Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:41])[CH2:7][N:8]([CH2:33][CH:34]([O:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH3:35])[C:9]1[C:14]([C:15]([NH:17][CH2:18][CH2:19][O:20]C2CCCCO2)=[O:16])=[CH:13][C:12]([N+:27]([O-:29])=[O:28])=[CH:11][C:10]=1[N+:30]([O-:32])=[O:31])(=[O:4])=[O:3].Cl>C1COCC1.O>[CH3:40][S:37]([O:36][CH:34]([CH3:35])[CH2:33][N:8]([CH2:7][CH:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH3:41])[C:9]1[C:10]([N+:30]([O-:32])=[O:31])=[CH:11][C:12]([N+:27]([O-:29])=[O:28])=[CH:13][C:14]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])(=[O:39])=[O:38]
Reactant: CC(CN(CC(C)OS(C)(=O)=O)c1c(C(=O)NCCOC2CCCCO2)cc([N+](=O)[O-])cc1[N+](=O)[O-])OS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(CN(CC(C)OS(C)(=O)=O)c1c(C(=O)NCCO)cc([N+](=O)[O-])cc1[N+](=O)[O-])OS(C)(=O)=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A solution of 19 (2.52 g, 4.03 mmol) in THF (150 mL) was treated with1 N HCl (100 mL), and the solution was stirred at 20° C. for 1 h, then diluted with water (100 mL), neutralized with satd. NaHCO3, and extracted with EtOAc (3×80 mL). The combined organic phases were washed with brine and dried, the solvent was evaporated, and the residue was purified by chromatography on silica gel, eluting with EtOAc/MeOH (100:1), to give 2-(2-{[(2-hydroxyethyl)amino]carbonyl}{2-[(methylsulfonyl)oxy]propyl}-4,6-dinitroanilino)-1-methylethyl methanesulfonate (20) (0.80 g, 37%): as a yellow foam; 1H NMR [(CD3)2SO] δ 8.94 (m, 1 H), 8.72 (m, 1 H), 8.35 (m, 1 H), 4.92 (m, 2 H), 3.56 (m, 2 H), 3.30 (m, 6 H), 3.16 (s, 6 H), 1.32 (m, 6 H); 13C NMR δ 165.9, 145.8, 143.4, 139.4, 133.6, 128.0, 123.1, 76.3, 59.2, 57.3, 42.2, 37.7, 18.6. HRMS (FAB) Calcd. For C17H27N4O12S2 [M+H+] m/z 543.1067. Found; 543.1074.
Reaction SMILES: [C:1]([N:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][CH:8]1[NH2:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([N:7]1[CH:12]=[C:11]([CH2:13][Br:22])[CH:10]=[CH:9][CH:8]1[NH2:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CN(C(=O)C(C)(C)C)C(N)C=C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)N1C=C(CBr)C=CC1N

Procedure:
N-Pivaloyl-2-amino-5-methylpyridine (5.12 g, 26.6 mmol) was dissolved in CCl4 (75 mL) at 23° C., and treated with NBS (9.69 g, 54.4 mmol), followed by AIBN (937 mg, 5.71 mmol) with stirring. The resulting orange, biphasic suspension was then warmed to reflux for 4 h. After 4 h at reflux, the rust-colored mixture was cooled to RT, filtered through a Celite® pad, and concentrated in vacuo to a red residue. Purification over silica gel (gradient, 0 to 25% EtOAc/hexanes) provided the title compound as a light yellow solid. MS m/z: 272 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2ccc(Cl)cc2N)c1
Yield: 41.7 %

Procedure:
Following General Procedure A, the title compound (1.4 g, 42%) was prepared from 2-amino-4-chlorobenzenethiol (1.7 g, 10.90 mmol), methyl 3-(bromomethyl)benzoate (2.5 g, 10.90 mmol) and K2CO3 (7.5 g, 54.50 mmol) in DMF (30 ml).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)C[C@H]1CCCOC1
Yield: 86 %

Procedure:
Hydrogenation of tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (146 mg, 0.51 mmol) was carried out in MeOH (10 mL), 10% Pd/C (25 mg) under 40 psi of H2 for 2 h. After filtration 114 mg of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was obtained, yield 86%. MS ESI +ve m/z 259 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[C:13]([C:31](=[NH:34])[NH:32][NH2:33])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.Cl[C:44](Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[C:13]([C:31]3[NH:34][C:44](=[O:46])[NH:33][N:32]=3)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(C(=N)NN)c2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(-c3n[nH]c(=O)[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3′-(N-aminocarbamimidoyl)-4′-[3-(3-trifluoromethyl-phenyl)-ureido]-biphenyl-4-carboxylic acid dimethylamide (322 mg) and triethylamine (212 microliters) dissolved in dichloromethane (5 ml) at -50° C. was treated with a solution of triphosgene (236 mg) in dichloromethane (5 ml). The mixture was stirred for 2.5 hrs at ambient temperature and poured into water. After adjusting to pH 7 with aq. sodium bicarbonate, the mixture was extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Column chromatography on silica afforded 3′-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-4′-[3-(3-trifluromethyl-phenyl)-ureido]-biphenyl-4-carboxylic acid dimethylamide as a white solid. Mp.=212° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].I[CH3:32].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH3:32])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N(C)S(C)(=O)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
(S)-2-Ethoxy-3-[4-{2-(4-[methylsulfonylamino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester (0.17 g; 0.39 mmole) was dissolved in tetrahydrofuran (10 ml). Iodomethane (0.277 g; 1.95 mmole) and sodium hydride (0.019 g; 0.79 mmole) were added and the reaction mixture was stirred at room temperature for 3 hours and then evaporated. The residue was redissolved and extracted with diethyl ether and water. The organic phase was washed once more with water, dried with sodium sulfate and evaporated. Chromatography with ethyl acetate:petroleum ether (1:1) gave 0.098 g (55.8% yield) of (S)-2-ethoxy-3-[4-{2-(4-[methylsulfonyl(methyl)amino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[C@:8]([C:18]([F:21])([F:20])[F:19])([C:13]#[C:14][CH:15]3[CH2:17][CH2:16]3)[O:9][C:10]([NH:12][C:3]=2[CH:2]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[C:30]([NH:37][CH2:38][CH2:39]Br)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1OCCOCCOCCOCCOCCOC1.FC(F)(F)C(O)=O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[C:33]([O:32][C:30](=[O:31])[NH:37][CH2:38][CH2:39][N:12]1[C:3]2[CH:2]=[CH:1][C:6]([Cl:7])=[CH:5][C:4]=2[C:8]([C:13]#[C:14][CH:15]2[CH2:16][CH2:17]2)([C:18]([F:20])([F:21])[F:19])[O:9][C:10]1=[O:11])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Temperature: 125 °C
Reaction time: 18 h
Yield: 6.9 %

Procedure:
To a solution of 250 mg of efavirenz in 10 mL of anhydrous DMF was added 600 mg of anhydrous K2CO3, 120 mg NaI, 490 mg of 2-(BOC-amino)ethyl bromide and 5 mg of 18-crown-6. The reaction mixture was heated at 125° C. for 2 hours. The reaction mixture was cooled to room temperature, and 1 g of 2-(BOC-amino)ethyl bromide and 20 mg of tetrabutylammonium iodide were added and allowed to stir at room temperature 18 hours. The reaction mixture was analyzed by reverse-phase high performance liquid chromatography (RP-HPLC, C-18 Vydac 218TP54 (4.6 mm×250 mm) using a gradient run with water-acetonitrile mixtures containing 0.1% trifluoroacetic acid (0-100% AcCN-0.1% TFA in 20 minutes). This indicated the formation of product with a substantial amount of efavirenz in the reaction mixture. An additional 1 g of 2-(BOC-amino)ethyl bromide was added, and the reaction mixture was heated at 60° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative RP-HPLC using a gradient run (CH3CN/water containing 0.1% trifluoroacetic acid). The column used was a Rainin C-18 (ODS) 60 Å (21.4×250 mm). The desired fractions were combined, concentrated in the rotary evaporator, and then lyophilized to give 25 mg of the desired product 7 as a white solid (M+Na, 481).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2)([O-:23])=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 33.4 %

Procedure:
159 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:34][CH2:35][CH:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O.C(OCC)(=O)C>[C:10]([C:5]1[N:6]=[C:7]([CH2:8][CH3:9])[C:2]([NH:34][CH2:35][CH:36]2[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]2)=[N:3][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:16]([CH3:33])[CH:15]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NCC1CN(C(=O)OC(C)(C)C)C1
Yield: 27.8 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (350 mg), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (266 mg), potassium carbonate (154 mg), and N-methylpyrrolidone (7 mL) was reacted at 100° C. for 11.5 hours. To the mixture were added ethyl acetate and water, followed by liquid separation. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain tert-butyl 3-({[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}methyl)azetidine-1-carboxylate (128 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Agent: CCOC(=O)C(=NOC)c1csc(=N)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer), which can be represented as ethyl 2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetate (syn isomer), (2.2 g.) in a 1 N aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetic acid (syn isomer), (1.1 g.).
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][CH:9]3[CH:13]=[CH:12][CH2:11][N:10]3[C:5]2=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][C:9]3[N:10]([CH:11]=[CH:12][CH:13]=3)[C:5]2=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCC1C=CCN21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cccn1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Methyl 7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 17, 0.370 g) was suspended in a mixture of DCM (6 mL) and pyridine (2.43 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.493 g) was added. The resultant deep red solution was stirred at room temperature overnight then concentrated in vacuo. The residue was diluted with DCM and water and passed through a phase separator. The organic layer was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-30% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.107 g) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][N:7]=1.CCO[C:18]([CH3:20])=O.[OH-].[Na+]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:20]2[CH:18]=[CH:14][CH:13]=[CH:9][CH:8]=2)=[CH:8][N:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
Aluminum chloride (100 g, 0.730 mol) was suspended in 200 ml benzene under N2. A solution of 6-chloronicotinoyl chloride (53 g, 0.30 mol) in 100 ml benzene was added to the rapidly stirring suspension then refluxed overnight. The reaction was cooled to RT, 1 L EtOAc was added, and the pH was adjusted to 8.5 with 5N NaOH. Aluminum salts precipitated and were filtered away. The filtrate was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The resulting tan solid was recrystallized from 3:2 Et2O:hexanes yielding 54.6 g (83%) of product as tan crystals. EA, MS(FD).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]1>>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Product: O=C(c1ccc(-c2ccc(OCCCN3CCC[C@@H](O)C3)cc2)cc1)N1CCCC1

Procedure:
The product from Example 11A and (3R)-3-piperidinol were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:12]=1)=[N+:6]([O-])[CH:7]=[CH:8][C:9]=2[CH3:10].C(Cl)(Cl)[Cl:14]>P(Cl)(Cl)(Cl)=O>[Cl:14][C:7]1[N:6]=[C:5]2[N:12]=[C:2]([CH3:1])[NH:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1nc2c([nH]1)c(C)cc[n+]2[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2nc(Cl)cc(C)c2[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide (4.45 g) in chloroform (4.5 ml) and phosphorous oxychloride (25.4 ml) was stirred at 80° C. for 3 hr and concentrated to dryness under reduced pressure. The residue was poured to ice (75 g), and which was neutralized with aqueous ammonia under ice-cooling. The mixture was stirred at room temperature for 30 min and the precipitated solid was washed with water to give the objective compound (3.66 g) as a gray powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:13][C:14]2[O:18][C:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][C:15]=2[C:29]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C.O.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([C:17]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][C:15]2[C:29]([C:30]([CH3:33])([CH3:32])[CH3:31])=[C:11]([OH:10])[C:12]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:13][C:14]=2[O:18]1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(CCC(C)C)(CCC(C)C)O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC1(CCC(C)C)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Lithium aluminum hydride (1.90 g) was suspended in tetrahydrofuran (200 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-2,2-diisoamyl-4,6-di-tert-butyl-2,3-dihydrobenzofuran (17.4 g) in tetrahydrofuran (60 ml) was added dropwise to the suspension under cooling with ice. After heating under reflux overnight, the mixture was cooled to room temperature and water and a saturated aqueous solution of ammonium chloride were added in that order. The resulting insolubles were filtered off on Celite. The filtrate was subjected to extraction with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (n-hexane) to afford 2,2-diisoamyl-4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [9.0 g (yield, 57%)] as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]3[S:29][C:30]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)=[CH:31][C:25]=3[N:24]=[CH:23]2)=[CH:18][C:17]=1[O:39][CH3:40])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:41][NH:42][CH3:43]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]2[S:29][C:26]3[C:27](=[O:28])[N:22]([C:19]4[CH:20]=[CH:21][C:16]([N:5]([CH2:4][CH2:3][CH2:2][N:42]([CH3:43])[CH3:41])[S:6]([C:9]5[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=5)(=[O:8])=[O:7])=[C:17]([O:39][CH3:40])[CH:18]=4)[CH:23]=[N:24][C:25]=3[CH:31]=2)=[CH:33][CH:34]=1
Reactant: CNC
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(CCCBr)S(=O)(=O)c1ccc(C)cc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(CCCN(C)C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by reaction of N-(3-bromopropyl)-N{4-[6-(4-chlorophenyl)4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-2-methoxyphenyl}4-methylbenzenesulfonamide (the title compound from Example K15) and dimethylamine. LCMS m/z 623 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(Br)cc3)nc2n(CC)c1=O
Yield: 21.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.20 g (11.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.78 g (12.2 mmol) of 4-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 930 mg (yield 22%) of Compound 140 as yellow columns.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1([CH2:26][CH2:27][CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:29]=[CH:28][CH2:27][CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: C=CCCc1ccccc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=CCCc4ccccc4)cc3c21
Yield: 51.7 %

Procedure:
8-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 9.4 mmol) was treated with 4-phenyl butene (4.2 mL, 28.2 mmol) according to the method described in Part B of Example 425. The reaction was heated overnight. Following chromatographic purification (eluting with 95:5 chloroform:methanol), 1.8 g of 1-(2-methylpropyl)-8-(4-phenylbut-1-enyl)-1H-imidazo[4,5-c]quinolin-4-amine were obtained as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])/[CH:9]=[CH:10]/[C:11]#[N:12])=[CH:4][CH:3]=1>CC(=O)OCC.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CCC#N)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (E)-N-(1-(3-(4-chlorophenyl)-1-cyanopent-1-en-3-yl)-1H-indazol-4-yl)methanesulfonamide (60 mg) and 10% Pd/C in EA (4 mL) was stirred at room temperature under H2 atmosphere for 16 h. The mixture was filtered and evaporated to give the title compound as a pale yellow solid. LC/MS m/z=417.2[M+H]+.