Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:33])=[CH:24][CH:25]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: Cc1ccc(-c2ccccc2C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4′-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C28H26N4O, 434.55; m/z found 435.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:15][S:16]([OH:19])(=[O:18])=[O:17]>[Pd].C(O)C.O>[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Amino-5-nitrobenzenesulfonamide (prepared as described in Example 1b, 100.00 g, 0.460 mol) and 5% palladium on carbon (wet, 5.00 g) were suspended in ethanol (2 L) and water (100 mL). Methanesulfonic acid (33 mL, 0.51 mol) was added, and the resulting mixture was heated to 55° C. and stirred under atmospheric hydrogen for 8 h. The mixture was filtered and the filtrate was concentrated in vacuo to a volume of about 450 mL. To the concentrate was added acetonitrile (1 L) and resulting mixture was stirred at 25° C. overnight. The suspension was filtered to afford the desired product, 2,5-diamino-benzenesulfonamide methanesulfonate (122.36 g, 0.432 mol, 93.8%) as a purple solid.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[N:1]1([C:10]2[S:14][C:13]([C:15](=[N:22][OH:23])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NO
Reactant: CCCCC(=O)c1ccc(-n2cnc3ccccc32)s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCC(=NO)c1ccc(-n2cnc3ccccc32)s1

Procedure:
To the solution of compound (84) (0.703 mmoles) in ethanol (10 ml) was added hydroxylamine HCl (2.878 mmoels) and pyridine (2.844 mmoles) at ambient temp. The reaction was heated to reflux for 2.0 hrs. After completion of reaction, distilled off the solvent completely, added water (20 ml) and the product was extracted in Ethyl acetate (2×100 ml), washed with 10% brine and dried over sodium sulphate. The solvent was distilled completely under reduced pressure to get the crude compound. This crude compound was purified by preparative HPLC to get the pure isomers (86 & 87).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]3[CH:24]=[CH:25][N:26]=[C:14]23)=[C:4]([F:27])[CH:3]=1.[Cu][C:29]#[N:30].Cl>[Fe](Cl)Cl.CS(C)=O>[C:29]([C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]3[CH:24]=[CH:25][N:26]=[C:14]23)=[C:4]([F:27])[CH:3]=1)#[N:30]
Reactant: N#C[Cu]
Reactant: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1C#N
Temperature: 160 °C

Procedure:
A mixture of 8-(4-bromo-2-fluoro-5-methylsulfonylaminophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (3.0 g), copper(I) cyanide (0.86 g) and dimethyl sulfoxide (30 ml) was heated for 7 hours at 160° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was added with iron(II) chloride (0.8 g) and 6N hydrochloric acid (1.5 ml), and then stirred for 30 minuets at room temperature. The reaction solution was poured into ice water, and the thus obtained solid was filtered off and washed with ethyl acetate. The solid was dissolved into acetonitrile and then a portion adjacent to the original point of the short column of silica gel was removed. The eluate was concentrated to such an extent that any crystal did not precipitate, added with alumina (5.0 g) for column chromatography and stirred for 15 minuets. The alumina was filtered off, washed with a small amount of acetonitrile and then eluted with an acetonitrile solution (30 ml) containing triethylamine (5%) and water (5%). The eluate was distilled off under reduced pressure and the residue was added with ethyl acetate (10 ml), water (20 ml) and 6N hydrochloric acid (10 drops), followed by stirring vigorously to obtain a solid, which was then filtered off. The thus obtained solid was washed with water and ethyl acetate, and dried to give the compound of interest (0.6 g) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24](C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([O:25][CH3:24])=[O:27])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.41 g, 8.4 mmol) in MeOH (500 mL) and water (30 mL) was added an aqueous solution of NaOH (7.0 mL, 5N). The reaction mixture was stirred at rt for 2 hrs and a yellow powder precipitated out progressively. Filtration and washing with water (2×) gave the title compound as a yellow powder. HPLC, Rt: 5.3 min (purity: 98.7%). LC/MS, M+(ESI): 498.3. 1H NMR (CDCl3) δ: 10.16 (s, 1H), 7.45 (m, 4H), 7.19 (m, 5H), 6.94 (dd, J=9.0, 3.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 3.28 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.60 (m, 4H), 1.30 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.C([O-])([O-])=O.[K+].[K+].[C:21]1(Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:14]=1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)N(c2ccccc2)c2cc(Cl)ccc21
Temperature: 110 °C

Procedure:
8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (500 mg, 2.4 mmol) was combined with K2CO3 (660 mg, 4.8 mmol) under an atmosphere of argon. Phenylbromide (370 mg, 2.4 mmol) and N,N′-Dimethyl-ethane-1,2-diamine (21 mg, 0.24 mmol, 10 mol %) were added, followed by 10 mL of toluene. The mixture was degassed with an argon sparge for 10 min. CuI (23 mg, 0.12 mmol, 5 mol %) was added and the reaction was heated to 110° C. for 48 h. The mixture was filtered and volatiles removed in vacuo. Chromatographic purification provided the desired product contaminated with 10% 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (172 mg, 34%) MS m/z=286 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](OC(=O)CC)(=O)[CH2:12][CH3:13]>>[CH2:12]([C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1)[CH3:11]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1ncccc1C(=O)O
Product: CCc1nc2ncccc2c(=O)o1
Temperature: 120 °C
Yield: 86 %

Procedure:
A suspension of 2-aminonicotinic acid (1.0 g 7.24 mmol) in propionic anhydride (10 mL) of was heated to 120° C. for 1 h under nitrogen atmosphere. The temperature was increased to 167° C. to remove the propionic acid and propionic anhydride under reduced pressure. The resulting brown solid was triturated with hexane and dried to give the title pyrido-oxazine (16) (1.10 g, 86%) as a white solid:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH2:43])[CH3:40].CN(C)C=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH:43][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)=[O:2])[CH3:40]
Reactant: CCC(CC)CN
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C(=O)O)cc23)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 77 %

Procedure:
A mixture of methyl 4-(7-carboxynaphth-1-ylmethyl)-3-methoxybenzoate (342 mg), 4-dimethylaminopyridine (358 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg), and 2-ethylbutylamine (198 mg), was dissolved in 3:1 methylene chloride:dimethylformamide (distilled over CaH2) (4 ml) and stirred for 18 h. Methylene chloride was added and the solution was washed (1N hydrochloric acid, brine), dried (MgSO4) and evaporated to give a yellow foam. Recrystallization from 1:2 methylene chloride:hexane (30 ml) gave methyl 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoate (326 mg, 77%) as a colorless solid; mp 129.5°-130.5° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.CN(C1C=CC=CN=1)C.[CH:18]1([N:24]=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[C:25]([NH:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of DPGS-ω-carboxy-PEG (200 mg), N-hydroxy-succinimide (6 mg), dimethylaminopyridine (DMAP) (2 mg) and acetonitrile (40 mL) in a 250 mL round bottom flask was added dropwise a solution of dicyclohexyl carbodiimide (DCC) (12 mg) in acetonitrile (10 mL). The resulting mixture was stirred for 5 hours and the white solid which formed (dicyclohexylurea) was removed by filtration. The filtrate was concentrated in vacuo to yield 200 mg of a white solid of 3-succinamoyl-oxycarbonyl-polyethyleneglycol-imino-succinate-1,2-dipalmitoyl-sn-glycerol (DPGS-ω-carboxy-PEG-succinimide).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]O)[CH:22]=1)[CH2:10][CH2:9]2>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][Cl:3])[CH:22]=1)[CH2:10][CH2:9]2
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CO)c1
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 121.7 %

Procedure:
Thionyl chloride (1.4 mL, 19.0 mmol) was added slowly at 0° C. to a solution of 6-chloro-2-(5-hydroxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 3 [B]) (1.1 g, 3.8 mmol) in DCM (50 mL). After the addition, the reaction mixture was stirred at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (1.42 g, 92%) as light yellowish solid. MS: 307.0 & 309.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][N:20]=[N+]=[N-])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>C(O)C.C(=O)([O-])[O-].[Ba+2].[Pd+2].C(=O)([O-])[O-]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH2:20])[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: COC(=O)c1cc(CN=[N+]=[N-])cc(-c2cccc(C#N)c2)c1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COC(=O)c1cc(CN)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
The compound obtained in Example 9 was dissolved in 66 ml of ethanol. To the resulting solution, was added 1.1 g of palladium-barium carbonate. The interior of the flask was then replaced with hydrogen. The solution was stirred at room temperature for 6 hours, and then the catalyst was filtered through Celite. The resulting filtrate was concentrated and then purified by silica gel column chromatography to provide 794 mg (94%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3](COCC[Si](C)(C)C)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][O:16][CH2:17][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:15][O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(Br)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]nc(Br)c2c1

Procedure:
tert-Butyl 4-(((3-bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (34 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by reverse phase HPLC to afford 5 mg (27%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.87 (s, 1H), 7.53 (s, 1H), 7.37-7.43 (m, 4H), 7.29-7.30 (m, 1H), 4.77 (s, 2H), 3.56 (s, 2H), 3.27-3.31 (m, 2H), 2.90-2.95 (m, 2H), 2.50-2.53 (m, 2H), 2.14-2.20 (m, 2H). Mass spec.: 468.08 (MH)+. Accurate mass spec.: m/z 468.1322 [MH]+, Δ=0.5 ppm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:33]=[CH:32][N:31]=[CH:30][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:29])[CH:27]=[CH2:28])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1>CO.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:33]=[CH:32][N:31]=[CH:30][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:29])[CH2:27][CH3:28])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: C=CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[4-(1-hydroxyprop-2-en-1-yl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one (0.010 g, 0.023 mmol) in 3 mL of methanol was added palladium on carbon (4.0 mg, 0.037 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 4 h and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 443.9 [M+H]+: 1H NMR (400 MHz, CDCl3 δ 9.37 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.26-6.88 (m, 4H), 4.65-4.45 (m, 3H), 4.07 (br s, 1H), 3.66-3.37 (m, 3H), 2.84 (br s, 1H), 2.31-2.23 (m, 1H), 2.07-1.67 (m, 5H), 1.40-0.86 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28]O[CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[C:31]1[CH:36]=CC(C(=C2CCCCCC2)C2C=CC(O)=CC=2)=C[CH:32]=1.C(OC(C)(C)C)(=O)C=C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[C:24]1(=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:11][CH:10]=2)[CH2:29][CH2:28][CH2:36][CH2:31][CH2:32][CH2:26][CH2:25]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Agent: [Pd+2]
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Yield: 49 %

Procedure:
Following the procedure described for compound 47, 4-[(4-bromophenyl)cyclooctylidene)methyl]phenol (9) (0.105 g, 0.283 mmole), tert-butyl acrylate (0.084 mL, 0.573 mmole), P(o-tolyl)3 (0.0097 g, 0.0319 mmole), Et3N (0.125 mL, 0.897 mmole), Pd(OAc)2 (0.0042 g, 0.0187 mmole) and DMF (1.5 mL) yielded 0.059 g (49%) of compound 50 as a white solid. 1H NMR (CDCl3): δ 7.54 (d, J=15.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.30 (d, J=15.9 Hz, 1H), 4.73 (s, 1H), 2.27 (m, 4H), 1.64 (m, 2H), 1.57 (m, 8H), 1.52 (s, 9H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:11]1)=[O:7])(C)(C)C.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN2C(=O)c3ccccc3C2=O)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCN2C(=O)c3ccccc3C2=O)C1

Procedure:
2-(2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethyl)-2,3-dihydro-1 H-isoindole-1,3-dione (1.5 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.81 g) to give 4-amino-5-chloro-N-(1-(2-(-2,3-dihydro-1 ,3-dioxo-1 H-isoindol-2-yl)ethyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.N>C(O)(=O)C>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(Br)cccc2[nH]1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2c(Br)cccc2N1
Temperature: 14 °C
Reaction time: 0.25 h

Procedure:
7.99 g of sodium cyanoborohydride are gradually added to a solution of 8.90 g of 4-bromo-2-methylindole (which can be prepared according to patent US2010/160647 A1, 2010) in 310 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and is then left to warm back up to ambient temperature. After 2 hours, the reaction mixture is poured into an Erlenmayer flask containing ice-cold water (200 ml) and the pH is then brought to 9 with an aqueous ammonia solution. The reaction medium is extracted with dichloromethane (2×200 ml) and then the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[CH:15]=[C:14]2[C:10](/[C:11](=[C:17](/[NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)\[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:4].[OH-].[Na+].Cl>CO.C(Cl)Cl>[C:3]([CH2:5][NH:6][C:7]1[CH:15]=[C:14]2[C:10](/[C:11](=[C:17](/[NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:29][CH:30]=3)\[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)/[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
180 mg of 6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone are placed in 10 ml of methanol, 1.0 ml of 1N sodium hydroxide solution are added and the mixture is stirred for 1 hour at 40° C. After cooling it is neutralised with 1.0 ml of 1N hydrochloric acid and the solvent is eliminated. The residue is dissolved in methylene chloride and a little methanol and dried over sodium sulphate.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:11]=[C:12]([OH:20])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:20][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1
Reactant: CC(C)(C)c1cc(O)c2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(OP(=O)(Cl)Cl)c2ccccc2c1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.143 mL, 1 equiv) and 3-tert-butylnaphthalen-1-ol (J. Org. Chem. 1995, 60, 2909-2911, 0.308 g, 1 equiv), were stirred in anhydrous diethyl ether (8 mL). Anhydrous triethylamine was added (0.214 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate is very unstable at room temperature. The reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH2:16][C:15](=O)[NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>CC1C=CC(C)=CC=1>[Cl:20][C:15]1[NH:14][C:11]2=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]2[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Solvent: Cc1ccc(C)cc1
Product: Fc1cccc(-c2cnc3[nH]c(Cl)cc3c2)c1
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A suspension of 5 (16.52 g, 72.4 mmol) in neat P(O)Cl3 (21.5 mL, 0.231 mol) was stirred at 100-105° C. for 4 h. The mixture was then cooled to r.t., diluted with p-xylene (100 mL) and concentrated to dryness in vacuum. The residue was separated between saturated aqueous NaHCO3—AcOEt. 10% aqueous solution of Na2CO3 was added to basify the aqueous layer to pH 9. Organic phase was separated and the aqueous layer was extracted with AcOEt (8×300 mL). Combined organic solutions were dried MgSO4, concentrated, and the residue was purified by silicagel chromatography (SGC) using CH2Cl2:AcOEt as eluent in gradient to afford recovered starting material 5 (0.76 g, 5%). The desired product was then crystallized from acetone to afford 6 (10.06 g, 56%), thin tan needles. 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 7.08 (tdd, J=8.1, 2.3, 1.5 Hz, 1H), 7.33 (ddd, J=9.9, 2.3, 1.6 Hz, 1H), 7.38-7.48 (m, 2H), 8.03 (d, J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 11.46 (bs, 1H).