Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[C:18]([OH:36])(=[O:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 0 °C

Procedure:
1.33 gr. of N-hydroxy succinimide (11.56 mmole, 1.5 eq.) and DIEA (1.35 ml), were dissolved in 50.0 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. Then, Oleoyl chloride (3.0 ml, 85% tech., 7.8 mmole, 1.0 eq.) dissolved in 50 ml of anhydrous THF was added dropwise during 1 h. The mixture was gently stirred for 2 h at 0° C. and over-night at room temperature. The resulting precipitate were discarded by filtration and the filtrate was evaporated under reduced pressure, redissolved in small amount of DCM and purified over silica-gel column using DCM as eluent. Fractions containing the product were combined and solvent was removed under reduced pressure. The resulting white solid was dried in vacuum over NaOH-pellets.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC[C@H]1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 215 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and (3R)-3-(2-Bromoethyl)tetrahydrofuran.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Cl:9][C:10]1[C:30]([Cl:31])=[CH:29][C:13]2[N+:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:15]([CH3:18])[N:16]([CH3:17])[C:12]=2[CH:11]=1.[BrH:32]>>[Br-:32].[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N+:14]1[C:13]2[CH:29]=[C:30]([Cl:31])[C:10]([Cl:9])=[CH:11][C:12]=2[N:16]([CH3:17])[C:15]=1[CH3:18])([OH:26])=[O:25]
Reactant: Br
Reactant: CCOC(=O)CCCCC[n+]1c(C)n(C)c2cc(Cl)c(Cl)cc21
Agent: O=S(=O)([O-])C(F)(F)F
Product: Cc1n(C)c2cc(Cl)c(Cl)cc2[n+]1CCCCCC(=O)O
Product: [Br-]
Temperature: 65 °C
Yield: 77 %

Procedure:
5 (4 g) was dissolved in 48% HBr aqueous solution (5 mL) and heated at 65° C. for 2 hrs and then evaporated to dryness. The residue was recrystalized from acetone to yield 2.5 g white crystal, yield 77%. See FIG. 12. 1H NMR: (DMSO) 1.36 (m, 2H), 1.54 (m, 2H), 1.74 (m, 2H), 2.21 (t, 2H), 2.87 (s, 3H), 3.95 (s, 3H), 4.46 (t, 2H), 8.49 (s, 1H), 8.54 (s, 1H). 13C NMR: (DMSO): 10.75, 23.92, 25.14, 28.19, 32.08, 33.37, 45.13, 114.78, 114.82, 128.73, 128.76, 130.04, 130.91, 154.26, 174.20. ESI-MS (m/z) calcd (found): 329.1 (329.1) for [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2ccncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2ccncc2c1
Temperature: 145 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A mixture of 7-hydroxyisoquinoline (1.15 g, 7.9 mmol), ethylene carbonate (0.98 g, 11.1 mmol), powdered K2CO3 (0.65 g, 4.7 mmol) in dry DMF (20 mL) was stirred at 145° C. for two hours. The reaction was quenched with MeOH (1 mL), filtered and the solvent was removed under reduced pressure. The residue was taken up between alkaline water (K2CO3) and CHCl3. Concentration of the dried (MgSO4) organic phase afforded 1.4 g (94%) of the title compound as a yellow oil that solidified upon standing. Purity 91% (HPLC). Fragmenting mass analysis supports the stated structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
30 mg (0.09 mmol) of the compound of Example 46A is reacted analogously to the synthesis of the compound of Example 4 with 9 mg (0.09 mmol) of 2-oxopiperazine. 42 mg (89% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]=1)[CH3:2].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:32][C:11]([F:10])([F:31])[C:12]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[C:8]2/[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6](=[O:9])[S:7]/2)[CH2:17][CH2:16]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
To a solution of 4-(ethylamino)-1,3-thiazol-2(5H)-one (310 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (802 mg) in 2-propanol (10 mL) was added piperidinium acetate (312 mg). The reaction mixture was stirred at 75° C. for 4 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give the title compound (110 mg).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=CC(S(O[N:28]2[C:32]3[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=3[N:30]=[N:29]2)(=O)=O)=CC=1>ClCCl>[C:1]([O:9][N:28]1[C:32]2[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(On1nnc2ccc(Cl)cc21)c1ccccc1
Reaction time: 4 h
Yield: 84.6 %

Procedure:
Benzoic acid (2.4 g) is dissolved in dichloromethane (30 ml), and thereto are added triethylamine (2.8 ml) and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (6.9 g) and the mixture is stirred for 4 hours. After the reaction, dichloromethane is distilled off and to the resulting residue are added water and ethyl acetate. The ethyl acetate layer is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and the solvent is distilled off to give white crystals of 1-benzoyloxy-6-chloro-1,2,3-benzotriazole (4.55 g). The product is recrystallized from ethanol to give pure product, melting point: 132° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH2:8][OH:9])[CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:35]=1)[CH:31]=O.[BH-](OC(C)=O)(OC(C)=O)[O:42][C:43](C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:13]([O:12][C:10]([N:4]1[CH2:5][C@H:6]([CH2:8][OH:9])[CH2:7][C@H:2]([NH:1][CH2:31][C:30]2[CH:33]=[C:34]([O:36][C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:28][C:29]=2[O:42][CH3:43])[C@@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: COc1cc(C=O)cc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 116 %

Procedure:
To a stirred solution of (2S*,3S*,5R*)-3-amino-1-benzyloxycarbonyl-5-hydroxymethyl-2-phenylpiperidine (0.405 g, 1.14 mmol) and 3-methoxy-5-trifluoromethoxybenzaldehyde (0.301 g, 1.71 mmol) in dry CH2Cl2 (25.0 ml) was added NaB(OAc)3H (0.362 g, 1.71 mmol) portionwise. The mixture was sonicated to dissolve the NaB(OAc)3H added, and then stirred at room temperature for 2 hours and 40 minutes. To this was added sat. Na2CO3 aq. solution (12.0 ml), and the CH2Cl2 layer was separated. The aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 layer and extracts were dried (K2CO3), and concentrated in vacuo to give a pale yellow oil (0.72 g). This was flash chromatographed over SiO2 (Merch Kieselgel 60, 14.0 g). Elution with CH2Cl2 --MeOH (300:1/200:1/100:1) gave title compound [0.416 g, overall 67.0% from (2S*,3S*,5R*)-1-benzyloxycarbonyl-3-(N-tert-butoxy-carbonyl)amino-5-hydroxymethyl-2-phenylpiperidine in two steps] as a colorless syrup. IRmax (film): 3450(s), 1700(s), 1682(s), 1670(s), 1652(s), 1610(w), 1497(s), 1490(s), 1260(br., s), 1220(br., s), 1152(br., s), 1030(s), 738(s), 700(s) cm-1 ; 1H-NMR δ: 7.50-7.11(m, 10H), 7.13-6.93(m, 1H), 6.69(br.d, J=8.4 Hz, 1H), 5.60-5.22(m, 1H), 5.20-4.95(m, 2H), 4.36-4.10(m, 1H), 3.79(d, J=13.9 Hz, 1H), 3.65-3.45(m, 3H), 3.59(br.s, 3H), 3.23-2.95(m, 2H), 2.15(br.s, 1H), 2.02-1.86(m, 1H), 1.86-1.68(m, 1H), 1.68-1.45)m, 2H) ppm.
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][CH:21]1[C:26]([F:28])(I)[CH:25]=[CH:24][CH:23]=[CH:22]1>>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[C:26]([F:28])[CH:25]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1C=CC=CC1(F)I
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Product: CC(C)(C)c1nc2ncc(C#Cc3ccc(F)c(F)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=313.1 (M+H+), can be prepared in accordance with the general method of example 43, step 2 from 2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3,4-difluoro-4-iodobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]([Cl:33])=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylic acid (126 mg, 0.37 mmol) from Step A and a drop of DMF (cat.) in methylene chloride (5 mL) was added oxalyl chloride (0.16 mL, 1.85 mmol). The reaction was stirred at rt for 2 h and was then evaporated to dryness in vacuo. The crude acid chloride was used directly in the subsequent amide formations.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:28])[NH:19][C:20]3[S:21][C:22]([C:25]([OH:27])=O)=[CH:23][N:24]=3)=[CH:12][C:11]=12.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([NH:19][C:20]3[S:21][C:22]([C:25]([NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:27])=[CH:23][N:24]=3)=[O:28])=[CH:12][C:11]=12
Reactant: O=C(NCc1ccn2ccnc2c1)Nc1ncc(C(=O)O)s1
Reactant: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting 3-methylbutan-1-amine for 3-methylbutan-1-amine and 2-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)thiazole-5-carboxylic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) ppm 8.49 (d, J=7.8 Hz, 1H), 8.21 (t, J=5.9 Hz, 1H), 7.88-7.89 (m, J=1.4 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.39 (s, 1H), 7.18 (t, J=5.8 Hz, 1H), 6.83 (dd, J=6.8, 1.7 Hz, 1H), 4.38 (d, J=6.1 Hz, 2H), 3.16-3.25 (m, 2H), 1.52-1.67 (m, 1H), 1.38 (q, J=6.9 Hz, 2H), 0.83-0.91 (m, 7H); MS (ESI(+)) m/e 387 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([OH:17])[C:13]=1[C:14]([OH:16])=[O:15].O[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1.[H-].[Na+].Cl[N:27]1[CH2:32][N:31]([O:33][CH3:34])[CH2:30][N:29]([O:35][CH3:36])[CH2:28]1.P(=O)(O)(O)O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16][N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:15])=[C:12]([O:17][N:27]2[CH2:32][N:31]([O:33][CH3:34])[CH2:30][N:29]([O:35][CH3:36])[CH2:28]2)[CH:11]=[CH:10][CH:9]=1
Reactant: CON1CN(Cl)CN(OC)C1
Reactant: On1cccn1
Reactant: Cc1ccccc1-c1cccc(O)c1C(=O)O
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CON1CN(OC)CN(Oc2cccc(-c3ccccc3C)c2C(=O)On2cccn2)C1
Reaction time: 14 h

Procedure:
1.75 g (10.8 mmol) of N,N'-carbonylbisimidazole is added to a solution of 2.12 g (10 mmol) of 6-(2-methylphenyl)-salicylic acid in 30 ml of tetrahydrofuran. After the mixture has been stirred for 30 minutes at room temperature 9.9 mmol of N-hydroxypyrazole is added and the mixture is stirred for a further 14 hours. The mixture is then hydrolyzed with 300 ml of 1N phosphoric acid and extracted several times with methyl tert-butyl ether. The organic phases are combined, dried over sodium sulfate and evaporated down under reduced pressure. The residue is taken up with 40 ml of dimethylformamide and 280 mg of sodium hydride (85% strength in paraffin, 10 mmol) is added. After the mixture has been stirred for 30 minutes at room temperature, 1.58 g (9 mmol) of 1-chloro-3,5-dimethoxy-s-triazine is added and the mixture stirred for 14 hours. It is then introduced into 300 ml of 0.1N phosphoric acid and extracted with diethyl ether. The ether phase is dried over sodium sulfate and evaporated down, and the residue is purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)c1c(O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2sc1=O

Procedure:
7-(3,5-Bis-trifluoromethyl-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3,5-Bis-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.47 (d, 1H), 8.03 (s, 2H), 7.937 (s, 1H), 7.66-7.56 (m, 2H), 4.03 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1.[Cl:41][C:42]1[CH:61]=[CH:60][C:45]([NH:46][C:47]2[C:56]3[C:51](=[CH:52][C:53](O)=[C:54]([O:57][CH3:58])[CH:55]=3)[N:50]=[CH:49][N:48]=2)=[C:44]([F:62])[CH:43]=1>C(Cl)Cl>[ClH:41].[Cl:41][C:42]1[CH:61]=[CH:60][C:45]([NH:46][C:47]2[C:56]3[C:51](=[CH:52][C:53]([O:32][CH2:33][CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[C:54]([O:57][CH3:58])[CH:55]=3)[N:50]=[CH:49][N:48]=2)=[C:44]([F:62])[CH:43]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCN(C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
Triphenylphosphine (615 mg, 2.3 mmol) followed by diethyl azodicarboxylate (369 μl, 2.3 mmol) were added to a solution of 4-hydroxymethyl-1-methylpiperidine (151 mg, 1.1 mmol), (J. Med. Chem. 1973, 16, 156), and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 7), in methylene chloride (5 ml). After stirring for 30 minutes at ambient temperature, 4-hydroxymethyl-1-methylpiperidine (51 mg, 0.39 mmol), triphenylphosphine (102 mg, 0.39 mmol) and diethyl azodicarboxylate (61 μl, 0.39 mmol) were added. After stirring for 15 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (70/10/20 followed by 75/5/20 and 80/0/20). The fractions containing the expected product were combined and the volatiles were removed by evaporation. The residue was dissolved in a mixture of methylene chloride and methanol and 5M hydrogen chloride in isopropanol was added. The suspension was concentrated and the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (16 mg, 4%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([S:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:13])=[O:12])[CH2:21]1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 89.7 %

Procedure:
A solution of 250 mg (1.06 mmol) of 4-nitrophenylmethanesulfonyl chloride and 133 mg (1.17 mmol) of cis-2,6-dimethylpiperazine in CH2Cl2 (10 mL) was treated with 325 μL (2.33 mmol) of triethylamine at RT for 20 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 298 mg (90%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.87 (d, 2H, J=8.8 Hz), 4.24 (s, 1H), 3.59-3.53 (m, 2H), 2.92-2.82 (m, 2H), 2.30-2.23 (m, 2H), 1.04 (d, 6H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H). found 314.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](SC)[CH:16]=2)[N:3]=1.Cl[C:24]1C=C(C=CC=1)C(OO)=O.[O-:34][S:35]([O-:38])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:35]([CH3:24])(=[O:38])=[O:34])[CH:16]=2)[N:3]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(SC)c1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(3-(methylthio)phenylamino)nicotinate (291.1 mg, 0.872 mmol) in DMF (10 mL) was added m-chloroperoxybenzoic acid (538.9 mg, 2.405 mmol) at 0° C. The mixture was stirred at RT for 16 h. Aqueous Na2S2O3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a yellow solid (158.2 mg, 50%). 1H-NMR (CDCl3) δ ppm 3.11 (s, 3H), 4.07 (s, 3H), 7.10 (s, 1H), 7.57-7.60 (m, 1H), 7.70-7.72 (m, 1H), 7.91-7.93 (m, 1H), 8.25-8.26 (m, 1H), 10.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][C:27]([CH3:29])=O.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([NH:11][CH:27]([CH3:29])[CH3:26])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N)c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(NC(C)C)c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A mixture of (2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine (Example 418, Step D) (270 mg, 0.843 mmol), acetic acid (0.243 mL, 4.22 mmol), acetone (3.10 mL, 42.2 mmol) and sodium cyanoborohydride (0.442 mL, 8.43 mmol) in methanol (4 mL) was heated to 65° C. overnight. After sixteen hours, an additional ten equivalents of sodium cyanoborohydride were added and heating continued for another five hours then equilibrated to room temperature and concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium hydroxide solution and ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford a yellow oil. The crude product was adsorbed onto silica and purified by chromatography (24 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 30 to 100% ethyl acetate gradient in hexane. Fractions containing product were combined and concentrated to afford the title compound as a colorless glass.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[NH2:20]Cl>CN(C=O)C.CCOCC>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:20])[CH:9]=[CH:8]2)(=[O:4])=[O:3]
Reactant: NCl
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of 5-methanesulfonyl-1H-indole (4.1 mmol) and potassium tert-butoxide (8.2 mmol) in DMF (20 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (41 mL) is added drop-wise for 15 min at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 10% Na2S2O3 aqueous solution, and extracted with ether (3×40 mL). The combined organic layer is washed with water (2×30 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc and heptane to afford 5-methanesulfonyl-indole-1-ylamine (230 mg, 32%) as a solid. MS: 211 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.08 (s, 3H), 4.94 (br, 2N—H), 6.55 (d, H), 7.34 (m, H), 7.57 (d, H), 7.73 (m, H), 8.21 (m, H).