Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[C:26]([C:50]([F:53])([F:52])[F:51])=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35]([N:37]([CH3:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=O)=[C:30]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:29]=[CH:28]2>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][O:24][C:25]1[C:26]([C:50]([F:53])([F:52])[F:51])=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35](=[S:10])[N:37]([CH3:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[C:30]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:29]=[CH:28]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CN(C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)CN(C)C(=S)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 64 %

Procedure:
Lawesson's reagent (3.20 g, 0.6 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester, prepared by the process of Example 3, Step 1 (6.00 g, 13.2 mmol) in toluene (60 mL) at room temperature under argon. The reaction was heated to reflux for 111/2 hours, with more Lawesson's reagent (4.8 g, 0.9 eq) added in two portions after 21/4 and 83/4 hours. The reaction was cooled to room temperature and diluted with methylene chloride (300 mL). The crude reaction mixture was preabsorbed onto silica gel and flash chromatographed (petroleum ether→7:3 petroleum ether:ethyl acetate eluent gradient, silica) to provide the product as a yellow foam (3.94 g, 64%). A small sample was washed with petroleum. The filtrate was evaporated to dryness to provide a yellow solid for analysis, m.p. 104°-105° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[C:26]1([S:32]([N:35]2[C:39]3=[N:40][CH:41]=[C:42]([CH:44]4[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]4)[CH:43]=[C:38]3[CH:37]=[C:36]2[CH:51]([OH:58])[CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([N:35]2[C:39]3=[N:40][CH:41]=[C:42]([CH:44]4[CH2:48][O:47][C:46]([CH3:49])([CH3:50])[O:45]4)[CH:43]=[C:38]3[CH:37]=[C:36]2[C:51](=[O:58])[CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCC(c2cnc3c(c2)cc(C(O)CC2CCCC2)n3S(=O)(=O)c2ccccc2)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)OCC(c2cnc3c(c2)cc(C(=O)CC2CCCC2)n3S(=O)(=O)c2ccccc2)O1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A Dess-Martin periodinane solution in dichloromethane (0.3 M, 9 mL, 2.7 mmol) was added to 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanol (610 mg, 1.3 mmol) at 25° C. and then stirred for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanone (600 mg crude) as a light yellow solid which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (m, 2H), 1.57-1.73 (m, 4H), 1.52 (s, 3H), 1.59 (s, 3H), 1.96 (m, 2H), 2.44 (m, 1H), 3.03 (d, J=7.2 Hz, 2H), 3.74 (dd, J=7.6 Hz, 8.4 Hz, 1H), 4.39 (dd, J=6.4 Hz, 8.4 Hz, 1H), 5.19 (dd, J=6.4 Hz, 7.6 Hz, 1H), 6.94 (s, 1H), 7.55 (m, 2H), 7.62 (m, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.39 (d, J=7.6 Hz, 2H), 8.56 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27]([N:16]([CH2:15][C:14]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:22])[CH2:9]1)=[O:21])[CH2:17][CH2:18][O:19][CH3:20])=[O:28]
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 52 mg of 3-chloro-4-methylbenzoic acid (0.31 mmol, 1.00 eq), 163 mg BOP (0.37 mmol, 1.20 eq), 171 uL (1.23 mmol, 4.00 eq), and 1.5 mL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-N-(2-methoxy-ethyl)-4-methyl-benzamide. MS (ES) M+H expected=478.0, found=478.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O.[Pd]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C@@H:10]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:24])=[O:25])=[C:14]([OH:26])[CH:13]=1
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3nc4ccccc4[nH]3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3nc4ccccc4[nH]3)cc2O)S(=O)(=O)N1

Procedure:
A solution of N-{(S)-1-(1H-benzoimidazol-2-yl)-2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-benzenesulfonamide and K2CO3 (50 mg) in 10 mL of EtOH/water (1:1) is hydrogenated over 10% Pd/C (100 mg) at 1 atm for 18 h. The catalyst is filtered and the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC followed by lyophilization to give the title compound as a pink solid. (M−1)−: 526. HPLC retention time: 0.98 min. (Method A).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=1.[OH-].[Na+]>CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1
Reactant: COC(=O)c1ccc(OCCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCC(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of methyl 6-(3,3,3-trifluoropropoxy)nicotinate (1.37 g, 5.50 mmol, Step-1) in methanol (30 mL) is added 2 M sodium hydroxide (5 mL), and stirred for 2 hours at 60° C. After removal of the solvent, the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.15 g (86% yield) of the title compound as white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:12]([NH2:28])=[CH:11][N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:29][C:30]1[CH:64]=[CH:63][C:33]([C:34](/[N:36]=[C:37]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:35])=[CH:32][CH:31]=1>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:10]=[CH:11][C:12]3[NH:28]/[C:37](=[N:36]\[C:34](=[O:35])[C:33]4[CH:63]=[CH:64][C:30]([F:29])=[CH:31][CH:32]=4)/[N:15]([C@H:16]4[CH2:17][CH2:18][C@@H:19]([C:22](=[O:23])[NH:24][CH:25]([CH3:26])[CH3:27])[CH2:20][CH2:21]4)[C:13]=3[CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCn3cncn3)ncc2N)CC1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OCCn4cncn4)cc32)CC1
Yield: 43 %

Procedure:
The title compound was prepared from cis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (62 mg, 43% yield, last step). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6.55 Hz, 6H) 1.57-1.62 (m, 2H) 1.69-1.73 (m, 2H) 2.02-2.16 (m, 2H) 2.50-2.51 (m, 1H) 2.57-2.79 (m, 2H) 3.92-4.02 (m, 1H) 4.60-4.65 (m, 4H) 4.70-4.80 (m, 1H) 6.99 (s, 1H) 7.25 (dd, J=8.85, 8.85 Hz, 2H) 7.65 (d, J=7.82 Hz, 1H) 7.98 (s, 1H) 8.22 (s, 1H) 8.28-8.36 (m, 2H) 8.53 (s, 1H) 12.70 (s, 1H). M/Z calc'd for C27H31FN8O3: 534.59. found 535 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:26]([C:25]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:24]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:27])[CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2Cl)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(2-Chloro-4-trifluoromethyl-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (74%, yellow solid, MS (m/e): 499.2 (M+H, 100%)
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:41]3[CH:40]=[CH:39][C:38]([N:35]5[CH2:34][CH2:33][O:32][CH2:37][CH2:36]5)=[CH:43][CH:42]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(N2CCOCC2)cc1)N1CCN(C2CCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-morpholinophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (31%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:11])[NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>>[CH3:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)[N:3]2[N:4]=1
Reactant: COC(=O)c1c(N)n[nH]c1C
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1c(C)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
As for Example 1, methyl 3-amino-5-methylpyrazole-4-carboxylate is reacted with 3-dimethylamino-3'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 177°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)c1ccc(Sc2cccc(O)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 26A) (0.356 g, 1.0 mmol), 3-hydroxythiophenol (0.126 g, 1.0 mmol) and cesium carbonate (0.65 g, 2.0 mmol) in N,N-dimethylformamide (5 mL) was heated to 95° C. for 3 hours. After cooling to room temperature the mixture was poured into ice water (20 mL) and the resultant solution acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.430 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=O)([O:11]C)[O:9][CH3:10])([O-:3])=[O:2].S(Cl)([Cl:32])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8]([Cl:32])(=[O:11])[O:9][CH3:10])([O-:3])=[O:2]
Reactant: COP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COP(=O)(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonate (0.5 g) in benzene (10 ml) is added thionyl chloride (8 ml) at RT. The mixture is allowed to return to RT and is stirred for 6 hours. The solvent and any excess thionyl chloride are then distilled off, yielding methyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonochloridate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8](COC)[C:7]=2[CH:20]=1)[CH3:2].[ClH:21]>C(O)C>[ClH:21].[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:20]=1)[CH3:2]
Reactant: CCc1ccc2c3c(c(=O)n(COC)c2c1)CCCN3
Agent: Cl
Solvent: CCO
Product: CCc1ccc2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
8-ethyl-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (130 mg, 0.48 mmol) prepared in step 5 of Example 38 was dissolved in ethanol (8 ml) and added with conc. hydrochloric acid solution (2.5 ml). The mixture was stirred overnight at 80° C. and the precipitate was collected by filteration to obtain the title compound (120 mg, yield: 95%, yellow solid).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)[OH:4].[CH:18]1([CH2:24][CH:25]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][C@H:25]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:26]([NH:1][C@H:2]([C:3]([C:5]2[O:6][CH:7]=[CH:8][N:9]=2)=[O:4])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: NC(CCc1ccccc1)[C@H](O)c1ncco1
Product: O=C(N[C@@H](CCc1ccccc1)C(=O)c1ncco1)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1

Procedure:
It is similarly prepared according to the general procedure for example 10 but using (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol and 2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid.
Reaction SMILES: [H][H].[F:3][C:4]([F:31])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18](=[N:26]O)[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1>C(O)C.O1CCCC1.[Ni]>[F:31][C:4]([F:3])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]([NH2:26])[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(OC(F)(F)F)ccc2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cc(OC(F)(F)F)ccc4[nH]3)cccc21
Yield: 90.9 %

Procedure:
The procedure used in Example 6 is followed. In a 111 ml autoclave, dissolve 730 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 25 ml of ethanol and 25 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 122 ml. After filtration of the catalyst over Celite, the filtrate is concentrated under reduced pressure and then taken up in dichloromethane and dried over magnesium sulphate. In this way, we obtain 640 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)amine, in the form of a beige foam, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:13]2[C:8]([C:9]3([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=32)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][S:2]([C:5]1[N:13]2[C:8]([C:9]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=32)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c2ccc1S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (200 mg, 0.48 mmol) in dry dichloromethane (1 mL) at 0° C. was added TFA (147 μL, 1.91 mmol). The cooling bath was removed and the mixture was stirred for 1.5 h at 25° C. The mixture was concentrated under reduced pressure and the residue obtained was taken up in dichloromethane (10 ml) and was washed with aqueous saturated NaHCO3 (5 ml). The aqueous phase was extracted twice with dichloromethane (2×10 ml) and the organic phases were combined, dried, filtered and concentrated to yield 1′-methylsulfonylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a light yellow foamy solid (150 mg, 99%). ESI-MS m/z calc. 318.1. found 319.3 (M+1)+; Retention time 0.93 minutes (3 min run). 1-(Methylsulfinyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] was also prepared using the procedure described above where only one aliquot of H2O2 was used in Step 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.9 %

Procedure:
To a solution of 4-fluorobenzenesulfonyl chloride (3.97 g, 20 mmol) in methylene chloride (40 ml), at 0° C., under nitrogen, with stirring, is added morpholine (4.4 mL, 50 mmol). The mixture is stirred at 0° C. for 15 min. and then warmed to room temperature for 18 hrs. The resulting suspension is filtered, and the filtrate is stirred with 10% potassium carbonate for 2 hrs. The methylene chloride is evaporated, and the aqueous suspension is filtered, and the precipitate is washed with water, and then dried in vacuo to give 5.0 g of a white solid; mp 106-107° C.; MS (APCI) m/z 246.1 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:31]6[CH2:32][CH2:33][O:28][CH2:29][CH2:30]6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, white solid (16.3 mg, 38.4%), MS (ISP) m/z=421.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-morpholinobenzoic acid.
Reaction SMILES: O.[C:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[OH-].[K+].[CH3:10][N:11]([CH3:15])[CH2:12]CO>CO>[CH3:10][N:11]([CH2:15][CH2:4][O:3][C:2](=[O:7])[O:5][CH2:6][CH2:10][N:11]([CH3:15])[CH3:12])[CH3:12]
Reactant: CN(C)CCO
Reactant: COC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCOC(=O)OCCN(C)C
Temperature: 80 °C

Procedure:
Into a flask equipped with a reflux cooler, a water separator and a dropping funnel, there were charged 113.5 grams (1.25 moles) of dimethyl carbonate. The substance was heated to 80° C. A solution of 1.4 grams (0.025 moles) of potassium hydroxide in 225.0 grams (2.5 moles) of dimethylethanolamine was then added in drops over a period of 30 minutes. The methanol formed during the reaction was removed by azeotropic distillation using cyclohexane as an entraining agent.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].Cl>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]([CH2:11]3)[CH2:10]1)[CH2:12]2
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
136 mg of 80% sodium hydride in oil are added to a solution of 8 g (16mmol) of benzyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in 100 ml of DMF. The mixture is left stirring for 1 h and 1.6 ml (16.4 mmol) of methyl bromoacetate are added. The reaction mixture is left stirring overnight, and it is then poured into ice cold water and acidified to pH 2 with concentrated HCl. The solid is filtered and recrystallized from ether. 8.52 g (95%) of the expected derivative are recovered, which derivative melts at 183° C.