Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]O)[CH3:2].C(=O)(O)[O-].[Na+].[NH3:15]>[Ni]>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:15])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: N
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCC(CC)CN
Reaction time: 8 h

Procedure:
The procedure described in Example 1 is followed. 650 parts of 2-ethyl-hexan-1-ol, 300 parts of a reduced nickel catalyst which contains 60% of nickel on kieselguhr and 7 parts of sodium bicarbonate are heated to 140° C. and at this temperature ammonia gas is passed into the well-stirred suspension at the rate at which it is converted. The reaction ends after 8 hours. The mixture is worked up by distillation and gives 96% of theory of di-2-ethylhexylamine, 1% of theory of 2-ethylhexylamine and 0.3% of theory of tri-2-ethylhexylamine.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)[Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>CS(C)=O>[O:31]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]#[C:26][Br:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:6][CH2:7]1
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: O=C1O[C@@H](Cn2cc(C#CBr)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.5 g, 0.87 mmol) was dissolved in DMSO (87 ml) and cooled to 15° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.262 ml, 1.75 mmol), dissolved in DMSO (1.7 ml), was added drop wise under stirring over 30 minutes. The temperature was maintained at 15–18° C. and after 6 hours more DBU (0.125 ml, 0.83 mmol) was added drop wise via a syringe and the resulting solution stirred for another 30 minutes. The reaction was quenched with cold aqueous HCl (0.5 M), extracted with dichloromethane, washed with water and dried over sodium sulfate. Chromatography on silica gel with hexanes/acetone (1.5:1 to 1:1) gave 108 mg (25%) of the title product as a colourless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[C:21]3[OH:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26](C)([O-])C.[K+].C(I)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[C:21]([O:24][CH2:25][CH3:26])[CH:20]=[CH:19][CH:18]=3)[CH:23]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cccc2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 37 g (0.116 mol) of 7-(4-benzyl-piperazin-1-yl)-naphthalen-1-ol and 15 g (0.134 mol) of potassium tert.butoxide in 150 ml of dimethylformamide is stirred for 30 minutes at ambient temperature and then slowly combined with 11 ml (0.135 mol) of ethyl iodide. It is then stirred for 14 hours at ambient temperature. Then the reaction mixture is concentrated by evaporation and the residue is extracted with dichloromethane and water. It is filtered through aluminium oxide, dried over sodium sulphate and the solvent is distilled off. The residue is recrystallised from isopropanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-nitro-5-trifluoromethylphenol (730 mg, 3.5 mmol), benzyl bromide (0.42 mL, 3.5 mmol), and potassium carbonate (200 mg) in DMF (10 mL) is stirred at RT for 48 h. The mixture is partitioned between water and EtOAc, the organic layer is concentrated and the residue is chromatographed using a gradient of 5-20% EtOAc/hexane as eluent to afford the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]([S-:20])#[N:19].[K+].BrBr.O>CN(C=O)C>[NH2:19][C:18]1[S:20][C:3]2[CH:4]=[C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc4nc(N)sc4c3)sc2c1
Reaction time: 20 h
Yield: 39.9 %

Procedure:
2-(4-aminophenyl)-6-methyl-benzothiazole 1 (4.0 g, 16.6 mmol) and KSCN (2.6 g, 26.7 mmol) were dissolved in DMF (20 ml) and cooled in an ice-bath. Br2 (0.9 ml, 17 mmol) in DMF (15 ml) was added dropwise under 3 h. The mixture was stirred for another 20 h. Water was added and the precipitate formed was collected by filtration and dried. The crude product was triturated on the sinter with several portions of boiling dichloromethane to afford 2 as a light green-yellow solid (1.97 g, 40%). Mp 250-251° C.; 1H NMR (DMSO): δ 2.45 (3H, s, Ar—CH3), 7.34 (1H, d, J=8.4, ArH), 7.50 (1H, d, J=8.4, ArH), 7.89 (1H, d, J=8.4, ArH), 7.91 (1H, s, ArH), 7.99 (1H, d, J=8.4, ArH), 8.51 (1H, s, ArH), 8.56 (2H, s, NH2); 13C NMR (DMSO): δ 21.10, 116.7, 120.7, 121.8, 122.1, 125.6, 126.9, 128.1, 129.7, 133.3, 134.5, 135.0, 151.7, 165.9, 169.3; HR-FAB-MS m/z Found: 298.0521 C15H12N3S2 (M+H+): requires M, 298.0473.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:23]2[C:22](=[O:27])[CH2:26][CH2:25][CH:24]=2)=[CH:6][C:7]([CH3:16])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:9]=1
Reactant: Cc1cc(C=O)c(Cl)nc1-c1ccccc1
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: Cc1cc(C(O)C2=CCCC2=O)c(Cl)nc1-c1ccccc1
Yield: 93 %

Procedure:
The clear solution of 2-Chloro-5-methyl-6-phenylnicotinaldehyde (10 mmol, 2.31 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 93% yield (2.84 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)[CH3:39]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CC)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M141) (0.33 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14].[CH3:18][N:19]=[C:20]=[O:21]>C(OCC)C>[CH3:18][NH:19][C:20]([NH:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:17])[F:1])=[O:21]
Reactant: CN=C=O
Reactant: NNC(=O)CCCCCCCCCC=C(F)F
Solvent: CCOCC
Product: CNC(=O)NNC(=O)CCCCCCCCCC=C(F)F
Yield: 81.9 %

Procedure:
A stirred solution of 0.5 gram (0.002 mole) of 12,12-difluoro-11-dodecenoic acid hydrazide and 0.11 gram (0.002 mole) of methyl isocyanate in 30 ml of diethyl ether was heated under reflux for three hours. The reaction mixture was concentrated under reduced pressure yielding 0.5 gram of N-methyl-2-(12,12-difluoro-11-dodecenoyl)hydrazinecarboxamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[C:25]2[C:20](=[C:21]([C:27]([O:29][CH3:30])=[O:28])[CH:22]=[C:23]([I:26])[CH:24]=2)[N:19]=[CH:18][N:17]=1.O.[OH-].[Na+]>CC#N>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:16]2[C:25]3[C:20](=[C:21]([C:27]([O:29][CH3:30])=[O:28])[CH:22]=[C:23]([I:26])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COC(=O)c1cc(I)cc2c(Cl)ncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(I)cc2c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)ncnc12
Yield: 14.3 %

Procedure:
Dissolved tert-butyl (35)-3-aminopiperidine-1-carboxylate (632.11 mg; 3.16 mmol; 1.10 eq.) in MeCN (18.00 ml) and TEA (1.00 ml). Added this mixture to methyl 4-chloro-6-iodoquinazoline-8-carboxylate (1000.00 mg; 2.87 mmol; 1.00 eq.). Stirred reaction at room temperature for 45 hours. LCMS indicated M+1=513 present. Diluted reaction with water and 1N NaOH. Filtered the resulting precipitate. Washed with water and dried to give a yellowish solid (210 mg). Carried material on without further purification. LCMS: M+1=513
Reaction SMILES: [N:1]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:20][C:19]=3[C:30]3[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=4)[CH:33]=[CH:32][N:31]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:57](Cl)(=[O:59])[CH3:58]>ClCCl>[C:57]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:20][C:19]=3[C:30]3[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:47])([F:46])[F:48])[CH:40]=4)[CH:33]=[CH:32][N:31]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3]1)(=[O:59])[CH3:58]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)n2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 6-((1,4-diazepan-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (135 mg, 0.19 mmol, 1.00 equiv, 95%) in dichloromethane (5 mL), triethylamine (40 mg, 0.39 mmol, 2.00 equiv, 99%), and acetyl chloride (18 mg, 0.23 mmol, 1.20 equiv, 99%). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with 2×10 mL of hexane. The product was obtained as 120 mg (87%) of a yellow solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.86 (s, 1H), 9.54-9.51 (t, 1H), 9.00 (s, 1H), 8.51-8.49 (d, J=6 Hz, 1H), 8.23 (s, 1H), 8.00 (s, 2H), 7.88-7.86 (d, 1H), 7.72-7.55 (m 5H), 7.33 (s, 1H), 7.14-7.11 (d, J=9 Hz, 1H), 4.63 (s, 2H), 3.91-3.88 (s, J=9 Hz, 2H), 3.52-3.50 (m, 4H), 3.21-3.19 (m, 4H), 2.78-2.63 (m, 4H), 2.01-1.98 (d, J=9 Hz, 3H), 1.79-1.55 (m, 8H). MS (ES, m/z): 714 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27]>CS(C)=O>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:22])[C:12]=2[C:10](=[O:11])[NH:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:24])([F:1])[CH2:3][CH2:4]2)[N:17]=1)[CH3:27]
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)CCNc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 by heating 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIEPA and 3-Amino-propionic acid ethyl ester hydrochloride in DMSO at 140° C. 1H NMR (400 MHz, DMSO-d6) δ 4.16 (s, 1H), 4.00 (t, J=13.2 Hz, 2H), 3.78 (t, J=7.60 Hz, 2H), 3.28 (d, J=6.04 Hz, 2H), 8.81 (s, 1H), 7.68-7.77 (m, 2H), 6.93-7.02 (m, 1H), 4.05-4.10 (m, 2H), 3.68-3.80 (m, 2H), 3.23 (t, J=6.03 Hz, 2H), 2.01-2.03 (m, 2H), 1.73-1.88 (m, 5H), 1.22-2.27 (m, 2H), 1.15-1.19 (m, 3H). m/z: 454.0 [M+H]+
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([Cl:39])(=[O:38])[CH3:37]>C(Cl)Cl>[ClH:39].[C:36]([N:6]1[CH2:7][CH2:8][N:3]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])=[CH:27][CH:28]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCN(C(C)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
The free amine of compound 64 (100 mg, 0.28 mmol) was dissolved in methylene chloride (5 ml), cooled to 0° C. Triethyl amine (43 μl, 0.31 mmol) was added and then acetyl chloride (22 μl, 0.31 mmol) was added dropwise. After 10 min, the solution was washed with potassium carbonate (10%), dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica (CH2Cl2 /MeOH/NH3, 95:5:0.5) to give 116 mg of compound 77 (~100 %).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[NH:15][C:14](=[O:20])[CH:13]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[C:14](=[O:20])[CH:13]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)cc(=O)n(Cc2ccc(C#N)cc2)c1=O
Reaction time: 1.75 h
Yield: 12.2 %

Procedure:
α-Bromo-p-tolunitrile (5.41 g, 27.6 mmol) was added at once with stirring to a solution of 6-amino-1-methyluracil (V. Papesch and E. F. Schroeder. J. Org. Chem. (1951), 16, 1879) (3.90 g, 27.6 mmol) in 1:1 ethanol: 1N sodium hydroxide (56 ml) at 42° C. After 1.75 hours. the mixture was cooled, filtered and washed with water. The resulting solid and second crop obtained by evaporation of the filtrate were combined (5.80 g) and partially purified by silica gel chromatography followed by repeated trituration with 1:2 methanol; ether to give crude 4-[(6-Amino-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-pyrimidinyl)methyl]benzonitrile (0.86 g), indentified by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.[NH2:41][C@H:42]([C:45]([NH2:47])=[O:46])[CH2:43][OH:44]>>[NH2:47][C:45](=[O:46])[C@@H:42]([NH:41][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:33])([F:35])[F:34])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH2:43][OH:44]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: NC(=O)[C@@H](N)CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@@H](CO)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-serinamide with System A used for purification by mass directed autopreparation.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1
Yield: 95.4 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-116, 0.400 g, 0.890 mmol), KOH (0.099 g, 1.78 mmol), water (2 mL) and THF (4.0 mL) to afford 0.300 g of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CC(C)(O)CCl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(O)COc1ccc(C#N)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100%) EtOAc/DCM as eluent to give 4-(2-hydroxy-2-methyl-propoxy)benzonitrile (3.0 g, 94%) as a yellow solid. ESI-MS m/z calc. 191.1. Found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([OH:8])=[CH:5][C:4]=1[OH:9]
Reactant: Cc1cc(O)cc(O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(O)c1N

Procedure:
2.43 g (14.4 mmol) 5-methyl-4-nitrobenzene-1,3-diol were placed in 200 mL methanol and hydrogenated under a hydrogen atmosphere and with the addition of 0.20 g Pd/C (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CO.C(OCC)C>[CH3:15][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][CH:11]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(I)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C=Cc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 4-iodo-cinnamic acid in methanol was treated with a solution of diazomethane in diethyl ether. The reaction mixture was allowed to warm to ambient temperature, the volatiles were evaporated in vacuo to afford the title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:22]=1[CH:27]=[O:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ncccc1-c1cccnc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 3-tributylstannanyl-pyridine (255 mg, 0.693 mmol), 3-Bromo-pyridine-2-carbaldehyde (123 mg, 0.660 mmol), and Pd(PPh3)4 (53.1 mg, 0.046 mmol) in toluene (4 mL) was heated to 90° C. for 23 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30, then 0:100) afforded [3,3′]Bipyridinyl-2-carbaldehyde (35 mg, 29%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:38])[C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]3)=[N:25][N:26]=1>>[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:23]([CH3:38])[C:24]([C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]5)=[N:25][N:26]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: CCc1nc2cc3c(cc2o1)CCNCC3
Product: CCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (1.5 mmol) and 5-{5-[(3 chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a faint yellow slightly hygroscopic solid (0.75 mmol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O>>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: NC=O
Solvent: O=CO
Product: CC(N)c1cccc(Br)c1
Temperature: 172.5 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of 3-bromoacetophenone (10.0 g, 50 mmol), formic acid (12.0 g, 250 mmol) and formamide (50 mL) was heated at 165-180° C. with stirring for 24 h. The reaction mixture was cooled to room temperature and extracted with toluene; the extract was concentrated in vacuo. The residue was mixed with 3N hydrochloric acid (20 mL) and heated at reflux for 48 h, cooled to room temperature, washed with ether and neutralized with 20% aqueous NaOH solution. The neutralized solution was extracted with ether; the extract was dried over solid KOH and concentrated in vacuo to provide the title compounds as a light brown oil (5.7 g, 57%). 1H NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.21 (t, 1H), 4.14 (br d, 3H), 1.39 (d, 3H). MS (ESI) m/z: Calculated: 199; Observed: 200 (M+H+).