Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[C:17]2[NH:18][C:19]([C:21]3[C:22](=[O:37])[NH:23][CH:24]=[CH:25][C:26]=3[NH:27][CH2:28][C@@H:29]([OH:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[C:17]3[NH:18][C:19]([C:21]4[C:22](=[O:37])[NH:23][CH:24]=[CH:25][C:26]=4[NH:27][CH2:28][C@@H:29]([OH:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[N:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Reactant: O=C=Nc1cccc(F)c1
Agent: N
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
3-Fluorophenylisocyanate (0.023 g, 0.166 mmol) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) in DCM (4 ml) and the reaction stirred at room temperature. After 20 hours methanolic ammonia was added (5 ml) and the reaction stirred for a further 20 hours. The reaction mixture was concentrated under reduced pressure and the crude solid washed with acetonitrile:water (1:1; 10 ml) to give the desired product (0.037 g; 45%).
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])CCC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:45])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCC(O)c2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-fluoro-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Upon boiling a solution of 7.8 g 1-naphthaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(naphth-1-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 162° - 163°C (ethanol) is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])[C:3]=12
Reactant: C#CC(C)(C)O
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(C#CC(C)(C)O)c2c(N)ncnc21
Yield: 68.1 %

Procedure:
To a solution of Example 57b (0.500 g, 0.981 mmoles) in THF (14 ml), 2-Methyl-3-butyn-2-ol (0.1 ml, 1.178 mmoles) diisopropylamine (0.70 ml, 4.90 mmoles), copper(I) iodide (18.6 mg, 0.098 mmoles) and) Tetrakistriphenylphosphine Palladium (0.113 g, 0.098 mmoles) were added and the system is degassed for 30 min. and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.311 g, 68% yield). MP: 109-113° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(m,3H), 7.83(dt, J=8.6, 1.5Hz, 1H), 7.61(d, J=8.4Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.30-7.11(m, 4H), 5.84(q, J=7.1z, 1H)5.74(s,1H), 1.82(d, J=7.0Hz, 3H),1.46(s,6H). Mass: 466.09(M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl 1-[(4-methoxyphenyl)methyl]-4-piperidinylcarbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ml. of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50% sodium hydroxide. Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C.O>O1CCOCC1>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:20])[CH3:19]
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
1.2 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are heated under reflux for 15 minutes with 0.4 g. acetyl chloride and 0.7 g. triethylamine in dioxan. Thereafter, the reaction mixture is poured into water and the precipitate obtained is filtered off with suction and recrystallised from ethyl acetate. There is thus obtained 3-(acetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide; m.p . 119°C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:37])([F:36])[C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]3[NH:15][C:16]4[CH:17]=[C:18]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=4[C:22]=3[N:23]=2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:15]2[C:16]3[CH:17]=[C:18]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=3[C:22]3[N:23]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:36])[F:37])[CH:6]=4)[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]2=3)=[CH:41][CH:42]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(OS(=O)(=O)C(F)(F)F)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
Sodium hydride (22 mg, 0.54 mmol, 60% dispersion in oil) was added to an ice-cooled stirred solution of methyl 2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (200 mg, 0.386 mmol) in DMF (4 ml). This was left stirring until gas evolution stopped. 1-(bromomethyl)-4-methoxybenzene (0.072 ml, 0.502 mmol) was added and the reaction was kept in the ice bath for 2 hr. After an additional 1 hr at RT, the reaction was quenched with a saturated aqueous solution of NH4Cl solution and extracted with EtOAc. The organic extracts were washed with water (5×), brine, and dried with sodium sulfate. Removal of the solvent, followed by radial chromatography (step gradient elution with hexane containing 0 to 5% DCM) afforded methyl 5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (91 mg, 0.14 mmol, 37% yield). MS (ESI) m/z 639.1 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.55 (1H, d, J=8.55 Hz), 8.42 (1H, s), 8.33 (1H, d, J=7.63 Hz), 8.08 (1H, s), 7.59-7.71 (2H, m), 7.40 (1H, d, J=2.14 Hz), 7.29 (1H, dd, J=8.55, 2.14 Hz), 6.88 (2H, d, J=8.85 Hz), 6.76 (2H, d, J=8.85 Hz), 5.71 (2H, s), 3.86 (3H, s), 3.73 (3H, s).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[F:11])[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(F)c(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(Br)c1
Yield: 83 %

Procedure:
Reduction of 3-bromo-4-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (83% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 3.99 (2H, s, NCH2), 7.08 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.57 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 150–151° C. Anal. calcd. for C8H9BrFNO—HCl: C, 35.52; H, 3.73; N, 5.18. Found: C, 35.54; H, 3.61; N, 5.12.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([C@]1(C(N2CCC(C3C=CC=CC=3C(F)(F)F)(O)CC2)=O)CC[C@@H](NC2CCOCC2OC)C1)(C)C>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)(C(C)C)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[NH2:37])[CH2:21][CH2:20]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[N:22]1([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[NH:37][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:3]=2[CH3:18])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2ccccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 2 using 4-chloro-3-methyl-2-(pyridin-2-yl)quinoline (77 mg, 302 μmol), 2,5-dimorpholinobenzenamine (80 mg, 302 μmol) and 4N hydrochloric acid solution in dioxane (7.6 μL, 30 μmol) in NMP (1 mL) to afford product as a colorless solid upon purification by reversed phase HPLC. 1H NMR (400 MHz, chloroform-d) δ ppm 8.58-8.72 (1H, m), 8.13 (1H, d, J=8.6 Hz), 7.74-7.90 (3H, m), 7.54-7.68 (1H, m), 7.39 (1H, td, J=7.6, 1.2 Hz), 7.25-7.35 (1H, m), 7.15 (1H, s), 7.02 (1H, d, J=8.6 Hz), 6.35 (1H, dd, J=8.6, 2.7 Hz), 5.95 (1H, d, J=2.7 Hz), 3.74-3.93 (4H, m), 3.52-3.72 (4H, m), 2.99 (4H, d, J=3.9 Hz), 2.72-2.89 (4H, m), 2.31 (3H, s). Mass Spectrum (ESI) m/e=482.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[CH:29][C:28]([I:31])=[CH:27][N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:30]=[CH:29][C:28]([I:31])=[CH:27][N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncc(I)cn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: Ic1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-5-iodopyrimidine, the title compound was obtained as a white solid (100%), mp 240° C. (dec); MS(CI): 509 (M+H); NMR (300MHz, DMSO-d6): 9.95(br s, 1H), 8.50-8.45(m, 2H), 7.68(b, 1H), 7.37-7.32(m, 4H), 7.03-6.95(m, 4H), 4.45(s, 1H), 4.35-4.31(m, 2H), 4.18-3.80(br m, 1H), 3.58-3.38(m, 4H), 2.73(s, 2H), 2.08-1.87(m, 4H).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH2:25]([N:30]1[C:38]2[C:33](=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=2)[C:32](=[O:40])[C:31]1=[O:41])[CH2:26][CH:27]([CH3:29])[CH3:28].[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51](=[O:53])[CH3:52])=[CH:43]1>>[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51](=[O:53])[CH2:52][C:32]2([OH:40])[C:33]3[C:38](=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[N:30]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:31]2=[O:41])=[CH:43]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: Cc1ccc2c(c1)C(O)(CC(=O)c1c[nH]c3ccccc13)C(=O)N2CCC(C)C

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isopentyl-5-methylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 9.21 (bs, NH), 8.34 (m, 1H), 7.67 (d, 1H), 7.38 (m, 1H), 7.30-7.23 (m, 3H), 7.08 (d, 1H), 6.73 (d, 1H) 5.74 (bs, 1H), 3.68 (t, 2H), 3.49 (d, 1H), 3.21 (d, 1H), 2.27 (s, 3H), 1.67-1.49 (m, 3H), 0.95 (dd, 6H).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]#[N:37].O>CC(C)=O>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:35][C:36]#[N:37]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
The mixture of 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.46 g, 3.45 mmol) and cesium carbonate (2.36 g, 7.23 mmol) in acetone (16 mL) was stirred at room temperature for 15 minutes. Bromoacetonitrile (0.50 mL, 7.2 mmol) was then added and the mixture was stirred for 4 hours at room temperature then poured into excess water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography (Biotage apparatus) using 5-20% tert-butyl methyl ether in hexane as an eluant to afford 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy} acetonitrile as a yellow solid (0.989 g), mp 100-102° C. Mass spectrum (−ESI, [M−H]−) m/z 460. 1HNMR (400 MHz, DMSO-d6): δ8.55 (d, 1H, J=0.98 Hz), 8.25 (d, 2H, J=9.3 Hz), 8.0-8.05 (m, 2H), 7.7-7.75 (m, 2H), 7.4-7.5 (m, 2H), 5.5 (s, 2H), 2.75 (t, 2H, J=7.2 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.2 Hz). Elemental Analysis for C25H20BrNO3: Calculated: C, 64.95; H, 4.36; N, 3.03. Found: C, 64.71; H, 4.32; N, 2.86.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:18])[CH:19]=1
Reactant: COc1ccc(O)cc1C=O
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(O)ccc2OC)cc1
Yield: 99.4 %

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (286 g) and magnesium turnings (38.5 g) in dry tetrahydrofuran (480 ml) was added, dropwise, with vigorous stirring, a solution of 5-hydroxy-2-methoxybenzaldehyde (100 g) in dry tetrahydrofuran (1 liter). The mixture was heated on a steam bath for 3 hours, cooled and decomposed with saturated ammonium chloride solution. The organic layer was removed and the aqueous extracted with ethyl acetate (twice). The combined organics were washed with water, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue was stirred with water (4 liters), and the buff coloured solid collected and dried to give crude 1-(5-hydroxy-2-methoxyphenyl)-1-(4-methoxy- phenyl)-methanol (170 g, 99%), m.p. 62°-68°. This carbinol (85 g) was dissolved in ethanol (700 ml) and 10% palladium on charcoal (10 g) added. The mixture was hydrogenated in a Parr apparatus at 45° until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated to dryness and the residue filtered through a column containing silica gel, eluting with dichloromethane, to give 2,4'-dimethoxy-5-hydroxydiphenylmethane (46 g, 58%), m.p. 56°-58° (from petroleum spirit (60°-80°)).
Reaction SMILES: [NH3:1].[CH2:2]([O:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:3]1[O:5][CH2:4]1>>[OH:5][CH:3]([CH2:2][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:4][NH2:1]
Reactant: Cc1ccccc1OCC1CO1
Reactant: N
Product: Cc1ccccc1OCC(O)CN

Procedure:
As previously described, the addition of ammonia to o-cresyl glycidyl ether is carried out in an autoclave. The amine so obtained has a purity of 96% and consists of colourless crystals with a melting point of 64° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[F:26])=[CH:9][C:8]([Br:27])=[C:7]([F:28])[CH:6]=2.CO.C(Cl)Cl.[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>>[Br:27][C:8]1[C:7]([F:28])=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:34]([CH3:35])[N:12]([C@H:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@@H:14]4[F:26])[C:11]=3[C:10]=2[CH:9]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2c(N)cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cnc3cc(F)c(Br)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F

Procedure:
(3S,4S)-tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate (27 g, 0.059 mol) was heated in triethylorthoacetate (150 mL) under N2 atmosphere for 5 h at 120° C. The reaction was monitored by TLC (5% MeOH/DCM). The volatiles were concentrated under vacuum, the obtained crude product was purified by column chromatography on silica gel (0-3% MeOH/DCM) to afford (3S,4S)-tert-butyl 4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (15 g, yield from two steps). 1HNMR (CDCl3, 400 MHz): δ 9.28-9.23 (d, 1H), 8.43-8.34 (dd, 1H), 8.01-7.99 (d, 1H), 5.60-5.35 (m, 1H), 5.25-4.85 (m, 1H), 4.75-4.35 (m, 2H), 3.15-2.95 (m, 2H), 2.79 (s, 3H), 2.40-2.05 (m, 2H), 1.57 (s, 9H); LCMS: 100%, m/z=480.8 (M+); HPLC: 97.31%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].CO.C1(C)C=CC=CC=1.C(O)(=O)C>[Pt]=O.C(O)C>[CH3:3][C:2]([CH3:19])([O:4][C:5]([NH:7][C@@H:8]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([OH:18])=[O:17])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=[Pt]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reaction time: 20 h

Procedure:
Platinum oxide catalyst (5 g) is added to a solution of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (120 g, 0.452 mole) in absolute ethanol (1 l). The mixture is placed on a Parr reduction apparatus at 50 lb. pressure. The absorption of hydrogen is rapid and the hydrogen reservoir needs continued refilling. The reduction proceeds overnight and after 20 hours is completed. The mixture is filtered through Celite and concentrated in vacuo to give 124.4 g of the title F compound as a glassy solid colorless residue; [α]D =-9.5° (c=1, methanol). TLC (silica gel; toluene:acetic acid, 4:1) Rf =0.62.
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[C:8]([Cl:11])[C:7]([Cl:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCC.ClCCl>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][C:9]1[C:2]([Cl:1])=[C:3]([C:13]#[N:14])[C:4](=[C:7]([Cl:12])[C:8]=1[Cl:11])[C:5]#[N:6]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCCCCC
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2-c2ccccc2)c(Cl)c1C#N

Procedure:
3,4,5,6-tetrachlorophthalonitrile (5 g), 2-phenylphenol (3.201 g), K2CO3 (3.898 g) and acetonitrile (50 ml) are put in a 100 ml flask and then heated and refluxed. When the reaction is complete, the resultant is filtered with tetrahydrofuran (THF) to obtain a solid, the solid is added to a small amount of dichloromethane and dissolved therein, and hexane is added thereto, obtaining a crystallized solid (4-(biphenyl-2-yloxy)-3,5,6-trichlorophthalonitrile). Herein, the obtained solid is washed several times, filtered and vacuum-dried.