Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:30](#[N:33])[CH:31]=[CH2:32]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:32][CH2:31][C:30]#[N:33])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: C=CC#N
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCN(CCC#N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (260 mg) obtained in Example 23-4 was dissolved in methanol (5.0 ml) and added with distilled water (1.0 ml) and acrylonitrile (87.4 μl) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and the resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (332 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=4[C:20]=3[CH3:29])(=[O:18])=[O:17])[C:11]2=[O:30])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:31]I>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([CH3:31])[S:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=4[C:20]=3[CH3:29])(=[O:17])=[O:18])[C:11]2=[O:30])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12
Reactant: CI
Product: Cc1c(S(=O)(=O)N(C)[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared from 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(2-cyanopyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using methyl iodide in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.C([O:21][C:22]([NH:24][NH2:25])=O)C>CC1C=CC(C)=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]3[C:22](=[O:21])[NH:24][N:25]=[C:9]3[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: CCOC(=O)NN
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Solvent: Cc1ccc(C)cc1
Product: O=c1[nH]nc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Temperature: 180 °C
Yield: 27.3 %

Procedure:
In a 10 ml microwave vial was 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (1 g, 3.11 mmol) and ethylhydrazine carboxylate (1.2 g, 12.44 mmol) in p-xylene (10 ml) to give a yellow suspension. The reaction mixture was heated to 180° C. for 45 minutes under microwave conditions. The crude residue was concentrated under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 100% ethyl acetate in n-hexane) to give the title compound (293 mg, 27%). LCMS (Method D) RT 1.069 min, M+1=346.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:27]12[C:35](=[O:36])[O:34][C:32](=[O:33])[C:28]=1[CH2:29][CH2:30][CH2:31]2.O>CN(C)C=O>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:35]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]([OH:34])=[O:33])=[O:36])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.4 %

Procedure:
To a solution of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline (3.63 g) in N,N-dimethylformamide (30 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (1.44 g), and they were stirred at room temperature for 6 hours. To the reaction mixture was added water (200 ml), and powders so precipitated were collected by filtration. The powders so obtained were washed successively with water and methanol and then dried, whereby 4.53 g of the title compound was obtained.
Reaction SMILES: [OH-].[K+].[C:3]([O:12]CC)(=[O:11])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].Cl>CCCCCCC>[C:3]([OH:12])(=[O:11])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: CC=CC=CCCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Product: CC=CC=CCCC(=O)O
Temperature: 45 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A20% aqueous solution of potassium hydroxide (477 g, 1.7 mol) and ethyl 4,6-octadienoate (c) (114.4 g, 0.68 mol) were put into a four-neck flask, followed by stirring at 45° C. for 3 hours. The reaction solution was cooled to room temperature, heptane (230 mL) was added thereto, and 35% hydrochloric acid (177 g) was added dropwise thereto. After separation of liquid, the organic layer was washed with water (230 mL), and the solvent was evaporated therefrom under a reduced pressure. Thus, 4,6-octadienoic acid (d) was obtained (90.6 g, yield 95%).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].Cl>CO>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: CC(C)C=O
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Product: CC(C)(C=O)CCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Isobutyraldehyde (1 g, 13.9 mmol) and acrylonitrile (0.81 g, 15 mmol) were mixed thoroughly and cooled with an ice-bath. Triton B (40% in MeOH, 0.58 g, 1.4 mmol) was added. The mixture was stirred at room temperature overnight. It was then neutralized with 0.1 M HCl (14 cm3) and extracted with CH2Cl2 (100 cm3) The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give the product 4,4-dimethyl-5-oxopentanenitrile (0.8 g, 50.7%) as an oil, bp 125-130° C./20 Torr.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[CH:28][CH:27]=[C:26]([C:37]([O-:39])=[O:38])[CH:25]=2)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[CH:28][CH:27]=[C:26]([C:37]([O:39][CH3:1])=[O:38])[CH:25]=2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1[nH]c2cc(C(=O)[O-])ccc2c1C1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (137 eq) was added to a solution of methyl 2-(2-{[(tert-butoxycarbonyl)amino]phenyl}-3-cyclohexyl-1H-indole-6-carboxylate in DCM (0.1 M) at 0° C. and the solution was allowed to stir at RT for 1 h. The volatiles were removed in vacuo, and the residue diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (twice) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound (quant.). MS (ES+) m/z 349 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[CH2:26][C:25]3[C:20](=[C:21]([N+:27]([O-])=O)[CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:30])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>CO.C(OCC)(=O)C.CO.[Pd]>[NH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[C:19](=[O:30])[N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:26]2
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A suspension of 2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro-isoindol-1-one (3.0 g, 6.9 mmol) and Pd/C (10% 350 mg) in methanol/ethyl acetate (150 mL each) was shaken under hydrogen (50-60 psi) in a Parr for 20 hours. The suspension was filtered thru a pad of Celite, and washed with acetone (300 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (10 mL) for 3 hours. The suspension was filtered and washed with methanol to give 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one as a white solid (1.5 g, 55% yield): mp, 135-137° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.66 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.06 (q, J=7 Hz, 2H, CH2), 4.13 (d, J=16 Hz, 1H, CHH), 4.22 (dd, J=10, 15 Hz, 1H, CHH), 4.35 (d, J=17 Hz, 1H, CHH), 5.19 (brs, 2H, NH2), 5.64 (dd, J=5, 10 Hz, 1H, NCH), 6.54 (d, J=8 Hz, 1H, Ar), 6.61 (d, J=7 Hz, 1H, Ar), 6.83 (d, J=8 Hz, 1H, Ar), 6.90-6.96 (m, 2H, Ar), 7.20 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.59, 41.28, 48.01, 51.81, 55.87, 56.14, 64.48, 110.98, 111.38, 112.22, 113.41, 114.75, 119.23, 129.89, 133.08, 142.36, 146.02, 148.72, 149.45, 170.57; Anal Calcd for C20H24N2O5S: C, 59.39; H, 5.98; N, 6.93. Found: C, 59.04; H, 6.04; N, 6.74.
Reaction SMILES: N#N.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[Cl:12].[C:14]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]>CN(C=O)C>[C:14]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH2:24][CH2:25][O:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Nc1ccc(OCCCCl)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCCCOc2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C

Procedure:
In a round bottomed flask equipped with magnetic stirring, reflux condenser, N2 atmosphere, and a heating mantle was placed DMF (80 ml) and to this was added cautiously NaH (60% by weight in oil, 1.76 g) followed by 3,4-dichlorophenol (7.15 g). This mixture was stirred for ten minutes then 1-[4-acetamidophenoxy]-3-chloropropane of Formula XXI (10.0 g) was added; and the reaction mixture heated at 80° C. overnight. The mixture was cooled and the DMF removed in vacuo. The residue was poured into ice water and the precipitated brown solid was collected by filtration. The crude product was recrystallized from ethanol to give an off white solid (9.8 g), mp 135°-7° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:38]=[CH:37][C:31]2[N:32]=[C:33]([C:35]#[N:36])[S:34][C:30]=2[CH:29]=1.N1C(C)=CC(C)=CC=1C>C1COCC1>[C:35]([C:33]1[S:34][C:30]2[CH:29]=[C:28]([O:27][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]4[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=4[CH3:24])[CH3:13])=[CH:5][CH:4]=3)[CH:38]=[CH:37][C:31]=2[N:32]=1)#[N:36]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CBr)cc2)=C(C)C1=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(COc3ccc4nc(C#N)sc4c3)cc2)=C(C)C1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of N-(4-(bromomethyl)phenyl)-3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide (0.23 g, 0.57 mmol), 6-hydroxy-2-cyanobenzothiazole (0.15 g, 0.86 mmol), 2,4,6-collidine (0.125 ml) and Ag2CO3 (0.24 g, 0.86 mmol) in 15 ml of dry THF was stirred at room temperature over night. After removal of solid by filtration, the compound was purified by silica chromatography using heptane and ethyl acetate as eluent to give a yield of 40%. The product was further purified by HPLC to remove small contamination of 2-cyano-6-hydroxybenzothiazole. 1H NMR (300 MHz, CD2Cl2) δ 7.4-7.5 (m, 3H), 7.35-7.42 (m, 2H), 7.32 (dd, 1H), 7.25 (s, br, 1H, NH), 7.18 (dd, 1H), 5.15 (s, 2H, CH2O), 2.99 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.92 (s, 6H, CH3), 1.47 (s, 6H, CH3). MS (m/e): 514.2 (M+).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=2)[C:8]=1[Br:32])C.[OH-].[K+].Cl>C1COCC1.O>[Br:32][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A mixture of [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.0932 g, 0.177 mmol) and potassium hydroxide (0.063 gm 1.1 mmol) in THF (5 mL) and water (5 mL) was stirred at ambient temperature for two hours. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated and dried in vacuo at 64° C. for 25 hours to yield [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid as a light yellow solid (0.0662 g, 75.2%): MP: 164–5° C.; mass spectrum (+EI, [M+H]+) m/z 497/499. 1H NMR (500 MHz, DMSO-d6): δ13.0–13.2 (br, 1H), 8.24 (d, 1H, J=8.70 Hz), 8.07–8.13 (m, 3H), 7.95–7.97 (m, 1H), 7.76 (dd, 1H, J=8.78 Hz and 1.91 Hz), 7.45–7.51 (m, 3H), 5.02 (s, 2H), 2.42 (t, 2H, J=7.22 Hz), 1.40–1.46 (m, 2H), 0.97–1.04 (m, 2H), 0.58 ppm (t, 3H, J=7.41 Hz). Elemental Analysis for C25H21BrO4S: Calcd: C, 60.37; H, 4.26; N, 0.00; Found: C, 60.23; H, 4.35; N, 0.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CN(CCCCN)CC2
Yield: 62.5 %

Procedure:
A solution of 7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (17.4 g 0.0478 mol) and hydrazine monohydrate (4.6 ml, 0.095 mol) in ethanol (300 ml) were stirred at room temperature for 18 h and at reflux for 1 h. The cooled reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in 2.5N hydrochloric acid, filtered through Kieselguhr and the filtrate basified with 0.880 ammonia. The product was extracted into dichloromethanc (4×200 ml), the combined extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a brown oil (7 g, 63%).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH:18]S(C(C)(C)C)=O)[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {(S)-1-[l-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propyl}-amide (1.00 g, 2.61 mmol) in MeOH was added a 4 M solution of HCl in dioxane (1 mL, 4 mmol). After 2 hours, the solvent was concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(Cl)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2-chloro-4-methoxyphenylboronic acid (187 mg, 1.0 mmol) to afford after chromatographic purification the title compound (133 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ7.23 (d, 1H, J=8.8 Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz), 3.84-4.24 (m, 2H), 3.84 (s, 3H), 3.68-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.26 (m, 3H), 1.84-1.8 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 441 [M+H+].
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]([C:37]5[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=5)=[N:29][N:28]=4)=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[N:11][CH:10]=1)C1C=CC=CC=1.CO.[H][H]>C(Cl)Cl.[Pd]>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([O:19][C:13]4[CH:14]=[CH:15][N:16]=[C:17]5[C:12]=4[N:11]=[CH:10][C:9]([OH:8])=[CH:18]5)=[CH:25][CH:24]=3)=[N:28][N:29]=2)=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: Clc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OCc6ccccc6)cnc45)cc3)c3ccccc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Oc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)ccnc2c1
Reaction time: 8 h

Procedure:
A round bottom flask was charged with N-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine (400 mg, 687 μmol), 10% Pd/C (73.1 mg, 687 μmol) and 3.4 mL MeOH. The flask was fitted with a hydrogen-filled balloon and the mixture was stirred overnight. The mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated and the crude material was purified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN in water over 15 min to provide 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-3-ol as a light yellow solid. MS: [M+H]=492.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:25][CH:24]=1
Reactant: COC(=O)CCCBr
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2C)cc1

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with methyl 4-bromobutyrate in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=482.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (98.6 mg, 86%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1([CH3:22])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([OH:19])[C:14]=2[CH3:18])[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[C:1]([NH:5][C:6](=[O:7])[C:8]([OH:23])([CH3:22])[CH2:17][CH2:16][C:15]1[C:10](=[O:9])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13](=[O:19])[C:14]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC(C)(C)C)=C(C)C1=O
Yield: 92.2 %

Procedure:
Oxidation as described in protocol B, using 95 mg (0.311 mmol) of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 358 mg CAN (0.653 mmol) yielded 92.2 mg of N-tert-butyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].CCOC(C)=O>CN(C=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:3][NH:30][CH2:31][CH2:32][CH2:33][OH:34])[N:13]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: NCCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(CNCCCO)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (100 mg, 0.286 mmol), Cs2CO3 (201 mg, 0.617 mmol) and 3-amino-propan-1-ol (44 μL, 0.58 mmol) in DMF (1 mL) was heated at 80° C. After 18 h, EtOAc (12 mL) was added and this was washed with water (2×2 mL) and satd NaCl (2×2 mL). The soln was dried (MgSO4), filtered through a plug of silica with a wash of 100:10:1 chloroform:methanol:concd NH4OH then purified by preparative TLC (SiO2/200:10:1 chloroform:2-propanol:concd NH4OH). A band was removed from this preparative TLC plate and further purified by preparative TLC (SiO2/100:10:1 chloroform:methanol:concd NH4OH) yielding the title compound as a yellow oil. The bis(hydrochloride) salt was formed by adding then evaporating a soln of HCl in i-PrOH, giving an off-white solid. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.78 (m, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.09 (m, 2H), 6.90 (m, 1H), 4.91 (t(br), 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.56 (t, J=6.2 Hz, 2H), 3.24 (m, 2H), 1.91 (m, 2H); LC-MS (ESI+; 353 ([M+H]+)).