Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([C:38]([CH3:40])=[CH2:39])[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>CCO.[Pd]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([CH:38]([CH3:40])[CH3:39])[N:21]=3)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.033 mmol) in anhydrous EtOH (3 mL), was added a catalytic amount of 10% of palladium on carbon. The mixture was stirred under 1 atm of hydrogen for 2 h. The reaction mixture was filtered through Celite. The solvent was concentrated in vacuo. Flash chromatography of the residue (Si, hexanes/EtOAc) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=613.2; found=613.3 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 7.88 (s, 1H); 7.75 (s, 2H); 7.45 (d, J=7.8 Hz, 1H); 7.17 (d, J=7.8 Hz, 1H); 7.04 (br, s, 0.5H); 6.98 (br, s, 0.5H); 6.70 (s, 0.5H); 6.68 (s, 0.5H); 5.72-5.56 (br, m, 1H); 4.95-4.76 (br, m, 1H); 4.41 (br, m, 0.5H); 4.23 (br, m, 0.5H); 4.18-3.89 (br, m, 1H); 3.77 (s, 3H); 3.25-3.19 (m, 1H); 3.16-3.08 (m, 1H); 1.37 (m, 6H); 1.28 (d, J=6.9 Hz, 6H); 0.73 (br, s, 1.5H); 0.62 (br, s, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:27][CH2:26]3)=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[CH:10][N:9]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[CH:12][N:13]=1
Reactant: COC(=O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Temperature: 60 °C
Yield: 81 %

Procedure:
The solid residue obtained in step A was dissolved in methanol (3 ml) and aqueous solution 2N NaOH (1 ml) was added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SiO2 eluting with DCM/MeOH 2% affording 0.170 g (yield 81%) of the expected product.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36][NH2:37]>>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:37]1
Reactant: NNc1cccc(Cl)c1Cl
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1Cl

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 2,3-dichloro-phenylhydrazine according to the method described for example 1. MS: M=515.0 (M+H)+
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[CH2:3][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cc2nccc(CCl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
4-(Chloromethyl)-6,7-dimethoxyquinoline hydrochloride (0.75 g, 2.74 mmol), tert-butyl piperidin-4-ylcarbamate (0.77 g, 3.84 mmol), and cesium carbonate (2.68 g, 8.23 mmol) were dissolved in DMF (14 mL) and heated to 80° C. while stirring. After 4 hours, the reaction was cooled, DMF was removed, and the compound was taken up in DCM (150 mL) and water (20 mL). The aqueous layer was extracted 2× with DCM (50 mL). The organics were washed with brine, dried with sodium sulfate, and concentrated to give the desired product tert-butyl 1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-ylcarbamate (1.04 g, 2.60 mmol, 95% yield). MS (ESI pos. ion) m/z: 402.2 (MH+). Calc'd exact mass for C22H31N3O4: 401. 1HNMR (400 MHz, CDCl3): 8.64-8.65 (d, J=4.4 Hz, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.23-7.24 (d, J=4.4 Hz, 1H), 4.57-4.59 (m, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.83 (s, 2H), 2.82-2.85 (bd, J=11.6 Hz, 2H), 2.18-2.24 (bt, J=10.8 Hz, 2H), 1.92-1.95 (bd, J=12.4 Hz, 2H), 1.44 (s, 9H), 1.41-1.44 (m, 2H, overlapping).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][S:5](=[O:7])[N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.I([O-])(=O)(=O)=[O:16].[Na+]>C(#N)C.O.C(OCC)(=O)C>[CH3:1][C@@H:2]1[O:6][S:5](=[O:16])(=[O:7])[N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (5.7 g, 25.8 mmol) in acetonitrile (60 mL) and H2O (30 mL) is added sodium periodate (8.3 g, 38.7 mmol). After 5 min, a few crystals of RuCl3 are added. The reaction is stirred for 3 hours and the resulting thick slurry is diluted with H2O (100 mL) and ethyl acetate (20 mL) and passed through a bed of Celite, rinsing with additional EtOAc. The filtrate is concentrated to remove the organic solvents and the resulting solid is isolated by filtration to afford the title compound (6.0 g, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCOCCl
Reactant: O=Cc1cccc(O)c1
Product: COCCOCOc1cccc(C=O)c1
Yield: 84.6 %

Procedure:
The hydroxyl group of 3-hydroxybenzaldehyde (1.5 g) was protected by use of 2-methoxyethoxymethyl chloride (1.4 g) in accordance with (production process 1), to thereby produce 3-methoxyethoxymethoxybenzaldehyde (2.0 g, yield: 76%). The thus-produced 3-methoxyethoxymethoxybenzaldehyde (1.9 g) and 3,4-dimethoxybenzyl cyanide (1.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield a methoxyethoxymethoxy form (hereinafter will be referred to as an “MEM form”) of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.2 g, yield: 48%).
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.C(S(O)(=O)=O)C.[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22].O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:25]1[CH2:26][NH:19][C@H:20]([C:21]([OH:23])=[O:22])[CH2:24]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCS(=O)(=O)O
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The cells, the treated cells or the enzyme preparation are added to 240 mM MES [2- (N-morphorino) ethanesulfonic acid] buffer containing 12 mM L-proline, 24 mM 2-ketoglutaric acid, 4 mM ferrous sulfate and 8 mM L-ascorbic acid to make 250 μl in total. The mixture is kept at 35° C. for 10 minutes. The reaction mixture is heated at 100° C. for 2 minutes to stop the reaction, and the amount of trans-4-hydroxy-L-proline produced in the reaction mixture is determined by HPLC.
Reaction SMILES: C(OC(=O)[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10]C(C)(C)C)=O)(C)(C)C.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOCC>CC(O)=O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>[Br:21][C:18]1[CH:17]=[C:16]2[C:15]([CH2:7][C:8](=[O:10])[N:22]2[CH2:34][C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=[CH:25][CH:26]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Reactant: O=Cc1ccnc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ccc(Br)cc2N1Cc1ccnc2ccccc12
Reaction time: 0.5 h

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (1.93 g, 5.0 mmol) and 4-quinolinecarboxaldehyde (890 mg, 5.50 mmol) were dissolved in 20 ml of AcOH under an atmosphere of dry N2. To this solution was added 95% NaHB(OAc)3 (1.45 g, 6.5 mmol) and the solution was stirred for 30 minutes. The reaction mixture was concentrated under vacuum and then stirred in 60 ml of a 1:1 solution of DCM/water. To this mixture was slowly added NaHCO3 until the pH˜8. The DCM layer was then washed with saturated aqueous NaHCO3 and dried over Na2SO4, filtered and concentrated under vacuum to give a golden oil which was subsequently dissolved in a solution of 20 ml of TFA and 2.5 ml of triethylsilane under an atmosphere of dry N2. The mixture was stirred overnight after which time the reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a brown solid which, after trituration with Et2O, gives the tilted compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(CC)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][N:17]2[C:18](=[O:27])[C:19]3[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
44.7 g (240 mmol) N-(tert-butoxycarbonyl)-piperazine, 60.9 g (240 mmol) N-(2-bromoethyl)-phthalimide, 49.8 g (360 mmol) potassium carbonate and 49.5 g (330 mmol) sodium iodide are heated in 1000 ml ethyl methyl ketone for five hours under reflux. After cooling the reaction mixture and concentrated under vacuum. The residue is taken up in 700 ml chloroform and extracted twice by shaking each with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is distilled off. The residue is crystallized from 110 ml methanol. Colorless crystals of MP. 136-138° C.: Yield 47.6 g (55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][O:22][CH:23]([C:27]2[C:35]3[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=3)[CH:30]=[C:29]([Cl:44])[CH:28]=2)[C:24](O)=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.C1C[N:49]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:49][C:24](=[O:25])[CH:23]([C:27]1[C:35]2[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=2)[CH:30]=[C:29]([Cl:44])[CH:28]=1)[O:22][CH2:21][C:11]1([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(C(N)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (100 mg, 0.154 mmol) and ammonia (7 M in methanol, 0.110 mL, 0.771 mmol) in dimethylformamide (2 mL) at 0° C. was added PyBOP (96 mg, 0.19 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of water and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%→85% ethyl acetate/n-hexane) gave 89 mg (89%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.27 (dd, J=8.9, 5.2 Hz, 2H), 7.00 (dd, J=8.6, 8.5 Hz, 2H), 6.95 (d, J=1.5 Hz, 1H), 6.48 (d, J=2.7 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 5.65 (s, 2H), 5.23 (s, 1H), 3.66 (m, 2H), 3.60 (t, J=8.1 Hz, 2H), 3.51 (d, J=8.9 Hz, 1H), 3.41 (d, J=8.9 Hz, 1H), 3.01 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 172.5, 161.5 (d, J=246 Hz), 155.0, 146.1, 138.42, 138.39, 128.7 (d, J=7.7 Hz), 128.5, 127.8, 125.5, 122.9, 122.6, 119.7, 115.4 (d, J=21 Hz), 82.1, 79.5, 78.3, 67.8, 41.2, 40.0 (br), 32.2, 32.1, 28.5, 17.9, −1.3. Mass spec.: 647.35 (MH)+.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:11]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butanesulphonyl chloride (7.8 g) was added dropwise to a stirred solution of 4-iodobenzeneamine (10 g) in pyridine (50 ml) at 0°. The bright red mixture was stirred at room temperature for 1 h, then concentrated to an oil which was partitioned between 2N hydrochloric acid (100 ml) and EA (100 ml). The organic layer was washed with 2N hydrochloric acid, water and brine, dried (MgSO4) and concentrated to a pale brown solid which was recrystallised from CX to give the title compound as white flakes (10.5 g) m.p. 80°-81°.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](Cl)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O.C1COCC1.O>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: NC(=O)c1cnc(Cl)nc1NC12CC(C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cnc(N[C@@H]2CCC[C@H](O)C2)nc1NC12CC(C1)C2
Temperature: 85 °C
Yield: 6.8 %

Procedure:
A mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxamide (44 g), (1S,3R)-3-aminocyclohexanol (27.6 g), potassium carbonate (38.2 g) and DMSO (300 mL) was heated at 85° C. for 12 h. After cooling to room temperature, water (2 L) and a mixture of THF and EtOAc (1:1, 2 L) were added. The aqueous phase was separated and the organic layer was washed with saturated brine (2 L). The organic layer was concentrated under reduced pressure to give the crude product as a purple foam which was triturated with hot acetonitrile (1 L). After cooling to room temperature the solid was filtered and washed with acetonitrile (200 mL). The solids was dried in a vacuum oven at 50° C. to give 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(((1R,3S)-3-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide as an off-white solid (4 g, 79% yield). 1H NMR (DMSO-d6) δ 0.91-1.31 (m, 4H), 1.60-1.89 (m, 3H), 2.01-2.20 (m, 7H), 3.34 (s, 1H), 3.37-3.52 (m, 1H), 3.58-3.85 (m, 1H), 4.65 (d, J=4.3 Hz, 1H), 6.90 (br. s., 1H), 7.20 (d, J=7.9 Hz, 1H), 7.61 (br. s., 1H), 8.37 (s, 1H), [9.23 (s, 0.14H)], 9.41 (s, 0.86H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH:23]5[CH2:25][CH2:24]5)=[CH:21][C:20]([CH:26]5[CH2:28][CH2:27]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C)n2)C1=O
Yield: 87.1 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (221 mg) described in Preparation Example 251 and 1-acetylimidazolidin-2-one (77 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (213 mg) was obtained.
Reaction SMILES: C(C(C1C=C([NH:16][C:17](=[O:40])[NH:18][CH2:19][C:20]([N:22]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][CH2:31][CH:23]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])C=CC=1)=O)C1C=CC=CC=1.CC1C=C(C2NC(C(OC(C)(C)C)=O)CC2)C=CC=1.[CH2:60]([O:67][C:68]([C:70]1[CH:71]=[C:72](NC(=O)NCC(O)=O)[CH:73]=[CH:74][CH:75]=1)=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH2:60]([O:67][C:68]([C:70]1[CH:75]=[C:74]([NH:16][C:17](=[O:40])[NH:18][CH2:19][C:20]([N:22]2[CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:31][CH:23]2[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:21])[CH:73]=[CH:72][CH:71]=1)=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)Cc2ccccc2)c1
Reactant: O=C(O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cccc(C2CCC(C(=O)OC(C)(C)C)N2)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1

Procedure:
tert-Butyl (2RS,5SR)-1-{2-[3-(3-benzylcarbonylphenyl)ureido]acetyl}-5-phenylprolinate may be prepared as described in Example 41 §A, but starting from 0.4 g of tert-butyl (2RS,5SR)-5-(3-methylphenyl)-prolinate, 0.5 g of 2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetic acid and 0.31 g of N,N'-dicyclohexyl-carbodiimide in 20 cm3 of acetonitrile. After treatment, 0.8 g of tert-butyl (2RS,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]-acetyl}-5-phenylprolinate is obtained in the form of a meringue-like product, used as it is in the subsequent syntheses.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[I-:6].O[CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[ClH:3].[I-:6].[Cl:5][CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCN(CCO)CCC[N+](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCN(CCCl)CCC[N+](C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A total of 28 ml of thionyl chloride was added dropwise, with stirring, to 27.35 g of 3-[(2-hydroxyethyl) ethylamino]-N,N,N-trimethyl-1-propanaminium iodide hydrochloride in 200 ml of toluene at 50° C. Upon completion of the addition the mixture was stirred at 50° for 15 minutes, and then heated at 80° C. for 3 hours. The reaction mixture was steam distilled to remove toluene. Organic chloride analysis on the resulting aqueous solution showed the corresponding alkyl chloride was obtained in 88% yield.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O>O1CCCC1.[Pd]>[NH:15]1[C:6]2[C:5](=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Yield: 85 %

Procedure:
A solution of methyl E-4-(2-dimethylaminovinyl)-3-nitrobenzoate (5.58 g) in tetrahydrofuran (100 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium on carbon (1.1 g) for 35 minutes. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution obtained was washed successively with 10% (v/v) hydrochloric acid, water, and brine, then dried (MgSO4) and evaporated to give methyl indole-6-carboxylate (3.32 g, 85%) as a white solid; NMR (80 MHz, CDCl3) 3.92(s, 3H, OCH3), 6.57(m, 1H, H3 -indole), 7.32(t, 1H, H2 -indole), 7.10(d, 1H, H4 -indole), 7.87(dd, 1H, H5 -indole), 8.16(broad s, 1H, H7 -indole).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@H:4]([CH:5]=[CH:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C@H:3]1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>Cl>[CH3:1][C:2]1([CH3:17])[C@H:4]([CH:5]=[CH:6][CH:7]([O:12][C:24](=[O:26])[CH3:25])[C:8]([Cl:9])([Cl:10])[Cl:11])[C@H:3]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1[C@@H](C=CC(O)C(Cl)(Cl)Cl)C1(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@@H](C=CC(OC(C)=O)C(Cl)(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 12.2 g of the product of Step A, 33.5 ml of pyridine and 16.8 ml of acetic acid anhydride was stirred at room temperature for 4 hours and then 40 g of ice were added thereto. The mixture was stirred for 30 minutes and was then poured in a mixture of 60 g of ice-water and 39 ml of concentrated hydrochloric acid. The mixture was stirred for 10 minutes and was extracted with methylene chloride. The organic phase was washed and dried and evaporated to dryness at 50° C. under reduced pressure to obtain 11.8 g of methyl (1R,trans) 2,2-dimethyl-3-(4',4',4'-trichloro-3'-acetoxy-buta-1-enyl)-cyclopropane-1-carboxylate.