Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
16-Hydroxyhexadecanoic acid (5.43 g, 19.9 mmol) was dissolved in tetrahydrofuran (190 ml) and pyridine (2.36 g, 29.9 mmol) was added. Palmitoyl chloride (5.48 g, 19.9 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water (3×50 ml), and the organic phase was dried (MgSO4). After evaporating under reduced pressure, the residue was purified on a silica column, eluting with chloroform with increasing methanol concentration (from 1% to 2% methanol in chloroform) to give 8.41 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.20-1.35 (s, 46H, --CH2 --), 1.55-1.70 (m, 6H, --CH2 --), 2.25 (t, 2H, --CH2 --C(O)--O), 2.45 (t, 2H, --CH2 --COOH), 4.05 (t, 2H, --O--CH2). 13C NMR (75 MHz, CDCl3): δ 14.01, 22.57, 24.10, 24.91, 25.82, 28.53, 28.75, 28.94, 29.08, 29.15, 29.25, 29.36, 29.54, 31.81, 34.29, 35.16, 64.27, 76.48, 76.90, 77.10, 77.32, 169.50, 173.91.
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]([F:12])([F:11])[C:5]([C:7]([F:10])([F:9])[F:8])=[O:6].S(F)(O[C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20])(=O)=O>COCCOCCOC>[F:8][C:7]([F:10])([F:9])[C:5]([F:1])([O:6][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20])[C:4]([F:12])([F:11])[Cl:3]
Reactant: O=C(C(F)(F)F)C(F)(F)Cl
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: FC(F)=C(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A suspension of potassium fluoride (5.80 g, 0.10 mol) and diglyme (100 ml) was stirred at 20° C. in a cooling bath while chlorpentafluoroacetone (18.3 g, 0.10 mol) was distilled in. After the potassium fluoride had dissolved, perfluoroallyl fluorosulfate (23.0 g, 0.10 mol) was added rapidly with cooling of the reaction mixture. The resulting exothermic reaction was accompanied by the precipitation of solid. The mixture was stirred at 25° C. for one hour, and then the volatile components were transferred to a trap cooled to -80° C. by heating the reaction mixture at 42` C. (5 mm Hg). The volatile product was distilled from phosphorus pentoxide to give 1-(1,1,1,2,3,3-hexafluoro-3-chloro-2-propoxy)-pentafluoro-2-propene, (19.6 g, 0.059 mol, 59%)pb 85°-86° C. which was characterized by: λmax 5.55 (CF=CF2) and 7-10 μm (CF, C--O); 19F NMR, -68.6 (m) 2F, CF2Cl, -69.1 (m) 2F, CF2O, -78.8 (m) 3F, CF3, -93.2 (d J=54.7 Hz, each member d J=39.8 Hz, t J=7.5 Hz), 1F, cis--CF2 -CF=CF, -105.9 (d J=116.7 Hz, each member, d J=54.7 Hz, t J=24.0 Hz) 1F, trans-CF2 -CF=CF, -141.2 (t J=22.8 Hz, each member m) 1F, CF, and -190.4 ppm (d J=116.7 Hz, each member d J=39.8 Hz, t J=13.4 Hz) 1F, --CF2CF=C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[C:21]([CH3:28])[C:20]=2[F:29])[CH:17]=1)[C:13]#[N:14].CCOC(C)=O>O.C1COCC1>[NH2:25][C:24]1[C:19]([O:18][C:16]2[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=2)[C:13]#[N:14])=[C:20]([F:29])[C:21]([CH3:28])=[CH:22][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Sodium hydrosulfite (10.2 g, 58.7 mmol) dissolved in water (66 ml) was added dropwise to a vigorously stirred solution of 3-chloro-5-[(2-fluoro-3-methyl-6-nitrophenyl)oxy]benzonitrile (3.0 g, 9.78 mmol) dissolved in THF (33 mL). The reaction was stirred for 1 h then EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (2.5 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.68 (d, 1H), 7.26 (dd, 1H), 7.16 (t, 1H), 6.85 (t, 1H), 6.51 (dd, 1H), 5.17 (d, 2H), 2.06 (d, 3H) MS: m/z 277.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.[Cl:21][C:22]1C(OC)=C(C=O)C=C[N:23]=1>>[Cl:21][C:22]1[C:3]([O:2][CH3:1])=[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:23]=1
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Reactant: COc1c(C=O)ccnc1Cl
Product: COc1c(C(O)C#Cc2ccccc2)ccnc1Cl
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 2-chloro-3-methoxy-pyridine-4-carbaldehyde was reacted to give the title compound (1.60 g, 100%) as a colourless solid, LCMS (Method A): RT=4.14 min, [M+H]+=274/276.
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[C:3]([S:8]([O-:11])(=[O:10])=[O:9])[CH:2]=1.[Na+:12].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=[O:30]>>[C:13]([O:25][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][C:3]=1[S:8]([O-:11])(=[O:10])=[O:9])(=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na+:12]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)Oc1ccccc1S(=O)(=O)[O-]
Yield: 85 %

Procedure:
One-hundred grams of sodium p-phenolsulfonate which was previously dehydrated was dispersed in 300 g of dimethylformamide (hereinafter simply referred to as "DMF"), and lauroyl chloride at 50° C. was added dropwise to the above mixture over a period of 30 minutes while stirring with a magnetic stirrer. After completing the dropwise addition, the components were allowed to react with one another for 3 hours. Thereafter, the DMF was distilled off at 100° C. under a reduced pressure of 0.5 to 1 mmHg. After rinsing the resulting mixture with acetone, recrystallization was carried out in a water/acetone solvent (molar ratio 1:1), to give sodium lauroyloxybenzenesulfonate (yield 85%).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>>[C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Nc1nccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1nccc2c1CCCC2
Yield: 59.1 %

Procedure:
Reaction of N-(isoquinol-1-yl)acetamide (159 mg, 0.854 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroisoquinolin-1-yl)acetamide (96 mg, 59%): 1H NMR δ 1.74-1.76 (m, 4H), 2.16-2.19 (m, 3H), 2.60-2.70 (m, 2H), 2.70-2.76 (m, 2H), 6.86 (d, 1H, J=5 Hz), 8.03 (d, 1H, J=5 Hz); 13C NMR δ 22.3, 22.8, 23.8, 25.1, 29.6, 122.9, 144.4 (2C), 149.5, 150.2, 170.6; MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide also was isolated (16 mg, 11%): 1H NMR δ 2.28 (m, 3H), 2.96-3.01 (m, 2H), 3.56-3.61 (m, 2H), 7.20 (d, 1H, J=8 Hz), 7.33-7.38 (m, 1H), 7.44-7.49 (m, 1H), 8.27 (d, 1H, J=8 Hz); 13C NMR δ 27.2, 28.7, 29.7, 39.3, 127.3, 127.5, 128.0, 132.6, 137.9, 162.8, 188.0; MS m/z: 191 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=S)[CH:5]=[C:6]([Br:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCC(C)(C)NC(=S)Nc1cc(Br)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)N=C=Nc1cc(Br)cc(Br)c1

Procedure:
To a solution of 2.4 g of N-(3,5-dibromophenyl)-N'-t-pentylthiourea produced in Example A-10 in 55 ml of dichloromethane were added 3.3 g of triphenylphosphine, 2.0 g of carbon tetrachloride and 1.3 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether and the extract evaporated in vacuo to give N-(3,5-dibromophenyl)-N'-t-pentylcarbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.2 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 3 hours, cooled to room temperature and poured into 600 ml of water. The resulting crystals were collected, washed with a small amount of cyclohexane and recrystallized from ethanol to give 0.9 g of the title compound as colorless needles melting at 168.0°-170.0° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCC(O)CCCl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC(Cl)CCCl
Temperature: 25 °C

Procedure:
To a solution of 2.4 g (11.0 mmoles) of the methyl ester of (+)-8-chloro-6hydroxy-octanoic acid (+)-(VIII) (R=Me) and 0.04 g (0.5 mmoles) of pyridine in 8 ml toluene, 1.6 g (13.5 mmoles) of thionyl chloride in 5 ml of toluene were added slowly. The mixture was then refluxed for 1 hour. After cooling to room temperature, the reaction mixture was added to 20 ml ice water and the organic phase was separated and washed with 10 mL of water and dried over magnesium sulfate. After that, the solvent was evaporated under vacuum. The methyl ester of (-)-6,8-Dichloro-octanoic acid (-)-(III), (R=Me) was obtained in a yield of 2.0 g (81% of the theoretical yield). [α]D20 =-30.0° (c=1, benzene).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].OO.CC(C)=[O:56]>CO.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N+:41]([O-:56])([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC(C)=O
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: OO
Solvent: O
Solvent: CO
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H]([N+](C)(C)[O-])[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
220.2 g(0.3 mol) of erythromycin A was dissolved in a mixture of 1,500 ml of methanol and 1,000 ml of water. 79 ml(0.9 mol) of 35% hydrogen peroxide was added dropwise to the solution at a temperature ranging from 15 to 20° C. and stirred at room temperature for 20 hours in a similar method described in E. H. Flynn et al., J. Am. Chem. Soc., 76, 3121(1954) and P. H. Jones et al., J. Org. Chem., 33, 665(1968). The resulting mixture was concentrated to a half volume under a reduced pressure and extracted successively with 1,000 ml and 500 ml portions of chloroform. The combined chloroform extract was washed with brine, dried over anhydrous magnesium sulfate, and then, concentrated under a reduced pressure to obtain a foamy residue. 1,000 ml of acetone was added to the residue and stirred at room temperature for 3 hours. The crystalline material formed was filtered and dried overnight at 45° C. to obtain 220 g of erythromycin a N-oxide in a yield of 98%.
Reaction SMILES: [CH2:1]([C:3](=[CH:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)[CH3:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[Na].[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:1]([C:3](=[CH:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([S:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCC(=CSc1ccccc1)C(=O)Nc1ccccc1
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of 3.68 g (13 mmol) of 2-ethyl-N-phenyl-3-(phenylthio)-2-propenamide, 1.9 ml (26 mmol) of thionyl chloride, 10 mg of DMF, and 20 ml of toluene was refluxed for 1 hour. After concentration of the mixture under vacuum, the residue was dissolved in 35 ml of DMF and then 2.0 g (15.1 mmol) of a benzenethiol sodium salt was added portionwise under ice cooling and stirred at room temperature for 1 hour. After dilution with tert-butyl methyl ether, the mixture was washed sequentially with water (three times) and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 2.03 g of phenyl 2-ethyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 14).
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])C.Cl.[NH:13]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[NH2:14].Cl>CO>[C:9]([C:5]1[CH:4]=[N:14][N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1ncc(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 3-(ethoxymethylene)pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 mL) was added a solution of ethyl hydrazinoacetate hydrochloride (2.09 g, 13.5 mmol) and conc.HCl (2.6 ml) in MeOH (10 ml) (pre-cooled to 0° C.) dropwise at −15° C. The resulting mixture was then stirred for 24 hours at room temperature. After removal of the solvent at room temperature, the residue was basified with 2N NaOH aq, and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The aqueous layer was acidified to pH 1 with 2N HCl aq. and extracted with EtOAc 6 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give the crude 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetic acid as a mixture of regioisomers (1.17 g, <51% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s), 2.43 (3H, s), 4.99 (2H, s), 7.81 (1H, s), 13.2 (1H, brs).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[C:10]([CH:12]2[C:25]3[CH:24]=[CH:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[NH:15][S:14](=[O:27])(=[O:26])[N:13]2[CH3:28])[CH:9]=[CH:8][C:7]=1[F:29]>O.C1COCC1.CO>[F:29][C:7]1[CH:8]=[CH:9][C:10]([CH:12]2[C:25]3[CH:24]=[CH:23][C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[NH:15][S:14](=[O:27])(=[O:26])[N:13]2[CH3:28])=[CH:11][C:6]=1[C:5]([OH:30])=[O:4]
Reactant: COC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
LiOH (10 mg, 0.25 mmol) in water (0.5 ml) was added to a solution of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid methyl ester 423 (50 mg, 0.12 mmol) in THF:MeOH (1:1; 2 ml) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, the residue was diluted in the minimum amount of water and acidified to pH=3-4 with 2 M HCl. The resulting precipitate was collected by filtration and dried. The crude solid was purified by preparative HPLC (acidic conditions 1) to give the title compound (8 mg, 17%).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>CN(C=O)C.O>[N:7]1[CH:8]=[CH:9][C:4]([S:3][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(Sc3ccncc3)ccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Sodium hydride (3.3 g of a 50% suspension in mineral oil, 69 mmol) was added to a solution of 4-mercaptopyridine (8.12 g, 73 mmol) in DMF (100 ml) and the mixture stirred for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1.5 g, 9 mmol) was added and the reaction heated at 100° C. for 4 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (500 mg, 6%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:23])[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
8-(4-Oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoline-2-carboxylic acid (Example 94e; 80 mg, 0.26 mmol) was dissolved in DMF (2.5 mL), HATU (119 mg, 0.31 mmol), Et3N (0.04 mL, 0.31 mmol), and aniline (0.05 mL, 0.52 mmol) were added, and the resulting mixture was stirred at RT for 20 min. The mixture was then treated with EtOAc and washed with water. The organic layer was separated, and the aq. layer was extracted with EtOAc (2×). The combined organic layers were then dried over MgSO4, filtered, and concentrated to in vacuo. DCM was added to the crude material and a precipitate was formed, which contained both the desired product and impurities. Most of the impurities crystallized from hot DCM, and were removed by filtration. The mother liquor was concentrated and the material (desired product and ca. 10% impurity) was suspended in EtOAc. The desired product was recrystallized from hot EtOAc and was isolated by filtration affording 8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-N-phenylquinoline-2-carboxamide (12.9 mg, 0.034 mmol, 13.0% yield) as an amorphous tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (br. s., 1H), 10.55 (s, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.72-7.81 (m, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.13-7.22 (m, 1H), 7.07 (d, J=10.8 Hz, 2H), 3.44-3.53 (m, 2H), 2.95 (t, J=6.7 Hz, 2H). m/z (ESI, +ve ion) 383.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH:10]([NH:18][C:19]([C:21]1([NH:36]C(=O)OC(C)(C)C)[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:36][C:21]1([C:19]([NH:18][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:9][NH2:8])=[O:20])[CH2:22][CH2:23][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.4 %

Procedure:
Trifluoroacetic acid (3 mL) was added to tert-butyl 4-(2-amino-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 6) (0.514 g) in DCM (100 mL) at 25° C. The resulting solution was stirred at 25° C. for 3 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness. This material was then further purified by flash silica chromatography, elution gradient 0 to 10% methanolic ammonia (7N) in DCM. Pure fractions were evaporated to dryness to afford 4-amino-N-(2-amino-1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a colourless gum (0.047 g, 11.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl.Cl>[CH3:31][N:32]([CH3:37])[S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:30])[C:20]3[C:25]([NH:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2)(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)N(C)C)ccc3[nH]2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (PREPARATION 56, 91 mg) in pyridine (0.5 ml) under nitrogen is added N,N-dimethylsulfamoyl chloride. The mixture is stirred at 20°-25° for 16 hr and then diluted with methylene chloride (35 ml) and 1M hydrochloric acid (20 ml). The layers are separated and the organic layer is washed with 1M hydrochloric acid (20 ml) and saline, dried over sodium sulfate, and concentrated to give a solid film which is then chromatographed on two 2000 μ preparative silica gel plates, eluting with methanol/chloroform (5/95). The desired band is extracted and concentrated to give the title compound, NMR (CDCl3) 10.34, 7.72, 7.64, 7.56, 7.37, 7.16, 6.95, 6.84, 6.70, 4.65, 4.50, 3.56, 3.46, 3.40-3.00, 2.80, 2.63, 1.93, 1.64 and 1.22 δ.