Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)CCC(C)(C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(CCC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-4-methylpentanoate (16 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 4 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 14 mg. MS: (−) m/z 417.99 (M−1).
Reaction SMILES: [C:1]12([C:11]([S:13]C)=S)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:16][NH2:17]>CO>[C:1]12([C:11]([NH:16][NH2:17])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CSC(=S)C12CC3CC(CC(C3)C1)C2
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=S)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of the product of step (a) (1 g) in methanol (50 ml) was treated with hydrazine hydrate (0.3 g) and the mixture stirred at room temperature for 1 hour. The solvent was evaporated, the residue triturated with water, and the pH adjusted to 7 to give the sub-title product (0.8 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][NH:13][C:14](=O)OC(C)(C)C)=[CH:8][C:7]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[CH:6][CH:5]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][NH:13][CH2:12][CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1[nH]c2ccc(S(=O)(=O)c3ccccc3)cc2c1CCNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCc1c(C)[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A solution of tert-butyl 2-[2-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.46 g, 1.10 mmol) in THF (2.0 mL) was added to a slurry of LiAlH4 (0.47 g, 12.3 mmol) in THF (4.0 mL) and the mixture was heated to reflux for 6.5 hours. The reaction was cooled to room temperature and quenched with water (12.0 mL) and 15% NaOH (12.0 mL). The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo and recrystallized from EtOAc/hexane to give 0.17 g (46%) of a white solid as the title compound: mp 164.6-166.0° C.; 1H NMR (400 MHz, Acetone-d6) δ 8.20 (d, J=1.6 Hz, 1H), 7.97-7.95 (m, 2H), 7.59-7.52 (m, 4H), 7.42 (d, J=8.6 Hz, 1H), 2.93-2.90 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, Acetone-d6) δ 145.0, 138.6, 135.9, 133.3, 132.4, 130.0, 129.5, 127.9, 120.3, 119.6, 111.8, 53.5, 36.7, 25.2, 11.6; IR (diffuse reflectance) 3028, 3021, 2939, 2909, 2870, 2843, 1449, 1307, 1301, 1152, 1087, 750, 719, 692, 623 cm−1; HRMS (FAB) calcd for C18H20N2O2S+H 329.1324, found 329.1326; Anal. Calcd for C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53. Found: C, 65.47; H, 6.21; N, 8.38.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:35][CH:36]([F:42])[C:37](OCC)=O>O1CCOCC1>[F:35][CH:36]([F:42])[C:37]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1
Reactant: CCOC(=O)C(F)F
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (65 mg, 0.14 mmol) and ethyl difluoroacetate (0.3 mL, 2.8 mmol) in 1,4-dioxane (0.5 mL) was heated at 100° C. for 3 days. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 30:70 to 2:98) to afford 184 as a white solid (26 mg, 35%). LCMS (Method G): RT=8.03 min, M+H+=543. 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=8.1 Hz, 1 H); 7.91 (d, J=7.8 Hz, 1 H); 7.60 (t, J=53.8 Hz, 1 H); 7.45-7.37 (m, 2 H); 4.43 (m, 4 H); 4.02 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.74 (t, J=4.5 Hz, 4 H); 3.69 (t, J=6.2 Hz, 2 H); 3.21-3.07 (m, 3 H) and 2.37 (m, 4 H)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C[CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C.C=O>[NH:1]1[C:5]2[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:3]=[CH:2]1
Reactant: C1CCNC1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1

Procedure:
Nitroindole AA1 was alkylated with an appropriately substituted alkyl or arylalkyl halide in the presence of a base such as cesium carbonate, potassium carbonate and the like also in the presence of a solvent such as DMF to provide a 1-substututed indole intermediate. The resulting intermediate was reacted with an amine such as pyrrolidine, piperidine and the like while dissolved in an organic acid such as glacial acetic acid in the presence of formaldehyde also in glacial acetic acid to provide a 3-substututed indole intermediate. The nitro group of the resulting intermediate was then reduced to an amino group by reaction with 1,1-dimethylhydrazine in the presence of an alcohol solvent such as MeOH and charcoal and ferric chloride hexahydrate which provided intermediate AA2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].[CH2:15](Br)[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:15]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
Ethyl 4-nitro-1H-pyrrole-2-carboxylate (2.022 g, 10.983 mmol; see Example 1, step (i) above) was dissolved in DMF (30 mL, dry) to which potassium (0.569 g, 14.552 mmol) was added with stirring under nitrogen. The reaction mixture was heated at 100° C. for 1 h and then the temperature was allowed to reach 50° C. Isoamyl bromide (2.498 g, 16.538 mmol) was then added, followed by KI (2.197 g, 14.552 mmol). The temperature was raised to 100° C. and stirring continued for 5 h, after which time the temperature was allowed to return to room temperature. The reaction mixture was then stirred overnight, following which the solvent was removed under reduced pressure at 50° C. The crude product was dissolved in DCM and the salt extracted with water. The organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure at 30° C. The crude product obtained was chromatographed over silica gel using 1/2 n-hexane/DCM as eluant. Material with Rf=0.3 was collected and the solvent was removed under reduced pressure to give white crystalline material (2.377 g, 85% yield). M.p. 46-47° C. (Lit. m.p. 46-47° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Cn1c2cccc(OCC(=O)O)c2c2c(C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of the {9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.5 mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 10 mg (63%) of the {9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.55 (br s, 1H), 7.5-7.0 (m, 7H), 6.9 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.6 (s, 2H), 4.35 (s, 2H), and 2.5 (s, 3H). IR (KBr, cm−1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e 387, 389.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][Br:11]
Reactant: Br
Reactant: CC(=O)c1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3 g of 2'-methylacetophenone in 60 ml of acetic acid was added successively 9.7 ml of 47% hydrobromic acid and 8.6 g of pyridinium hydrobromide perbromide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and a saturated sodium carbonate solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 5.4 g of the title compound as a colorless oily material.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])[C:17](=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH2:32])[CH3:31]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:32][CH2:30][CH3:31])=[O:24])[C:17](=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C(=O)O)c3)C2)cc1OC1CCCC1
Product: CCNC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1

Procedure:
3-[4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzoic acid and ethyl amine was treated according to General Procedure V to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:29]=2[N:30]=1.Cl>C(O)CCC.O1CCOCC1.C(OCC)C>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:27][C:28]=2[CH:34]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C(F)(F)F)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A mixture of methyl (1R,2R)-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (150 mg, 0.464 mmol) and 2-chloro-6-(trifluoromethyl)-1,3-benzothiazole (132 mg, 0.557 mmol) was diluted with n-butanol (3 mL) and treated with a catalytic amount of 4 M HCl in dioxane. The suspension was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel, eluting with a gradient from 9:1 to 3:2 hexanes/ethyl acetate. The product obtained was suspended in diethyl ether, and the resulting solid was collected by filtration and washed with additional diethyl ether and hexanes. LC-MS for the n-butyl ester: LC-MS m/z 567.3 (MH+), 4.67 min; 1H NMR (300 MHz, CDCl3) δ 8.14-8.10 (m, 3H), 7.80-7.71 (m, 6H), 7.62 (d, 2H), 4.17-4.13 (m, 1H), 4.09-4.04 (m, 2H), 3.51-3.41 (m, 1H), 2.21-2.13 (m, 2H), 1.97-1.90 (m, 1H), 1.81-1.78 (m, 3H), 1.58-1.51 (m, 2H), 1.35-1.28 (m, 2H), 1.23-1.18 (t, 3H), 0.88 (t, 2H). The off-white solid was diluted with methanol (2 mL) and tetrahydrofuran (2 mL) and treated with 2 M aqueous sodium hydroxide solution (2 mL). The solution was stirred overnight at rt. The mixture was acidified by the addition of an excess of 2 M aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate. The organic phases were combined, dried (MgSO4), and concentrated under reduced pressure. The residue was suspended in methanol and the resulting solids were removed by filtration. The filtrate, which contained the product, was concentrated under reduced pressure to provide the title compound as a pale orange solid (30 mg, 13% overall yield). 1H NMR (tetrahydrofuran-d8) δ 10.85 (s, 1H), 8.11-8.07 (m, 3H), 7.96-7.91 (m, 2H), 7.79-7.71 (m, 5H), 7.63-7.59 (dd, 1H), 4.18 (q, 1H), 3.37 (q, 1H), 2.2-1.77 (m, 6H); LC-MS m/z 511.3 (MH+), retention time 4.27 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C@H:20]([CH3:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C@H:20]([OH:19])[CH3:23])=[O:14]
Reactant: C[C@@H](O)CN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: C[C@@H](O)CNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[(2R)-2-hydroxypropyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 3 mmol of 2-(R)-hydroxypropylamine LC/MS [8.33 min; 416 (M+1)]
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1>CN(C)C=O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=2)=[CH:26][CH:25]=1)#[N:34]
Reactant: CCOC(=O)c1cn(C)nc1N
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1NCc1ccc(-c2ccccc2C#N)cc1
Yield: 75.5 %

Procedure:
To a mixture of ethyl 3-amino-1-methylpyrazole-4-carboxylate (P. Schmidt et al. Hel. Chim. Acta., 1959, 41, 349.) (2.30 g) and potassium carbonate in N,N-dimethylformamide (70 ml), was added portionwise 4-bromomethyl-2'-cyanobiphenyl (4.81 g). The solvent was distilled under reduced pressure. To the residue was added ice-water and an aqueous solution of potassium carbonate. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crude crystals, which were recrystallization from ethyl acetate-isopropylether to afford the title compound as white crystals (3.7 g, 76%), m.p. 151°-152° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)cc1F
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc(N)c(C(=O)O)cc1F

Procedure:
525 g of 2-nitro-4-methyl-5-fluoro-benzoic acid are hydrogenated in 3 l of dioxane with 50 g of 5% strength Pd-C catalyst at 30°-40° under 20-30 bar. The catalyst is filtered off with suction and the solution is poured onto water. The crystals which have precipitated are filtered off with suction and dried. Yield: 357 g (80.1% of theory), melting point: 201°-202° C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[F:19][C:16]([F:17])([F:18])[C:11]1[N:10]=[C:9]([NH2:8])[C:14]([NH2:15])=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2nc(C(F)(F)F)ccc2N)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(F)(F)F)nc1N

Procedure:
A solution of N2-(4-methoxy-benzyl)-6-trifluoromethyl-pyridine-2,3-diamine from step (a) above (220 mg, 0.7 mmol) in 1:1 TFA/DCM (4 mL) was stirred at room temperature for 90 min. The reaction mixture was concentrated to yield a gummy residue, which was dissolved in MeOH (2 mL) and purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 178 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([CH:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:39]([NH2:44])(=[O:43])[CH:40]([CH3:42])[CH3:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1>[F:24][C:22]([F:23])([F:25])[CH:21]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([NH:44][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[CH:3][CH:4]=4)[N:9]=3)=[N:13][N:14]=2)[CH:17]=1
Reactant: CC(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)Nc1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 90 °C
Yield: 108.3 %

Procedure:
tert-Butyl (3S)-1-(1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (50 mg, 0.085 mmol), isobutyramide (18.4 mg, 0.211 mmol), K3PO4 (53.8 mg, 0.254 mmol), and Cu(I)I (1.61 mg, 0.0085 mmol) were weighed into a 40 mL Teflon® capped vial. The vial was purged with N2, followed by addition of toluene (20 mL) and N1,N2-dimethylethane-1,2-diamine (4.55 μL, 0.042 mmol). The reaction was sealed and heated to 90° C. overnight, after which the reaction complete by TLC. The crude reaction was concentrated, then purified by flash column chromatography (eluting with 10% MeOH/DCM), affording the desired product (55 mg, 97% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-Bromohexanoic Acid (10.0 g, 0.051 mol), benzyl alcohol (6.1 g, 0.056 mol) and DMAP (dimethylaminopyridine, 0.63 g, 0.005 mol) were dissolved in 100 mL CH2Cl2, then cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 10.8 g, 0.056 mol) was added and the reaction stirred overnight at room temperature. The organics were diluted with CH2Cl2 and washed with water, aq. NaHCO3, and brine. The organic phase was dried (Na2SO4), filtered, and solvent was removed. Intermediate 12 was obtained as a colorless oil (11.6 g, 0.04 mol). MS(MH+): m/z=286.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].CC1(C)[O:18][C:17](=O)[CH:16]=[C:15]([CH3:20])[O:14]1.CCCCCC.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1)[NH2:6].[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:17](=[O:18])[CH2:16][C:15](=[O:14])[CH3:20])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: COc1cc(N)cc(OC)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: COc1cc(NC(=O)CC(C)=O)cc(OC)c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 186.2 %

Procedure:
A solution of 3,5-dimethoxy aniline 1 (5 g, 32.6 mmol) in xylene (20 mL) was taken in a 100 mL round bottom flask equipped with a reflux condenser and a dropping funnel and heated at 130° C. under nitrogen atmosphere. 2,2,6-trimethyl4H-1, 3-dioxin-4-one (4.64 g, 32.6 mmol) was then added dropwise for 25 min. Heating was continued at 125-130° C. for additional 3 h (TLC hexane : ethyl acetate, 6:4 Rf=0.3). The reaction mixture was cooled to 50° C. and xylene was removed under vacuum to get oily residue. The residue obtained was purified by column chromatography (silica gel hexane:ethyl acetate 4:1) to get product 1 N-(3,5-dimethoxyphenyl)-3-oxo-butanamide (9, 7.2 g) in 93% yield as an oily liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1ccc(NCc2ccc(F)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 20.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-fluorophenyl)methyl](4-isopropylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (2.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)urea (0.82 g) was obtained. melting point: 80° C.