Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].[CH3:22][Mg]Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]=[C:9]([CH3:22])[C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)Oc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Oc1cc(CC(=O)OC(C)(C)C)cc(C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A stirred solution of t-butyl 3-acetoxy-4-nitrophenylacetate (8.0 g, Reference Example 18) in tetrahydrofuran (350 mL) at −15° C. under argon was treated dropwise with methyl magnesium chloride solution in diethyl ether (7 mL, 3M) and after 2 hours a further aliquot of methyl magnesium chloride solution in diethyl ether (7 mL, 3M). After stirring for a further 1 hour the reaction mixture was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.4 g), then stirred at room temperature overnight, then partially evaporated and then treated with dichloromethane. The mixture was washed with water, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with dichloromethane to give the title compound (1.66 g) as a yellow oil.
Reaction SMILES: COC1C=CC([C@@H]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)C)=CC=1.FC(F)(F)C(O)=O.CC1C(C)=C(C)C(C)=C(C)C=1>>[NH2:11][C@@H:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]2N[C@@H](C)c1ccc(OC)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC[C@@H]2N
Temperature: 70 °C
Reaction time: 96 h
Yield: 62.1 %

Procedure:
To 452 mg of methyl (1S)-1-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-5-carboxylate were added 34 ml of trifluoroacetic acid and 1.03 g of pentamethylbenzene, followed by stirring at 70° C. for 4 days, and the solvent was evaporated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 165 mg of methyl (1S)-1-aminoindane-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]Cl)=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:6][CH:7]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc[nH]c1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Sc2ccc(Cl)cc2)[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-nitropyrrole (4.88 g, 21.9 mmol) in methylene chloride is cooled to 0° C., treated dropwise over 30 minutes with a solution of p-chlorophenylsulfenyl chloride (4.32 g, 24 mmol) in methylene chloride, stirred at 0° C. for 3 hours, stirred overnight at room temperature, diluted with methylene chloride, washed sequentially with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark residue. Flash column chromatography of the residue using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a yellow solid (2.38 g, mp 195°-197° C.).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CN(C1CCCCC1)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[OH:12].Cl[CH2:17][Si:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][CH3:21]>C(OCC)C>[CH3:17][Si:18]([CH2:23][O:14][C:10](=[O:15])[CH:11]([OH:12])[CH3:13])([CH3:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCC[Si](C)(C)CCl
Reactant: CC(O)C(=O)O
Solvent: CN(C)C1CCCCC1
Solvent: CCOCC
Product: CCC[Si](C)(C)COC(=O)C(C)O
Temperature: 100 °C

Procedure:
12.7 of N,N-dimethyl-cyclohexylamine were dropped into 9.8 g (0.1 mole) of the S-enantiomer of the lactic acid and 30 g of chloromethyl-dimethyl-n-propyl-silane at room temperature with stirring. The reaction mixture was heated to 100° C. for 16 hours. After cooling the reaction mixture to room temperature 50 ml of diethylether were added, the precipitate which deposited was filtered with suction, the filtrate was concentrated under reduced pressure and the remaining residue was distillated under reduced pressure. 11.7 g (54.2% of theory) of S-enantiomer of the 2-hydroxypropionic acid (dimethyl-n-propyl-silyl)-methylester of a purity of 90% were obtained in this manner. Boiling point: 105°-108° C./18.6 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([O:29]C)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].CC(C)([O-])C.[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:22][CH2:23][S:24][CH2:25][CH2:26]3)=[O:20])[CH2:16][CH:15]([C:27]([OH:29])=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:11])([F:12])[F:10]
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 4.29 g (9.57 mmol) of the compound from Example 78A in methanol (190 ml) were added, at RT, 10.7 g (112 mmol) of potassium tert-butoxide. The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, and the residue was admixed with water and acidified (pH=1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 3.94 g (76% of theory, purity 80%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N(CC1C=CC=CC=1)C1C=CC(C2C3C(=CC(N(C)C)=CC=3)C(=O)O2)=CC=1)C>C(OC(=O)C)(=O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]3[C:20]4[C:16](=[CH:15][C:14]([N:13]([CH3:23])[CH3:12])=[CH:22][CH:21]=4)[C:17](=[O:18])[O:7]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CCN(Cc1ccccc1)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc2c(c1)C(=O)OC2c1ccc2c(c1)OCO2
Yield: 6.1 %

Procedure:
Following a procedure similar to that described in Example 1, part A above, 7.5 g of 3,4-(methylenedioxy)benzaldehyde and 9.1 g of 3-dimethylaminobenzoic acid were interacted in acetic anhydride to obtain 0.9 g of 3-(3,4-methylenedioxyphenyl)-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=1-[3,4-(OCH2O)C6H3 ]) a light yellow solid melting over the range 134°-143° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]=3[CH2:10]2)=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH:2]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]=3[CH2:10]2)=[N:7][CH:8]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)n1c2c(c3ccccc31)CCN(c1ncc(CO)cn1)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1c2c(c3ccccc31)CCN(c1ncc(C=O)cn1)C2
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a stirred solution of tert-butyl 2-[5-(hydroxymethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (2.0 g, 0.0053 moles) in dry DCM (20 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.68 g, 0.0063 moles). After stirring for 5.0 hours, Na2S2O3 (1.0 g), NaHCO3 (1.0 g) in water (15 mL) was added. The two layers were separated. The organic layer was washed with water (20 mL), dried (Na2SO4) and concentrated. The crude product was crystallized using mixture of diethyl ether-hexane to give pure tert-butyl 2-[5-(formyl)pyrimidin-2-yl]-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (1.4 g, 74% yield). Rf=0.4. 1H NMR (DMSO-d6, 400 MHz) ppm: 9.8 (s, 1H, CHO), 8.8 (s, 2H, 2Ar—H), 8.06 (d, 1H, J=8 Hz, 1Ar—H), 7.52 (d, 1H, J=8 Hz, 1Ar—H), 7.33-7.24 (m, 2H, 2Ar—H), 5.32 (s, 2H, CH2), 4.28 (t, 2H, J=8 Hz, CH2), 2.82 (t, 2H, J=8 Hz, CH2), 1.69 (s, 3H, 3CH3); m/e=379 (M+1) (M, 378.425 Calcd. for C21H22N4O3).
Reaction SMILES: BrN1C(=O)CCC1=O.CN(C=O)C.[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:47][C:24]3=[N:25][CH:26]=[C:27]([NH:29][C:30](=[O:46])[C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:41])=[O:40])[C:32]=4[F:45])[CH:28]=[C:23]3[CH:22]=2)[CH:18]=[CH:19][CH:20]=1.FC1C(NS(CCC)(=O)=O)=CC=C(F)C=1C(NC1C=C2C=C(C3C=CC=CC=3)NC2=NC=1)=O.C(Cl)(Cl)[Cl:82]>>[Cl:82][C:22]1[C:23]2[C:24](=[N:25][CH:26]=[C:27]([NH:29][C:30](=[O:46])[C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:40])=[O:41])[C:32]=3[F:45])[CH:28]=2)[NH:47][C:21]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1
Reactant: ClC(Cl)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(Cl)c4)cc3c2)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4ccccc4)cc3c2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(Cl)c4)c(Cl)c3c2)c1F
Yield: 38 %

Procedure:
N-(3-chloro-2-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (38%) was prepared according to Example 25, substituting N-chlorosuccinimide for N-bromosuccinimide, DMF for CHCl3, and N-(2-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide for 2,6-difluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide. 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 11.11 (s, 1H), 9.82 (s, 1H), 8.49-8.46 (m, 2H), 8.01-7.99 (m, 1H), 7.96-7.93 (m, 1H), 7.63-7.52 (m, 3H), 7.32-7.26 (m, 1H), 3.16-3.11 (m, 2H), 1.82-1.74 (m, 2H), 1.03-0.98 (m, 3H); m/z (APCI-pos) M+1=539.0.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33]([CH3:42])([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:23])[F:22])[C:12]2=[O:24])[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C:33]([O:32][CH3:31])([CH3:41])[CH3:42])[N:36]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL, 0.18 mmol) and stirred at 0° C. for 10 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 25 min. After this time, the reaction mixture was then concentrated in vacuo and the residue taken up in methylene chloride (2 mL) and added dropwise to a separate reaction flask containing a mixture of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 37 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (4 g silica gel column, 50% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (51 mg, 71%) as a white foam: [α]32D=−41.1°, (c=0.09, methylene chloride); HR-ES(+) m/e calcd for C25H31N4O3F3 [M+H]+ 493.2421, observed 493.2419; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.01 (t, J=8.60 Hz, 2H), 7.68-7.81 (m, 1H), 7.49 (d, J=1.81 Hz, 1H), 6.44 (d, J=2.11 Hz, 1H), 4.97-5.17 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 3.92-4.08 (m, 2H), 3.06-3.22 (m, 3H), 0.93-2.16 (m, 17H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1

Procedure:
30 g (113.1 mmol) of 11-bromoundecanoic acid, 18.35 g (169.7 mmol) of benzyl alcohol and 0.5 g of p-toluenesulfonic acid are heated in 200 ml of toluene for 12 hours in a water separator. It is allowed to reach room temperature, and the organic phase is washed twice with 100 ml of 5% aqueous potassium carbonate solution each. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/acetone=30:1).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[C:36]([F:44])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[C:36]([F:44])[CH:35]=1)[CH3:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Compound 29 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a pale yellow solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d, J=3.7 Hz, 1H), 9.25 (d, J=7.8 Hz, 1H), 9.01 (d, J=4.5 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=4.5 Hz, 1H), 8.19 (d, J=3.8 Hz, 1H), 7.73 (t, J=7.9 Hz, 1H), 7.62 (d, J=12.0 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 5.51 (q, J=4.9 Hz, 1H), 3.20 (dd, J=12.5, 8.1 Hz, 1H), 3.03 (dd, J=12.4, 5.2 Hz, 1H), 2.70-2.53 (m, 2H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C:10]3=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:10]3=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CNCCC2
Reaction time: 2 h
Yield: 141.5 %

Procedure:
Intermediate 39A (1.22 g, 3.17 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, toluene was added and the mixture was concentrated again and dried under vacuum to give 1.28 g of intermediate 64A which was used in the next step without purification. LCMS (+ESI) m/z 286.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[Cl:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][N:32]=[CH:31][CH:30]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:35](=[O:36])[C:34]3[C:29]([Cl:28])=[CH:30][CH:31]=[N:32][CH:33]=3)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: O=C(Cl)c1cnccc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)c1cnccc1Cl

Procedure:
A solution of 150 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)aniline and 116 mg of triethylamine in 5 mL of tetrahydrofuran was stirred with 100 mg of 4-chloronicotinoyl chloride hydrochloride for about 50 minutes, and after addition of water, the precipitated crystals were recovered by filtration. The recovered crystals were washed with ether and dried to 106 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl)-4-chloronicotinamide having a melting point of 178-180° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[N:7]2.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[N:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[NH:36][N:35]=2)[CH2:30][CH2:29]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:28]3[CH2:33][CH2:32][CH:31]([C:34]4[NH:38][C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[N:36][N:35]=4)[CH2:30][CH2:29]3)=[CH:14][CH:13]=1)=[N:7]2
Reactant: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-1 (4.9 g, 14.2 mMol) and 8-5 (4.2 g, 15.6 mMol) in NMP (50 mL) was added triethylamine (6 mL, 42.6 mMol) followed by acetic acid (1.6 mL, 28.4 mMol). After stirring at ambient temperature overnight, sodium triacetoxyborohydride (3.6 g, 17 mMol) was added in portions. Upon completion, the reaction was diluted with ethyl acetate and washed with saturated NaHCO3, followed by water, then brine. The organic layer was dried with Na2SO4 and MgSO4, filtered and concentrated in vacuo. The crude residue purified using flash chromatography on silica (gradient: 0% to 10% MeOH in CHCl3 over 25 min) to yield 9-2 as an orange solid. LC/MS (M+1) calculated: 559.1; observed: 559.2
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)=[C:4]([CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:3]=1[F:31].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5](=[C:4]([CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:26])[CH3:25])[C:3]=1[F:31])[N:6]=[CH:7][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]2[OH:11]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)c(F)c1CCO[Si](C)(C)C(C)(C)C)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(CCO[Si](C)(C)C(C)(C)C)c(F)c(Cl)cc2c1O
Temperature: 200 °C
Yield: 76.8 %

Procedure:
To 8.35 g (17.1 mmol) of the compound (128), 80 ml of Dowtherm A (Trademark) was added, and the solution was heated until a fraction of 200° C. was taken out. The solution was further heated at reflux for 5 minutes. After air-cooling, 50 ml of ether was added to the solution, and the crystals were filtered off to obtain 5.62 g of the subject compound (129) in a 74% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[OH:16])=[C:13]([F:19])[CH:12]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(F)cc1F)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (25.91 mmol) of 2,4-difluorobromobenzene and 4.93 g (31.09 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 3.34 g (47% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[CH3:29][C:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[O:32][N:31]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:35]([C:33]4[O:32][N:31]=[C:30]([CH3:29])[CH:34]=4)=[O:36])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: Cc1cc(C(=O)O)on1
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3cc(C)no3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and 3-methylisoxazole-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 516.1 [M+H]+.