Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:21]=[C:20]([OH:22])[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C1CC(O)CC1C(=O)NC1(C(OCC)=O)CC1C=C)=O)(C)(C)C.[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62](OC3C4C(=C(C)C(OC)=CC=4)N=C(C4C=CC=C(C)N=4)C=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]>>[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62]([O:22][C:20]3[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=[C:12]([C:10]4[N:11]=[C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[S:8][CH:9]=4)[CH:21]=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Reactant: COc1ccc2c(O)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Agent: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(C5CCCCC5)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Yield: 50 %

Procedure:
The title compound 121 was prepared in 50% yield from 2-(2-cyclohexylthiazol-4-yl)-4-hydroxy-7-methoxy-8-methylquinoline (119) and 2-(1-ethoxycarbonyl-2-vinylcyclo-propylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ester following the procedure reported for the preparation of 17-[2-(6-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid ethyl ester (101): m/z=715 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1nnc(-c2ccc(Cl)cc2)c(C)n1
Solvent: O
Solvent: CCO
Product: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Yield: 15 %

Procedure:
A solution of 6-(4-chlorophenyl)-5-methyl-3-methylthio-1,2,4-triazine (32.4 g) and hydrazine hydrate (40.8 g) in ethanol (110 ml) was heated for 2 hours. After cooling, the precipitates were collected by filtration, washed with ethanol, dried and recrystallized from ethanol to give 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.54 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH:15]=1)=[O:12])=[O:5])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C1CCCN1C(=O)Sc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the title C compound, 1-(3-hydroxy-phenylsulfanylcarbonyl)-pyrrolidine-2-carboxylic acid ethyl ester (1.1 g, 3.73 mmol) and potassium carbonate (0.78 g, 5.59 mmol) in DMF (25 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.78 g, 3.73 mmol) at RT. The reaction mixture is stirred for 16 h. The stirring is continued for another 3 h at 40° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester as a clear, heavy oil.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>O1CCCC1.O>[C:21]([O:20][C:18]([NH:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred solution of 2-amino-2,4-dimethylpentanoic acid (1 g, 6.89 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added K2CO3 (3.81 g, 27.5 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the resultant mixture (BOC)2O (3.20 mL, 13.77 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate (3×15 mL) and acidified with a saturated aqueous solution of citric acid (25 mL) then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentanoic acid (1.6 g, 6.89 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.36 (bs, 1H), 2.10 (m, 1H), 1.77 (m, 2H), 1.74-1.65 (m, 3H), 1.59 (s, 9H), 0.89 (m, 3H), 0.94 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:20]
Reactant: O=C(Br)CBr
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(NC(=O)CBr)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of 2-methyl-3-nitroaniline (5.0 g, 32.9 mmol) in 120 ml of CH2Cl2 was added 120 ml of saturated NaHCO3 and bromoacetyl bromide (2.85 ml, 6.6 g, 32.9 mmol). The reaction was stirred at room temperature for 64 hours. The layers were separated, and the organic layer was washed with water, brine and then dried over MgSO4. Solvent evaporation afforded 2-bromo-N-(2-methyl-3-nitrophenyl)acetamide as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(N)cc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-iodo-6-methylpyridin-3-amine (125 mg, 0.534 mmol) in methylene chloride (1 mL) was added triethylamine (0.087 mL, 0.627 mmol) and cooled at 0° C. Into the reaction was added 3-(trifluoromethyl)benzoyl chloride (0.0812 mL, 0.538 mmol) dropwise and stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water saturated Na2CO3, saturated NaCl, dried (MgSO4) and stripped in vacuo. The product was used in the next reaction without purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:13][C:12]2[N:11]3[C:14]([CH3:17])=[N:15][N:16]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:6]=2[CH:5]=1)[CH3:3].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][CH:2]([C:4]2[S:13][C:12]3[N:11]4[C:14]([CH3:17])=[N:15][N:16]=[C:10]4[CH2:9][N:8]=[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[C:6]=3[CH:5]=2)[CH3:3])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccccc1C1=NCc2nnc(C)n2-c2sc(C(C)O)cc21
Solvent: c1ccncc1
Product: Cc1ccccc1C1=NCc2nnc(C)n2-c2sc(C(C)OC(=O)c3ccc(Cl)cc3)cc21
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
To a solution of 1.1 g of 2-(1-hydroxyethyl)-4-(2-methyl-phenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 14 ml of pyridine is added 0.63 g of 4-chlorobenzoyl chloride under ice-cooling and then stirred for 2.5 hours. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure to give 0.5 g of 2-(1-(4-chlorobenzoyl)oxyethyl)-4-(2-methylphenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine as an amorphous powder.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1>C(O)C>[CH2:2]([O:9][NH:10][C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S1(=O)N=C(NOCc2ccccc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of O-benzylhydroxylamine hydrochloride (500 mg) and triethylamine (200 mg) in ethanol (10 ml) was added 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg). The mixture was stirred for 3 h and concentrated in vacuo. The crude product was taken up in hot ethyl acetate (50 ml) and cooled to room temperature and the precipitate was collected by filtration to give the title compound (200 mg, 59%); m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 11.2 (br s, 1H, NH), 7.7-7.35 (m, 9H, arom. and NH), 4.49 (s, 2H, CH2). Analysis: C14H12ClN3O3S requires C, 49.78; H, 3.58; N, 12.44; (found C, 49.49; H, 3.80; N, 12.09).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=34)[CH:3]=[N:2]2)[CH2:29][N:28]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([NH:36][CH:37]([CH3:38])[CH3:39])=[O:35])=[CH:32][CH:31]=2)[CH2:27]1)#[N:24]
Reactant: CC(C)NC(=O)c1ccc(N2CC(=CC#N)C2)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (0.811 g, 2.58 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-N-isopropylbenzamide (0.625 g, 2.45 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (190 μL, 1.3 mmol) in acetonitrile (8 mL, 200 mmol) was heated at 50° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was diluted with dichloromethylene, neutralized with 0.5 N HCl aqueous solution to about pH 7. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (1.40 g, 84.3%), which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=570.3.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([Si:10]([O:13][CH:14]([C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20]1)[CH2:15][CH:16]=[CH:17]I)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH2:26]=[O:27]>CCCCC.C1COCC1>[Si:10]([O:13][CH:14]([C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20]1)[CH2:15][CH:16]=[CH:17][CH2:26][OH:27])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CCCC1(C(CC=CI)O[Si](C)(C)C(C)(C)C)CCC1
Reactant: C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCC1(C(CC=CCO)O[Si](C)(C)C(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
tert-Butyllithium (1.32 mL of a 1.7M solution in pentane, 2.25 mmol) was added to a solution of the vinyl iodide 6 (460 mg, 1.25 mmol) in THF (2.2 mL) at −78° C. After 0.5 h paraformaldehyde (50 mg, 1.67 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 4:1 hex/EtOAc) yielded 103 mg (33%) of the alcohol 7 as a clear, colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.39 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, and N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The stirring was continued at ambient temperature for 6 hours, and another portion of N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The reaction mixture was heated for 23 hours at 110° C. and cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 15% yield (0.06 g): mp 163-164° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2 H), 7.41 (d, J=8.1 Hz, 2H), 4.55 (s, 2H), 4.15-4.09 (m, 2H), 3.51-3.45 (m, 2 H), 2.68 (s, 3H), 2.41 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 170.8, 167.3, 160.5, 155.3, 154.5, 139.6. 128.5, 125.9, 125.8, 122.1, 109.0, 47.6, 421 41.9, 17.5, 11.6: MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.O>[OH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:3]=2[CH:2]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: OCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 14 g (103 mmol) of 3-phenyl-1-propanol and 18.2 g (123 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 15 g (113 mmol) of aluminum chloride. After the addition of aluminum chloride was complete, the reaction was heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature and 100 mL of water was added, followed by 100 mL of 1N HCl. The reaction mixture was stirred for 2 hours, filtered through a Celite pad and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 13.45 g (53%) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc2[nH]nnc2c1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A1, except reacting 5-bromooxindole (39 mg, 0.185 mmol) with 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (30 mg, 0.204 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, d6-DMSO) δ 15.97 (s, 1H), 10.85 (s, 1H), 9.27 (s, 1H), 8.37 (d, J=9.2 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H); MS ESI 341.0 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.00.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:21](OC)=[O:22])=[N:11][C:12]([O:19][CH3:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>CO.O>[NH:26]([C:21]([C:10]1[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][C:13]([C:15]([F:18])([F:16])[F:17])=[C:12]([O:19][CH3:20])[N:11]=1)=[O:22])[NH2:27]
Reactant: NN
Reactant: COC(=O)c1nc(OC)c(C(F)(F)F)cc1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: COc1nc(C(=O)NN)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 97.1 %

Procedure:
A suspension of methyl 3-(tert-butoxycarbonylamino)-6-methoxy-5-(trifluoromethyl)picolinate (step 2) (3.1 g, 8.85 mmol) in dry MeOH (20 ml) was treated with hydrazine monohydrate (1.108 g, 22.12 mmol) and the suspension was heated at reflux overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration and dried in a vacuum oven to afford the title compound as a light brown solid (3.01 g). LC-MS Rt=1.27 min [M+H]+ 251 [−minus Boc group] (Method HighpH_v003.).
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:25]=[C:26]([C:30]1[N:38]2[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][C:31]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:17][C:2](=[CH2:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])[C:26](=[O:25])[C:30]3[N:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: C=C(C)CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CN1CCN(c2ccc(NC(=O)C(=O)c3c(-c4ccccc4)cc4n3CCCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To an ice-cold solution of 4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 89, 500 mg, 2.16 mmol) and triethylamine (0.6 mL, 4.32 mmol) in dry DCM (12 mL) was added a solution of oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 726 mg, 2.52 mmol) in DCM (5 mL). The mixture was warmed to room temperature and stirred for 30 min then diluted with DCM, washed successively with water, sodium bicarbonate solution and brine, then dried over sodium sulfate. Concentration gave a residue which was purified by preparative TLC using ethyl acetate and hexane (3:7) as eluent to afford N-{4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (220 mg, 21%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]=[C:10]([OH:17])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][C:10]([OH:17])=[N:11][C:12]=1[CH:14]([CH3:15])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)nc(O)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Temperature: -3 °C
Yield: 98.5 %

Procedure:
4-(4-Fluorophenyl)-6-isopropylpyrimidin-2-ol (8.00 g, 34.1 mmol) was charged to a reactor followed by DMF (100 mL). The suspension was stirred, cooled to −3° C. and N-bromosuccinimide (6.25 g, 34.8 mmol) added. The reaction mixture was warmed to 20° C. and stirred overnight. Water (100 mL) was charged to the reaction mixture and the crystalline mixture stirred for 1 hour before filtering off. The isolated solid was washed twice with water (25 mL) and the solid dried in a vacuum oven at 50° C. 5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (10.45 g, 97% yield) was obtained as a white solid;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:15])=[CH:4][N:3]=1.[CH2:16]([N:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)[CH3:17].Cl.O1CCOCC1>C(O)(C)C>[Cl:15][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:29][C:26]2[CH:27]=[CH:28][C:21]3[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)CCNc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCCC(=O)NC)n3)cc2CC1
Yield: 23.9 %

Procedure:
A solution of 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-propionamide (35 mg, 0.14 mmol) in isopropanol (3 mL) was treated 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (27 mg, 0.14 mmol) and 4N HCl/dioxane (0.035 mL, 0.14 mmol). The reaction was irradiated at 130° C. for a total of 20 minutes. A white precipitate formed in the reaction mixture, which was collected via vacuum filtration and triturated with acetonitrile (5 mL) to afford 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-propionamide (13.5 mg) as the HCl salt. LC/MS (ESI)=403.02 (M+H), MP=206.1° C. 1H NMR (400 MHz, DMSO, d6) δ 10.51 (m, 1H), 10.05 (m, 1H), 8.12 (s, 1H), 7.88 (m, 1H), 7.59 (s, 1H), 7.42 (m, 1H), 7.17 (d, 1H, J=8.34 Hz), 3.62 (m, 7H), 3.29 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.59 (s, 3H), 2.45 (m, 2H), 1.27 (m, 3H).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:10][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)[O:12][N:11]=1
Reactant: CC=NO
Reactant: C#Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)nc2)ccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)OC(C)(C)C)nc3)ccn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of NCS (0.36 g, 2.70 mmol) in DMF (2 mL) was treated with acetaldoxime (0.16 g, 2.70 mmol), stirred at RT for 0.5 h, added to a solution of tert-butyl (5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.28 g, 0.90 mmol) and TEA (2 mL) in DMF (2 mL) and heated at 60° C. for 2 h. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford tert-butyl (5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate (250 mg, 75%). MS (ESI) m/z: 369.1 (M+H+).