Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([Cl:6])(=[O:5])=[O:4])[CH3:2].Cl.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH:30]4[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]4)[CH2:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[ClH:6].[CH2:1]([S:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([C@@H:25]3[CH:30]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:31]4)[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
39.1 mg (0.30 mmol) of ethanesulfonyl chloride and 84.8 μl (0.61 mmol) of tiethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated, mixed with 2 ml of a 1:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 26 mg (35.2% of theory) of the title compound are obtained. HPLC (Method 1): Rt=3.71 min. MS (ESIpos): m/z=414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:7]([OH:16])[CH:6]=[CH:5]2.[C:17]([Cl:20])(=[O:19])[CH3:18]>C(Cl)Cl>[ClH:20].[C:17]([O:16][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]=1[CH2:12][N:13]([CH3:14])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN(C)Cc1c(O)ccc2cc(Br)ccc12
Solvent: ClCCl
Product: CC(=O)Oc1ccc2cc(Br)ccc2c1CN(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-1-[(dimethylamino)methyl]-2-naphthol (5.6 g, 0.02 mol) was stirred in methylene chloride (120 mL). Acetyl chloride (3.0 mL, 0.042 mol) was added. The mixture was stirred at room temperature for 1 hour and the solvent was concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[C:8]4[C:15]([CH3:23])([CH3:22])[C:16]5[C:21]([C:7]4=[CH:6][C:5]3=2)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:26][CH:25]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2oc2ccccc24)cc13

Procedure:
32 g (90.6 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno-[2,1-b]fluorene, 19.9 g (94 mmol) of dibenzofuran-4-boronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1640 ml of toluene and 164 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh)3 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The yield is 26.7 g (59 mmol), corresponding to 65% of theory.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:74][C:75]1([C:81](O)=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>ClCCl>[NH2:74][C:75]1([C:81]([NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCCC1)C(C)C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of #50 (120 mg, 0.18 mmol, 1 eq.), Brop (84 mg, 0.21 mmol, 1.2 eq.) and diisopropylethylamine (0.1 mL, 0.54 mmol, 3 eq.) in dichloromethane (15 mL, 0.009 M) at 0° C. was added 1-aminocyclohexanecarboxylic acid (31 mg, 0.21 mmol, 1.2 eq.). After 2 hours, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #52 (50 mg, 35%). Rf 0.6 (10% methanol in dichloromethane). LC-MS (Protocol K): m/z 783.79 [M+H+]; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.87 (br d, J=9 Hz), total 1H], 8.18-8.28 (m, 1H), [7.77 (d, J=3.5 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.12-7.31 (m, 5H), 5.35-5.43 and 5.49-5.57 (2 m, total 1H), [4.51 (dd, J=9, 8 Hz), and 4.61 (dd, J=9, 7 Hz), total 1H], 3.16, 3.19, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), [1.05 (d, J=6.8 Hz) and 1.10 (d, J=6.8 Hz), total 3H].
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[SH:11].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[S:11][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cc(C)cc(S)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(C)cc(OC)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-fluoro-3-methoxy-5-methylbenzenethiol (289.4 mg) and DMF (dry) (12 mL) were added K2CO3 (255 mg) and methyl 4-chloro-3-oxobutanoate (0.217 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (330 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:31](Br)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[C:31]([N:18]1[C:19](=[O:20])[C:21]([F:23])=[CH:22][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]2)[C:16]1=[O:17])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Br)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OC(C)=O
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry dioxane, and the resulting mixture was cooled with ice. To the mixture was added 850 mg of benzoyl bromide, and the resulting mixture was allowed to stand at room temperature for 15 minutes and then at 70° C. for 30 minutes. The same procedure as in Example 8 gave 400 mg (yield: 60.5%) of 3-benzoyl-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine. The absorption spectra of the present product were identical with those of the compound obtained in Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1N2CCN(CC2)C1.[CH3:15][N:16]([CH3:21])[S:17](Cl)(=[O:19])=[O:18]>CC#N>[CH3:15][N:16]([CH3:21])[S:17]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)(=[O:19])=[O:18]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Brc1cn[nH]c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1cc(Br)cn1
Reaction time: 20 h

Procedure:
To a solution of 4-bromopyrazole (2.20 g, 15 mmol) and DABCO (1.85 g, 16.5 mmol) in anhydrous MeCN (15 ml) at room temperature was added dimethylsulfamoyl chloride (1.61 ml, 15 mmol). The reaction mixture was stirred for 20 h, then partitioned between 1N HCl(aq) and EtOAc. The aqueous layer was extracted with EtOAc (×2), the organics combined, washed with brine (×1), dried (MgSO4), filtered and the solvent removed in vacuo to afford a colourless liquid. (3.79 g). 1H NMR (400 MHz, CDCl3): 8.00 (1H, s), 7.70 (1H, s), 2.99 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14](F)[CH2:15][CH:16]([F:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([CH:14]([N:38]3[CH2:37][CH2:36][C:35]([OH:41])([C:32]4[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=4)[CH2:40][CH2:39]3)[CH2:15][CH:16]([F:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C(F)CC(N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone (3.94 g), 4-(p-chlorophenyl)-4-hydroxypiperidine (2.24 g) and dimethylsulfoxide (30 ml) was stirred at room temperature for 14 hours. The mixture was poured into 300 ml of water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield γ,4-bis-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-fluorobutyrophenone. M.P. 190° - 193°C.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: Cc1cccc(Cl)n1
Product: Cc1ccnc(N2C[C@@H]3CCNC[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-4-methylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCSc1ccc(C(=O)O)nn1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 2 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-Ethylsulfanyl-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.78 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.43 min (96.78%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.98-2.13 (m, 1H, CHH), 2.43-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 3.24-3.42 (m, 2H, CH2), 4.69 (d, J=6.2 Hz, 2H, CH—), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.75-7.93 (m, 4H, Ar), 7.97 (d, J=9.1 Hz, 1H, Ar), 9.98 (t, J=6.3 Hz, 5H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.18, 21.99, 24.01, 30.93, 42.42, 48.99, 122.15, 123.53, 124.92, 126.89, 129.85, 131.57, 133.60, 147.19, 149.74, 162.99, 165.00, 166.97, 167.12, 169.82, 172.73; LCMS: MH=454; Anal Calcd for C21H19N5O5S: C, 55.62; H, 4.22; N, 15.44. Found: C, 55.43; H, 4.09; N, 15.22.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH3:17].[H-].[Na+].O>CN(C=O)C>[CH3:17][O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 0.1 g (0.46 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine and 0.1 mL (1.6 mmol) of iodomethane in 2.5 mL of DMF was added 0.022 g (0.92 mmol) of NaH (80% dispersion in mineral oil). After 2 h, 10 mL of H2O was added to the reaction mixture and it was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O>CO>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:19]=1[OH:20]
Reactant: Cc1cc(C(=O)CCCCCC(=O)O)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCCCCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid.--To a cooled (-5° C.) solution of 103 parts of ethyl 6-chloroformyl hexanoate in 100 parts by volume of ethylene chloride is rapidly added with stirring 133 parts of granular anhydrous aluminum chloride. To this mixture is next added a solution of 88 parts of 2-methyl-6-t-butylphenol in 500 parts by volume of ethylene chloride. The reaction mixture is stirred at -5° C. for 5 hours and then allowed to slowly attain room temperature overnight. At the end of this time the material is poured over ice, rendered acidic with 6N hydrochloric acid and extracted with ether. The combined extracts are successively washed with water, dilute aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution. After drying over sodium sulfate, the solvent is removed under reduced pressure to yield ethyl 6-(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoate, which is saponified with excess potassium hydroxide in methanol. After acidification of the reaction mixture, the solid, comprising 6-( 3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoic acid, is subjected to a Clemmenson reduction as modified by Martin [J.A.C.S. 58, 1438 (1936)] to yield 7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid which is esterified with ethanol and p-toluenesulfonic acid to yield the corresponding ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.C([Cl:22])(=O)C>>[Cl-:22].[CH3:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C=O)c1OC
Reactant: C1COCCN1
Reactant: CC(=O)Cl
Product: COc1cccc(C=[N+]2CCOCC2)c1OC
Product: [Cl-]

Procedure:
The reaction of 7.3 ml (0.084 mol) morpholine and 5.8 g (0.035 mol) 2,3-dimethoxybenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 2.1 ml (0.035 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 5.6 g (corresponding to 59% of the yield calculated by theory) 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:14][C:15]3[N:16]2[CH:19]=[N:20][N:21]=3)=[CH:11][CH:10]=1)C.[Li+].[OH-].C1COCC1.Cl>O.CO>[C:22]1([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:10][CH:11]=3)[N:16]3[CH:19]=[N:20][N:21]=[C:15]3[CH:14]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1

Procedure:
11d (40 mg, 0.10 mmol) was treated with 1N aqueous LiOH (2 mL) in 3:3:1 THF:MeOH:H2O (2 mL) overnight at room temperature. 1N aqueous HCl was added to adjust to pH 4, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 11e.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[ClH:22].Cl[C:24]([NH2:26])=[NH:25]>COCCOCCOC>[NH2:26][C:24]1[N:25]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][CH:4]=[C:5]([C:10]([Cl:22])=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=3)[N:6]=2)[N:1]=1
Reactant: N=C(N)Cl
Reactant: N#Cc1nc(C#Cc2ccc(C(F)(F)F)cc2)cnc1N
Reactant: Cl
Solvent: COCCOCCOC
Product: Nc1nc(N)c2nc(C(Cl)=Cc3ccc(C(F)(F)F)cc3)cnc2n1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 7, using 2.9 grams (0.009 mole) of 2-amino-3-cyano-5-[(4-trifluoromethylphenyl)ethynyl]pyrazine and 0.9 gram (0.009 mole) of chloroformamidine hydrochloride in 20 mL of diglyme, yielding 2,4-diamino-6-[1-chloro-2-(4-trifluoromethylphenyl)ethenyl]pteridine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)C(C)C)(C)C.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 61.1 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (5 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (6 gm) was added N,N-diisopropylethylamine (60 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added methylene chloride (300 ml) and water (250 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 5 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.ClC[C:35]1[C:36](C)=[N:37][O:38][C:39]=1[CH3:40]>ClCCl>[CH3:35][C:36]1[C:2]([CH2:1][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=4[C:11]([NH2:15])=[N:12][C:13]=3[CH:14]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCc4c(C)noc4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Chloromethyl)-3,5-dimethylisoxazole (160 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 4-(chloromethyl)-3,5-dimethylisoxazole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-5% methanol in dichloromethane for over 1000 mL and then with 5% methanol in dichloromethane over 400 mL. The resulting solid was recrystallized from acetonitrile to provide 156 mg of 7-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-propylthiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 178.0-180.0° C. MS (ESI) m/z 369 (M+H)+; Anal. calcd for C19H20N4O2S: C, 61.94; H, 5.47; N, 15.21. Found C, 61.98; H, 5.25; N, 15.26.
Reaction SMILES: [C:1]([C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:16]([O:18][C:19]([C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1C(=O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C(=O)C(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-isobutyryl-3-methyl-benzoic acid (227) (200 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (220 mg, 1.07 mmol), HATU (441 mg, 1.16 mmol) in anhydrous DMF (10 mL) is added DIPEA (192 μL, 1.16 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in DCM (50 mL) and washed with water (1×5 mL) and brine (1×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (228) as a pale yellow solid (340 mg, 89%).