, concentrated and the residue was purified on silica gel using methanol/methylene chloride to give the title compound. LC/MS: (M+1)+: 489.15.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[O:29]=[C:28]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][N:9]2[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: Nc1cccc2c1cnn2CCN1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-piperidin-1-yl-ethyl)-1H-indazol-4-ylamine (mmol), tert-butoxycarbonylamino-acetic acid (mmol), ethyldimethylpropylcarbodiimide hydrochloride (mmol), N-hydroxybenzotriazole (mmol) and N-methyl morpholine (mmol) were dissolved in 15 mL of DMF and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.34 (m, J=4.41 Hz, 6 H), 1.41 (s, 9 H), 2.37 (m, 4 H), 2.69 (t, J=6.78 Hz, 2 H), 3.86 (d, J=6.10 Hz, 2 H), 4.46 (t, J=6.78 Hz, 2 H), 7.08 (s, 1 H), 7.32 (m, 2 H), 7.64 (m, 1 H), 8.23 (s, 1 H), 9.96 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1>>[O:53]=[S:50]1(=[O:54])[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][NH:43][CH2:37][C@:21]23[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]2[C@@H:23]2[C@@:18]([CH3:39])([CH2:19][CH2:20]3)[C@@:17]3([CH3:40])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:41])([CH3:42])[C:12]([C:10]3[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24]2)[CH2:52][CH2:51]1
Reactant: NCCCN1CCS(=O)(=O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following steps 5 and 6 using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-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)benzoate and 4-(3-aminopropyl) thiomorpholine 1,1-dioxide as the reactant amine. The product was isolated as a white solid (50 mg, 55.0%). LCMS: m/e 737.5 (MH+), 2.53 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.85 (d, J=3.8 Hz, 1H), 7.01-7.14 (m, 1H), 6.98 (br. s., 1H), 5.37 (br. s., 1H), 4.78 (br. s., 1H), 4.67 (br. s., 1H), 3.56 (br. s., 4H), 3.43 (br. s., 4H), 3.21 (m, 3H), 3.12 (br. s., 2H), 2.90 (br. s., 1H), 2.53 (br. s., 1H), 2.16 (br. s., 4H), 1.75 (br. s., 10H), 1.53 (br. s., 8H), 1.31 (br. s., 3H), 1.19 (br. s., 5H), 1.10 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (d, J=8.5 Hz, 6H). 19F NMR (376 MHz, MeOD) δ ppm −112.6 (s, 1 F).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NOCC.[CH3:24][O:25][C:26]1[C:27]([C:45]([F:48])([F:47])[F:46])=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36](O)=[O:37])=[C:31]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:30]=[CH:29]2.Cl.[NH2:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].C(N(CC)CC)C>CN(C)C=O.O>[CH3:24][O:25][C:26]1[C:27]([C:45]([F:46])([F:47])[F:48])=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([NH:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:37])=[C:31]([O:39][CH2:40][C:41]([F:42])([F:43])[F:44])[CH:30]=[CH:29]2
Reactant: COc1ccc2c(C(=O)O)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN
Agent: CCON=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Reaction time: 2 h
Yield: 73 %

Procedure:
1-Hydroxybenzotriazole (4.27 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (4.84 g, 1.2 eq), were added to a stirred solution of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)naphthoic acid (7.75 g, 21.0 mmol, prepared by the process of Example 11, Step 3) in anhydrous dimethylformamide (135 mL) under a dry nitrogen atmosphere at room temperature. After 11/4 hours, glycine, t-butyl ester hydrochloride (7.06 g, 2.0 eq) and anhydrous triethylamine (9.68 mL, 3.3 eq) were added. After another 2 hours, the reaction mixture was diluted with water (1.5 L) and extracted with ether (4×200 mL). The extracts were combined and the ether was removed. The crude product was flash chromatographed (7:3 petroleum ether:ethyl acetate, silica) to provide the title compound as a white solid (7.39 g, 73%), m.p. 146°-174.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(C(F)(F)F)ccc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 496.0 (M+H+).
Reaction SMILES: CC1C(/C(/C)=C/C2C=CC(C(O)=[O:23])=CC=2)=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH3:28][C:29]1[C:30](/[C:43](/[CH3:55])=[CH:44]/[C:45]2S[CH:47]=[C:48]([C:50]([O:52]CC)=[O:51])[CH:49]=2)=[CH:31][C:32]2[C:33]([CH3:42])([CH3:41])[CH2:34][CH2:35][C:36]([CH3:40])([CH3:39])[C:37]=2[CH:38]=1.CC1C(/C(/C)=C/C2SC=C(C(O)=O)N=2)=CC2C(C)(C)CCC(C)(C)C=2C=1.CC1C(/C(/C)=C/C2NC(C(O)=O)=CN=2)=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:28][C:29]1[C:30](/[C:43](/[CH3:55])=[CH:44]/[C:45]2[O:23][CH:47]=[C:48]([C:50]([OH:52])=[O:51])[CH:49]=2)=[CH:31][C:32]2[C:33]([CH3:41])([CH3:42])[CH2:34][CH2:35][C:36]([CH3:39])([CH3:40])[C:37]=2[CH:38]=1
Reactant: CCOC(=O)c1csc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: C/C(=C\c1nc(C(=O)O)cs1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: C/C(=C\c1ncc(C(=O)O)[nH]1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Product: C/C(=C\c1cc(C(=O)O)co1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
4-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]benzoicacid; 2-[(E)-2-(4,4,7-trimethyl-6-thiochlomanyl)-propen-1-yl]-4-thiophenecarboxylic acid; ethyl 2[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-4-thiophenecarboxylate; 2-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-4-thiazolecarboxylic acid and 2-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-5-imidazolecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]([O:30][C:31]([CH2:33][S:34](Cl)(=[O:36])=[O:35])=[O:32])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([S:34]([CH2:33][C:31]([O:30][CH2:28][CH3:29])=[O:32])(=[O:36])=[O:35])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccccc1NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc(Cl)cc1)c1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a stirred solution of 48 g of methyl 2-(4-chlorophenylmethylamino)-phenylacetate in 1.2 l of toluene containing 26 ml of triethylamine is added 31 g of ethoxycarbonylmethylsulfonyl chloride in 50 ml of toluene in a dropwise manner over a period of 15 minutes maintaining the temperature of the reaction below 10°. The reaction mixture is then allowed to stir overnight at room temperature and poured into 2 1 of ice-water and the organic layer separated. The toluene extracts are washed with 3×750 ml brine, separated, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 40 g of methyl 2-[N-(4-chlorophenylmethyl)-ethoxycarbonylmethylsulfonylamino]-phenylacetate which may be crystallized from ether-hexane (4:1); m.p. 86°-88°.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6](=O)[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl.[NH:40]=[N+:41]=[N-:42].[CH:43]1C=CC=CC=1>>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:6]2[N:5]([C@:4]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)([CH3:43])[C:3]([OH:2])=[O:33])[N:42]=[N:41][N:40]=2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=N
Reactant: c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2nnnn2[C@@](C)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
N-(Toluene-4-sulfonyl-L-prolyl-(4-nitro)phenylalanine methyl ester was mixed with an equimolar amount of PCl5 in dry benzene and stirred for 90 minutes. The yellow solution was treated with a solution of hydrazoic acid in benzene and the mixture was stirred at room temperature for 2 hours, then it was diluted with benzene and washed with satd. NaHCO3 and brine. The organic layer was dried and evaporated to give a light yellow foam. The title compound was prepared from the product of the last reaction using standard basic hydrolysis techniques, yielding an off-white fluffy solid, mp 150-160° C.