Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH3:32])[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH3:32])[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[O:25])[CH:22]=3)[C:17]([S:33]([CH3:34])=[O:40])=[CH:16]2)=[N:13][CH:14]=1
Reactant: CNC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNC(=O)CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Oxidation of 304d) (0.1 g, 0.209 mmol) with m-chloroperoxybenzoic acid (77%, 0.038 g, 0.167 mmol) in dichloromethane (10 mL). White solid. Yield: 0.065 g (63% of theory)
Reaction SMILES: C(O)C.[C-:4]#[N:5].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1>O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]#[N:5])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
150 g of ethanol, 28 ml of water, and 31.5 g of sodium cyanide were initially charged, and 127.5 g of 4-bromomethyl-1-trifluoromethoxybenzene were added. The reaction mixture was stirred at 90° C. for 3.5 hours and then poured into 250 ml of water and extracted twice with 50 ml portions of dichloromethane. The combined organic phases were concentrated and the residue was distilled at 18 hPa. This gave 81.5 g of (4-trifluoromethoxyphenyl)acetonitrile as a colorless liquid (76.3% of theory) of b.p. 110-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:3]=1.C(N(CC)CC)C.[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][NH:36][CH3:37]>O1CCCC1>[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][N:36]([CH3:37])[S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Reactant: CNCC(O)C1COC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(O)C1COC(C)(C)O1)S(=O)(=O)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
8.36 g (20 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzenesulfonic acid chloride is dissolved in 40 ml of tetrahydrofuran, 2.52 g (25 mmol) of triethylamine and 4.03 (25 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-methylethylamine are added and stirred for 3 hours at 45° C. The reaction mixture is then concentrated by evaporation under reduced pressure, the residue is extracted with ethyl acetate and the extract is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 9.35 g (16.8 mmol)=84% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52]>>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3]2)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52]
Reactant: COCCCOc1cc(CBr)ccc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br

Procedure:
Analogously to Method D, 2.0 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.77 g of 1-bromo-4-bromomethyl-2-(3-methoxypropoxy)benzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.34 (1:1 EtOAc-heptane); Rt=6.23.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH2:23][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-(piperazin-1-yl)pyrimidine (144.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 192 mg (95%) of methyl 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=O)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11](=[O:13])[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=2)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (2R,5S)-1-benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester (2 g, 7.21 mmol) in DMF (25 mL) was added 3-(trifluoromethoxy)aniline (1.53 mL, 8.65 mmol), HBTU (4.19 g, 10.8 mmol) and diisopropylethylamine (3.78 mL, 21.6 mmol). The reaction mixture was stirred at RT overnight. EtOAc and 1N HCl were added, the layers were separated and the aqueous one was back-extracted with EtOAc (×3). The combined organic extracts were washed with an aqueous solution containing 5% of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 80:20) to give the title compound. MS (LC/MS): 437.2 [M+H]+; tR (HPLC conditions b) 5.50 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11]Br.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][C:18]=1[O:20][CH2:11][CH2:10][CH2:9][O:8][CH3:7]
Reactant: COCCCBr
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(Br)ccc1OC

Procedure:
6.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Rf (hexanedethyl acetate=4: 1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:22][C:23]1[C:40]([F:41])=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:49][C:50]([NH:52][C:53]1[C:54]([O:66][CH2:67][C:68]([F:71])([F:70])[F:69])=[N:55][C:56]([CH3:65])=[CH:57][C:58]=1[O:59][CH2:60][C:61]([F:64])([F:63])[F:62])=[O:51]>C(#N)C.O>[F:22][C:23]1[C:40]([F:41])=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:49][C:50]([NH:52][C:53]4[C:54]([O:66][CH2:67][C:68]([F:71])([F:69])[F:70])=[N:55][C:56]([CH3:65])=[CH:57][C:58]=4[O:59][CH2:60][C:61]([F:63])([F:64])[F:62])=[O:51])[CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1
Reactant: Fc1cc2nc(SCCN3CCNCC3)[nH]c2cc1F
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4cc(F)c(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
1-[2-(5,6-Difluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (4.00 g, 6.25 mmol) and potassium carbonate (31.26 mmol) were dissolved in acetonitrile (100 mL) and water (30 mL). While the solution was stirred under cooling with ice, 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (2.20 g, 5.22 mmol) was added thereto over 15 minutes. The temperature of the mixture was allowed to room temperature, and the mixture was stirred for 15 hours. Thereafter, the reaction mixture was diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (silica gel 150 g, hexane: acetone=4:1 to 2:1 to 1:1). The thus-obtained crystals were recrystallized from chloroform-hexane, to thereby yield 2-[4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (3.04 g, yield 91%) as a pale yellow powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]([C:19]([O:21]CC)=O)([F:18])[CH2:13][CH2:14][C:15](O)=[O:16].C(C1NC=CN=1)(C1[NH:27]C=CN=1)=O.CN(C1N=CC=CN=1)C>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:18])[CH2:13][CH2:14][C:15](=[O:16])[NH:27][C:19]1=[O:21]
Reactant: CCOC(=O)C(F)(CCC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ncccn1
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)-4-(ethoxycarbonyl)-4-fluorobutanoic acid (0.9 g, 2.8 mmol), carbonyl diimidazole (0.46 g, 2.8 mmol) and dimethylaminopyrimidine (0.68 g, 5.6 mmol) in tetrahydrofuran (30 mL) is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is stirred with methylene chloride (50 mL) for 10 minutes. The organic layer is washed with water and brine (40 mL each) and dried over sodium sulfate. The solvent is removed in vacuo to give 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which is further purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C@@H:16]1[CH2:20]OS(=O)(=O)[N:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:20])[NH:17][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:11][CH2:10]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](C)Nc2ccccn2)CC1
Yield: 77.4 %

Procedure:
12.02 grams of 1-(2-methoxyphenyl)piperazine and 13.4 grams of (R)-4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide were stirred together in 50 millilitres of acetonitrile at room temperature overnight. The solvent was removed in vacuo. The residue was heated in 100 millilitres of dilute hydrochloric acid for 30 minutes. The mixture was cooled, washed with dichloromethane, basified by using dilute sodium hydroxide solution and extracted by means of dichloromethane. The organic phase was washed with water, dried and evaporated to dryness to give 15.8 g of the title compound as a slightly crude product. The product was 85 to 95% pure and contained 2 main impurities derived from the sulphone. The crude product was used directly, i.e. without purification, by acylation by means of cyclohexanecarbonyl chloride to yield (R)-N-[1-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.S(Cl)([Cl:12])=O>>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:12]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1I
Product: ClCc1ccccc1I

Procedure:
o-Iodobenzyl chloride was prepared from o-iodobenzyl alcohol using thionyl chloride according to the procedure described by Brooks et al, Org. Syn. Coll. Vol. 3, p. 698 (1955). The crude product was distilled at reduced pressure to yield a clear, colorless liquid having a bp of 143°/4 mm Hg.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH:18]1([CH:23]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH:23]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:35][CH:34]=2)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NCC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C1CCCC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C2CCCC2)cc1
Yield: 19 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (500 mg, 1.6 mmol) was reacted with tert-butyl 2-cyclopentyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (1.3 g, 3.2 mmol) to afford the desired product (150 mg, 19%) as a yellow solid: ESI MS m/z 519 [C30H34N2O4S+H]+.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH:30]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:4]([NH:3][CH2:28][C:29]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:23]=1)[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a methanol (8 ml) solution of 2-amino-5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.83 g) were added trimethyl acetaldehyde (220 mg) and acetic acid (170 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (160 mg). The mixture was stirred overnight at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)-2-neopentylaminobenzyl alcohol (0.99 g) as a colorless oily product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:24][C:25]4([CH2:28][OH:29])[CH2:27][CH2:26]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Reactant: NC1(CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and (1-aminocyclopropyl)methanol (34 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered. The crude product was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(1,6-dimethyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 36%) as a white solid. MS: (M+H)+=377; 1H NMR (300 MHz, DMSO): δ 13.84 (s, 1H), 9.12 (s, 1H), 8.74 (s, 1H), 8.43-8.40 (m, 2H), 7.56 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 4.89 (brs, 1H), 4.16 (s, 3H), 3.62 (s, 2H), 2.55 (s, 3H), 0.97-0.86 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]CBr)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:20].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CCBr)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromethyl)-4(1H)-quinazolinone (from Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:25]=[C:24]1S(C)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:22][N:23]1[C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:26][N:25]=[C:24]1[NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)nnc1S(C)(=O)=O
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Oc3ncccc3-c3ccnc(N)n3)cc2)nnc1-c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a slurry of 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.150 g, 0.54 mmol) and 4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole (0.14 g, 0.59 mmol) in 0.6 mL THF was added lithium bis(trimethylsilyl) amide, 1.0 m solution in tetrahydrofuran (1.1 ml, 1.1 mmol). The reaction became a solid, and was sealed and heated to 70° C., at which point it became a heterogeneous brown mixture that could be stirred. After 2 h, the reaction did not appear to make further progress. The reaction was quenched with sat'd aqueous NH4Cl and partitioned between DCM and water. The aqueous layer was extracted 1×DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was absorbed onto silica gel from MeOH/DCM and dried. The residue was purified by silica gel chromatography, 40 g (0-100% 90/10 DCM/MeOH in MC) to give 4-(2-(4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=437 [M+H]+. Calc'd for C24H20N8O: 436.5.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N:24]1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:36]([NH2:24])(=[O:38])=[O:37])=[CH:3][C:4]=3[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][C:7]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1-c1ccc(-c3ccccc3S(N)(=O)=O)cc1C(c1ccccc1)O2

Procedure:
A solution of Example 5F (50 mg. 0.16 mmole), pyridine (75 mg) and benzenesulfonyl chloride (86 mg., 0.5 mmole) in chloroform (1 mL) was stirred for 1 hour, washed with aqueous HCl (1M), dried (Na2SO4), filtered and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC with CH3CN/water to provide the titled product. MS (ESI(−)Q1MS) m/z 442 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.22 (d, J=9 Hz, 1H), 7.70-7.50 (m, 5H), 7.36-7.29 (m, 3H), 7.16-7.06 (m, 4H), 6.76 (s, 1H), 6.69 (d, J=8 Hz, 1H), 6.62(d, J=8 Hz, 1H), 6.11 (s, 1H), 3.85 (s, 3H).