Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=O)C>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:22])[CH2:19][C:13]2[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1cc(Cl)ncc1Br
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 mol/L in tetrahydrofuran; 11.00 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (0.95 g) dissolved in tetrahydrofuran (15 mL) at −40° C. under argon atmosphere. The mixture is stirred for 2 h at −35 to −45° C. prior to addition of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.33 g) dissolved in tetrahydrofuran (15 mL). The reaction mixture is allowed to warm to room temperature over a period of 1 h. Ice-cold water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40) to give the title compound. Mass spectrum (ESI+): m/z=417/419/421 (Cl+Br) [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>CN(C=O)C>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4]
Reactant: CCOC(=O)c1ccccc1NC(=O)CBr
Reactant: Nc1ccccc1F
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NC(=O)CNc1ccccc1F
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of ethyl 2-((bromoacetyl)amino)benzoate (1.0 g, 3.5 mmol) and 2-fluoroaniline (1.0 g, 0.87 mL, 9 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with 3×50 mL of ethyl acetate. The layers were separated, and then the organic layer was dried (MgSO4), filtered and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 0.75 g (68%) of the title compound, mp 79°-81° C.: 1H NMR (DMSO-d6) δ11.41 (s, 1H), 8.59 (dd, J=8.4, J=0.8, 1H), 7.91 (dd, J=8.0, J=1.2, 1H), 7.61 (ddd, J=8.8, J=7.6, J=1.6, 1H), 7.17 (ddd, J=8.0, J=7.6, J=1.2, 1H), 7.08 (ddd, J=9.2, J=8.0, J=1.2, 1H), 6.93 (ddd, J=8.8, J=8.0, J=1.2, 1H), 6.63-6.54 (m, 2H), 6.34 (t, J=5.6, 1H), 4.18 (q, J=7.2, 2H), 3.90 (s, J=5.6, 1H), 1.21 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ170.08, 166.60, 151.12 (d, J=237), 139.59, 135.99 (d, J=11.3), 134.19, 130.67, 124.76 (d, J=3.1), 123.04, 120.08, 117.07 (d, J=6.9), 116.37, 114.49 (d, J=18.2), 112.12 (d, J=3.0), 61.13, 48.31, 13.86; MS (EI, m/z) 316 (M+). Anal. Calcd for C17H1 7N2O3F: C, 64.54; H, 5.42; N, 8.86. Found: C, 64.18; H, 5.37; N, 8.83.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[NH:20][NH2:21]>C(Cl)Cl>[NH:21]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:20][C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (100 mL) and benzyl chloroformate (103 mL) were added to ethyl carbazate (50.0 g) in methylene chloride (400 mL) at 0° C., followed by stirring at room temperature for 18 hours. The reaction mixture was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was washed with brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give benzyl ethyl hydrazine-1,2-dicarboxylate as an oily product (31.7 g, 27.7%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[CH2:14]=[C:15]1[CH2:24][CH2:23][C:18]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>>[CH3:12][C:8]1[CH:7]=[C:6]([C:5]#[C:4][C:3]2[CH2:14][C:15]3([CH2:16][CH2:17][C:18]4([CH2:19][CH2:20][CH2:21][CH2:22]4)[CH2:23][CH2:24]3)[O:1][N:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(C#CC(Cl)=NO)c1
Reactant: C=C1CCC2(CCCC2)CC1
Product: Cc1cccc(C#CC2=NOC3(CCC4(CCCC4)CC3)C2)c1

Procedure:
The title compound was prepared following the procedure described for Compound 3c, using Compound 91d instead of Compound 3b and Compound 89a instead of Compound 3a. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (ISOLERA®TM-Biotage; gradient Petroleum Ether-EtOAc from 97:3 to 9:1) to give the title compound as a white-yellowish solid. Yield: 55.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].I[CH3:34].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH3:34])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.435 mmol) in dry DMF (2.0 mL) is added iodomethane (0.136 mL, 2.18 mmol), the mixture is cooled to 0° C., and NaH (60% suspension in oil, 35 mg, 0.87 mmol) is added in portions over 5 min. The mixture is stirred at 0° C. for 1 h 40 min, and it is quenched by addition of water and acidified with 2N HCl. The mixture is diluted with ethyl acetate and washed with brine. The organic layer is separated, dried over Na2SO4, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with 0→50% ethyl acetate in hexane to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (65 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
2.5 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine were dissolved in 50 ml of pyridine and treated at room temperature with a solution of 1.7 g of benzoyl chloride in 20 ml of tetrahydrofuran. After stirring at room temperature for two hours the reaction mixture was poured on to ice-water and, after acidification with 3N hydrochloric acid, extracted with ethyl acetate. The oil obtained after drying and evaporating the organic phase was crystallized from hexane/ethyl acetate and gave 3 g of N-(5,6,7,8-tetrahydro-5,5,8.8-tetramethyl-2-naphthyl)benzamide in white crystals, m.p. 146° C.-148° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:6]2.[C:19](#[N:23])[CH2:20][C:21]#[N:22].C([O-])(=O)C.[K+].II>CO>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[C:20]([C:19]#[N:23])[C:21]#[N:22])[CH:10]=[CH:11]1)[S:6]2
Reactant: FC(F)(F)c1ccc2c(c1)Sc1ccccc1N2
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: II
Agent: [K+]
Solvent: CO
Product: N#CC(C#N)=c1ccc2c(c1)Sc1cc(C(F)(F)F)ccc1N=2

Procedure:
To a stirred solution of 2.6 g 7-trifluoromethylphenothiazine, 1 g malononitrile and 4 g potassium acetate in 70 ml methanol was added a solution of 4 g iodine in 50 ml methanol. The precipitated dye was filtered, washed repeatedly with methanol and recrystallised in chloroform-methanol. Yield 0.6 g (18%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34](Cl)=[O:35])=[CH:33][C:28]=2[O:27][CH2:26]1>C(OCC)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34]([C:32]4[CH:31]=[CH:30][C:29]5[O:25][CH2:26][O:27][C:28]=5[CH:33]=4)=[O:35])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc3c(c1)OCO3)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 67 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 67%. Melting point: 165-167° C. (Ethyl ether-hexane).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=429.13.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]2([CH:16]([CH3:18])[CH3:17])[O:13][C:12](=[O:14])[CH:11]=[C:10]([OH:15])[CH2:9]2)=[CH:2]1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:11]1[C:12](=[O:14])[O:13][C:8]([CH2:7][CH2:6][C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)([CH:16]([CH3:18])[CH3:17])[CH2:9][C:10]=1[OH:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCc2ccoc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccoc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-18; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1 mmol), potassium carbonate (4 mmol) in DMF (4 mL). The product was flash chromatographed over silica gel using 70:20:10 hexane:EtOAc:CH2Cl2, mp 62-70° C. MS (APCI): 457 (M−H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:10])[CH2:8][CH3:9]>P(=O)(O)(O)O>[CH3:9][C:8]([C:7](=[O:10])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4]
Reactant: CCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CC(=O)C(C)=CC(=O)O

Procedure:
Prepared from glyoxylic acid (16.1 g, 0.18 mol), 2-butanone (45.6 g, 0.63 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 2.07, s, 3H, CH3; 2.40, s, CH3; 6.57, s, 1H, H2. 13C n.m.r. δ (CDCl3): 13.2, CH3; 26.2, CH3; 125.2, C2; 152.6, C3; 171.2, C1; 199.8, C4.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1([OH:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1)=O)(C)(C)C.C(Cl)Cl.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1([OH:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of benzyl 3-{3-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-3-hydroxypyrrolidine-1-carboxylate (4.38 g, 0.0106 mol) in methylene chloride (12.00 mL, 0.1872 mol) at rt was added trifluoroacetic acid (10.00 mL, 0.1298 mol) and the reaction mixture was stirred at rt for 4 h, LCMS (m+1, 3142) indicated that the reaction was complete. The volatiles were removed and NMR data supported the formation of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14](F)=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[Br:28]C1C(Cl)=NC(Cl)=NC=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([Br:28])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2Br)CC1

Procedure:
The titled compound was synthesized analogously as compound 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one, by using 5-bromo-2,4-dichloropyrimidine. MS 431.4 and 433.3 (M+N, Br pattern); UV 222.3, 263.9 nm.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].N1CCCC1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CCOC(C)=O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH2:14][CH2:13]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 4-bromo-2-chloro-5-fluorobenzoic acid (50 g, 0.25 mol) in 200 mL of EtOAc at 0° C. (ice/water bath) was added triethyl amine (237 mL, 0.50 mol), pyrrolidine (41.2 mL, 0.5 mol), followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (CAS #68957-94-8) (237 mL, 0.37 mol, 50 wt %, EtOAc). After 1 hr, the reaction was quenched with a saturated solution of NaHCO3, and extracted with EtOAc, and CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75 L column, eluting with a gradient of 2%-50% EtOAc/hexanes. The product containing fractions were collected and concentrated to give the title compound (52 g, 68% yield) as a white solid: Rf=0.23 (40% EtOAc/hexanes); LRMS m/z Calcd for C11H10BrClFNO, 306.6, found, 306, 308, 310 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J=6.2 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.54 (apt t, J=6.6 Hz, 2H), 3.13 (apt t, J=6.6 Hz, 2H), 1.92-1.83 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 164.5, 158.1 (d, JC-F=249.5 Hz), 138.2, 134.3, 126.0, 115.5 (d, JC-F=25.5 Hz), 110.3 (d, JC-F=22.5 Hz), 47.0, 45.8, 26.0, 24.6.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-thiazole (1.90 g) and triethyl phosphite (3.49 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate as a pale-yellow oil (2.48 g, yield 83%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1)(=[O:4])=[O:3].[C:16](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:16][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Reaction time: 3 h

Procedure:
To a 25 ml round bottom flask under N2 was added (101.8mg, 0.4346 mmoles) ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (180.2 mg, 1.3038 mmoles, 3.0 eq.) potassium carbonate, and (5 ml) acetonitrile. The mixture was then agitated at ambient temperature while (33.8 μl, 0.5429 mmoles, 1.25 eq.) iodomethane was added. The reaction was allowed to run at ambient temperature for 3 hours. An electrospray mass spec indicated mostly starting material. The N2 line was removed and an additional (40 μl, 0.6425 mmoles, 1.5 eq.) iodomethane were added. The reaction was left at ambient temperature overnight. The reaction was quenched with (5 ml) 1N HCl and was extracted with dichloromethane. The organic layer was washed with water and then evaporated to dryness. The resulting oil was purified by preparative HPLC, yielding (70 mg) of ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[C:15]([F:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(F)c(Cl)cc21
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75 C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 1.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>N1C=CC=CC=1.ClCCl>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a stirred suspension of 3-bromophenol (50 g, 0.29 mol) in pyridine (200 mL) and dichloromethane (100 mL) was added dropwise acetyl chloride (25 mL, 0.35 mol) at 0° C. and the mixture was stirred 18 h at room temperature. LC-MS showed that the reaction was complete. Pyridine and dichloromethane was evaporated in vacuo. Water (600 mL) was added and acidified with hydrochloric acid at pH 2. The reaction mixture was extracted with ethyl acetate (500 mL×3) and the organic phase was dried over anhydrous sodium sulfate, filtrated, concentrated and purified by column chromatography (PE:EA=60:1) to afford compound E-1 as a colorless liquid (46 g, 74%).
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[N:19]=[C:18]([SH:21])[S:20][C:2]=2[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1sc(S)nc1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
50.0 g. (0.157 m.) 3-bromo-3-p-chlorobenzoylpropionic acid, ethyl ester and 17.5 g. (0.157 m.) ammonium dithiocarbamate in 500 ml. absolute ethanol are heated at gentle reflux for 5 hours. The reaction mixture is allowed to stand at room temperature overnight. The solid which results is dissolved in 800 ml. of methylene chloride and the solution is washed with 500 ml. of water. The methylene chloride layer is dried over anhydrous magnesium sulfate, and after removal of the methylene chloride the residual solid is recrystallized from ethanol. 39.2 g. (80% yield) of title product is obtained, m.p. 176°-178° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(C(C)C)CC)(C)C>CCCCO>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncncc2c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1ccc2ncncc2c1
Temperature: 120 °C
Yield: 38.9 %

Procedure:
To the solution of C-quinazolin-6-yl-methylamine (1.2 g, 7.916 mmol) and 2.06 gram of 3,5-dibromo-pyrazin-2-ylamine (2.06 g, 7.916 mmol) in n-BuOH (18 mL) was added diisopropylethylamine (7.0 mL, 40 mmol) at room temperature. The reaction mixture was heated up to 120° C. for two days under nitrogen. The reaction was cooled down, n-BuOH is evaporated directly via rotavapor, followed by purification via a silica gel column to get 5-Bromo-N*3*-quinazolin-6-ylmethyl-pyrazine-2,3-diamine (1.02 g, yield 42%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])[CH2:13]2)=[O:11])[CH:8]=1)[CH2:2][CH3:3].O.[OH-].[Li+]>CO.O>[CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13]2)=[O:11])[CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1cn(CC(=O)N2CCOC(C(=O)OCc3ccccc3)C2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1cn(CC(=O)N2CCOC(C(=O)O)C2)nn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a 25-mL RBF, benzyl 4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylate (0.105 g, 0.282 mmol) was taken up in MeOH (1.0 mL). Lithium hydroxide hydrate (0.0130 g, 0.310 mmol) was added as a solution in water (1.0 mL). The mixture was stirred at ambient temperature for 14 h, then concentrated, and used crude in the subsequent step. MS m/z 283 (M+1).