Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH2:18][OH:19])=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([OH:30])=[CH:25][CH:24]=2>>[OH:19][CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:30][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:20])=[CH:29]3)[CH:8]=1)=[O:12]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@@H]1CO
Product: Cc1cc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@@H]5CO)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS: 408.3 (MH+); HPLC Rf: 5.146 min.; HPLC purity: 98%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[CH:16]([CH3:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC>C1COCC1>[CH:16]([C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=2)[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=1)([CH3:18])[CH3:17]
Reactant: COc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chroman-4-one (Compound 14, 290 mg, 0.94 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (0.63 mL, 1.88 mmol) to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][O:14][C:15]=2[CH3:16])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:33].[Mg+2].O>ClCCl.CO>[F:10][C:6]1[CH:5]=[C:4]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][O:14][C:15]=2[CH3:16])[CH:3]=[C:2]([F:1])[C:7]=1[S:8]([CH3:9])=[O:33]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)=O)c(F)c1
Reaction time: 1.5 h

Procedure:
To a solution of 4-[3,5-difluoro-4-(methylthio)phenyl]-5-methyl-3-phenylisoxazole in dichloromethane (75 mL) and methanol (15 mL) cooled in an ice bath was added magnesium monoperoxyphthalate hexahydrate (4.4 g 80%, 7.1 mmol) in portions over 5 minutes. The reaction mixture was stirred for 90 minutes, then poured into water and extracted with dichloromethane (1×250 mL, 1×75 mL). The combined extracts were washed with dilute ammonium chloride, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 25% ethyl acetate/25% hexanes/50% dichloromethane gave 4-[3,5-difluoro-4-(methylsulfinyl)phenyl]-5-methyl-3-phenylisoxazole as a white solid. 1H NMR (CDCl3/400 MHz) 7.37-7.44 (m, 5H), 6.77-6.81 (m, 2H), 3.13 (s, 3H) 2.50 (s, 3H). HRMS m/z 334.0698 (M+H+, calcd 334.0713). Anal. Calcd for C17H13F2NO2S: C, 61.25; H, 3.93; N, 4.20; Found: C, 61.22; H, 4.00, N 4.02.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:31])[N:21]([CH3:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:31])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (1.84 g, 4.12 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The solution was stirred for 10 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 350 mg of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)c1

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-5-methoxybenzoic acid (21 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was performed according to the method described in example 11.,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:13]5C=CC=C[C:14]=5[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]=3[CH:21]=2)=[CH:4][CH:3]=1.[CH2:26]([Li])[CH2:27][CH2:28][CH3:29].[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.Cl>CCOCC.CCCCCC>[CH:26]1[C:20]2[C:19]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:15]=4[CH:16]=[CH:17][C:18]=3[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:31]([OH:36])[OH:32])=[CH:3][CH:4]=3)[C:21]=2[CH:29]=[CH:28][CH:27]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc(-c2ccc3c(ccc4ccc5ccccc5c43)c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc(-c2cc3ccc4ccccc4c3c3ccccc23)cc1
Temperature: -40 °C
Yield: 60 %

Procedure:
Under an argon atmosphere, 7.66 g of 10-(4-bromophenyl)benzo[c]phenanthrene was placed in a flask. 400 mL of dehydrated ether was added to the flask. The reaction solution was cooled to −40° C. Then 14 mL of a 1.6M hexane solution of n-butyllithium was added. After heating to 0° C., the solution was stirred for an hour. The reaction solution was cooled to −60° C. Then, 20 mL of a dehydrated ether solution in which 9.41 g of triisopropyl borate was solved was dripped. The reaction solution was stirred for five hours while heating to room temperature. 100 mL of a 10% hydrochloric acid solution was added and further stirred for an hour. An aqueous phase was removed, and an organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting solids were washed with hexane, whereby 4.18 g (yield: 60%) of 4-[benzo[c]phenanthrene-5-yl]phenylboronic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[BH4-].[Na+]>O1CCOCC1.CO.O.[Ni](Cl)Cl>[NH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([Cl:1])[N:3]=[C:4]2[CH3:15]
Reactant: Cc1nc(Cl)cc2c([N+](=O)[O-])cccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(Cl)cc2c(N)cccc12
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-methyl-5-nitroisoquinoline (2.0 g, 9.0 mmol) in dioxane (48 mL) and MeOH (10 mL) was added nickel (11) chloride hydrate (66 mg, 0.4 mmol), followed by sodium borohydride (0.7 g, 18 mmol). After stirring for two hours, the mixture was quenched by the addition of water (30 mL). The mixture was extracted with EtOAc, then the combined organics were washed with 10% NH4OH (aq) then saturated NaCl (aq). The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 7.55 (s, 1H), 7.53 (d, J=8.5 Hz, 1H); 7.39 (t, J=8.5 Hz, 1H); 6.96 (d, J=8.0 Hz, 1H); 2.98 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[Cu][C:15]#[N:16]>CN(C=O)C.O>[CH2:12]([O:11][C:8]1[C:9]([OH:10])=[C:2]([CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1)[C:15]#[N:16])[CH3:13]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)cc(C#N)c1O
Yield: 45 %

Procedure:
A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].[CH3:25][I:26]>CC(C)=O>[I-:26].[CH3:25][N+:20]1([CH2:19][C:16]2[CH:17]=[CH:18][C:6]3[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:7]=3[CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CI
Reactant: O=[N+]([O-])c1oc2ccc(CN3CCCC3)cc2c1-c1ccccc1
Solvent: CC(C)=O
Product: C[N+]1(Cc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)CCCC1
Product: [I-]

Procedure:
Using the method of Example 8, 2-nitro-3-phenyl-5-(1-pyrrolidylmethyl)benzofuran (the product of Example 2) is reacted with methyliodide in acetone to provide tan solid N-methyl-N-(2-nitro-3-phenyl-5-benzofuranylmethyl)pyrrolidinium iodide, m.p. 235°-237° C., having the structure
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 65 °C
Yield: 76.9 %

Procedure:
To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.1 mmol) in DMF (5 mL) was added 1-chloro-3-(methylsulfonyl)propane (19 mg, 0.12 mmol) followed by K2CO3 (42 mg, 0.3 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 77%). The crude was used to the next step without further purification. LCMS: (M+H)+=715.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:16][CH:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:14]2)=[O:12])=[CH:7][CH:6]=1)(=O)C.[Li+].[OH-].Cl>C1COCC1.CO.O>[C:25]1([C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH:15]3[CH2:16][N:13]([C:11]([C:8]4[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=4)=[O:12])[CH2:14]3)[CH2:18][CH2:19]2)=[O:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)Oc1ccc(C(=O)N2CC(N3CCN(C(=O)c4ccccc4)CC3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 26c (420 mg, 1.03 mmol) and LiOH (100 mg, 4.0 mmol) in a solvent mixture of THF/MeOH/H2O (2/2/2 mL) was stirred at room temperature for 4 h, at which time it was brought to pH 5 by the addition of 2N HCl (aq). The mixture was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue (crude compound 26d) was dried under reduced pressure for 18 h, and used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:30]>CC(O)C>[NH2:30][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A solution of benzyl {[trans-4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.70 g, 0.00324 mol) in IPA (30 mL) was cooled to −78° C., treated with a stream of ammonia gas over 3 min. and then heated at 110° C. in a Parr vessel overnight. The reaction solution was concentrated in vacuo and residue washed with water to afford 1.37 g of desired product 1H NMR (400 MHz, CDCl3): δ=1.08-1.17 (m, 2H), 1.88 (m, 1H), 1.71-1.81 (m, 2H), 1.91-1.94 (m, 2H), 2.00-2.04 (m, 2H), 2.90 (m, 1H), 3.13 (t, J=6.4 Hz, 2H), 4.86 (br, 1H), 5.11 (s, 2H), 5.76 (br, 2H), 7.00 (d, J=5.2 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.31-7.37 (m, 5H). MS (ES+): m/z 5.7.36 [MH+].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N+:8]=2[O-:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C

Procedure:
While stirring at room temperature, 4.8 g (28.5 mmol) of 2-phenyl-6-methyl-pyridine were dissolved in 50 ml of chloroform after which a solution of 7.8 g of 75% mCPBA (33.9 mmol) in 75 ml of chloroform were added dropwise. The reaction mixture showed only a slight rise in temperature. After stirring for 1.5 hr, the reaction mixture was shaken twice with 5% aqueous NaHCO3 solution and twice with an aqueous solution of Na2S2O3 to remove the excess of mCPBA, after which the reaction mixture proved to be negative on wet Kl/starch paper, The organic layer was dried on MgSO4. Removal of the drying agent by filtration and solvent by evaporation in vacuo yielded an oil which crystallized upon scratching to give 5.5 g (105%) of crude of 2-phenyl-6-methyl-pyridine-N-oxide, which was employed in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:9][CH:8]=2)[N:6]=1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([NH:25][CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:15])=[CH:16][CH:17]=2)[N:6]=1
Reactant: NCC1CCCCC1
Reactant: Nc1nc(-c2ccc(OCC(=O)O)cc2)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccc(OCC(=O)NCC3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of the product of example 3 (358 mg, 1.0 mmol) in DMF (10 mL) were added successively cyclohexanemethylamine (130 μL, 1.0 mmol), DIPEA (700 μL, 4.0 mmol) and TBTU (321 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The mixture was washed with a saturated aqueous solution of NaHCO3 and then brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 4:1, EtOAc:hexane) to afford the title compound (300 mg, 87% yield) as a white solid: M.p. 145-147°; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (broad t, J=6.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 6.98 (s, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.84 (s, 1H), 4.48 (s, 2H), 2.97 (t, J=6.4 Hz, 2H), 0.82-1.66 (m, 11H); MS (FAB) m/z 346 (MH)+. Anal. Calcd for C18H23N3O2S: C, 62.58; H, 6.71; N, 12.16. Found: C, 62.48; H, 6.74; N, 12.17.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[NH:9][CH2:8][C:7]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:6]2[N:5]=1)[CH3:2].[C:17]([Cl:20])(=[O:19])[CH3:18]>C(O)(=O)C>[ClH:20].[CH2:1]([N:3]([C:4]1[NH:9][CH2:8][C:7]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:6]2[N:5]=1)[C:17](=[O:19])[CH3:18])[CH3:2]
Reactant: CCCc1nc(C)c2n1N=C(NCC)NC2
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CCCc1nc(C)c2n1N=C(N(CC)C(C)=O)NC2
Product: Cl

Procedure:
2-Ethylamino-3,4-dihydro-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 12e) (1.1 g.) and acetyl chloride (1.65 ml.) in glacial acetic acid (10 ml.) were heated on a steam bath for 16 hours. The acetic acid was distilled off and the residue was crystallised from a mixture of isopropanol and ether to give a solid, m.p. 190°-192° (73%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[C:5]([Br:15])=[CH:4][CH:3]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:15])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2c3c([nH]c12)CCNC3
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Brc1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: 25 °C
Yield: 114.3 %

Procedure:
A suspension of 6,9-dibromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (700 mg, 2.121 mmol) in dichloromethane (10 mL) was stirred on an ice-water bath and treated with TEA (0.591 mL, 4.24 mmol), DMAP (25.9 mg, 0.212 mmol) and trityl chloride (1.183 g, 4.24 mmol). The mixture was allowed to warmed to room temperature and stirred for 71 h. The solution was concentrated under vacuum and the residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexane (gradient from 5:95 to 50:50) to provide the desired product as a yellow glassy foam (1.388 g) contaminated with a trityl derivative (probably trityl chloride or triphenylmethanol), estimated purity 75% (estimated yield of desired product 82%). This material was used without further purification. LCMS m/z 243.2 (trityl cation), 329, 331, 333 (M+H-trityl)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a stirring mixture of 2-(6-methoxy-2-naphthyl)-1-benzofuran (4.02 g, 14.7 mmol) in chloroform (70 mL) chilled in an ice bath was added valeryl chloride (2.6 mL, 22 mmol). The reaction mixture was chilled to −20° C. and tin (IV) chloride (2.2 mL, 19 mmol) was added, dropwise. The mixture was then stirred at room temperature for one hour and then refluxed for 3 hours, 20 minutes. It was allowed to cool to room temperature and poured into ice. The organic phase was diluted with excess ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified twice by flash chromatography (Biotage apparatus) using 2% ethyl acetate in hexane and 10-50% chloroform in hexane to afford 1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow gum (3.17 g). Mass spectrum (+EI, M+) m/z358. 1HNMR (400 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0-8.05 (m, 3H), 7.8 (dd, 1H, J=8.5 Hz and 1.7 Hz), 7.7-7.75 (m, 1H), 7.4-7.45 (m, 3H), 7.25-7.3 (m, 1H), 3.9 (s, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:42][N:43]([CH3:48])[S:44]([N:27]([CH:28]([CH3:29])[CH3:30])[CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)(=[O:46])=[O:45]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)N(C)C
Temperature: 80 °C
Yield: 8.2 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.100 g, 0.203 mmol, Example 195, Step 1) in pyridine (3.0 mL) was added 4-dimethylaminopyridine (5.0 mg, 0.040 mmol), Hünig's base (0.1 mL, 0.6 mmol), and dimethylsulfamoyl chloride (0.05 mL, 0.4 mmol, Aldrich, St. Louis, Mo.). The resulting mixture was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (24 g of silica, 10% to 40% EtOAc in hexanes) to afford N,N-dimethyl-N′-(1-methylethyl)-N′-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)sulfamide (0.010 g) as a mixture of two isomers: