Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][CH2:4][CH3:5].O1CCOCC1>CO>[NH2:25][C:9]1[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@@H](C)Oc1nc(N)c2[nH]c(=O)n(CCC3CCCO3)c2n1
Temperature: 37 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(tetrahydro-2-furanyl)ethyl]-9H-purin-6-amine (50 mg, 0.143 mmol) in methanol (10 ml) at room temperature was added 4M HCL in 1,4 dioxane (0.894 ml, 3.58 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at 37° C. for 3 hours, and the solvent removed on a nitrogen blowdown unit overnight. The residue was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge and eluted with methanol. The appropriate fractions were combined and dried under a stream of nitrogen in a blowdown apparatus to give the title compound as a white solid (26 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[N:7]=1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:6]1[N:7]=[C:2]([OH:1])[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=1
Reactant: O=C(O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Yield: 63 %

Procedure:
To a solution of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid (3 g, 0.01 mol) in methanol (15 ml) was added catalytic amount of sulphuric acid (0.2 ml) and the solution was refluxed for 2 hrs. The methanol was distilled off, and the residue was washed with sodium bicarbonate solution to give 2 g (63%) of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester as an off-white solid, which was used without further purification. 1H NMR (400 MHz, DMSO) δ ppm=1.73 (m, 4H), 2.6 (m, 2H), 2.78 (m, 2H), 2.83 (m, 4H), 3.37 (s, 3H), 12.18 (s, 1H). LC-MS: [M+H]=293.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(F)cc2)c1C

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 94%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01 (m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □□□11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93, 130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.79, 14.38; CH2 carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93, 130.77 ppm. LC/MS: 77.48%, m/z=289.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[CH2:3][C@@H:4]([CH2:6][OH:7])[NH2:5].CC(=C)C[C@H]1C[O:16][C:15](=O)N1>N1C=CC=CC=1>[F:1][C:2]([CH3:9])([CH3:8])[CH2:3][C@H:4]1[CH2:6][O:7][C:15](=[O:16])[NH:5]1
Reactant: C=C(C)C[C@H]1COC(=O)N1
Reactant: CC(C)(F)C[C@H](N)CO
Solvent: c1ccncc1
Product: CC(C)(F)C[C@H]1COC(=O)N1

Procedure:
The 4-fluoroleucinol may be synthesized according to Scheme 5. 4,5-Dehydroleucine is converted to (4S)-4-(2-methylprop-2-enyl)-1,3-oxazolidin-2-one as described in the scheme below. This intermediate is then treated with a hydrofluorination reagent such as BF-pyridine to give (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-one. Basic hydrolysis (i.e. Ba(OH)2 or NaOH) then affords (2S)-2-amino-4-fluoro-4-methylpentan-1-ol, which may be used as shown in Scheme 2. Selective protection of the alcohol provides an intermediate that can be used in Scheme 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[CH3:22][N:23]1C(=O)CCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:22]#[N:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cc(C#N)c(F)c(F)c1Nc1ccccc1F
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)-benzoic acid methyl ester (1.00 equiv.), dppf (0.02 equiv.), Pd2dba3 (0.01 equiv.), and Zn(CN)2 (0.60 equiv.) in NMP is stirred at 120° C. in a sealed tube. After stirring for 20 hours, the reaction mixture is cooled to room temperature and quenched with a 4:1:4 (volume) mixture solution of saturated aqueous NH4Cl-conc NH4O-water. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous NH4Cl/concentrated NH4OH/water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[N:23][CH:24]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:24][N:23]=4)=[CH:33][CH:32]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 52 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (230 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)amino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (217 mg, 52% yield).
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[N:15]1S(C1C=CC(C)=CC=1)(=O)=O)=O)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:11][CH2:12][C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:16](=[O:27])[NH:15]1
Reactant: Cc1ccc(S(=O)(=O)N2C(=O)N([C@H](C)c3ccccc3)C[C@@H]2C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](CO)NC1=O
Reaction time: 0.75 h

Procedure:
2.26 g (R)-2-Oxo-1-((R)-1-phenyl-ethyl)-3-(toluene-4-sulfonyl)-imidazolidine-4-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (I.24) was placed in 20 mL tetrahydrofuran at 0° C. under nitrogen, then 1.12 mL lithium aluminium hydride (2.3M in tetrahydrofuran) was added. The reaction was stirred for 1 h 45 min and then a 10 mL of a saturated solution of sodium sulfate was added. The mixture was extracted with ethyl acetate (×2), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Purification by silica gel chromatography (dichloromethane/ethyl acetate 100:0 to 70:30) gave the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To N-tert-butyl-3-(6′-methyl-6″-trifluoromethyl-[2,2′;4′,3″]terpyridin-6-yl)-benzenesulfonamide (Example 29) (0.075 g, 0.142 mmol) was added TFA (2 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.032 g, 48%). MS (ISP) 471.0 [(M+H)+]; mp 233-234° C.
Reaction SMILES: C(OCC)(=O)C.[NH2:7][C:8]1[C:9]([I:22])=[C:10]([C:14]([I:21])=[C:15]([C:18]([NH2:20])=[O:19])[C:16]=1[I:17])[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C)C(=O)N(C)C.O>[NH2:7][C:8]1[C:9]([I:22])=[C:10]([C:14]([I:21])=[C:15]([C:18]([NH2:20])=[O:19])[C:16]=1[I:17])[C:11]([Cl:25])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C(=O)N(C)C
Product: NC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Temperature: 74 °C
Yield: 79.8 %

Procedure:
A 4000 L glass-lined reactor was charged with ethyl acetate (2250 kg), 3-amino-5-(aminocarbonyl)-2,4,6-triiodobenzoic acid (1125 kg) and tetramethylurea (4.75 kg). The reaction mixture was stirred and heated to 74° C. Thionyl chloride (528 kg) was charged over 1 hour. The reaction mixture was maintained at 74° C. for 12 hours. While cooling to 45° C., additional ethyl acetate (180 kg) was charged. Water (73 kg) was charged over 1 hour and the reaction mixture was cooled to 28° C. After stirring for 7 hours, the solid product was isolated by filtration and the solids were washed with ethyl acetate (250 kg). After drying at 40° C. under vacuum, 927 kg of 3-amino-5-(aminocarbonyl)-2,4,6-triiodobenzoyl chloride were isolated which had a chromatographic purity of 92.4 area %.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetate (14.9 g), 5% palladium-carbon (15.0 g), tetrahydrofuran (150 ml) and ethanol (150 ml) was stirred for 2 hours under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-ylacetate (9.76 g, yield 88%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 156–157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:28]1[C:37]2[CH:36]=[C:35]([CH:38]=O)[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:19]3[CH2:20][CH2:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18]3)[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 2 mL of dichloromethane solution containing 80 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 41 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 14 μL of acetic acid were added at room temperature, 78 mg of sodium triacetoxyborohydride was added under ice-cooling, and stirred at room temperature for 1 hour. To the reaction mixture, water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1], to give 65 mg of ethyl 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][CH2:35][CH2:36][CH3:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCOc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.3 g) obtained in Example 2 was suspended in dimethyl sulfoxide (30 ml), and to the suspension was added potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 30 minutes. 1-iodobutane (0.1 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (0.25 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C@H:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([Cl:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COC[C@H](N)c2ccccc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, 4-[(R)-2-amino-2-phenylethoxy-methyl]piperidine-1-carboxylic acid tert-butyl ester (3 g, 9.0 mmol) and 3-chloroindole-6-carboxylic acid (1.7 g, 9.0 mmol) afforded the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:20].[Na+]>CO>[NH2:20][CH:10]1[CH:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][N:2]([CH3:1])[CH2:11]1
Reactant: [BH3-]C#N
Reactant: CN1CC(=O)c2ccccc2C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CN1CC2=CC=CCC2C(N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
According to Scheme 23, a mixture of 2-methyl-2,3-dihydro-4-(1H)-isoquinolone (630 mg, 3.9 mmol, Nichols, D. E. et al.; WO9706799), ammonium acetate (3.0 g, 39 mmol) and NaCNBH3 (491 mg, 7.8 mmol) in 25 mL of dry methanol was stirred for 2 days at RT. The solvent was removed and the residue was acidified to pH 2 to destroy the excess NaCNBH3. After basification with aq Na2CO3 to pH 10, the product was extracted into ether. The ether layer was dried (K2CO3) and the solvent was evaporated to provide 330 mg of the racemic 4-amino-2-methyltetrahydroisoquinoline. 1H NMR (CDCl3): δ 2.20 (bs, 2H, NH2), δ 2.60 (s, 3H, NCH3), δ 2.90 (d, 2H, CHCH2N), δ 3.55 (d, 1H, ArCH2N), δ 3.90 (d, 1H, ArCH2N), δ 4.15 (t, 1H, ArCHN), δ 7.20-7.60 (m, 4H, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:13])(=[O:24])(=[O:23])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CCO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CCOS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
The product of example 22 (a) (1.06 g, 5.6 mmol) was dissolved in CH2Cl2 (10 ml) and cooled in an ice bath while stirring under argon. Triethylamine (0.667 g, 6.6 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (0.687 g, 6 mmol). After 10 minutes the ice bath was removed and the mixture stirred at rt for 2 h. The solvent was stripped off and the title compound was isolated as a yellow oil. ES (+) MS m/e=268 (MH+), 290 (MNa+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:35][CH:32]2[CH2:34][CH2:33]2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 60.5 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (1.0 g, 2.27 mmol) was dissolved in anhydrous DMF (80 mL), NaH (60% wt. in paraffin oil, 0.109 g, 2.72 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which cyclopropyl methyl bromide (0.24 mL, 2.5 mmol) was added in a dropwise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. upon which saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give colorless oil, which was purified by flash column chromatography to yield compound ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(OC(C)C)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Reactant: C1COCCN1
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)cc1/C=C/C(=O)N1CCOCC1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and morpholine as a yellow solid following crystallisation from isopropyl alcohol and trituration with diisopropyl ether:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCOCCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 58.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 1.3 g of 4-(2-ethoxyethoxy)-benzyl bromide, and then 1.0 g of anhydrous potassium carbonate was added thereto. The mixture was heated with stirring on an oil bath at 90° to 100° C. for 3 hours, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting oil was purified by means of column chromatography (on silica gel, eluting with benzene/ethyl acetate=18/1) and recrystallization (from n-hexane-benzene) to obtain 1.1 g of the aimed compound, m.p. 82.0°~83.0° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][NH:2][CH2:1]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CNC2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
To the suspension of isoindoline (2 g, 16.8 mmol) in 98% H2SO4 (10 mL) was added dropwise the mixture of concentrated nitric acid (2 mL) and 98% sulfuric acid (2 mL) at 0° C. The mixture was stirred at 0° C. for 45 minutes. The resulting yellow solution was then poured into ice water. The white solid precipitate was collected by filtration. The solid was washed with water (20 mL×2) and dried in vacuum to afford 231a as a white solid (700 mg, 51%). MS: [M+H]+ 165.