Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:48])=O>O1CCCC1>[Cl:48][C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pivalic acid 6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (54 mg) in tetrahydrofuran (1.5 ml) were sequentially added N,N-dimethylformamide (in catalytic amounts) and oxalyl chloride (0.027 ml) under a nitrogen atmosphere, the solution was stirred for 30 minutes at room temperature, then the solvent was evaporated in vacuo to provide pivalic acid 6-{2-[(4-chlorocarbonylmethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (74 mg). A solution of this compound (37 mg) and dimethylamine (2.0 M solution in tetrahydrofuran) (0.08 ml) in tetrahydrofuran (0.7 ml) was stirred for 30 minutes at room temperature. To a suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (2 ml) was added aluminum chloride (267 mg) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 1 hour at room temperature. Among the resulting suspension, 0.5 ml was added dropwise thereto followed by stirring for 2 hours at room temperature. Tetrahydrofuran and concentrated aqueous ammonia were sequentially added thereto, the solution was filtered through celite pad, and concentrated under a nitrogen stream. A solution of the resulting residue in N,N-dimethylformamide was purified by LC-MS, and the title compound (7.1 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li]C(C)(C)C.[Si:14]([O:21][CH2:22][CH:23]=[N:24][S@@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[Li]>CCOCC>[Si:14]([O:21][CH2:22][C@H:23]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Agent: [Li]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)S(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 2-bromo-5-fluoropyridine (1.3 g, 7.2 mmol) in Et2O (8 ml) at −68° C. was added a solution of t-BuLi (1.7 M in pentane, 8.5 ml, 14.4 mmol) carefully. The temperature of the mixture was kept below −65° C. and the mixture was allowed to stir for 15 minutes at −70° C. A solution of (R)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide (Intermediate 21, 1.0 g, 3.6 mmol) in Et2O (24 ml) was cooled to −75° C. To it was cannulated a solution of the above lithium compound for a duration of 15 minutes. More Et2O (2 ml) was used to rinse the lithium compound solution. The mixture was allowed to stir at −78° C. for 3 hours. To it was added saturated NH4Cl solution. EtOAc was added and the organic layer was washed with brine and concentrated. Column chromatography (20-40% EtOAc in hexanes) gave the desired product (RS)—N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide* as a solid (higher Rf on TLC, 1.19 g) together with diastereoisomer (lower Rf on TLC, 166 mg). 1H NMR (300 MHz, CDCl3) □ ppm 8.41 (s, 1H) 7.35 (d, J=6.78 Hz, 2H) 4.59 (t, J=5.65 Hz, 1H) 4.43 (d, J=5.28 Hz, 1H) 3.82-4.02 (m, 2H) 1.23 (s, 9H) 0.81 (s, 9H)-0.06 (d, J=12.06 Hz, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH2:9][N:8]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:13][CH2:12][C:11]=2[CH3:14])=[CH:20][CH:19]=1)=[O:31]
Reactant: CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)C1
Temperature: 110 °C
Yield: 97 %

Procedure:
Compound 11 (31 mg, 0.074 mmol) was dissolved in methylene chloride (2 mL) at room temperature. Ethyl chloroformate (14 ul, 2 eq) was added to the solution and it was heated to 110° C. in the microwave for 1 hour. The solvent was removed and the crude mixture was flashed with ethyl acetate/hexane to produce 28.4 mg (97% yield) of Compound 12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>>[CH:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CC(C)[Mg]Cl
Product: COc1cc2c(cc1C)C(C(C)C)=CCC2(C)C
Yield: 52.2 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30) (1.5 g, 6.9 mmol) was reacted with a solution of 2 M isopropylmagnesiumchloride (17 mL, 34.5 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.88 g (53%) of the title product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>ClC1C=C([N+]([O-])=O)C=C(Cl)C=1OC1C=NC2C(C=1)=CC=CC=2.C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Oc2cnc3ccccc3c2)c(Cl)c1
Temperature: 20 °C
Yield: 98 %

Procedure:
The nitro functionality of 3-(2,6-dichloro-4-nitro-phenoxy)-quinoline (4) was catalytically reduced under hydrogen with 5% weight/weight (catalyst/compound 4) of a 1% platinum/2% vanadium on carbon catalyst suspension in ethyl acetate at 0° C. The material was heated to 20° C., filtered through Celite. The Celite was washed with THF, and the filtrates were combined and evaporated to give 3,5-dichloro-4-(quinolin-3-yloxy)-phenylamine (5) in 98% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:24])C>O.[O-2].[O-2].[O-2].[Cr+6]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:24])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1cc(CS(=O)c2ccc(O)cc2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (500 mg, 1.63 mmol), prepared as described in Example 1, was dissolved in 10 mlof acetic acid, and heated to 80° C. A solution of chromium trioxide in 30 ml of distilled water was added dropwise to the above solution. The mixture was stirred for 30 min, cooled to room temperature, diluted with 20 ml of water, and then extracted with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified on silica gel column chromatography (ethyl acetate/n-hexane=1/4) to give 348 mg (66% yield) of 3,4,5-trimethoxybenzyl 4-hydroxyphenyl sulfoxide as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])=[O:4].[CH3:19][N:20]1[C:29]2[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[NH:25][CH2:24][C:23]=2[CH:22]=[N:21]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:25]2[CH2:24][C:23]3[CH:22]=[N:21][N:20]([CH3:19])[C:29]=3[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=3)=[O:15])=[CH:11][C:10]=1[CH3:18]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: COC(=O)CCCCc1ccc(C(=O)O)cc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)cc1C
Yield: 46 %

Procedure:
WSCD (822 mg, 4.3 mmol) and DMAP (273 mg, 2.2 mmol) were added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid from Example E31 (571 mg, 2.3 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (424 mg, 2.1 mmol) in dichloromethane (50 ml) and triethylamine (0.6 ml, 4.3 mmol). The mixture was heated at reflux for 72 h, diluted with dichloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 5% triethyamine: 95% EtOAc) to yield the title compound (424 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1ccc(CCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 4 h

Procedure:
4-(4-Methylphenyl)butanol (0.5 g, 3.04 mmol) is dissolved in 5 ml DMF and to it is added imidazole (310 mg, 4.56 mmol) and tert-butyldimethylsilyl chloride (685 mg, 4.56 mmol). The reaction is stirred for 4 hrs after which it is extracted in ethyl acetate and washed with water to remove all DMF. The organic layer is then dried and concentrated. The crude mixture is then purified by flash chromatography using a mixture of ethyl acetate-hexanes as the eluting medium to afford the above mentioned product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([CH3:21])[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:22](Cl)=[O:23].[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][CH2:32][NH:33][C:22]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([CH3:21])[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1cc2nccc(Oc3ccc4c(C(=O)Cl)c(C)sc4c3)c2s1
Reactant: NCCN1CCOCC1
Product: Cc1cc2nccc(Oc3ccc4c(C(=O)NCCN5CCOCC5)c(C)sc4c3)c2s1
Yield: 74.8 %

Procedure:
This material was prepared from 2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbonyl chloride 139d (112 mg, 0.3 mmole) and 2-(morpholin-4-yl)ethylamine (157 mg, 1.2 mmole) in a similar manner as that described for example 108 to give a yellow solid (105 mg, 75%). 1H NMR (DMSO-d6) δ 8.44 (1H, d, J=5.5 Hz), 8.29 (1H, t, J=4.8 Hz), 7.94 (1H, d, J=8.7 Hz), 7.92 (1H, d, J=2.3 Hz), 7.31 (1H, s), 7.30 (1H, dd, J=2.3, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.60 (4H, t, J=4.2 Hz), 3.45 (2H, dt, J=4.8, 6.2 Hz), 2.64 (3H, s), 2.62 (3H, s), 2.55–2.41 (6H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2=[O:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: O=C1CC(c2cccnc2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2cccnc2)O3)c1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 33.7 %

Procedure:
A mixture of 6-bromo-2-(pyridine-3-yl)chroman-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (294 mg, 2 mmol), Cs2CO3 (2 M, 5 mL) and Pd(PPh3)2Cl2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile (110 mg, 34%). 1H-NMR (MeOD): 2.97-3.02 (d, 1H), 3.25-3.33 (m, 1H), 5.74-5.78 (d, 1H), 7.23 (d, 1H), 7.52 (m, 1H), 7.60-7.64 (m, 2H), 7.70 (d, 1H), 7.90-7.95 (m, 2H), 7.99 (s, 1H), 8.07 (d, 1H), 8.15 (s, 1H), 8.57 (d, 1H), 8.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=5)[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.98 (M+H+); retention time=1.07 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([OH:30])(=O)=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.C[N:32](C)C=O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH2:32])(=[O:30])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(S(N)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Reaction time: 0.05 h

Procedure:
To a solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (137.2 mg, 0.33 mmol, 1.00 equiv) in thionyl chloride (12 mL) was added N,N-dimethylformamide (2 mL) dropwise with stifling. The mixture was stirred at reflux for 3 hr in an oil bath. The resulting mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (10 mL) and added to a solution of ammonia (2 g) in acetonitrile (10 mL) dropwise at 0° C. The resulting mixture was stirred overnight at room temperature, then concentrated in vacuo. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 65% in 2.8 min, hold 65% in 2.5 min, up to 100% in 0.1 min, hold 100% in 0.6 min, down to 10% in 0.1 min); Detector, UV 254 nm. This resulted in 16 mg (12%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonamide as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[C:20]2[N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:36])[C:20]2[N:19]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)nc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (0.83 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A79. A solution of 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (256.9 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B79. Solution B79 was added to Solution A79 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-amide (98.7 mg, 30%) as a white solid: MS (ESI) M+1=471.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 72 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv.), 2-amino-5-chloropyridine (9.02 g, 1.3 equiv.), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv.) for 30 minutes. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The product was triturated with diethyl ether to give N-(5-chloro-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (11.5 g, 72%). MS found for C12H7ClFN3O'(M+H)+: 296, (M+2+H): 298.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:34])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[Cl:34][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:17]2)[CH2:14][CH2:15]1)=[O:9]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(N)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(NC(C)=O)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.18 g of 2-{1-[(5-amino-2-chlorophenyl)carbonyl]piperidin-4-yl}-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 91) are dissolved in 5 ml of DCM, 0.17 ml TEA and 0.032 ml acetyl chloride are added, and the reaction mixture is stirred at RT for about 16 h until the reaction is completed according to TLC analysis. The mixture is washed with 0.5 M aqueous sulfuric acid, twice with 1 M aqueous sodium carbonate solution and with brine. The organic phase is dried over MgSO4, and the solvent is removed under reduced pressure resulting in the crude product, which is purified by column chromatography (silica gel and EA) yielding the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:47]1([C:53]2[O:57][C:56]([C:58]([NH2:61])([CH3:60])[CH3:59])=[N:55][N:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([NH:61][C:58]([C:56]3[O:57][C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[N:54][N:55]=3)([CH3:60])[CH3:59])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(N)c1nnc(-c2ccccc2)o1
Reactant: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(COc2cc(C(=O)NC(C)(C)c3nnc(-c4ccccc4)o3)ncc2C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of the acid 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinic acid (20 mg, 76.0 μmol) in dichloromethane (1 ml) was added DIPEA (24.5 mg, 33.2 μl, 190 μmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (23.1 mg, 83.6 μmol). The reaction is stirred for 30 minutes at room temperature followed by addition of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-amine (CAN 68176-04-5, 15.4 mg, 76.0 μmol) and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (5 mL) and washed with a 0.2M aqueous solution of hydrochloric acid (3×10 mL) and brine (15 mL). The organic phase is dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (24.3 mg, 71%). MS (ESI, m/z): 449.7 (M+H+).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.Br.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH2:17][Br:1])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)OCCc1cc(C(C)=O)ccc1O
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCc1cc(C(=O)CBr)ccc1O

Procedure:
A solution of bromine (0.8 ml, 2.5g) in chloroform (20 ml) was added over 20 min to a stirred solution of 1-[3-[2-(acetyloxy)ethyl]-4-hydroxyphenyl]ethanone (3.26 g ) in chloroform (50 ml) containing a few drops of 45% hydrogen bromide in acetic acid. The red solution was diluted with ER (200 ml) washed with water (100 ml), 8% sodium bicarbonate (100 ml), brine (100 ml), dried and evaporated to give the title compound as an oil which solidified on standing to give a pale pink solid (4.1 g) m.p. 89°-92°. Two recrystallisations from chloroform gave a sample with m.p. 98°-99°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=1[F:13]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (ii) and the product of example 1 step (iii).