Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[O:24][CH3:25])[OH:4].C(N(C(C)C)CC)(C)C.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:21]([C:19]1[CH:18]=[CH:17][C:16]([O:24][CH3:25])=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:5]=2[CH:3]2[O:4][C:36](=[O:38])[NH:1][CH2:2]2)[CH:20]=1)([CH3:23])[CH3:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CNC(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 0.44 g of 2-amino-1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanol in 15 mL of CH2Cl2 was added 0.241 g of diisopropylethylamine, then 0.185 g of triphosgene. The mixture was stirred at 0° C. for 30 min, and then diluted with 30 mL of EtOAc and 20 mL of saturated NaHCO3. The phases were separated and the organic phase was washed with 20 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 5 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 380.2 (M+1). 1H NMR signals are doubled because of atropoisomerism 1H NMR (500 MHz, CDCl3): δ 7.90, 7.86 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.27 (dd, J=2.5 Hz, 8.5 Hz 1H), 7.03 (d, J=2.5 Hz, 0.5H), 6.87-6.93 (m, 1.5H), 5.65, 5.50 (t, J=8 Hz, 1H), 5.23, 5.09 (s, 1H), 3.75 (s, 1.5H), 3.69 (s, 1.5H), 3.68, 3.51 (t, J=9 Hz, 1H), 3.31, 3.19 (t, J=8.5 Hz, 0.5H), 2.90 (septet, J=7 Hz, 1H), 1.25, 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]([CH3:22])([CH3:21])[C:11](=[O:20])[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.O>CS(C)=O>[C:10]([C:11]1([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:4][O:20]1)([CH3:22])([CH3:21])[CH3:9]
Reactant: CC(C)(C)C(=O)COC1CCCCO1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C1(COC2CCCCO2)CO1
Temperature: 10 °C
Yield: 93.1 %

Procedure:
880 ml of absolute dimethylsulphoxide are added dropwise to a mixture of 38.2 g (1.27 mols) of sodium hydride (80% strength) and 271.5 g (1.23 mols) tri-methyl-oxosulphonium iodide at 10° C. under a nitrogen atmosphere, with stirring. The mixture is subsequently stirred for a further hour at room temperature and is then cooled to 10° C., and a solution of 219 g (1.1 mols) of 3,3-dimethyl-1-(tetrahydro-2H-pyran-2-yloxy)-butan-2-one in 250 ml of absolute dimethylsulphoxide is added dropwise at this temperature. The reaction mixture is stirred at room temperature for 48 hours and then poured into water. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the diluent under reduced pressure. 219.4 g (94% of theory) of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxymethyl) oxirane are obtained in this manner.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 72.5 %

Procedure:
The starting 2,6-difluoroaniline (18.1 g, 0.140 mol) was dissolved in 45 ml of pyridine and 36.1 g (0.155 mol) of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was stirred at room temperature for 15.5 hours. The pyridine was removed by evaporation at reduced pressure, and the residue was treated with 600 ml of 0.5N NaOH. After stirring to dissolve all soluble material the mixture was filtered through celite and the filtrate was acifified with 3N HCl. The precipitate which separated upon acidification was collected by filtration and dried to yield 33.0 g (73%) of the desired product as a pale red solid, mp 245°-247° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH:12]C(OC(C)(C)C)=O)=[CH:9][CH:8]=2)=[CH:5][C:4]([C:20]([F:23])([F:22])[F:21])=[N:3]1.FC(F)(F)C(O)=O.[Cl:31]CCl>>[ClH:31].[NH2:12][C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:5]=2)=[CH:8][CH:9]=1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)OC(C)(C)C)s1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(N)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbamate, trifluoroacetic acid and dichloromethane was stirred at room temperature for 2 days and then subjected to purification and salt formation in the usual way to give 5-(5-amino-2-thienyl)-1-methyl-3-trifluoromethyl-1H-pyrazole hydrochloride as light yellow powder crystals.
Reaction SMILES: [N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[Cl-].[Cl-].[NH3+:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][NH+:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:34])[F:35])=[CH:27][N:26]=3)[CH3:24])=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: O=C(O)Cc1ccc(-c2cnn3ncccc23)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](NC(=O)Cc1ccc(-c2cnn3ncccc23)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 0.69 g (2.74 mmol) (4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)acetic acid in 10.0 ml CH2Cl2 was added 0.96 g (3.28 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.48 g (3.56 mmol) of HOAt, 0.68 g (3.56 mmol) of EDC, and 1.43 mL (8.21 mmol) of DIEA. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient 0-100% EtOAc in hexanes) afforded 0.85 g (68%) of 2-(4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 8.40 (m, 2-H); 8.28 (s, 1H); 8.27 (d, J=2.93 Hz, 1H); 7.61 (dd, J=1.83, 6.41 Hz, 2H); 7.43 (m, 3H); 7.31 (d, J=8.61 Hz, 1H); 7.22 (dd, J=4.58, 9.07 Hz, 1H); 5.04 (quintet, J=6.86 Hz, 1H); 4.62 (q, J=8.43 Hz, 2H); 3.61 (s, 2H); 1.46 (d, J=7.05 Hz, 31-1). HRMS (ES) [M+1]+calcd for C23H21F3N5O2: 456.1647, Found: 456.1652. FLEPR alpha1I IP=5.0 nM.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([CH3:27])[CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N=C(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)OC1C
Agent: ClC(Cl)(Cl)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)oc1C
Reaction time: 3 h
Yield: 40 %

Procedure:
A solution of methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (108c) (4.4 g, 11.5 mmol) in dichloromethane (50 mL) was cooled to 0° C., and bromotrichloroethane (3.20 g, 16.1 mmol) and DBU (2.45 g, 16.1 mmol) were added. The mixture was stirred at the same temperature for three hours, washed with a 1 N aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. Following concentration, the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/2, 2/1) to obtain 1.75 g of the title compound as a colorless solid (40%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1>CN(C=O)C>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)c3ccccc3)c12
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Reaction time: 72 h
Yield: 92.8 %

Procedure:
N-Hydroxyphthalimide (2.60 g, 16.0 mmol) and triethylamine (2.20 mL, 16.0 mmol) were added to a suspension of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide (4.70 g, 11.4 mmol) in DMF (285 mL). The reaction mixture was allowed to stir for 3 days, then was concentrated under reduced pressure to a white slurry. Methanol was added and a white solid was isolated by filtration, washed with methanol, and dried under vacuum to afford 5.70 g of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.BrCC(C1C(C)=C(SCC)C=CN=1)=O.C([O-])([O-])=O.[K+].[K+]>>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][CH:2]=1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CCSc1ccnc(C(=O)CBr)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2[nH]cnc2c1

Procedure:
2-Chlorobenzimidazole is reacted with 2-bromoacetyl-4-ethylthio-3-methylpyridine in the presence of K2CO3 to give 2-chloro-1-[2-[4-ethylthio-3-methylpyridyl])-2-oxoethyl]benzimidazole. This is reacted with thiourea and treated with NH4OH to give 2-mercapto-1-(2-(2-(4-ethylthio-3-methylpyridyl))-2-oxoethyl)benzimidazole. Reduction of this product using NaBH4 gives 1-[2-hydroxy-2-(4-ethylthio-3-methylpyrid-2-yl)ethyl]-2-mercaptobenzimidazole.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[C:19]2[NH:18][C:17](=[O:20])[CH2:16][CH2:15][C:14]=2[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[CH2:23]([N:18]1[C:19]2[C:10]([O:9][CH3:8])=[CH:11][CH:12]=[C:13]([CH:21]=[O:22])[C:14]=2[CH2:15][CH2:16][C:17]1=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2c1N(Cc1ccccc1)C(=O)CC2
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium hydride (60% in oil) (1.07 g) was added at 0° C. to a DMF solution (50 ml) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (5.0 g), followed by stirring for 30 minutes. Benzyl bromide (3.47 ml) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 6.6 g (yield: 92%) of 1-benzyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a white powder.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]([OH:37])([CH2:33][CH:34](O)[CH3:35])[CH3:32]>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH:34]([CH3:35])[CH2:33][C:31]([OH:37])([CH3:32])[CH3:30])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(O)CC(C)(C)O
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Product: CC(CC(C)(C)O)Oc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-Methyl-pentane-2,4-diol by method Y. The product with the molecular weight of 493.63 (C29H36FN3O3) was obtained in this way; MS (ESI): 494 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1)[C:19](O)=[O:20].N1C=CC=CC=1.[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1>C(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)c2Cl)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C(=O)OC(C)(C)C)n4)c3)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 52.5 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.09 mL, 0.37 mmol) was added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (145 mg, 0.34 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.055 mL, 0.67 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (123 mg, 0.67 mmol) were added and the reaction stirred for 2 hours at RT. The reaction mixture was evaporated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a pale yellow oil (107 mg). m/z 611 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[C:36]([NH:38][C:39](=[O:51])[C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]4[CH2:50][CH2:49][CH2:48][NH:47]4)[CH:41]=3)[S:37][C:31]=2[CH2:30]1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:47]1[CH2:48][CH2:49][CH2:50][CH:46]1[C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[C:39]([NH:38][C:36]1[S:37][C:31]2[CH2:30][N:29]([CH3:28])[CH2:34][CH2:33][C:32]=2[N:35]=1)=[O:51])=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CN1CCc2nc(NC(=O)c3cccc(C4CCCN4)c3)sc2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2c2cccc(C(=O)Nc3nc4c(s3)CN(C)CC4)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
Stir a solution of 3,4-dimethoxybenzoic acid (49 mg, 0.265 mmol) and CDI (44 mg, 0.265 mmol) in DMF (2.5 mL) for 10 min at room temperature. Add the N-(5-Methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-pyrrolidin-2-yl-benzamide di-HCl (100 mg, 0.241 mmol) followed by Et3N (0.118 mL, 0.844 mmol), and stir the solution at room temperature for 24 h. Purify the crude reaction by reverse-phase prep-HPLC (10% to 90% CH3CN/water). Concentrate the fractions containing product to give the title compound as a solid (100 mg). MS, electrospray 507.5 (M+H), rt 1.13 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[C:13](OC)(=[O:18])[C:14](OC)=[O:15].[CH3:21]O>>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:14](=[O:15])[C:13](=[O:18])[NH:12][C:3]=2[C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: COC(=O)C(=O)OC
Reactant: Cc1ccc(N)c(N)c1C(=O)[O-]
Reactant: CO
Product: COC(=O)c1c(C)ccc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C

Procedure:
A solution of 2,3-diamino-6-methylbenzoic acid, methyl ester (compound 6) (1.14 g, 6.35 mmol) and dimethyl oxalate (3.34 g, 28.5 mmol) in MeOH (30 mL) was refluxed for 6 days. Upon cooling to room temperature, the precipitated product was collected and washed with a small amount of MeOH to give 1.02 g (69%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC>[C:12]([CH:4]([C:5]([CH3:7])=[O:6])[C:3]([O:9][CH2:10][CH3:11])=[O:8])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)C(C(C)=O)C(=O)OCC
Yield: 80.2 %

Procedure:
Sodium hydride (50% in oil, 39.6 g) was added portionwise to a solution of ethyl acetoacetate (107.5 g) in dry ether under nitrogen. Valeryl chloride (100 g) was added dropwise over 21/2 hours to the stirred suspension, and then poured into distilled water (500 ml.), and the ether layer was separated off and dried. The ether was removed to give ethyl 2-valerylacetoacetate (142 g) as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)=[O:21])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:38])[CH3:37])[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2].[ClH:41]>O1CCOCC1>[ClH:41].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:21])[NH:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:37])[CH3:38])[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}carbonyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see Intermediate 37)(90 mg, 0.163 mmol) in dioxane (2 ml) was treated with hydrogen chloride in 1,4-dioxane (4N, 2 mL, 8.00 mmol) and the resulting mixture stirred at room temperature for 5 h, then concentrated in vacuo. The resulting residue was triturated with Et2O and isolated by filtration to give isopropyl ((2S,4R)-1-acetyl-6-(4-((2-aminoethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate hydrochloride (68 mg, 0.139 mmol, 85% yield) as a pale yellow solid. LCMS (HpH, 2 min), Rt=0.78 min.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:20])=[N:12][C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:6])C.CC(C[AlH]CC(C)C)C.[H-].[Na+]>C1COCC1>[Cl:20][C:11]1[N:12]=[C:13]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:8]2[O:7][C@H:5]([CH3:6])[CH2:4][O:3][C:9]=2[N:10]=1
Reactant: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1COc2nc(Cl)nc(N3CCOCC3)c2O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propionic acid ethyl ester (175 mg, 0.50 mmol) in THF (5 mL) at −78° C. was added DIBAL-H (2.0 mL, 2.0 mmol, 1M solution in THF) and the resulting mixture warmed to 0° C. over 30 minutes. The reaction mixture was quenched with Rochelle's salt (1M aqueous solution) and the aqueous extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was taken up into THF (10 mL), to the resultant solution was added sodium hydride (60 mg, 1.50 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at RT for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording (R)-2-Chloro-6-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (157 mg, quantitative). LCMS: RT=2.89 min, [M+H]+=272/274.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CCCCCCC.C(OCC)(=O)C>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: Clc1nc2ccccc2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: N#Cc1nc2ccccc2s1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.1 %

Procedure:
A suspension of potassium cyanide (1.50 g, 23.0 mmol) in dimethylsulfoxide (DMSO, 100 mL) was prepared in a 1-L 3-necked flask fitted with a reflux condenser, a heating mantle and an internal temperature probe. The 2-chlorobenzothiazole (2.6 g, 2.0 mL, 15.3 mmol) was added to the reaction flask via pipet and the reaction was heated at 80° C. (internal temperature). The reaction was monitored periodically by TLC (9:1 heptane-ethyl acetate). After 5 hours the reaction appeared to be about 50% complete. After 17 hours the reaction was judged complete by TLC analysis. The reaction mixture was allowed to cool to room temperature and was then extracted with ether (5×100 mL). The extracts were dried over sodium sulfate and concentrated to give a yellow-orange solid. The crude solid was purified on silica gel (100 g) using 9:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.4 g (57%) of the desired product as a yellow-orange solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.