Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[S:50][N:49]=[C:48]([CH3:51])[CH:47]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[S:50][N:49]=[C:48]([CH3:51])[CH:47]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: Cc1cc(C=O)sn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2cc(C)ns2)cc1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-3-methyl isothiazole (0.44 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added sodium triacetoxyborohydride (0.22 g) was added to the mixture, and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-isothiazol-5-ylmethyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 92) (154.0 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: COc1ccc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (116 mg, 0.4 mmol) and 4-chloro-7-methoxyquinazoline (78 mg, 0.4 mmol) as described in Example 46 and its corresponding hydrochloride salt was prepared as described in Example X4 Step 2 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-ylthio)phenyl)urea as the mono-hydrochloride (143 mg, 0.30 mmol, 75%). 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.20 (d, 1H), 7.87 (s, 1H), 7.55 (d, 1H), 7.48-7.42 (m, 2H), 7.38 (s, 1H), 7.29 (d, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:31]=[CH:30][C:18]([O:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)=[CH:13][C:12]([C:32]([F:35])([F:34])[F:33])=[N:11]2)=[CH:6][CH:5]=1>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:31]=[CH:30][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:32]([F:35])([F:33])[F:34])=[N:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCN)cc2)cc1

Procedure:
To a solution of hydrogen chloride in ethyl acetate (4N, 1.0L) was added powdered tert-Butyl 2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamate obtained by Example 73 (500 g) at 5° C. over 20 min.
Reaction SMILES: C1C2C(=CC=CC=2)CCC21CC[C:13](=[O:16])[CH2:12]C2.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24]1([CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[CH2:23]2)[CH3:18].Cl>CC(C)=O>[CH2:13]1[O:16][C:25]2([C:26]3[C:22](=[CH:21][C:20]([O:19][CH2:17][CH3:18])=[CH:28][CH:27]=3)[CH2:23][C:24]32[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[O:29][CH2:12]1
Reactant: O=C1CCC2(CC1)CCc1ccccc1C2
Reactant: CCOc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Agent: Cl
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)CC1(CCC(=O)CC1)C21OCCO1

Procedure:
A mixture of 1.86 g. (0.0072 mole) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal (8) (prepared in Example 7C) and 2 ml. of 2.5 N hydrochloric acid in 40 ml. of acetone is heated at reflux for about 17 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and then evaporated to dryness to give 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Temperature: 25 °C

Procedure:
To 475 mg (1.46 mmol) 2-[4-((S)-1-amino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester (example XXXV) in 5 mL AcOH are added 152 μL (1.61 mmol) acetic anhydride and the mixture is stirred at r.t. over night. After that time, the reaction mixture is quenched by the addition of a sat. aq. NaHCO3 solution and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: OB(O)c1ccsc1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Product: O=C(c1ccc(-c2ccsc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 3-Thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 56 mg (56%). MS (ES+) 341.2
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[C:8]=1[C:16]#[N:17].[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:16]([C:8]1[C:9]([O:12][CH2:13][CH2:14][CH3:15])=[N:10][S:11][C:7]=1[N:6]=[CH:18][N:19]([CH3:22])[CH3:20])#[N:17]
Reactant: CCCOc1nsc(N)c1C#N
Reactant: CN(C)C=O
Agent: CS(=O)(=O)Cl
Product: CCCOc1nsc(N=CN(C)C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 13.7 g of methanesulfonyl chloride in 25 ml of dimethylformamide was stirred at room temperature for about 16 hours. Into the mixture was stirred 11 g of 5-amino-4-cyano-3-propoxyisothiazole which addition caused an exothermic reaction. The mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 2.7 g of crystalline N'-(4-cyano-3-propoxy-5-isothiazolyl)-N,N-dimethylformamidine, m.p. 117°-118°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12][CH:11]=1>C1COCC1.O>[F:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:7][OH:8])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ON=Cc1ccc(F)c2ccccc12
Reaction time: 3 h

Procedure:
Sodium acetate (4.8 g) is added to a solution of hydroxylamine hydrochloride (2.9 g) and 4-fluoro-naphthalene-1-carbaldehyde (8.1 g, example 1 step B) in THF (40 ml) and water (10 ml). After 3 hours at room temperature, the reaction is quenched with water and ethyl acetate. The organic, phase is separated and the water phase is extracted with ethyl acetate. The combined organic phases are washed with water and with a saturated aqueous solution of NaCl, dried over Mg2SO4 and concentrated in vacuo to yield 4-fluoro-naphthalene-1-carbaldehyde oxime. The crude product obtained is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][O:12]C)=[CH:6][CH:5]=1.Cl>C1COCC1.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1
Reactant: COC=Cc1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC=O)cc1
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a 0° C. solution of 4-(2-Methoxy-vinyl)-benzoic acid methyl ester (930 mg, 4.84 mmol) in THF (50 mL) is added conc. HCl (7 mL) dropwise. After 2 h, the reaction is diluted with water and the pH is adjusted to 7. The aqueous layer is extracted with Et2O (2×200 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 30% EtOAC/Hex) to yield the title compound (613 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 9.77 (t, 1H, J=2.2 Hz), 8.04 (d, 2H, J=8.4 Hz), 7.30 (d, 2H, J=8.8 Hz), 3.92 (s, 3H), 3.77 (d, 2H, J=2.2 Hz).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21]C(=O)C)=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Agent: Cl
Product: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCOCC1
Temperature: 95 °C
Yield: 113 %

Procedure:
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]acetamide (20.7 g, 62.8 mmol) was dissolved in 37% HCl (120 mL). The solution was heated at 95° C. for 20 h. After concentration, 20.4 g (100%) of a purple solid was obtained. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.47-1.52 (m, 4 H), 1.54 (s, 9 H), 2.23-2.31 (m, 1 H), 3.28-3.36 (m, 2 H), 3.96 (t, J=3.12 Hz, 1 H), 3.97-4.00 (m, 1 H), 4.13 (d, J=7.62 Hz, 2 H), 6.66 (dd, J=8.40, 2.15 Hz, 1 H), 7.06 (d, J=2.15 Hz, 1 H), 7.10 (d, J=8.40 Hz, 1 H); MS (ESI) (M+H)+=288.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Se](=O)=[O:16]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH:14]=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Br)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2Br)n1
Yield: 54.1 %

Procedure:
6-(2-bromophenyl)-2-methylpyridine (3.5 g) was dissolved in 150 ml 1,4-dioxane. Selenium dioxide (Aldrich, Gold Label, 2.0 g) was added and the mixture was refluxed for a total of 50 hours. The solids were removed by filtration and the mixture was diluted with ether. The solution was washed several times with water, dried over magnesium sulfate, filtered and evaporated to afford 2.0 g of crude 6-(2-bromophenyl)-2-pyridinecarboxaldehyde as a yellow semi-solid.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Temperature: 120 °C
Reaction time: 15 h
Yield: 477.4 %

Procedure:
To ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (2.85 g, 10 mmol) was added phosphorus oxychloride (10 mL, 2 mmol) and the mixture was stirred at 120° C. for 15 h. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution (×3) and saturated brine (×1) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound (2.9 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.N1C2C(=CC=CC=2)C=C1.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl.CN(C1C=CN=CC=1)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:36])[C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A 100-mL, one-necked, round bottomed flask with a magnetic stirring bar and a septum was charged with 2-(2-aminophenyl) indole (210 mg; 1.01 mmol). The indole was dissolved in ca. 7 mL of dichloromethane to give a very pale yellow solution. DMAP (143 mg; 1.17 mmol; 1.16 equiv) and phthalic anhydride (179 mg; 1.21 mmol; 1.20 equiv) were added sequentially each dissolving completely with a resulting yellow solution. The solution was stirred at room temperature, and the reaction was followed by TLC, and showed complete conversion in ca. 30 min as indicated by the disappearance of the 2-(2-aminophenyl) indole. The reaction mixture was poured into a 125-mL separatory funnel and extracted with 15 mL HCl (aq, ca. 1 M). The aqueous layer was washed with 2×5 mL CH2Cl2, and the combined organic layer was dried (anhydrous Na2SO4), filtered, and concentrated by rotary evaporation to yield a canary yellow foamy solid (0.377 g) of N-[2-(1H-indol-2-yl)-phenyl]phthalamic acid. MS (M+H+: calcd 357; found 357).
Reaction SMILES: C([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([Cl:16])=[C:9]([Cl:17])[N:8]=1)=O)C.C(OC(C(C(OCC)=O)C1C(Cl)=CC([N+]([O-])=O)=C(Cl)N=1)=O)C.C(C(CC)(C([O-])=O)C([O-])=O)C.NC1C(C(C(OCC)=O)C(OCC)=O)=NC(Cl)=C(Cl)C=1.NC1(Cl)C=CC(Cl)=NC1C(C(OCC)=O)C(OCC)=O>C(O)C.[Ni].O.Cl.CCCCCC.C(OCC)(=O)C>[Cl:17][C:9]1[N:8]=[C:7]2[C:12](=[CH:11][C:10]=1[Cl:16])[NH:13][C:4](=[O:3])[CH2:6]2
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: CCOC(=O)C(C(=O)OCC)C1N=C(Cl)C=CC1(N)Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: O=C1Cc2nc(Cl)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
The mixture of 2-bis(ethoxycarbonyl)methyl-5,6-dichloro-3-nitropyridine, 2-bis(ethoxycarbonyl)methyl-3,6-dichloro-5-nitropyridine and diethylmalonate was dissolved in ethanol (100 mL) and added to a suspension of 50% Raney nickel in water (30 g) diluted with ethanol (10 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure for 5 hours and then filtered through diatomaceous earth (Celite (trademark)) to remove the catalyst. The solvent was removed in vacuo to leave an oil which was subjected to flash chromatography on silica gel eluting with 4:1 hexane/ethyl acetate. Each of the fractions was separately concentrated and the residues examined by 1H NMR in deuterochloroform. Eluted after diethylmalonate was the desired product, 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine, followed closely thereafter by the unwanted isomer, 5-amino-2-bis(ethoxycarbonyl)methyl-3,6-dichloropyridine. Although clean separation from diethyl malonate was achieved, the bulk of the mass of desired product and the isomer eluted as mixed fractions. Leading fractions containing only 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine and mixed fractions containing at least 10% of this material were combined to afford a solid consisting of 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine (3.17 g) and the unwanted isomer, 3-amino-2-bis(ethoxycarbonyl)methyl-3,6-dichloropyridine (4.03 g). This mixture was taken up in 6N HCl solution (120 mL) and heated at reflux for 3 hours. After cooling to room temperature the volatiles were removed in vacuo. Ethanol was added and then evaporated to help remove water. This process was repeated. The resulting brown solid was subjected to flash chromatography on silica gel using 9:1 chloroform/methanol as eluant. All fractions containing the desired product were combined and concentrated to leave a solid which was triturated with methanol to afford 5,6-dichloro-4-azaoxindole (1.42 g, 71%) from 3-amino-2-bis(ethoxycarbonyl)methyl-5,6-dichloropyridine, 13% overall from 3-nitro-2,5,6-trichloropyridne). M.p. 230°-233° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:34]([CH:30]5[O:31][CH2:32][CH2:33][NH:28][CH2:29]5)=[O:35])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=C(O)C1CNCCO1
Product: O=C(C1CNCCO1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 8 %

Procedure:
According to the procedure for compound 398 using morpholine 2-carboxylic acid (25 mg, 0.11 mmol) afforded 3.6 mg (8% yield) of 483 as a solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH:12]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH:9]([CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:11][CH:12]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH:13]([CH3:15])[CH3:14])=[O:8]
Reactant: COCCOc1cccc2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1cccc2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.04 ml of triethylamine and then a solution of 1.31 g of sulphur trioxide-pyridine complex are added at 0° C. to the solution of 0.86 g of tert-butyl {1-hydroxymethyl-3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methylpentyl}carbamate in 8 ml of dichloromethane. After 45 minutes, the reaction mixture is admixed cautiously with ice-water. The resulting mixture is poured onto 1N HCl/ice and extracted with ethyl acetate (3×). The combined organic phases are washed successively with water (2×) and brine, clarified by filtration through Hyflo®, dried over sodium sulphate and concentrated by evaporation. In this way, the crude title compound is obtained.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17]C)=O)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([NH:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]([NH2:1])=[O:17])[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1CC[C@H](NCc2ccccc2)C1
Reactant: N
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@H](NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonia gas was passed into a solution of (1R,3S)-methyl 3-(benzylamino)cyclopentanecarboxylate (250 mg, 1.14 mmol) in MeOH (5 ml) at −78° C. in a steel bomb. The reaction mixture was slowly warmed to room temperature, heated further to 100° C. and stirred for 24 h. The reaction mixture was concentrated and dried under vacuum to afford 250 mg of (1R,3S)-3-(benzylamino)cyclopentanecarboxamide with 50% purity as brown liquid which was proceeded as crude compound for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7]([S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5](=[O:19])[CH:4]=1.[Br:20]Br.CO>C(O)(=O)C>[Br:20][C:6]1[C:5](=[O:19])[CH:4]=[C:3]([O:2][CH3:1])[C:16]2[C:7]=1[S:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1)[N:15]=2
Reactant: COc1ccc2nc3c(OC)cc(=O)cc-3sc2c1
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc3c(OC)cc(=O)c(Br)c-3sc2c1
Reaction time: 0.25 h

Procedure:
To a suspension of 1,7-dimethoxy-3H-phenothiazin-3-one (300 mg) in acetic acid (9 ml) was added a 0.63M solution of Br2 in acetic acid (1.92 ml). After 15 minutes, methanol was added and the solid filtered, washed with ether and air dried to afford the title compound (353 mg), m.p. 267°-270° C. (dec).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[NH2:27])[C:20]([O:22][CH3:23])=[O:21]>>[NH2:27][C:26]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[NH:16][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 44 %

Procedure:
Using the procedure described in Example 146, Part A, 4-tert-butylbenzoyl chloride (6.00 mmol) was reacted with methyl 3,4-diaminobenzoate dihydrochloride. As the product did not precipitate directly, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to provide 0.885 g (44%) of the title compound as a crystalline solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:27][CH:28]([CH3:32])[CH2:29][CH:30]=[O:31]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:30]([OH:31])[CH2:29][CH:28]([CH3:32])[CH3:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 19.3 mmol) in dry tetrahydrofuran (125 mL) at −78° C. was added lithium diisopropylamide (14.5 mL, 29 mmol) dropwise. The mixture was stirred at −78° C. for 10 min and then treated with 3-methylbutanal (3.9 g, 45 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1.5 h. At this time, the reaction was quenched with a saturated aqueous sodium chloride solution. The resulting mixture was then extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (10-15% ethyl acetate/petroleum ether) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-ol (3.4 g, 51.8%) as a white solid: 1H NMR (300 MHz, d6-DMSO): δ 8.29 (d, 1H, J=3.3 Hz), 8.10 (d, 2H, J=7.8 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.72-7.59 (m, 3H), 7.28-7.24 (m, 1H), 6.81 (s, 1H), 5.55-5.46 (m, 2H), 2.05-1.90 (m, 1H), 1.81-1.73 (m, 1H), 1.04 (d, 3H, J=6.3 Hz), 0.97 (s, 3H), 0.95 (s, 3H).