Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[OH:71][CH:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>O>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([N:75]5[CH2:76][CH2:77][CH:72]([OH:71])[CH2:73][CH2:74]5)=[O:32])=[CH:34][CH:35]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCNCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)O)cc2)c(=O)n(C)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCC(O)CC3)cc2)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
A solution of 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid (7) (56 mg; 0.11 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58 mg; 0.13 mmol) and N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 h. 4-Hydroxypiperidine (56 mg; 0.55 mmol) was added and the mixture was stirred at room temperature for 16 h. Water (15 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was slurried with diethyl ether and filtered to give 4-tert-butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide (8) as a light brown solid (40 mg), MS 593.41 (M+H)
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([O:18][CH3:19])[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].O>C1COCC1.CCO>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:20])=[O:3])=[CH:9][C:10]=1[O:18][CH3:19])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC(C)C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C(=O)O)ccc1OC(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid ethyl ester (Compound L3-1, 1.45 g, 5.17 mmol) was dissolved in THF (13 mL) and EtOH (13 mL), added with 1 N aqueous solution of sodium hydroxide (10.3 mL, 2.0 eq.), and stirred at 80° C. overnight. The reaction solution was added to water and extracted with ethyl acetate. The aqueous layer was acidified by using 1 N aqueous solution of hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white solid, 1.10 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][C:9](=[O:24])[C:10]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[Br:25]C[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:36](#N)C>>[Br-:25].[OH:23][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]([O:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N+:2]([CH3:36])([CH2:1][CH:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])[CH2:3]1)=[O:24]
Reactant: BrCCCOc1ccccc1
Reactant: CN1CCC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1
Reactant: CC#N
Product: CC(C[N+]1(C)CCC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1)Oc1ccccc1
Product: [Br-]
Temperature: 60 °C

Procedure:
Hydroxy-diphenyl-acetic acid (R)-methyl-piperidin-3-yl ester (1.7 g, 0.00523 mol) and (3-bromo-propoxy)-benzene (1.2 ml, 0.00781 mol) are dissolved in acetonitrile (2 ml) and stirred at 60° C. over night. The reaction mixture is cooled to room temperature and evaporated to dryness. The residue is taken up in DCM and extracted with water. The aqueous layer is washed with DCM (3×20 ml) and evaporated to dryness. The residue is purified by flash chromatography over C18 silica gel (70 g) using a gradient of water/acetonitrile 100/0 to 0/100 over 25 minutes at 20 ml/min. The product containing fractions were combined and evaporated to yield 700 mg of the title compound as a white foam.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO.C(N(CC)CC)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([O:10][CH3:11])[CH:6]=3)[C:3]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.28 g, 4.94 mmol, 1.0 equiv) in methanol (9 mL) and triethylamine (0.83 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 5.19 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice/diluted HCl, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaHCO3 and water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (3:7) yielding 0.84 g (49%) of the title compound as white crystals. MS (ISP): 347.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:3](=[O:5])[CH:2]([CH3:1])[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7]
Reactant: NCc1ccccc1F
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C(=O)NCc1ccccc1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and 2-fluorobenzylamine (7.4 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=446.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17](=[O:49])[CH2:18][C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:45][C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:46])[C:39]=1[CH2:38][S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:47])/[C:26]/2=[CH:25]\[C:22]1[NH:21][C:20]([CH3:48])=[C:19]([CH2:18][C:17]([NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:49])[C:23]=1[CH3:24])(=[O:37])=[O:36]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (from the above reaction) and TFA (1 mL) in DCM (10 mL) was stirred at rt for overnight. The reaction was concentrated and purified to give 590 mg of the titled compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:5]=1[C:6]([OH:8])=O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36]2[CH2:43][CH:42]3[CH:38]([CH2:39][NH:40][CH2:41]3)[CH2:37]2)[N:30]=1>CC(O)=O.C1(C)C=CC=CC=1>[CH3:35][C:33]1[CH:34]=[C:29]([CH3:28])[N:30]=[C:31]([N:36]2[CH2:43][CH:42]3[CH2:41][N:40]([C:6]([C:5]4[C:9]([N:13]5[N:17]=[CH:16][CH:15]=[N:14]5)=[CH:10][CH:11]=[CH:12][C:4]=4[F:3])=[O:8])[CH2:39][CH:38]3[CH2:37]2)[N:32]=1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a 3-necked, 3 L, round-bottomed flask equipped with a nitrogen line, temperature probe, heating mantle, reflux condenser, mechanical stirrer, and 1 N aq. NaOH scrubber were added 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 12, 120.98 g, 75 wt %, 90.74 g actual, 438 mmol) and toluene (1 L). The mixture was warmed to 50° C. for 1 h with stirring. The mixture was then cooled to 25° C. and thionyl chloride (47.9 mL, 657 mmol) was added. The mixture was warmed back to 50° C. and held for 1 h. During this time, in a separate 5 L jacketed reactor equipped with a mechanical stirrer and temperature probe were added toluene (600 mL), aqueous sodium carbonate (185.7 g, 1.75 mol in 1.6 L water), and 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (Intermediate 23, 122 g, 438 mmol). This biphasic mixture was cooled to 0° C. After cooling to 0° C., the original slurry was poured through a filter and over the stirring biphasic mixture of amine and aqueous sodium carbonate. The mixture was allowed to warm to room temperature. After 2 h, additional 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (4 g, 14 mmol) was added and the mixture was stirred for 30 additional minutes. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic layer was dried over MgSO4, filtered, and concentrated to a white solid. This solid was taken up in ethanol (1.4 L) and warmed to 77° C. The mixture was then cooled to 55° C. and seeded with previously crystallized material. (Note: The seeds were generated from slurrying the initial product in 2-propanol at room temperature [100 mg/mL]). The mixture was cooled to room temperature at a rate of 5° C. per hour. After stirring at room temperature for 14 h, the mixture was filtered and dried to provide the final product as a white crystalline solid (136.84 g, 74%). 1H NMR (400 MHz, CDCl3): 7.88-7.78 (m, 1.78H), 7.75-7.69 (s, 1.22H), 7.51-7.43 (m, 1H), 7.17-7.11 (m, 1H), 6.30-6.28 (m, 1H), 4.03-3.48 (m, 7H), 3.29-3.21 (m, 1H), 3.15-2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass calcd for C21H22FN7O, 407.19; m/z found, 408 [M+H]+. Anal. calcd. for C21H22FN7OC, 61.90, H, 5.44; N, 24.06. found C, 61.83, H, 5.42; N, 24.08.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.781 g, 1.80 mmol) (from example 140, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.072 g, 1.80 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.12 mL, 1.96 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(3-fluoro-4-(trifluoromethyl)-benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (678 mg, 94%) was isolated as an off-white foam. MS m/z 403 (M+H)+
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C)C=CC=1C(O)=O.CC1C=C(C)C=CC=1C(Cl)=O.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1ccc(C(=O)N=C=S)c(C)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cc1ccc(C(=O)O)c(C)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,4-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,4-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,4-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 97%).
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1.CS[C:20](SC)=[CH:21][N+:22]([O-:24])=[O:23].[C:27](#[N:29])C>>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:20]([NH:29][CH3:27])=[CH:21][N+:22]([O-:24])=[O:23])[CH2:11]2)[N:9]=1
Reactant: CC#N
Reactant: CN=C(N)Nc1nc(C2CCCC(N)C2)cs1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CN=C(N)Nc1nc(C2CCCC(NC(=C[N+](=O)[O-])NC)C2)cs1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-methylguanidino)-4-(3-aminocyclohexyl)thiazole (0.2 g.) in acetonitrile (20 ml.) was added 1,1-di(methylthio)-2-nitroethylene (0.125 g.) and the mixture heated under reflux for 7 hours. The reaction mixture was evaporated to dryness and the residue of 1-[3-[2-(2-methylguanidino)thiazol-4-yl]cyclohexylamino]-1-methylthio-2-nitroethylene, dissolved in ethanol (20 ml.), was treated with 20 ml. of a solution of methylamine in ethanol (33% w/v). The reaction mixture was allowed to stand overnight. Evaporation of the solvent and recrystallisation of the residue from methanol gave 1-[3-[2-(2-methylguanidino)thiazol-4-yl]cyclohexylamino]-1-methylamino-2-nitroethylene, m.p. 164°-174° (decomp.).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCOC(C)=O.C(Cl)Cl.[NH3:52]>CO>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([NH2:52])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)C1CC[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCC(C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 80 %

Procedure:
In a sealed tube a solution of Methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (diastereoisomer 1) (Intermediate 7, 6 mg, 9.94 μmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day and then it was left still for 2 days. The solvent was evaporated to dryness and the crude was purified by silica cartridges twice (1st time: from 1:0 to 95:5 DCM/MeOH; 2nd time: EtOAc and then 97.5:2.5 DCM/0.5M NH3 in MeOH) to give the title compound (4.7 mg, 7.99 μmol, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95-8.03 (m, 1H) 7.63-7.73 (m, 2H) 7.29-7.37 (m, 1H) 7.12-7.20 (m, 1H) 7.00-7.06 (m, 1H) 6.86-6.92 (m, 1H) 6.71-6.79 (m, 1H) 5.27-5.38 (m, 1H) 4.34-4.43 (m, 1H) 3.54-3.64 (m, 1H) 3.16-3.25 (m, 1H) 3.03-3.14 (m, 1H) 2.67-2.84 (m, 3H) 2.30-2.41 (m, 3H) 1.96-2.08 (m, 1H) 1.62-1.80 (m, 2 H) 1.38-1.58 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:24]=[C:19]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])[CH:20]=[CH:21][C:22]=2[OH:25])([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: C=C(C)c1ccc(F)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(F)cc2)c1
Yield: 76 %

Procedure:
4-Fluoro-α-methylstyrene (18 g) as prepared in Example 2 and 20.6 g of 4-tert-octylphenol are reacted according to the procedure of Example 3 to yield 26 g of the title compound as a reddish, viscous oil whose structure is consistent with 1Hnmr and mass spectroscopy.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([N:24]4[C:36]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:23]=3)[C:17]([O:19]C)=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C1COCC1.CO.O>[CH:10]1[C:11]2[N:12]([C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([N:24]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=5[C:31]5[C:36]4=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:23]=3)[C:17]([OH:19])=[O:18])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 4.5 h

Procedure:
To a solution of methyl 3,5-di(carbazol-9-yl)benzoate (1.0 g, 2.14 mmol) in THF/methanol (25.0 ml, 15:10) was added KOH (0.6 g, 10.69 mmol) in water (2.0 ml) at room temperature under stirring. The reaction was carried out at room temperature for 4.5 hours. The THF was evaporated. Next, methanol (20.0 ml) was added and then HCl water solution (80.0 ml; 15.0 ml of 36-38% HCl in 65.0 ml of water) was added. The mixture was stirred for 1 hour and a pale yellow solid product was obtained by filtration. The product was purified by recrystallization from acetone/water: 0.95 g (97.9%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:21][C:19]([CH3:22])([S:23]([NH:25][CH:26]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])[CH3:20]
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: COc1ccc2ccccc2c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 1-bromo-2-methoxynaphthalene (0.839 g; 2.14 mmol) in anh. THF (20 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.35 ml; 2.16 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (0.500 g; 2.14 mmol) in anh. THF (2 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (35 ml), Et2O (75 ml) and water (20 ml). The separated organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=15/1) afforded methyl 5-(1,1-dimethylethylsulfinamido)-5-(2-methoxynaphthalen-1-yl)pentanoate as a yellow oil. LC-MS (conditions A): tR=0.83 min. and [M+H]+: 391.93 g/mol.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:18][CH2:17]2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[CH:16]1([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([N:5]=[C:1]=[S:2])=[CH:7][CH:8]=2)[CH2:18][CH2:17]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C2CC2)c2ccccc12
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Yield: 86 %

Procedure:
Thiophosgene (1.1 g, 9.7 mmol) was added to a solution of 1-amino-4-cyclopropyl-naphthalene (1.8 g, 9.7 mmol) and diisopropylethylamine (2 eq) in dichloromethane (50 mL) stirred at 0° C. The reaction mixture was stirred for 5 min at this temperature, then a 1% solution of HCl in water was added and the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Hexane was added, and the resulting precipitate was filtered. The solvent was evaporated to yield 1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86%).