Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=1)=[O:20]
Reactant: CC(C)(C)c1ccc(CO)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CC(C)(C)c1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-t-butylbenzyl alcohol (5.0 g; 30 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 0.84 g (52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[N:37]1([CH2:43][C:44]2[CH:45]=[C:46]([CH:52]=[CH:53][CH:54]=2)[O:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:25]([NH:51][CH2:50][CH2:49][CH2:48][O:47][C:46]2[CH:52]=[CH:53][CH:54]=[C:44]([CH2:43][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:45]=2)=[O:26])[CH3:22])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: COc1ccc(CN(CCN(C)CCCNC(=O)NCCCOc2cccc(CN3CCCCC3)c2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.54 g (1.65 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=603 ([M+H]+, 10), 121 (100); IR (KBr): 1639 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 120° C. (isopropanol/ether).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>C1COCC1.CCCCCC.C(OCC)C>[CH:11]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:13])[CH3:12]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1cc[nH]c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Yield: 91.9 %

Procedure:
To a solution of pyrrole (33.54 g) in THF (700 ml) at -78° C. under nitrogen was added a solution of 2.5M n-butyl lithium(200 ml) in hexane. After one hour triisopropylsilyl chloride (98 g) was added. After 24 hours the reaction was diluted with diethyl ether, washed with water, dried over sodium sulfate, filtered and evaporated to a tan oil which was distilled at 115°-119° C. (0.2 mm Hg) to give 102.6 g of a colorless mobile liquid. 1H NMR is consistent with proposed structure.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)[C:20]([NH:22][CH2:23][CH:24]2[CH2:29][CH:28]3[CH2:30][CH:25]2[CH:26]=[CH:27]3)=[O:21])C=CC=CC=1.CN(C)C=O.[H-].[Na+]>CCOCC>[CH:28]12[CH2:30][CH:25]([CH:24]([CH2:23][NH:22][C:20]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:21])[CH2:29]1)[CH:26]=[CH:27]2
Reactant: O=C(NCC1CC2C=CC1C2)N(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(NCC1CC2C=CC1C2)NS(=O)(=O)C=Cc1ccccc1

Procedure:
To a solution of 1.8 g. of 2-phenylethenesulfonamide and 4.8 g. of 1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml. of N,N-dimethylformamide, is added, with stirring, 0.64 g. of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature overnight, during which time a heavy precipitate forms. To the reaction mixture is then added 200 ml. of ether. After stirring for 15 minutes, the precipitate is filtered off. It is dissolved in 50 ml. of water, and then the crude product is precipitated by acidification using concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone. The yield is 1.9 g. (56%) of a solid, m.p. 161°-163.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([C:9]#[N:10])[C:7]=1F.NC1C=C(C(F)(F)F)C=C(Cl)C=1F.[Cu]C#N.[CH3:31][C:32]1[C:37](=[O:38])[NH:36][CH:35]=[N:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([C:9]#[N:10])[C:7]=1[N:36]1[C:37](=[O:38])[C:32]([CH3:31])=[C:33]([C:39]([F:40])([F:41])[F:42])[N:34]=[CH:35]1
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Cc1c(C(F)(F)F)nc[nH]c1=O
Agent: N#C[Cu]
Agent: Nc1cc(C(F)(F)F)cc(Cl)c1F
Solvent: CC#N
Solvent: O
Product: Cc1c(C(F)(F)F)ncn(-c2c(Cl)cc(C(F)(F)F)cc2C#N)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(2-Chloro-6-cyano-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylpyrimidin-6-one was prepared by the reaction of the product of Preparation 2 of EP 0 398 499 (i.e., 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene, produced as follows: A solution of 3-amino-5-chloro-4-fluorotrifluoromethylbenzene (3 g) in acetonitrile (10 ml) was added dropwise to a stirred suspension of copper (I) cyanide (1.26 g) in dry acetonitrile (50 ml) whilst the reaction temperature was maintained at 0° C. After the addition was complete, the reaction mixture was allowed to warm to the ambient temperature (about 23° C.) and left overnight. The reaction mixture was poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent, under reduced pressure, gave a brown oil, which was flushed through a plug of silica gel using petroleum ether (boiling range 60°-80° C.) containing diethyl ether (20% by volume) as eluent. After removal of the solvent, under reduced pressure, Kugelrohr distillation of the residue gave two fractions, the first of which (boiling point 110° C. at 15 mmHg) was predominantly composed of 3-chloro-4-fluoro-5-cyano-trifluoromethylbenzene and 5-methyl-4-trifluoromethylpyrimidin-6-one. The product had a melting point of 154.1°-154.9° C.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=O)=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:28][N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([NH:40][NH2:41])=O)[C:32]=2[CH:31]=[CH:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:18][N:17]1[C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:32]=2[CH:31]=[CH:30][N:29]3[CH3:28])=[N:40][N:41]=[C:15]1[C:14]1[CH:19]=[CH:20][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: Cn1ccc2c(C(=O)NN)cccc21
Reactant: CNC(=O)c1ccc(O)cc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(O)cc2)nnc1-c1cccc2c1ccn2C
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Methyl trifluoromethanesulfonate (200 μL, 1.76 mmol) was added to 4-hydroxy-N-methylbenzamide (6-A) (133 mg, 0.881 mmol) and the mixture stirred at 65° C. for 10 min. Toluene (0.6 mL) was added and the suspension stirred rapidly at 65° C. for 30 min. Toluene (0.4 mL), triethylamine (370 μL, 2.67 mmol) and a solution of 1-methyl-1H-indole-4-carbohydrazide (6-B) (100 mg, 0.528 mmol) in toluene (1.0 mL) and DMF (250 μL) were added and the mixture stirred at 65° C. for 3 h and then at 125° C. for 18 h. The mixture was evaporated in vacuo and the residue purified by preparative TLC (silica gel, methylene chloride:methanol, 95:5) to provide 4-[4-methyl-5-(1-methyl-1H-indol-4-yl)-4H-1,2,4-triazol-3-yl]phenol (6-C). 1H NMR (500 MHz, CD3OD): δ 3.63 (s, 3H); 3.92 (s, 3H); 6.53 (d, 1H); 7.00 (d, 2H); 7.37 (m, 3H); 7.64, (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[C:6]([N:16]2[CH2:21][CH2:20]C(C)CC2)[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.[CH3:26][O-:27].[Na+].[CH3:29]O>>[CH3:26][O:27][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[C:6]([NH:16][CH:21]([CH3:20])[CH3:29])[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1
Reactant: CC1CCN(c2c(-c3c(F)cccc3Cl)c(Cl)nc3ncnn23)CC1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1nc2ncnn2c(NC(C)C)c1-c1c(F)cccc1Cl

Procedure:
To a solution of 65 mmol 5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo[1,5-α]pyrimidine [cf. EP-A 550 113] in dry methanol 71.5 mmol of a 30% solution of sodium methanolate were added at 20 to 25° C. After having stirred this mixture for about 16 hours at this temperature methanol ws evaporated nad the residue was dissolved with dichloromethane. The organic phase was separated, washed with water, dried and filtered. Distillative removal of the solvent from the filtrate and chromatography over silica gel gave 4.2 g of the title compound of mp. 182° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][C:14](=O)[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[OH:16])[CH2:6][CH2:5]2.B.CSC.CO.Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][CH2:14][CH:15]([OH:16])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:6][CH2:5]2
Reactant: O=C(NCC1CCc2cc(O)ccc2C1)C(O)c1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Oc1ccc2c(c1)CCC(CNCC(O)c1ccc(Cl)cc1)C2

Procedure:
A solution of the compound obtained in step (i) above (3.2 g, 0.0092 mol) in anhydrous tetrahydrofuran (65 ml) is heated to the reflux temperature under nitrogen atmosphere and a 10M solution of borane-methyl sulfide (2.8 ml, 0.028 mol) and anhydrous tetrahydrofuran (10 ml) are then added thereto. The mixture is refluxed for 4 hours, methanol (30 ml) is slowly added thereto and refluxing is prolonged for an additional hour. lN HCl (60 ml) is then added thereto and the mixture is refluxed for 1 hour, and concentrated under reduced pressure. The residue is taken up in ethyl acetate, the organic solution is washed with ammonium hydroxide and then with water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure affording a solid which is washed with isopropyl ether (2.3 g). M.p. 150°-153° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(I)ccnc1Cl
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccnc(Cl)c1C(=O)O
Yield: 89.6 %

Procedure:
In a similar manner to Reference Example 4, 2-chloro-4-iodonicotinic acid (Compound of Reference Example 1; 5.67 g) was reacted with 2-methylphenylboronic acid (3.00 g) to obtain 2-chloro-4-(2-methylphenyl)nicotinic acid (4.44 g, 90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:32])[C@H:5]([CH2:28][CH2:29][S:30][CH3:31])[NH:6][C:7](=[O:27])[CH2:8][N:9]([CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.Cl.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1CC(O)=O.O.[OH:44][C:45]1C2N=NNC=2C=C[CH:46]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:2][O:3][C:4](=[O:32])[C@H:5]([CH2:28][CH2:29][S:30][CH3:31])[NH:6][C:7](=[O:27])[CH2:8][N:9]([CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:45](=[O:44])[CH2:46][C:37]1[N:36]=[CH:35][NH:34][CH:38]=1)[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ncc[nH]1
Reactant: COC(=O)[C@H](CCSC)NC(=O)CN(Cc1cccc2ccccc12)C[C@@H]1CCCN1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)CN(Cc1cccc2ccccc12)C[C@@H]1CCCN1C(=O)Cc1c[nH]cn1
Reaction time: 3 h

Procedure:
N-(pyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (0.200 g, 0.387 mmol), imidazoleacetic acid hydrochloride (0.094 g, 0.581 mmol), hydroxybenzotriazole hydrate (0.086 g, 0.639 mmol), EDC hydrochloride (0.134 g, 0.697 mmol) and TEA (0.340 mL, 2.44 mmol) were dissolved in dry DMF (4 mL) and stirred under Ar for 3 h. The mixture was concentrated in vacuo and the residue taken up in aq satd NaHCO3 soln and extracted with EtOAc (2×40 mL). The organics were washed with H2O and brine, dried over MgSO4, filtered and the solvent removed in vacuo to give an oil which was chromatographed on silica gel (5:95 MeOH:CH2Cl2) to give the title compound. 1H NMR (CD3OD) δ 8.32 (d, 1H, J=8 Hz), 7.90 (d, 1H, J=8 Hz), 7.83 (d, 1H, J=8 Hz), 7.39-7.62 (m, 5H), 6.92 (br s, 1H), 4.34-4.52 (m, 3H), 3.94 (d, 1H, J=13 Hz), 3.59-3.78 (m, 2H), 3.67 (s, 3H), 3.21-3.56 (m, 6H), 2.93 (dd, 1H, J=4, 13 Hz), 2.51 (dd, 1H, J=9, 13 Hz), 2.02-2.14 (m, 1H), 1.68-2.02 (m, 6H), 1.92 (s, 3H), 1.39-1.52 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:30]([CH3:31])=[C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:5][CH:4]=1
Reactant: CCC(=O)CCCCC(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)c(C)c(CCCCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)-hydrazine hydrochloride and methyl 6-oxooctanoate as the starting materials and methanol as the solvent, the title compound was prepared.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([OH:22])=O)[CH3:3].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([NH2:25])=[O:22])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(-c3ccccc3)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(N)=O)oc2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A suspension of 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxylic acid (173 mg, 0.58 mmol) and 1,1'-carbonyldiimidazole (116 mg, 0.72 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 2 hours. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxamide in 94% yield; mp=192°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[BH3-]C#N.[Na+].C(=O)C1C=CC=CC=1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:22][CH:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCC(NCc2cncc(-c3c(C#N)c4ccc(Cl)cc4n3C)c2)CC1
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126, 0.150 g, 0.482 mmol) in THF (3 mL) and DMF (1 mL) is added 4-amino-1-methylpiperidine (0.067 g, 0.578 mmol), followed with MP—NaBH3CN (2.42 mmol/g, 0.498 g, 1.205 mmol). After 16 h, MP—NaBH3CN (2.42 mmol/g, 0.200 g, 0.484 mmol) is added. After another 46 h and PL-benzaldehyde (1.8 mmol/g, 0.268 g, 0.482 mmol) is added and after another 8 h, the mixture is filtered and the solids are washed with THF. After evaporation of the solvents, the residue is purified by reverse phase HPLC on a Sunfire C18, eluting with a gradient of 0.1% aqueous TFA-acetonitrile to give 6-chloro-1-methyl-2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile as a gum which is triturated with 1M HCl in ether to give the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ ppm (HCl salt) 1.46-1.66 (m, 2H), 1.93-2.04 (m, 2H), 2.50-2.57 (m, 4H), 2.66-2.76 (m, 2H), 3.10-3.20 (m, 2H), 3.80 (s, 3H), 3.95 (br. s., 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.16 (s, 1H), 8.79 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 394.1804 [(M+H)+ Calcd for C22H25ClN5: 394.1798].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.C(#N)C.O>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combined with 10 g of H2O. 1.11 g (10.45 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 14 mg of CuBr and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL acetonitrile under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 2 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The purity was determined by 1H NMR to be >99%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:24][C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:26]=1[NH2:27]>CC(C)=O.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:27][C:26]2[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:25]=2[CH3:24])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Cc1cccc(C)c1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Cl)nc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A slurry of 25 g of 6-chloronicotinic acid in approximately 300 ml of acetone was treated with 22.6 ml of triethylamine. The reaction mixture was cooled to approximately -10° C. by means of an external ice/methanol bath. A solution of 15.5 ml of ethyl chloroformate in acetone was added to the mixture at a rate to maintain the temperature below 0° C. After stirring with the cold bath for 2 hours, a solution of 38.5 g of 2,6-dimethylaniline in approximately 150 ml of acetone was added while maintaining the temperature below 0° C. After the addition was complete, the mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted into ethyl acetate. The organic layer was washed with water, dilute hydrochloric acid, water, a dilute sodium bicarbonate solution, water (twice), and a saturated sodium chloride solution. The organic solution was dried over sodium sulfate and concentrated in vacuo to provide 30.5 g of a solid. Crystallization from methanol/water provided 14.6 g of the desired title product, m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[N:42]1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[C:65]([O:68]CC)(=[O:67])C>ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3([CH2:40][OH:41])[CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:42][C:65](=[O:67])[O:68][N:26]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: Cc1cccc(C)n1
Reactant: CCOC(C)=O
Reactant: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.42 g) and 2,6-lutidine (0.27 mL) in dichloromethane (10 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.35 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL), hydroxylammonium chloride (0.91 g) and sodium hydrogen carbonate (1.3 g) were added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (4 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 58%).