Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(O)[CH:14]=[CH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[OH:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C)C=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH2:15][O:25][C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH:18]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=CC(O)(c1ccccc1)c1cccnc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Phosphorus pentachloride (3.0 g, 14.2 mmoles) was suspended in dichloromethane (4 ml). To the suspension was added dropwise a solution of 1-phenyl-1-(3-pyridyl)-2-propen-1-ol (2.0 g, 9.5 mmoles) in dichloromethane (20 ml) at 0° C., then the mixture was stirred for one hour at room temperature, followed by washing with water, saturated aqueous solution of sodium hydrogen carbonate in the order. The organic layer is dried (magnesium sulfate), and concentrated to about 20 ml at a temperature not exceeding 30° C. The solution was further dried with molecular sieves 4A. This solution was named as (a) solution. Separately, sodium hydride (400 mg, 10 mmoles) is suspended in dimethylformamide (5 ml). To the suspension was added dropwise methyl metahydroxybenzoate (1.37 g, 9.0 mmoles) dissolved in dimethylformamide (5 ml). The mixture was stirred for 30 minutes at 0° C., to which was added dropwise the (a) solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured in ice-water, which is subjected to extraction with ethyl acetate, washed with water and dried (magnesium sulfate), followed by removing the solvent by evaporation under reduced pressure. The residue was subjected to silica-gel column chromatography, using ether-ethyl acetate (7:3) as eluant to yield methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56) (3.0 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:67]I>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH3:67])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CI
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C)C(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3R,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (49 mg) was reacted with methyl iodide (15 mg) according to General Procedure T to obtain (S)-2-({(3R,8S)-7-[2-(acetyl-methyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound (11 mg). LCMS: (m/z) 924.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][N:5]1[CH2:3][C:2]([NH2:1])([CH3:15])[CH3:16]
Reactant: CC(C)(N)C(=O)N1CCc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(N)CN1CCc2ccccc2C1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 42 (0.20 g, 0.91 mmol) in anhydrous THF (4 mL) at 0° C. was added LiAlH4 (1.0 M in THF, 3.0 mL, 3.0 mmol). The resulting mixture was heated under reflux overnight before it was allowed to cool to room temperature. Excess LiAlH4 was destroyed with slow addition of Na2SO4.10H2O at 0° C. until gas evolution ceased. The solids were filtered off and the filtrate was concentrated to give 43 (0.14 g, 79%).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:35][CH2:34][C@H:33]3[C@@H:24]([CH2:25][CH2:26][C:27]4[CH:28]=[C:29]([O:36][C:37](=[O:39])[CH3:38])[CH:30]=[CH:31][C:32]=43)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:37]([O:36][C:29]1[CH:30]=[CH:31][C:32]2[C@@H:33]3[C@H:24]([C@H:21]4[C@@:19]([CH2:35][CH2:34]3)([CH3:20])[C:18]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[CH:23][CH2:22]4)[CH2:25][CH2:26][C:27]=2[CH:28]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12

Procedure:
The method followed that described in Example 1(b), but using diethyl(3-pyridyl)borane (1.65 g, 11.2 mmol), 3-acetoxyestra-1,3,5[10],16-tetraen-17-yl trifluoromethanesulphonate (3.56 g, 8.0 mmol), THF (40 ml), bis(triphenylphosphine)palladium(II) chloride (56 mg, 0.08 mmol), and aqueous sodium carbonate (2M, 15 ml).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([NH:17][CH:18]2[CH2:20][CH2:19]2)[N:11]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:18]1([NH:17][C:12]2[N:11]=[C:10]([NH:9][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[N:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[N:13]=2)[CH2:20][CH2:19]1
Reactant: Nc1nc(N)nc(NC2CC2)n1
Reactant: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)COC(=O)Nc1nc(NC(=O)OCC(C)C)nc(NC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.4 g (0.12 mol) of isobutyl chloroformate are added dropwise to a mixture of 8.3 g (0.05 mol) of 2,4-diamino-6-cyclopropylamino-s-triazine, 0.5 g of 4-dimethylaminopyridine and 125 ml of pyridine. The batch is stirred for 1 hour at room temperature and then for 1 hour at 55°-60° C. After the precipitate has been filtered off, the reaction mixture is concentrated by evaporation in a water-jet vacuum, the residue is taken up in 150 ml of chloroform and extracted with 100 ml of water. After drying over sodium sulfate, the solvent is distilled off, and the crude product is purified by column chromatography through silica with methylene chloride as eluant.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2].[C:25]([Cu])#[N:26].Cl>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2cc(Oc3cccnc3)ccc2c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Temperature: 120 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of 4-hydroxy-1-iodo-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (215 mg) and CuCN (89 mg) in NMP (2 mL) was heated at 120° C. for 2 h; the reaction was then cooled, diluted with DCM, and stirred at rt overnight; then diluted HCl solution was added and stirred for 1 h; the solids were filtered off, and DCM phase was separated, washed with water, and dil. NaCl solution, dried over anhydrous sodium sulphate, filtered, concentrated and the residue was column purified to give product (53 mg). LCMS ESI+: 336 (M+1)+.
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13](Cl)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=O)C.C[O-].[Na+].CO>C1COCC1>[CH3:24][C:15]1[C:14]([C@@H:13]2[S:4][CH2:5][C@@H:6]3[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][CH2:10][N:11]3[CH2:12]2)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][O:18][C:19]2=[O:23]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc2c(c1C)COC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-chloro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate (596 mg, 1.234 mmol) in anhydrous THF (20 mL) was treated dropwise with sodium methoxide, 25% solution in methanol (0.846 mL, 3.70 mmol). The reaction mixture was stirred for 2 hours under nitrogen at room temperature. LCMS showed formation of the desired product. Solvent was removed under reduced pressure. Residue was redissolved in dichloromethane and washed with brine. Organic layer was dried over MgSO4, filtered and concentrated. Residue was purified on Biotage SP1, eluting with 20-80% ethyl acetate/hexanes, 16 CV: 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 5.29 (s, 2H), 3.81-4.20 (m, 3H), 3.38 (dd, J=2.3, 12.6 Hz), 3.00-3.22 (m, 2H), 2.57-2.82 (m, 2H), 2.24-2.56 (m, 7H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1)[CH3:2].[OH-].[Na+]>C(O)(C)C.O>[CH2:1]([C:3]1[C:8]([C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=3)=[N:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([C:35]([OH:37])=[O:36])[CH2:33][CH2:34]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.4 %

Procedure:
To a solution of ethyl 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-4-piperidinecarboxylate (D81) (160 mg) in isopropanol (3 mL) and water (0.750 mL) stirred under nitrogen at room temperature was added a solution of NaOH (26.8 mg) in water in one charge. The reaction mixture was stirred at room temperature for 2 h. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-4-piperidinecarboxylic acid (E32) (28 mg). δH (DMSO-d6, 400 MHz): 1.07 (3H, t), 1.33 (6H, d), 1.53 (2H, m), 1.77 (2H, m), 2.03 (2H, m), 2.22 (1H, m), 2.77 (4H, m), 3.49 (2H, s), 4.89 (1H, m), 7.24 (1H, t), 7.30 (1H, d), 7.38 (1H, d), 7.44 (1H, d), 7.86 (1H, s), 8.15 (2H, m), 12.09 (1H, br s). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C28H31F3N2O3S requires 532. found 533.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4].[CH2:25]=O>C(O)(=O)C>[F:24][C:2]([F:1])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C:14]2[N:19]3[C:20](=[CH:21][N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH2:25]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(NCCCCCNCc1cccc2nccn12)C(F)(F)F
Reactant: C=O
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 2.52 g (6.91 mmol) of 5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 8 ml of acetic acid was added 7.8 ml (103.7 mmol) of a 37% aqueous solution of formalin. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure. The residue was dissolved in 50 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography to give 1.79 g of the desired compound (69.0%, colorless liquid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].ClC[C:24](Cl)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:25]=[C:24]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN2CCNCC2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TEA (1 eq) was added dropwise to a solution of tert-Butyl (2-{[2-(5-cyanopyridin-2-yl)ethyl]amino}ethyl)carbamate (1 eq) and chloroacetyl chloride (1 eq) in 200 mL of DCM at 0° C. The mixture was stirred at room temperature for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum. The resulting solid (1.0 g, 2.7 mmol) was added to the mixture of 10 mL TFA and 10 mL of DCM and stirred at RT for 1 hour then concentrated by vacuum. The residue was re-dissolved in CH3CN, K2CO3 was added and the mixture was stirred at RT for 2 hours. The mixture was poured into water and extracted with EtOAc twice. The combined organic layers were concentrated and the residue was purified by flash chromatography (DCM:MeOH=10:1) to afford the title compound 1H-NMR (400 MHz, CDCl3) δ ppm 8.74 (d, J=1.6 Hz, 1H), 7.81-7.83 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.71 (t, J=7.2 Hz, 2H), 3.42 (d, J=7.2 Hz, 2H), 3.24 (t, J=5.6 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:24][CH2:23]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(N)c2c1=O
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 48.0 g of ethyl 5-benzylamino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.111 mol) dissolved in a mixture of 200 ml of acetic acid and ethanol was added 0.5 g of 5% Pd/C catalyst. Hydrogen gas was introduced at room temperature. The reaction was monitored with TLC and carried out for around 3 hours. Precipitates collected by filtration were dissolved in chloroform and filtered to remove the catalyst. After removing the solvent by evaporation, the residue was recrystallized from a mixture of chloroform and ethanol to give 32.0 g of ethyl 5-amino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.093 mol) in 83.9% yield.
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:12](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:13].C(N(CC)CC)C>ClCCl>[N:1]([C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:12]=[O:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)N=C=O
Reaction time: 0.5 h
Yield: 298.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask was placed a solution of tert-butyl 2-amino-2-methylpropanoate (1.2 g, 7.54 mmol, 1.00 equiv) in dichloromethane (20 mL). This was followed by the addition of ditrichloromethyl carbonate (750 mg, 2.53 mmol, 0.34 equiv), in portions at 0° C. After 30 min, triethylamine (2.3 g, 22.73 mmol, 3.02 equiv) was added dropwise with stirring. The resulting solution was stirred for 5 h at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of ethyl ether. The solids were filtered out. The filtrate was concentrated under vacuum. Purification afforded 1.4 g (crude) of tert-butyl 2-isocyanato-2-methylpropanoate (110.2) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11]([Cl:23])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(Br)cc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(Br)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-bromophenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
0.2 mol (39 g) of 4-hydroxy-4′-cyanobiphenyl, 2 mol (487.5 g) of 1,6-dibromohexane, 1.45 mol (200 g) of potassium carbonate anhydride and 800 ml of acetone were placed in a 2 l three-neck flask equipped with a mechanical stirrer and the mixture was reacted under reflux for 20 hours by using a water bath. The reaction mixture was cooled to ambient temperature and then undissolved salts were removed by filtration. The resulting reaction solution was concentrated to a volume of about ½ by using a rotary evaporator, to which was then added 500 ml of hexane, followed by heating with stirring. Then, the resulting solution was cooled gradually to ambient temperature and then allowed to stand in a freezing chamber to crystallize. After the crystallized product was subjected to vacuum filtration, it was washed with n-hexane and dried under reduced pressure to obtain a crude target product (yield: 85% (61.3 g)), which was then recrystallized from ethanol to obtain a purified target product 4-(6-bromohexyloxy)-4′-cyanobiphenyl (yield: 58% (41.8 g)).
Reaction SMILES: P(Cl)(Cl)Cl.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>N1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][CH2:13][C:14]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[Cl:17])=[O:16]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CSc1ccccc1Br
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CSc1ccccc1Br)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
PCl3 (0.39 mL, 4.45 mmol) was added to an ice-cold solution of 2-{(2-bromophenyl)thio}acetic acid (1.00 g, 4.05 mmol) and 2-chloroaniline (0.47 mL, 4.45 mmol) in pyridine (15 mL). The reaction mixture was stirred at room temperature for 30 min. Water (few drops) was added and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2) to give the title compound (957 mg, 66% yield) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:8]2[CH:9]=[C:5]([C:3]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:4])[NH:6][N:7]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: C1COCCN1
Product: CCCCc1noc(C)c1COc1cc(C(=O)N2CCOCC2)[nH]n1
Yield: 51 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 51%) which was obtained as a colorless oil. MS: m/e=349.2 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:23].[Br:24][C:25]1[CH:26]=[C:27]([N+]([O-])=O)[C:28]([C:31]#[N:32])=[N:29][CH:30]=1>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:23])[C:28]([C:31]#[N:32])=[N:29][CH:30]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1F
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a mixture of H2SO4 (0.2 ml) and TBAF solution (131 ml, 131 mmol, 1M in THF) was added DMF (40 ml) dropwise at −40° C. Then a solution of 5-bromo-3-nitro-pyridine-2-carbonitrile (10 g, 43 mmol) in DMF (130 ml) was added at −40° C. and the reaction mixture was stirred for 1 h. The reaction was then quenched by addition of 2M HCl solution at −40° C. adjusting the pH to 3. The resulting mixture was extracted twice with EtOAc and the combined organic extracts were washed twice with water, with brine, dried with Na2SO4 and evaporated in vacuo. The remaining residue was purified by chromatography (silica gel; hexane/EtOAc 90:10-80:20) to obtain the title compound as yellow solid (5.2 g, 59%).