Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+:1].C([O-])(=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22](Cl)=[O:23]>CC(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22]([NH2:1])=[O:23]
Reactant: [NH4+]
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C(N)=O)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
Acetic acid, ammonium salt (3 g) was added at RT to a solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in 2-propanone (30 ml). The mixture was stirred at RT for 5 hours. Acetic acid, ammonium salt was filtered off and the solvent was evaporated. The residue was taken up in CH2Cl2, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.6 g (57%) of (±)-2-chloro-a-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetamide (comp. 1.18).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].[CH3:7][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:38])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH3:16].Br[CH2:60][CH2:61][CH2:62][CH2:63][C:64](OCC)=O>CC#N>[C:1]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][N:10]([CH2:9][C:8]([CH3:7])([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:38])[CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:16])[CH3:17])([OH:4])=[O:2]
Reactant: CC(C)(CNCCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CNCCN(CCCCCC(=O)O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 66.8 %

Procedure:
K2CO3 (1.92 g, 13.9 mmol, 100 mol %) was added to N,N'-bis (2-methyl-2-triphenylmethylthiopropyl)ethylenediamine (10.03 g, 13.9 mmol) in CH3CN (60 mL), followed by ethyl 5-bromovalerate (3.30 mL, 20.8 mmol, 150 mol %). The reaction was heated at reflux under argon overnight. The solution was then concentrated to a paste and partitioned between 0.25M KOH (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL) and the combined ethyl acetate layers were washed with 50 mL water and NaCl solution (2×50 mL), dried with Na2SO4 and concentrated to an orange oil. Purification by flash chromatography (300 g flash silica, 100% CHCl3 to 5% MeOH/CHCl3) gave pure title compound (7.75 g, 66% yield). FABMS analysis yielded an (MH+) of 849 (compared with a calculated molecular weight of 849.24 for the compound C55H64N2O2 S2).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][N:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[C:15]1([C:21]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][C:11]([F:14])([F:13])[C:5]1[N:6]=[CH:7][C:8]2[CH2:9][N:34]([C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:2][C:3]=2[CH:4]=1
Reactant: FC(F)(F)c1cc(CCl)c(CCl)cn1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cc2c(cn1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2 (b) from 4,5-Bis-chloromethyl-2-trifluoromethyl-pyridine and triphenylmethylamine. White solid.
Reaction SMILES: C1(C)C=CC(S(OC([C:13]2[N:14]=[C:15]([C:21](=[S:23])[NH2:22])[NH:16][C:17]=2[N+:18]([O-:20])=[O:19])C)(=O)=O)=CC=1.[Cl:25][CH2:26][C:27]([CH2:29]Cl)=O.O.O1CCOC[CH2:33]1>>[CH3:33][N:16]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:13][N:14]=[C:15]1[C:21]1[S:23][CH:29]=[C:27]([CH2:26][Cl:25])[N:22]=1.[Cl:25][CH2:26][C:15]1[N:14]=[CH:13][S:23][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)OC(C)c2nc(C(N)=S)[nH]c2[N+](=O)[O-])cc1
Solvent: O
Product: ClCc1cscn1
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Temperature: 130 °C

Procedure:
The 2-thiocarbamyl compounds from Example 1 (0.27 mole) and 1,3-dichloroacetone (0.55 mole) in dioxan (55 ml.) were stirred and heated at 130° C. for 2 hours. The mixture was poured into water, the resultant precipitate washed with hot water and dried to yield 2-(1-methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole m.p. 160°-2° C. and 2-(1-p-toluenesulphonyloxyethyl)-5-nitroimidazol-2-yl)-4-chloromethylthiazole respectively. The 1-p-toluenesulphonyloxy compound, on treatment as described at the end of Example 2, yielded 2-(1-vinyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH:27]([O:34][CH3:35])[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH3:33].[CH:36]([C:39]1[S:40][CH:41]=[C:42]([C:44]([N:46]2[CH2:51][C:50]3([CH2:56][CH2:55][N:54]([CH2:57][CH2:58][O:59][C:60]4[CH:73]=[CH:72][CH:71]=[CH:70][C:61]=4[CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])[CH2:53][CH2:52]3)[O:49][CH2:48][CH2:47]2)=[O:45])[N:43]=1)([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:27]([O:26][CH3:25])[O:34][CH3:35])[C:67](=[O:68])[CH2:66][CH2:65][O:64][CH2:63][CH2:62][C:61]1[CH:70]=[CH:71][CH:72]=[CH:73][C:60]=1[O:59][CH2:58][CH2:57][N:54]1[CH2:53][CH2:52][C:50]2([O:49][CH2:48][CH2:47][N:46]([C:44]([C:42]3[N:43]=[C:39]([CH:36]([CH3:38])[CH3:37])[S:40][CH:41]=3)=[O:45])[CH2:51]2)[CH2:56][CH2:55]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCC(OC)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)O)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC(OC)OC)C(=O)CCOCCc1ccccc1OCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reaction time: 1 h

Procedure:
HATU (0.337 g) was added to a stirred solution of N-(2,2-dimethoxyethyl)butan-1-amine (0.105 g), 3-(2-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-acid (0.390 g) (example 178 step d) and Hunig's Base (0.516 mL) in N,N-dimethylformamide (3 mL). After 1 h, the solution was partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with brine (×3) and evaporated in vacuo. Purification was silica gel chromatography eluting with 10% triethylamine in ethyl acetate. Yield 0.4 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-fluorobenzenesulfonyl chloride (0.051 g, 0.263 mmol) the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide was obtained (66 mg, 0.125 mmol, 52.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.98 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 2H), 7.36-7.46 (m, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.20-7.29 (m, 1H), 6.75 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.40 (s, 9H). MS (ES+): 502 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO.CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Reaction time: 16 h
Yield: 721.6 %

Procedure:
To a mixture of 5-Iodo-isophthalic acid dimethyl ester (9.00 g, 3.12 mmol) in methanol/acetone (3:1, 18 ml) was added 4 N aqueous lithium hydroxide (0.78 ml, 3.12 mmol). This mixture was stirred for 16 hours, neutralized with 1 N hydrochloric acid, extracted with ethyl acetate, dried over magnesium Sulfate and the solvent removed under reduced pressure. The crude was purified by silica gel chromatography to afford 5-iodo-isophthalic acid monomethyl ester (6.89 g, 80% yield) as a white solid. MS: m/z 306.1 (M+H+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: C1COCCN1
Reactant: Clc1ccc2c(I)cccc2n1
Product: c1ccc2c(c1)CC[C@H]2Nc1ccc2c(N3CCOCC3)cccc2n1

Procedure:
The title compound, MS: m/e=346.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, (R)-1-aminoindane and morpholine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[N:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH2:20])[CH:11]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C>[Br:9][C:4]1[N:3]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:7]=[C:6]([NH:20][C:12]2[CH:11]=[N:10][C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cc(Br)nc(Br)n1
Reactant: Nc1cnc2ccccc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Temperature: 45 °C

Procedure:
To a solution of 2,4,6-tribromopyrimidine (5.40 g, 17.2 mmol) in acetonitrile (60 mL) was added quinolin-3-amine, followed by DIEA (8.99 mL, 51.6 mmol). The reaction mixture was heated to 45° C. overnight. Morpholine (1.50 mL, 17.2 mmol) was then added, and the reaction mixture continued heating for 4 h. The reaction mixture was then cooled to room temperature, concentrated and dissolved in EtOAc (about 500 mL), the organic solution was washed with saturated NaHCO3 (3×), H2O (2×), brine (1×) and dried over Na2SO4. The solution was then evaporated in the presence of silica gel and purified by column chromatography (SiO2, 15-25% EtOAc/Hexanes) to yield N-(6-bromo-2-morpholinopyrimidin-4-yl)quinolin-3-amine. LC/MS (m/z): 386.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[CH2:36][C@H:35]([CH3:37])[NH:34][CH2:33][C@H:32]2[CH3:38])=[CH:28][CH:27]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:34]1[CH2:33][C@H:32]([CH3:38])[N:31]([CH2:30][C:29]2[CH:39]=[CH:40][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:36][C@H:35]1[CH3:37])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of tert-butoxycarbonylamino-acetic acid (0.71 g, 4.05 mmol) in dichloromethane (40 mL) was added 4-dimethylaminopyridine (0.74 g, 6.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g, 6.07 mmol) and 1-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine (0.90 g, 4.05 mmol). The reaction was stirred overnight at ambient temperature. The reaction was diluted with dichloromethane and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.45 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=1[O:25][CH3:26].C(O)(=O)C.C(OCC)(=O)C>O>[CH3:26][O:25][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:17][C:12]=1[NH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(N)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Nc2ccc([N+](=O)[O-])cn2)c(OC)c1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
To 2-chloro-5-nitropyridine (3.11 g, 20 mmol) were added ethyl 3-(4-amino-3-methoxyphenyl)propionate (4.38 g, 20 mmol) and acetic acid (10 mL), and the resulting solution was stirred for 13 hours at 100° C. To the reaction solution were added ethyl acetate and water. The ethyl acetate layer was separated, washed with brine, a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 3.78 g of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:8][CH2:9][CH2:10][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:16]([CH3:30])[C:15]1=[O:31])[CH2:12][OH:13])([CH3:6])([CH3:5])[CH3:4].I[CH3:45]>CN(C)C=O>[C:3]([Si:7]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:8][CH2:9][CH2:10][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=2)[CH:16]([CH3:30])[C:15]1=[O:31])[CH2:12][O:13][CH3:45])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC1C(=O)N(C(CO)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1c1cccc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Yield: 61.1 %

Procedure:
NaH (55% dispersion in mineral oil, 20 mg, 0.45 mmol) was added at 0° C. to a solution of 1-[3-(tert-butyl-diphenyl-silanyloxy)-1-hydroxymethyl-propyl]-3-methyl-4-(3-trifluoromethyl-phenyl)-piperazin-2-one (224 mg, 0.38 mmol) in N,N-dimethylformamide (3.5 mL), then after 5 min a solution of iodomethane (54 mg, 0.45 mmol) in N,N-dimethylformamide (1.5 mL) was added, then after 3 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 19:1) afforded the title compound (139 mg, 61%). Light yellow oil, MS: 599.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[N:15][CH:16]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2cncc(Cl)n2)cc1
Yield: 98.9 %

Procedure:
In a procedure analogous to example 1, reaction of 4-fluorobenzylamine (3.75 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) furnished the product (2.35 g, 99%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.[OH-].[Na+].[CH3:20][C:21]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>[Cu]>[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:30])[F:31])[C:21]=2[CH3:20])=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: Cc1c(Nc2ccc(Cl)cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a solution of 25 g. of 2,5-dichlorobenzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of 2-methyl-3-trifluoromethylaniline and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to yield the product which is recrystallized from methanol, m.p. 220°-222° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:29][C:30]([F:45])([C:41]([F:44])([F:43])[F:42])[C:31]([F:40])([F:39])[C:32]([F:38])([F:37])[S:33](F)(=[O:35])=[O:34].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:33]([C:32]([F:37])([F:38])[C:31]([F:39])([F:40])[C:30]([F:29])([F:45])[C:41]([F:44])([F:43])[F:42])(=[O:35])=[O:34])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (1.257 g, 4.26 mmol), DMAP (26 mg, 0.213 mmol), and triethylamine (0.71 mL, 0.51 g, 5.11 mmol) in anhydrous DCM (15 mL) was cooled to 0° C. Then nonafluorobutanesulfonyl fluoride (0.82 mL, 1.41 g, 4.68 mmol) was added in one portion. The mixture was allowed to warm and stirred at room temperature. After 18 hours, the mixture was poured into water (80 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 50 g silica gel cartridge by eluting with 0-10% EtOAc in 1:1 Hexane/DCM over 10 column volumes. The product fractions were combined and concentrated under reduced pressure to give the desired product as a clear, colorless oil. LC-MS: calculated for C19H20F9NO7S 577.08, observed m/e: 478.14 (M+H with loss of BOC)+ (Rt 2.67/4 min).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc2ccccc2cn1
Solvent: ClCCl
Product: S=C=Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85% yield) a white solid. LCMS R.T.=2.47; [M+H]+=187.23.
Reaction SMILES: [OH:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:3]1=[O:17])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(N2CCOCC2)c2ccccc2C1(O)Cc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(Cc2ccccn2)C(=O)N(N2CCOCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of alcohol from Example 26 (63 mg, 0.194 mmole) 4-dimethylaminopyridine (78 mg, 0.639 mmole) , acetic anhydride (0.06 ml, 0.639 mmole) in dichloromethane (10 ml) was stirred at 0° C. for 8 hours. The volatiles were removed and the crude mixture applied directly to a silica gel column and eluted with 5% methanol in chloroform (Rf =0.34). The product slowly crystallized from hexane-ethyl acetate at 0° C. to give 41 mg of colorless cubes, m.p. 107°-110° C. after filtration. IR (KBr): 1702 cm-1. High Res. Mass Spec. Calcd. for C20H21N3O4 : 368.1610 (M+H) . Found: 368.1611.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH:9]([NH:19][CH3:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[K+].[K+].[C:37]([O:46]N1C(=O)CCC1=O)([O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=O>C1COCC1.O>[C:14]([O:13][C:12]([NH:11][CH2:10][CH:9]([N:19]([CH3:20])[C:37]([O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])=[O:46])[CH2:8][C:2]1([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:18])([CH3:16])([CH3:17])[CH3:15]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: CN(C(=O)OCC[Si](C)(C)C)C(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of above mixture of tert-butyl 3-(1-hydroxycyclohexyl)-2-(methylamino)-propylcarbamate and naphthalene in 3:1 THF/H2O V/V (4 mL) was added K2CO3 (100 mg, 0.72 mmol), followed by Teoc-OSu (70 mg, 0.27 mmol). The resulting solution was stirred at rt for 30 min and the organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel to give 1-(3-(t-butoxycarbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol (100 mg, 86% for three steps). MS m/z 453 (M+Na+).