Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C@H:17]2[CH2:21][CH:22]=[CH:23][CH2:24][C@@H:16]12>ClCCCl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:15]([CH:16]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:21][CH:22]=[CH:23][CH2:24]1)=[O:25])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccccc2c1C(=O)C1CC=CCC1C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
2-Methyl indole (50 mmol, 6.55 g) and AlCl3 (50 mmol, 7.3 g) were stirred in 500 mL DCE. cis-1,2,3,6-Tetrahydrophthalic anhydride (50 mmol, 7.6 g) was added and the reaction was heated to 65° C. for 6 h. The reaction was carefully quenched with 10 mL water and stirred overnight. The resulting red solid was filtered, washed with water, and dried to give 15 g of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCC=C(c1cccnc1)c1cccc(NC(=O)COc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.25 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate are dissolved in 30 ml of methylene chloride. At 0° C., 1.65 g of 4-chlorophenoxyacetic acid chloride and 2.5 ml of triethylamine are added successively to this solution which is then stirred for 2 hours at ambient temperature. The reaction mixture is washed with water and then evaporated down. The residue is dissolved in a mixture of 20 ml of ethanol and 16 ml of 0.5N sodium hydroxide solution and stirred for 24 hours at ambient temperature. The reaction mixture is evaporated down at ambient temperature, water is added and the resulting mixture is washed with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down and the residue is recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Cl:33][CH2:32][CH2:31][O:14][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nc1cc(OCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)phenol (2.10 g, 10.1 mmol) and cesium carbonate (4.00 g, 12.2 mmol) in acetonenitrile (50 ml) was added 2-chloroethyl p-toluenesulfonate (2.9 g, 12 mmol) slowly. The resulting mixture was stirred at RT for 5 hr, poured into water (100 ml) and then extracted with EtOAc (3×80 ml). The combined organic layer was washed with brine (100 ml) and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=5 to 25%) to afford the desired compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:34].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:32]=2)(=[O:34])=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)C)CC3)ccc1OCC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(S(=O)(=O)C3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidine-4-sulfinyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 204 (40 mg, 0.088 mmol) in DCM (10 mL) was added TFA (34 μL, 0.44 mmol) followed by a slow addition of a solution of m-CPBA (23 mg, 0.132 mmol) in DCM (2 mL) and the resulting mixture was stirred for 1 h at RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 205 as a white solid (28 mg, 68%). LCMS: RT 2.04 min [M+H]+ 467.1. 1H NMR (DMSO, 400 MHz): δ 8.94 (1H, d, J=2.41 Hz), 8.42 (1H, dd, J=4.69, 1.62 Hz), 7.93 (1H, s), 7.70-7.63 (2H, m), 7.29 (1H, d, J=8.61 Hz), 7.20 (1H, dd, J=7.64, 4.66 Hz), 4.67-4.56 (4H, m), 3.21-3.11 (1H, m), 2.86-2.78 (2H, m), 2.72 (3H, s), 2.69-2.60 (1H, m), 2.09 (2H, bt, J=11.50 Hz), 1.89 (2H, bd, J=12.09 Hz), 1.50-1.38 (2H, m), 0.90 (6H, d, J=6.55 Hz)
Reaction SMILES: C([O:8][C:9](=[O:45])[C:10]([C:13]1[CH:14]=[C:15]2[C:41](=[CH:42][CH:43]=1)[O:40][C:18]1([CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]4[C:28](=[C:29]([O:38][CH3:39])[CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[O:25])[CH2:20][CH2:19]1)[CH2:17][C:16]2=[O:44])([CH3:12])[CH3:11])C1C=CC=CC=1>CO.[Pd]>[CH3:37][O:36][C:34]1[C:33]2[C:28](=[C:29]([O:38][CH3:39])[CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:24]([N:21]2[CH2:22][CH2:23][C:18]3([CH2:17][C:16](=[O:44])[C:15]4[C:41](=[CH:42][CH:43]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([OH:45])=[O:8])[CH:14]=4)[O:40]3)[CH2:19][CH2:20]2)=[O:25])[CH:35]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(C)(C)C(=O)OCc4ccccc4)ccc2O3)nc2c(OC)cccc12
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(C)(C)C(=O)O)ccc2O3)nc2c(OC)cccc12

Procedure:
2-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chromane-2,4′-piperidin]-6-yl}-2-methylpropanoic acid benzyl ester (830 mg) was dissolved in 25 mL of MeOH and hydrogenated at 1.5 atmosphere over 100 mg of 10% Pd/C for 5 hrs. The mixture was filtered and the filtrate was concentrated and purified on preparative SiO2 PTC (CHCl3/MeOH=10:1) to give the intended compound as a colorless amorphous solid. 1H-NMR (400 MHz, CD3OD), 7.93 (1H, s), 7.88 (1H, d, J=2.3 Hz), 7.81 (1H, d, J=8.8 Hz), 7.65 (1H, dd, J=8.8 Hz, 2.3 Hz), 7.55 (1H, t, J=8.2 Hz), 7.27 (1H, J=8.2 Hz), 7.17 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.5-4.6 (1H, m), 4.15 (3H, s), 4.06 (3H, s), 3.3-3.7 (3H, m), 2.90 (1H, d, J=16.5 Hz), 2.84 (1H, d, J=16.5 Hz), 1.9-2.3 (4H, m). MS [M+H]+=519.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]1=[O:21].C([O-])([O-])=O.[K+].[K+].[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([OH:36])=[C:31]([F:37])[CH:30]=1>CN(C=O)C.O.CCOC(C)=O>[Br:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[C:3]2=[O:21])=[C:31]([F:37])[CH:30]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC(Br)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(Oc3cc(F)c(Br)cc3F)C2=O)CC1
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To a solution of tert-butyl 3-bromo-2-oxo-1,4′-bipiperidine-1′carboxylate (723 mg, 2.00 mmol) in DMF (5 mL) was added K2CO3 (553 mg, 4.00 mmol) and 4-bromo-2,5-difluorophenol (460 mg, 2.20 mmol). The reaction was heated at 60° C. overnight. The reaction was cooled and diluted with water and EtOAc. The organic layer was separated and the aqueous washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 73%) as a white solid.
Reaction SMILES: [C:1]([OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].C1(BC2CCCCC2)CCCCC1.C([O-])(=O)C.[Na+].[I-:40].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>>[I:40][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:21])=[O:20]
Reactant: [I-]
Reactant: C=CCCCCCCCCCCCCCCCCC(=O)O
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Product: O=C(O)CCCCCCCCCCCCCCCCCCI

Procedure:
18-Nonadecenoic acid (100 mg, 0.34 mmol) was hydroborated with dicylohexylborane (0.7 mmol) at 0° C. The organoborane was iodinated with sodium aceate (0.7 mmol), sodium iodide (0.35 mmol), and chloramine-T (0.7 mmol). The product was isolated by column chromotography on silica gel (10% ethyl acetate:hexane):yield 129 mg (89%); m/e=424.5 (calcd 424.5); NMR (CDCl3) 1.2 δ (s, 30H, alkane), 2.1 (m, 4H, --CH2CO2H--CH2I), 3.0 (t, 2H, --CH2I), 11.9 (s, 1H, --CO2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:29][C:26]([OH:27])([CH3:28])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:25])=[CH:7][C:2]=1[F:1])(=[O:12])[CH3:11]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1F
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
The compound was synthesised according to the procedure described in Example 1c. N-(2-Fluoro-4-hydroxyphenyl)acetamide (0.5 g, 3.0 mmol) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.6 g, 2.5 mmol) was used as starting materials. The product was crystallised from the mixture of ethyl acetate and diethyl ether (1:1). The yield was 0.39 g. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:3]1=2.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:14]([Cl:19])=[O:16])=[CH:13][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: Cn1c2ccccc2c2oc(C(=O)O)cc21
Solvent: c1ccccc1
Product: Cn1c2ccccc2c2oc(C(=O)Cl)cc21
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride (2.5 g) in dimethylformamide (100 ml), a solution of ethyl furo[3,2-b]indole-2-carboxylate (20 g) in dimethylformamide (100 ml) was added dropwise with stirring, then the mixture was stirred for 0.5 hour at room temperature. Methyl iodide (30 g) was added, and the resulting mixture was stirred for 5 hours at room temperature to give ethyl 4-methyl-furo[3,2-b]indole-2-carboxylate (18 g), which was hydrolyzed in a solution of sodium hydroxide (20 g) in water (200 ml) with stirring for an hour to give 4-methyl-furo[3,2-b]indole-2-carboxylic acid (15 g). This carboxylic acid was treated with thionyl chloride (50 ml) in benzene (70 ml) with stirring for an hour at 50° C. to give 4-methyl-furo[3,2-b]indole-2-carbonyl chloride (12 g).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:26](NC3C=CC=CC=3)=[O:27])[CH:5]=[CH:4][C:3]1=2.FC(F)(F)C([O-])=O>>[OH:27][CH2:26][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[CH:2]([OH:1])[CH:11]([CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[CH2:10][CH2:9]2
Reactant: O=C(Nc1ccccc1)c1ccc2c(c1)CC[C@H](CCN1CCC(c3ccccc3)CC1)[C@@H]2O
Agent: O=C([O-])C(F)(F)F
Product: OCc1ccc2c(c1)CCC(CCN1CCC(c3ccccc3)CC1)C2O

Procedure:
cis-5,6,7,8-Tetrahydro-5-hydroxy-N-phenyl-6-[2-(4-phenyl-1-piperidinyl)ethyl]-2-naphthalenecarboxamide, trifluoroacetate;
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>CS(C)=O>[CH3:34][N:35]([CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CNCc1cccnc1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3cccnc3)c2C1
Reaction time: 8 h
Yield: 53.3 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. N-methyl-1-(pyridin-3-yl)methanamine (8.55 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-(Methyl(pyridin-3-ylmethyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (17 mg, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C-:20]#[N:21].[Na+].[Na+].[I-].Cl>O.CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])#[N:21]
Reactant: [C-]#N
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCCCCCCCCCCC(=O)O
Temperature: 120 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
A mixture of 16-bromohexadecanoic acid (16.61 g, 49.5 mmol), DMSO (150 ml), NaCN (12.5 g, 255 mmol), and NaI (1.92 g, 12.8 mmol) was stirred at 120° C. for 20 h. The mixture was allowed to cool to room temperature, and was then poured into a stirred mixture of water (1.7 l) and concentrated HCl (30 ml). Rinsing with water (100 ml). The resulting suspension was stirred at room temperature overnight. The product was filtered and washed with water (2×100 ml), and the solid was recrystallized twice from MeCN (90 ml and 50 ml). 10.1 g (72%) of 16-cyanohexadecanoic acid was obtained.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[NH:4][C:5]([CH:23]([F:25])[F:24])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[F:26][CH:2]([F:1])[C:3]1[N:4]([CH3:27])[C:5]([CH:23]([F:24])[F:25])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10]
Reactant: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)N(C)C(C(F)F)=C3C#N)cc12
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.277 mmol) 2,6-bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 13) in DMF (1.5 ml) was cooled to 0° C., and 108 mg (0.33 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 21 μl (0.33 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μl) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA isocratic 40:60 v/v) to give 12 mg (11% of th.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27](Cl)(=[O:29])=[O:28])=[CH:22][CH:21]=1>>[CH3:8][C:5]1[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3](=[O:17])[C:2]([NH:1][S:27]([CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:31])[F:32])=[CH:25][CH:24]=2)(=[O:29])=[O:28])=[CH:7][CH:6]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccc(C(F)(F)F)cc1
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (EXAMPLE 1, STEP 1-3), and [4-(trifluoromethyl)phenyl]methanesulfonyl chloride using the procedure of EXAMPLE 9 (STEP 2), and was obtained as a white solid compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=[O:8])[CH2:3][CH2:4][C:5]#[N:6].[O-:10][Mn](=O)(=O)=O.[K+].C(Cl)Cl>CC(O)(C)C>[C:5]([CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[C:7]([OH:10])=[O:8])#[N:6]
Reactant: CC(C)(C=O)CCC#N
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(CCC#N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4,4-dimethyl-5-oxopentanenitrile (1.0 g, 7.98 mmol) in t-BuOH (2 mL) was cooled to 0° C. and 5% aqueous NaH2PO4 solution (11 mL) was added dropwise. 1M KMnO4 solution (16 mL) was added dropwise to the reaction mixture at 0° C. followed by few drops of CH2Cl2 (0.5 mL). The reaction mixture was allowed to stir at 0° C. for 1 h, and quenched with sodium sulfite. 1.5N HCl was then added to adjust the pH of the solution to ˜3. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to get 4-cyano-2,2-dimethylbutanoic acid (0.9 g, crude), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 5.55 (br s, 1H), 2.43-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.28-1.27 (m, 6H).
Reaction SMILES: Cl[C:2]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3].[BH4-].[Na+].Cl.OCC(CCCC(OC(=O)C)CCCCC)CCCCCCC([O-])=O>COCCOCCOC.O>[OH:3][CH2:2][CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Agent: CCCCCC(CCCC(CO)CCCCCCC(=O)[O-])OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: COCCOCCOC
Product: CCCCCC(CCCC(CO)CCCCCCC(=O)OCC)OC(C)=O
Reaction time: 2 h

Procedure:
Ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (Example 7, Step D) (14.0 g., 0.0335 mole) is added all at once to a solution of sodium borohydride (2.7 g., 0.07 mole) in dry diglyme (75 ml.). An exothermic reaction occurs with foaming and a rise in temperature to 55°. After 2 hours, the reaction mixture is cooled in an ice bath and 10% hydrochloric acid is added dropwise until the mixture is acidic to Congo Red. Water (250 ml.) is then added; the oily product is extracted into ether, washed with after, and dried over sodium sulfate. The ether is evaporated to leave 12.2 g. of 8-hydroxymethyl-12-acetoxyheptadecanoate as a yellow oil. The product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([OH:13])=[O:12].CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.ClC1C(Cl)=CC([N+]([O-])=O)=CC=1C=O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 22.5 °C

Procedure:
A solution of 40 g of 2,3-dichlorobenzaldehyde (compound IX) in 160 mL of concentrated sulfuric acid (95-98% w/w) is heated to 40° C. and stirred to form a solution, then cooled to 20-25° C. Concentrated nitric acid (69-71 % w/w; 24.7 g) is added to this solution over 20 minutes (an ice bath is used to maintain a reaction temperature of 20-30° C.). The reaction mixture is stirred at room temperature for 1 hour, and then added in portions to 600 mL of water. The resulting suspension is stirred for 2 hours and filtered. The filter cake is washed (3×50 mL of water). The filter cake is agitated with 200 mL of water for 2 hours and filtered. The filter cake is washed (3×50 mL of water) and dried in vacuo to give a mixture of the compound X and the isomer, 2,3-dichloro-5-nitrobenzaldehyde.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)[CH:14]2[CH2:23][CH2:22][CH2:21][C:20]3[N:19]=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[CH:16][C:15]2=3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:54])[F:56])=[CH:51][CH:52]=3)=[CH:43][CH:44]=2)[CH:14]2[CH2:23][CH2:22][CH2:21][C:20]3[N:19]=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[CH:16][C:15]2=3)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCN(CCc2ccccc2OCc2ccc(CCc3ccc(C(F)(F)F)cc3)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
98 mg (0.13 mmol) of ethyl 5-[{2-[4-(methoxycarbonyl)phenyl]ethyl}(2-{2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 156A) were dissolved in 2.5 ml of dioxane, 0.4 ml of 1 N aqueous sodium hydroxide solution was added and the mixture was then stirred at room temperature overnight. After the reaction had gone to completion, the dioxane was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified with acetic acid to pH 4-5. The precipitated solid was filtered off with suction, washed repeatedly with water and then dried in a drying cabinet under reduced pressure at 40° C. for three days. This gave 71 mg (73% of theory) of the title compound.