Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[CH3:17][O:18][C:19]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])=[O:20]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1NC(=S)NC(=O)OC

Procedure:
1.2 G. of 2-amino-4-(4-chlorophenoxy)-1-nitrobenzene in 3ml. concentrated hydrochloric acid is treated with a solution of 6 g. stannous chloride in 3 ml. concentrated hydrochloric acid. The mixture is heated briefly (about ten minutes) on a steam bath, then cooled and treated with potassium bicarbonate and chloroform. The chloroform layer is removed from the filtered mixture, dried and evaporated. 1,2-diamino-4-(4-chlorophenoxy)benzene is isolated as a gum. 1G. of 1,2-diamino-4-(4-chlorophenoxy)benzene in 20 ml. acetone is treated overnight at room temperature with 2.5 g. methoxy carbonyl isothiocyanate. The mixture is concentrated under vacuum and the residue triturated with methanol. Recrystallization from methanol gives pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-(4-chlorophenoxy)benzene.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(Oc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in dioxane. EI-MS m/e (%): 339 (M{81Br}+, 15), 337 (M{79Br}+, 16), 257 ([M—C6H10]+, 97), 255 ([M—C6H]+, 100).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[Mg]Br.CO>C1COCC1.C(Cl)Cl>[CH3:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:15]=1)=[O:9]
Reactant: COc1ccc([Mg]Br)c(C)c1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Yield: 54.9 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.6 g, 3.6 mmol) in THF (12 mL) was treated with a 0.65 M THF solution of 2-methyl-4-methoxyphenylmagnesium bromide (20 mL, 13.0 mmol) (prepared from 4-bromo-3-methylanisole, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 1.02 g (55%) of the title compound as a dark oil: 1H NMR d 1.46 (m, 2H), 1.63 (m, 4H), 2.26 (s, 3H), 2.54 (m, 4H), 2.79 (t, J=5.8 Hz, 2H), 3.47 (s, 3H), 3.89 (s, 3H), 4.12 (t, J=5.8 Hz, 2H), 6.60 (m, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.98 (dd, J=2.4, 8.9 Hz, 1H), 7.19 (d, J=9.3 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.69 (d, J=8.8 Hz, 2H); MS (FD) m/e 515 (M+); Anal. calc'd. for C31H33N1O4S1 : C, 72.20; H, 6.45; N, 2.72. Found: C, 72.50; H, 6.56; N, 2.80.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[C-:33].[H-].[Na+].C1COCC1>C1COCC1>[CH2:38]([O:37][C:35]([C:34]1[N:32]=[CH:33][N:6]2[C:7]=1[CH:8]([CH3:17])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]2=1)=[O:36])[CH3:39]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccc2)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
7-Bromo-3-methyl-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-2-one 111 (16.6 g, 0.052 mol) was suspended in dry THF (250 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 4.36 g, 0.109 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (12.7 ml, 0.09 mol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 4.2 g, 0.1 mol) was suspended in dry THF (250 mL) at −10° C. in another flask. Ethyl isocyanoacetate (6.78 mL, 0.06 mol) was added to the NaH/THF suspension, the solution which resulted was allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:2, 1:1, 2:1). The ester 112 was a white solid (8.76 g, 40%). mp 164-165° C.; IR (KBr, cm−1) 2925, 1706, 1622, 1557, 1495, 1266, 1185; 1H NMR (CDCl3) δ 7.89 (s, 1 H), 7.73 (dd, J=1.73 Hz, 1 H), 7.51-7.36 (m, 7 H), 6.66 (q, J=7.30, 1 H), 4.45-4.30 (m, 2 H), 1.40 (t, J=7.11, 3 H), 1.25 (d, J=7.38 Hz, 3H). MS (EI) m/e (relative intensity) 426 (M++2, 15), 425 (M++1, 58), 424 (M+, 15), 423 (58), 380 (24), 379 (71), 378 (35), 377 (69), 352 (50), 351(100), 350 (67), 349 (92), 270 (38), 229 (16); [α]26D=−38.0 (c 0.45, EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1.[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[C:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Solvent: c1ccncc1
Product: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a reactivial containing ethyl [2-methyl-4-({[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (100 mg, 0.225 mmol) was added pyridine (0.321 mL, 3.97 mmol) and 1-propanesulfonyl chloride (25.3 μL, 0.225 mmol). The resulting mixture was stirred in a sealed reactivial at 80° C. for 16 h. The reaction mixture was allowed to cool to room temperature and was partitioned between CH2Cl2 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (12 g Silica column) eluted with 1:9 EtOAc:cyclohexane afforded the title compound as a yellow oil (20 mg).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56].[NH2:58][C:59]1[N:67]=[C:66]2[C:62]([NH:63][C:64](=[O:74])[N:65]2[CH:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)=[C:61]([Cl:75])[N:60]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:75][C:61]1[N:60]=[C:59]([NH:58][C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[N+:55]([O-:57])=[O:56])[N:67]=[C:66]2[C:62]=1[NH:63][C:64](=[O:74])[N:65]2[CH:68]1[CH2:69][CH2:70][O:71][CH2:72][CH2:73]1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Cl)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To an oven-dried 2-neck flask under Ar was added racemic BINAP (2.27 g, 3.64 mmol, 0.35 equiv.) followed by anhydrous toluene (20 mL) and Pd(OAc)2 (1.05 g, 1.56 mmol, 0.15 equiv.) and the mixture was stirred under Ar, at room temperature for 15 min. A deep yellow paste is formed. Then, 2-bromo-4-chloro-1 nitrobenzene (3.19 g, 13.52 mmol, 1.3 equiv.), 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (2.80 g, 10.4 mmol, 1.0 equiv.) and cesium carbonate (5.08 g, 15.6 mmol, 1.5 equiv.) were added as solids, under Ar, followed by anhydrous toluene (22 mL), and the reaction mixture was stirred at room temperature for 10 min, then stirred at 100° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with toluene (450 mL) and passed through Celite. The filtrate was concentrated in vacuo to give a dark brown residue. Flash chromatographic purification (silica gel, gradual elution with 1 to 5% methanol in methylene chloride), followed by recrystallization from hot ethyl acetate gave the desired product as a bright yellow solid (1.63 g, 37% yield) in high purity. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.05 (s, 1H), 8.24 (d, 1H), 7.06 (d, 1H), 4.56-4.52 (m, 1H), 4.16 (dd, 2H), 3.58 (app t, 2H), 2.72 (tdd, 2H), 1.81 (br d, 2H); MS (EI) m/z 425.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[CH3:20][O:21][C:22]1[C:27]2[CH:28]([NH2:31])[CH2:29][O:30][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:31][CH:28]3[C:27]4[C:22]([O:21][CH3:20])=[CH:23][CH:24]=[CH:25][C:26]=4[O:30][CH2:29]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: COc1cccc2c1C(N)CO2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Product: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Yield: 49.7 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and rac-4-methoxy-2,3-dihydro-benzofuran-3-ylamine (Example 5, step B) (1.84 g, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a white solid (2.09 g, 50%), m.p. 132.5° C.; MS (ISP) m/e=375.1 [(M+H)+].
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)[OH:23])=[CH:18][CH:17]=1)=[O:15].[K+].[Br-]>C(Cl)Cl>[CH3:33][O:32][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[O:23])=[CH:29][CH:28]=1)=[O:31]
Reactant: COC(=O)c1ccc(C(O)c2ccc(C(=O)OC)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(C(=O)OC)cc2)cc1

Procedure:
(Kirste, B.; Grimm, M.; Kurreck, H. J. Am. Chem. Soc. 1989, 111, 108-114.) To a suspension of PCC (3.10 g, 14.4 mmol) in anhydrous CH2Cl2 (25 ml) at RT, a solution of the benzyl alcohol 5 (2.70 g, 8.99 mmol) is added slowly dropwise into anhydrous CH2Cl2 (10 ml), and the preparation is stirred at this temperature over night. Subsequently, the mixture is filtered through a small amount of silica gel (CH2Cl2 as eluent). Following the distillation of the solvent, 2.44 g (91%) of compound 6 could be isolated in form of a colorless solid. Melting point 228-230° C. (Kirste et al. 1989, see above, 229.5-230° C.); IR (KBr) 1705, 1630 cm−1; 1H-NMR (CDCl3) δ 8.17 (d, 8.4 Hz, 4H), 7.85 (d, 8.4 Hz, 4H), 3.98 (s, 6H); MS (EI) m/z 298 (M+). Anal. calc. for C17H14O5: C, 68.45; H, 4.73. Found C, 68.30; H, 4.69.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:28]C)[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1P(C1CCCCC1)C1CCCCC1.[OH-:30].[K+]>>[CH3:6][CH2:7]/[CH:8]=[CH:3]/[CH:4]=[CH:5]/[CH:14]=[CH:13]/[CH:12]=[CH:11]/[CH2:10][CH2:9][CH2:8][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:28])=[O:30]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: [OH-]
Agent: [K+]
Product: CC/C=C/C=C/C=C/C=C/CCCCCCCC(=O)O

Procedure:
The machine was equipped with a deprotection tube (empty, but used for sparging the MIDA boronate solution) and a reaction tube charged with the Pd-mixture (60 mg), the SPhos-mixture (60 mg), KOH (75 mg, 1.7 mmol) and halide 3 (11 mg, 0.037 mmol).
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH:50]([F:52])[F:51])[C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.B>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH:50]([F:51])[F:52])[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(Cc2ccccc2OC(F)F)OCCN1Cc1ccccc1
Agent: B
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: FC(F)Oc1ccccc1CC1CN(Cc2ccccc2)CCO1

Procedure:
N-Benzyl-2-(2-difluoromethoxy-benzyl)-morpholine was prepared as described for example 70, intermediate (a), but using N-benzyl-2-(2-difluoromethoxy-benzyl)-morpholin-3-one and borane and was isolated as a pale yellow oil.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1([C:42](=[O:44])[CH3:43])CCNCC1>C(#N)C>[C:42]([N:3]1[CH2:7][CH2:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)=[O:9])[CH2:4][CH2:2]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)/N=c2\sc(C)cn2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial were combined a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) and diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added 1-(piperazin-1-yl)ethanone (13 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to supply the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH2:7])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[S:24])[NH2:7])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution (30 mL) of the compound (3.7 g, 14 mmol) obtained in Example 77a in tetrahydrofuran was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (5.5 g, 14 mmol), and the mixture was stirred at 80° C. for 5 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (3.2 g, 83%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]([OH:18])=O)=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:19])=[O:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:43]([O:47][C:48](=[O:54])[NH:49][CH2:50][CH2:51][CH2:52][NH2:53])([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16](=[O:18])[NH:53][CH2:52][CH2:51][CH2:50][NH:49][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:54])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC(=O)CC1Cc2ccc(C(=O)O)cc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1Cc2ccc(C(=O)NCCCNC(=O)OC(C)(C)C)cc2NC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (1.0 g, 3.8 mmol) in DMF (20 mL) at 25° C. was added 1-hydroxy-benzotriazole hydrate (HOBT) (0.565 g, 4.18 mmol). The solution was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DAEC) (0.801 g, 4.18 mmol) was added. After 10 min the reaction mixture was allowed to warm to 25° C. After 2 h triethylamine (1.3 mL) was added and tert-butyl-N(3-aminopropyl)carbamate (0.66 g, 3.8 mmol) added after 30 minutes. After 20 h ethyl acetate was added and the mixture washed with 0.1 N aqueous hydrochloric acid (3×), aqueous sodium bicarbonate (3×) and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a light brown powder. NMR (dmso-d6, 200 MHz) : δ1.4 (s, 9H, tert-butyl), 1.6 (m, 2H, CH2), 2.7-3.3 (m, 9H, CH2CHCH2, NCH2, NCH2), 3.6 (s, 3H, CH3), 6.8 (t, 1H, NH), 7.2-7.4 (m, 3H, ArH), 8.3 (t, 1H, NH), 10.3 (s, 1 H. NH).
Reaction SMILES: [Br:1][C:2]([Br:10])([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([O-:5])=[O:4].[NH+]1C=CC=CC=1.Cl>>[Br:1][C:2]([Br:10])([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)C(Br)(Br)C(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Product: CC(C)(C)C(Br)(Br)C(=O)O

Procedure:
A mixture of 10 parts of pyridinium 2,2-dibromo-3,3-dimethylbutyrate and 50 parts of 50% aqueous hydrochloric acid resulted in precipitation of 2,2-dibromo-3,3-dimethylbutyric acid in quantitative yield. The solid was recrystallized from butyl chloride, m.p. 241° - 243° C. It can then be reacted with thiocarbohydrazide as described in Example 1 to form 4-amino-6-t-butyl-3-mercapto-1,2,4-triazin-5-one.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30](=[O:51])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48]CO)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:51])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:1][Br:5])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCBr
Reaction time: 5 h
Yield: 91.9 %

Procedure:
Carbon tetrabromide (9.0 g, 27 mmol) and triphenyl phosphine (1.2 g, 4.5 mmol) were added to a solution of compound 2 (1.8 g, 4.5 mmol) in dry CH2Cl2 (100 mL). After stirring the reaction mixture for 5 h, the solvent was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (200 g) and eluted with CH2Cl2:MeOH 100:0 to 20:1 (v/v) to afford compound 3 as a colorless oil (1.9 g, 91%).
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[C:15]([NH2:31])=[CH:14][N:13]=2)=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:4])=[O:3].C1C[O:37][CH2:36]C1>>[CH3:4][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]3[C:15]([NH:31][C:36](=[O:37])[N:18]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:14][N:13]=2)=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:1])=[O:3]
Reactant: COc1cc(P(C)(C)=O)ccc1Nc1ncc(N)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Reactant: C1CCOC1
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc2[nH]c(=O)n(-c3ccccc3S(=O)(=O)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine (as prepared in Example 28: 40 mg, 0.082 mmol) in THF was added N,N′-Carbonyldiimidazole (40 mg, 0.25 mmol). The solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and diluted with water and extracted with Ethyl Acetate. The combined organic layer was washed with brine and dried over Magnesium Sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by RP Prep-HPLC to obtain the desired product as an off white solid. MS/ES+: m/z=516
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[N:27]=[CH:26]1>>[F:23][C:4]1[CH:3]=[C:2]([N:27]2[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Reactant: CC1(C)C=NC(=O)O1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)nc1
Yield: 54.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (567 mg) described in Preparation Example 184 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (335 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17][N:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.[Br:29][Si](CC)(CC)CC>C1COCC1>[Br:29][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17][N:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1)[OH:1]
Reactant: CCCc1c(-c2nc(-c3ccc(C4CO4)cc3)no2)noc1-c1ccccc1
Reactant: CC[Si](Br)(CC)CC
Solvent: C1CCOC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazole (205 mg, 0.549 mmol) in THF (5 mL) at −78° C. was slowly added bromotriethylsilane (100 μL, 0.582 mmol). The reaction mixture was stirred for 1 hour at −78° C. LC/MS was employed to determine extent of reaction. An aliquot was removed and concentrated in vacuo. Crude NMR indicated mostly desired regioisomer. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated. The solids were purified on a silica cartridge using an EtOAc/hexanes gradient to yield 130 mg of Preparation 1C as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.24 (2H, m), 7.72-7.81 (2H, m), 7.61 (2H, m, J=8.13 Hz), 7.49-7.58 (3H, m), 5.12 (1H, dd, J=7.47, 5.93 Hz), 4.09-4.17 (1H, m), 4.01-4.08 (1H, m), 2.97-3.05 (2H, m), 1.70-1.83 (2H, m), 1.06 (3H, t=7.36 Hz).