Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:33]C(=O)OC(C)(C)C)[CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]3[N:22]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:21]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:20]=4[N:19]=3)[CH2:13]2)=[O:11])=[CH:3][CH:2]=1.ClCCl.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>CO.CC#N.O>[NH2:33][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:6][CH:5]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:21]3[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:20]=3[N:19]=2)[CH2:13]1)=[O:11].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccccc4)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccccc4)cc3)C2)nc2c(Cl)cccc21

Procedure:
tert-Butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48C) (0.245 mmol, crude oil) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were then added and the solution was stirred at room temperature for 2 hr. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (15-65% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-4-(biphenyl-4-yl)-1((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (118) as its trifluoroacetic acid salt and as a white flocculent solid (0.134 mmol, 0.088 g, 55% yield over 4-steps). ESI-MS: 545.2 m/z (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.55 (m, 1H) 1.70-2.14 (m, 5H) 2.61-2.87 (m, 3H) 2.87-3.09 (m, 4H) 3.09-3.31 (m, 5H) 3.40-3.85 (m, 2H) 3.95-4.62 (m, 5H) 7.17-7.30 (m, 2H) 7.33-7.42 (m, 3H) 7.42-7.56 (m, 3H) 7.58-7.72 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][N:20]=2)[N:17]=1>CN(C=O)C.O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:13]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Fc1ccccc1-c1nnc2cc(-c3cccs3)c(Cl)nn12
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.11 g, 1.0 mmol) (prepared using the conditions described in EP-A-421210) in DMF (5 ml) was added sodium hydride (0.04 g of a 60% dispersion in oil, 1 mol eq) and the reaction mixture was stirred at room temperature for 30 min. After this time 6-chloro-3-(2-fluorophenyl)-7-(thien-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (0.19 g, 0.57 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (70 ml) and the precipitate was collected. The solid was purified by boiling in ethyl acetate and collecting the title compound as a yellow solid (0.01 g, 12%). 1H NMR (250 MHz, d6-DMSO) δ 3.83 (3H, s), 5.64 (2H, s), 7.24 (1H, dd, J 4 and 4 Hz), 7.44-7.55 (2H, m), 7.66-7.71 (1H, m), 7.82 (1H, d, J=5 Hz), 7.96-8.01 (3H, m), 8.23 (1H, s). MS (ES+) m/e 408 [MH]+. Anal. Found C, 53.81; H, 3.62; N, 23.42%. C19H14FN7OS.0.9(H2O) requires C, 53.87; H, 3.76; N, 23.14% m.p. 189-190° C.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][NH2:37])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:36]([C:34]5[CH:33]=[CH:32][C:31]6[O:26][CH2:27][CH2:28][O:29][C:30]=6[CH:35]=5)[N:37]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1ccc2c(c1)OCCO2
Yield: 22 %

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for Example 91 in 22% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol) dissolved in DCM (30 ml), cooled to 0° C. and added oxalyl chloride (3.4 ml, 38.6 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Hydroxy-3-amino-5-bromopyridine (2.4 g, 11.1 mmol) dissolved in DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (2.4 g, 13.3 mmol). After continuing stirring at rt for 30 mins, reaction mass diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified on column using 60-120 mesh silica gel and a gradient mixture of MeOH and DCM (2:98) as eluent to afford the titled compound (2.1 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.43 (bs, 1H), 9.58 (s, 1H), 8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J 8.2, 2H), 7.48 (d, J 2.6, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6].C(O)(C(F)(F)F)=O>ClCCl>[NH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([C:5]([C:4]2[CH:22]=[CH:23][N:24]=[C:2]([F:1])[CH:3]=2)=[O:6])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Reaction time: 10 h

Procedure:
To a solution of tert-butyl (1-(2-fluoroisonicotinoyl)piperidin-4-yl)methylcarbamate 93-3 (1.81 g, 5.0 mmol) in dichloromethane (10 mL) was added TFA (5 mL) dropwise at room temperature. The mixture was stirred for 10 hours, and then the solvents were removed by rotary evaporation. The residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous NaHCO3 solution, H2O and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation to give (4-(aminomethyl)piperidin-1-yl)(2-fluoropyridin-4-yl)methanone 93-4 as a yellow oil. MS m/z 238.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:16])([F:18])[F:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)(F)F)C1CCOCC1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (572 mg, 1.4 mmol) in a mixture of THF (14 ml) and MeOH (2.1 ml), was added 4M NaOH (aq) (13.9 ml). The reaction mixture was stirred at 50° C. for 5.5 hours and then stirred at room temperature for 17 hours. THF was removed by concentrating in-vacuo and the aqueous residue was acidified to pH 4 with 6M HCl (aq) (9.5 ml). The resulting suspension was allowed to stand at room temperature for 20 minutes before collecting the solid by filtration. The solid cake was washed with water (20 ml) and dried under high vacuum for 2 hours to give the title compound (507 mg, 90%) as a white solid. LC-MS 98%, 2.04 min (3.5 minute LC-MS method), m/z=395.9, 396.9, 397.9, 398.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.97 (d, J=1.73 Hz, 1H) 7.48 (d, J=1.73 Hz, 1H) 4.02 (dd, J=11.35, 3.94 Hz, 2H) 3.65 (br. s, 2H) 3.33 (t, J=11.59 Hz, 2H) 3.00 (tt, J=11.49, 3.80 Hz, 3H) 2.55 (s, 3H) 1.82 (d, J=11.98 Hz, 2H) 1.55-1.69 (m, 2H). OH not visible.
Reaction SMILES: C1(CC(N[C@H](C(=O)N)CCC(O)=O)=O)C=CC=CC=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35]>>[C:20]1([CH2:26][C:27]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: NC(=O)[C@H](CCC(=O)O)NC(=O)Cc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Phenylacetylisoglutamine can be synthesized by the reaction of phenylacetyl chloride with L-glutamine to yield phenylacetylglutamine, with subsequent heating under vacuum at 160° C. to yield 3-phenylacetylamino-2,6-piperidinedione, which can then be treated with sodium hydroxide. Also, phenylacetylisoglutamine can be prepared by treatment of phenylacetic acid with N,N′-disuccinimidyl carbonate in acetonitrile followed by reaction with L-isoglutamine in the presence of NaHCO3 in a 1:1 acetonitrile/water mixture. However, the second synthesis requires L-isoglutamine, which is expensive, so the former route of synthesis is preferred on economic grounds.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Cl-].[Ca+2].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CO)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)CBr)cc1

Procedure:
20.2 g (0.1 mol) of bromoacetyl bromide are dissolved in 100 ml of toluene, this solution is cooled to -10° C. (CaCl2 tube) and 8.7 g (0.11 mol) of pyridine are added dropwise at -10° C. Thereafter, 13.8 g (0.1 mol) of 4-methoxybenzyl alcohol, dissolved in 20 ml of toluene are added dropwise to this mixture in the course of 20 minutes at -10° C., and the mixture is allowed to react for 1 hour at this temperature.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Yield: 68.7 %

Procedure:
A mixture of 13.6 g of imidazole, 43.2 g of p-bromomethylnitrobenzene and 55.2 g of anhydrous potassium carbonate in 300 ml of dry toluene was refluxed for 18 hours. After concentration under reduced pressure, 200 ml of dichloromethane was added to the residue and insoluble salts were filtered off. The filtrate was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 27.9 g of p-(1-imidazolylmethyl)nitrobenzene as pale yellow platelets. Then, a solution of 2.0 g of this product in 50 ml of ethanol was hydrogenated over 0.2 g of palladium on carbon at room temperature under a hydrogen pressure of 4 atms. After filtration and evaporation, the residual solid was recrystallized from ethanol-diethyl ether-petroleum ether to give 1.4 g of p-(1-imidazolylmethyl)aniline as colorless needles. M.P.: 134°-137° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCc3cccnc3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4cccnc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (1.33 g) in water (15 ml) and 1,4-dioxane (15 ml), 2N hydrochloric acid (2.5 ml) was added at 0° C. and sodium nitrite (0.332 g) in water (3 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 1.14 g brown solid. Purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1, 1:1, 1:2 to 0:1 then ethyl acetate:methanol=25:1, 20:1 to 15:1 then dichloromethane:methanol=15:1, 10:1), fractions were passed through Strata SCX column (5 g) to give 560.7 mg light brown solid as 1-methyl-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (41%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH3:18])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CCC(O)N1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1CCC(OC)N1C(=O)OC(C)(C)C
Yield: 83 %

Procedure:
To a solution of 5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 2, (48.1 g, 196 mmol) in methanol (500 mL), is added p-toluenesulfonic acid (1.0 g, 5.8 mmol). Once consumption of the starting material is complete, the solvent is removed under in vacuo and the residue purified over silica (hexanes/ethyl acetate 75:25) to afford 42 g (83% yield) of the desired product as a clear oil. 1H-NMR (300 MHz, CDCl3): δ 5.334–5.142 (m, 1H), 4.36–4.24 (m, 1H), 3.75–3.72 (m, 3H), 3.44–3.36 (m, 3H), 2.45–1.71 (m, 4H), 1.51–1.42 (m, 9H); 13C-NMR (75.5 MHz, CDCl3): δ 200.16, 199.70, 173.31, 172.99, 154.28, 154.13, 153.98, 89.37, 89.27, 88.62, 88.41, 81.27, 81.04, 80.75, 80.54, 59.65, 59.33, 58.97, 58.84, 56.38, 56.14, 55.92, 55.79, 55.38, 55.00, 52.07, 51.99, 32.95, 32.29, 31.79, 31.14, 30.20, 28.35, 28.17, 27.11, 24.86, 21.06, 14.29; MS (ESI): m/e=282.07 (M+Na).
Reaction SMILES: [OH:1][C@@:2]1([CH2:17][OH:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:16])[F:15])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.O.C(=O)([O-])[OH:21].[Na+]>CC(C)=O.[Pt]>[OH:1][C@@:2]1([C:17]([OH:21])=[O:18])[C:11]2[C:6](=[C:7]([O:13][CH:14]([F:15])[F:16])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: OC[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Reactant: O=C([O-])O
Agent: [Pt]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of (S)- or (R)-4-hydroxy4-hydroxymethyl-6-chloro-8-difluoromethoxychromane (3.2 g, 11.4 mmol, from step (vii) above) in acetone (25 mL) was added non-ionized water (110 mL), then sodium hydrogencarbonate (2.13 g, 22.2 mmol) and Pt/C 5%, 58% water (2.13 g). A stream of air was bubbled through the solution with stirring at 75° C. (oil-bath) overnight. The solution was filtered through Celite and the filter-cake was washed with water. The acetone-water solution was acidified (HCl, 2M) to pH 2, saturated with NaCl and extracted with EtOAc (3×). The combined ethyl acetate phases were washed with water (2×) and with brine, then dried (Na2SO4) and concentrated. The residue was dissolved in ether. The ether solution was washed with water (3×) and concentrated, yielding 2.4 g (71%) of the sub-title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][CH3:28])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Product: CCc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1

Procedure:
The title compound was synthesized from 1-Cyano-6-(2-ethyl-6-methyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=404.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[C:22]([CH3:25])[CH:21]=1)=[CH:16][CH:15]=3.I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[C:22]([CH3:25])[N:23]([CH2:32][CH3:33])[N:24]=1)=[CH:16][CH:15]=3
Reactant: CCI
Reactant: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1
Product: CCn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1C

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(3-methyl-1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one described in Example 46 above and iodoethane.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH:6]([CH3:13])[CH2:7][CH2:8][C:9]([CH2:11][F:12])=[O:10])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[BH4-].[Na+].Cl>O1CCCC1.CO>[F:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][CH:6]([N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])[CH3:13]
Reactant: CC(CCC(=O)CF)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCC(O)CF)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimido-3-methylpropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20° C. is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20° C. The reaction mixture is stirred for 15 minutes at -20° C. and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford 1-fluoro-5-phthalimido-5-methyl-2-pentanol. A mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-5-methylpentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25° C. the solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give 1-fluoromethyl-4-methyl-1,4-butanediyl-bis-phthalimide. A suspension of 3.1 g of 1-fluoromethyl-4-methyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4° C. is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4° C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([C:55]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[C:57]([F:63])[CH:56]=1)[C:51]([NH:53][NH2:54])=O>C(Cl)Cl.O>[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([C:51]1[O:28][C:26](/[CH:25]=[CH:24]/[C:14]2[CH:15]=[CH:16][C:17]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:12]([O:11][CH3:10])[CH:13]=2)=[N:54][N:53]=1)[C:55]1[CH:56]=[C:57]([F:63])[C:58]([F:62])=[C:59]([F:61])[CH:60]=1
Reactant: NNC(=O)C(CCCCCl)c1cc(F)c(F)c(F)c1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/c2nnc(C(CCCCCl)c3cc(F)c(F)c(F)c3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (30 mL) was added to tert-butyl N′-[6-chloro-2-(3,4,5-trifluorophenyl)hexanoyl]hydrazinecarboxylate synthesized according to the method described in Examples 112 and 113 (ESI-MS; m/z 417 [M++Na], 2.08 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (1.81 g). IPEA (1.5 mL), (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid (450 mg) and BOPCl (0.53 g) were added to a solution of 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (612 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the resulting residue in phosphorus oxychloride (8 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 430 mg of the title compound. The property value of the compound is as follows.