Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[NH2:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:19]1=[O:36]>>[CH2:1]([O:3][P:4]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:19]1=[O:36])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O

Procedure:
Ethoxy(4-phenylbutyl)phosphinyl chloride is reacted with (S)-3-amino-2-oxohexahydro-1H-azepine-1-acetic acid, phenylmethyl ester according to the procedure of Example 2(e) to give (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[OH:11])/[S:8][CH3:9]>>[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[O:11][C:3](=[O:4])[NH:2][CH3:1])/[S:8][CH3:9]
Reactant: CN=C=O
Reactant: CS/C(=N\O)C(F)(F)F
Product: CNC(=O)O/N=C(\SC)C(F)(F)F
Yield: 95.6 %

Procedure:
A mixture of 17.12 g (0.3 mol) of methyl isocyanate and 47.74 g (0.3 mol) of S-methyl (Z)-2,2,2-trifluoro-N-(hydroxy)thioacetimidate was sealed in a glass tube and heated at 100° in a steam bath for 17 hours. The contents of the tube were distilled at reduced pressure to give 62.02 g (96%) of S-methyl (Z)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as a colorless, viscous liquid: bp 96° (0.6 mm); nD25 1.4638; ir (neat) 5.73μ (C=O); 19F NMR (CFCl3) δ -64.6 ppm (q, J=1.2 Hz); 1H NMR (CFCl3) δ 2.63 ppm (q, J=1.2 Hz, 3H), 2.88 ppm (d, J=4.5 Hz, 3H) and 6.47 ppm (NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a suspension of 4-bromophenol (2.00 g, 11.56 mmol) and potassium carbonate (4.79 g, 34.68 mmol) in DMF (12 mL) was added 1,3-dibromopropane (7.00 g, 37.3 mmol). The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-5% ethyl acetate/petroleum ether to afford the title compound (2.35 g, 69%) as a colorless oil. 1H NMR (400 MHz, CDCl3) ppm 7.39 (d, 2 H), 6.80 (d, 2 H), 4.16-4.01 (m, 2 H), 3.55-3.53 (m, 2 H), 2.41-2.26 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1)([O:32][CH3:33])[CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C:30]([O:32][CH3:33])([O:29][CH3:28])[CH3:31])=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(C)(OC)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(C)(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 1.59 g, 4.805 mmol) in methylene chloride (24 mL) and N,N-dimethylformamide (2 drops) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (855 μL, 9.609 mmol). The reaction mixture was stirred at 0° C. for 30 min and then warmed to 25° C. where it was stirred for 2 h. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (24 mL) and then cooled to 0° C. To this solution was added a solution of 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine (880.4 mg, 4.805 mmol) and pyridine (466 μL, 5.766 mmol) in methylene chloride (24 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched with a saturated aqueous sodium chloride solution (50 mL), and the layers were separated. The aqueous layer was back-extracted with methylene chloride (50 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (75 mL), an aqueous copper(II) sulfate solution (2×50 mL), and a saturated aqueous sodium chloride solution (75 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-propionamide (1.25 g, 52%) as a white foam: mp 85–88° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H30ClN3O5S (M+Na)+ 518.1487, found 518.1488.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([C:36](O)=[O:37])[CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:32]=[C:31]([CH3:30])[NH:35][N:34]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1cc(C(=O)O)n[nH]1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>O>[CH2:45]1[CH2:46][O:47][CH:7]2[CH:8]([C@@H:9]([C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:21]1
Reactant: OCCO
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 3.4 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 85 ml. of benzene containing 30 mg. of p-toluensulfonic acid monohydrate and 2 ml. of ethylene glycol is stirred at the reflux temperature for 18 hours. The water formed is removed by means of a Dean-Stark distilling receiver. The cooled solution is washed with 5% aqueous sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3.78 g. (99%) of oil; λ max. 2.93 (hydroxy group) and 5.77 β (ester carbonyl group).
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][NH:14][CH:3]12.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1c2ncncc2C=C2OCNC12
Product: Clc1c2ncncc2cc2ocnc12
Reaction time: 18 h
Yield: 22 %

Procedure:
A suspension of 4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98 g, 5.24 mmol) in POCl3 (30 mL) is heated under reflux with vigorous stirring for 18 h, and then concentrated to dryness. The residue is partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion is worked up to give 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 22%) as a yellow solid which is used directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29]COC)=[CH:25][C:4]=1/[CH:5]=[C:6]1/[C:7](=[O:24])[N:8]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][C:10](=[O:13])[NH:11][CH2:12]/1.[OH:33][C:34]1[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][C:35]=1/[CH:36]=[C:37]1/[C:38](=[O:55])[N:39]([S:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:40][C:41](=[O:44])[NH:42][CH2:43]/1>>[CH3:1][O:2][CH2:3][O:33][C:34]1[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][C:35]=1/[CH:36]=[C:37]1/[C:38](=[O:55])[N:39]([S:45]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)(=[O:46])=[O:47])[CH2:40][C:41](=[O:44])[NH:42][CH2:43]/1.[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([N:8]2[C:7](=[O:24])/[C:6](=[CH:5]/[C:4]3[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:3]=3[O:2][CH3:1])/[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)(=[O:15])=[O:16])=[CH:18][CH:19]=1
Reactant: Cc1ccc(O)c(/C=C2\CNC(=O)CN(S(=O)(=O)c3ccc(Cl)cc3)C2=O)c1
Reactant: COCOc1ccc(OC)c(/C=C2\CNC(=O)CN(S(=O)(=O)c3ccc(Cl)cc3)C2=O)c1
Product: COCOc1ccc(C)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Product: COc1ccc(O)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O

Procedure:
(6E)-6-[2-methoxy-5-(methoxymethoxy)benzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione, synthesized by using, instead of the starting material of Reference Example 117, that is, the compound S6, the compound S22 for the similar procedure as in Reference Example 117, Reference Example 122, and Example 1, was used instead of the starting material compound of Example 193, that is, (6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione, for the similar procedure as in Example 193 to obtain the title compound.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>C1COCC1.CO>[F:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCC(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (1M (aq), 24.3 ml, 24.3 mmol) is added to a solution of 4-[8-(3-fluorophenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (4.60 g, 12.14 mmol) in THF/methanol (40 ml:20 ml) and stirred at room temperature overnight. The organic solvents are removed by evaporation, then the aqueous residue diluted with water and basified to pH9 with 1M KOH. The aqueous layer is then washed with ethyl acetate (3×). The aqueous layer is acidified to pH 4 with 1M HCl to give a white precipitate, which is extracted into ethyl acetate. The ethyl acetate layer is then dried over sodium sulfate, filtered and concentrated to yield the desired product as a yellow foam. Further trituration with 1M HCl yields the product as a pale yellow powder (2.153 g). MS (AP+) 350.6
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([CH2:9][CH2:10][NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:8].N1C=CC=CC=1>C(OCC)(=O)C>[C:7]([CH2:9][CH2:10][N:11]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:8]
Reactant: N#CCCNN=Cc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N(CCC#N)N=Cc1ccccc1

Procedure:
1.08 g (10-2 moles) of ethyl chloroformate in solution in 5 ml of anhydrous ethyl acetate are added dropwise to a solution containing 10-2 moles of benzaldehyde (2-cyanoethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold. The reaction mixture is slowly heated to reflux temperature and left stirring for 2 hours and then filtered hot.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C)C=O.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C>CO.C(Cl)(Cl)Cl>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Chloro-6-methylnicotinic acid (25.0 g) was suspended in a mixed solvent of dimethylformamide (100 mL) and chloroform (100 mL), and to this suspension were added dimethylaminopyridine (21.3 g) and methanol (4.67 g). Finally, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (33.5 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated, ethyl acetate (300 mL) was added thereto. The mixture was washed successively with water, 10% ammonium chloride, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4, v/v) to give the title compound (24.6 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4](=[O:24])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1.CN1CCCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:41][C:42]1[C:47]([OH:48])=[CH:46][CH:45]=[CH:44][N:43]=1>O>[CH:11]1([C:7]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:5]3[C:4](=[O:24])[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:2]([O:48][C:47]4[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=4)=[N:10][C:9]=3[N:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ncccc1O
Reactant: CC(C)Cn1c(Cl)nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c1=O
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncccc1Oc1nc2nc(C3CCCC3)n(COCC[Si](C)(C)C)c2c(=O)n1CC(C)C
Temperature: 87.5 °C
Yield: 85.3 %

Procedure:
A mixture of 2-chloro-8-cyclopentyl-1-isobutyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.11 g, 0.259 mmol), N-methylpyrrolidine (1 ml), potassium carbonate (0.11 g, 0.778 mmol) and 2-methyl 3-hydroxy pyridine (0.034 g, 0.31 mmol), was heated at 85-90° C. overnight. Reaction mixture was cooled room temperature, diluted with water (10 ml), extracted with ethyl acetate. The ethyl acetate layer was washed with brine and water, dried over sodium sulphate, filtered and concentrated to obtain 8-cyclopentyl-1-isobutyl-2-(2-methyl-pyridin-3-yloxy)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.11 g, 75%) as crude oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[C:12]([C:14](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:13])C1C=CC=CC=1.CS(O)(=O)=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[CH:18]([NH-:17])([CH3:20])[CH3:19].[OH:8][C:9]1[CH:10]=[C:11]2[C:28](=[CH:29][CH:30]=1)[CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:14]([C:15]([O-:33])=[O:16])[C:12]2=[O:13]
Reactant: CS(=O)(=O)O
Reactant: CC(C)NC(=O)C(=Cc1ccccc1)C(=O)c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[NH-]
Product: O=C([O-])C1C(=O)c2cc(O)ccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4150.9 %

Procedure:
2-(3-Benzyloxybenzoyl)-N-isopropyl-3-phenylacryl amide (106.74 g, 267.19 mmol) was dissolved in dichloromethane. Methanesulfonic acid (256.78 g, 2.672 mmol) was added thereto and the mixture was stirred for 3 hours at room temperature. After the reaction was completed, the mixture was cooled to 0° C. followed by adding saturated sodium bicarbonate, and the organic layer extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain 5-hydroxy-3-oxo-1-phenylindane-2-carboxylate isopropyl amide (36.086 g, yield 44%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCCN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1CNCCCN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 11.0 g (0.026 mol) of the product of Example 45 in 50 mL of ethanol was added 4.40 g of 20% palladium hydroxide on carbon (Pearlman's catalyst) and the resulting suspension was shaken at room temperature in a Parr reactor under 44 psi of hydrogen for 4 h. The reaction mixture was then filtered through Celite and the filter cake was washed with 100 mL of methanol. The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The solution was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was pure enough for use in the next step. Electrospray Mass Spec: 328.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Reactant: C#CCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(Cl)c2)c1

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenylphosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 mm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20]C(O)[CH2:22]2.[Na]>C1(C)C=CC=CC=1>[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20][CH:10]([O:9][C:7]([C:6]([OH:11])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22]2
Reactant: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Reaction time: 5 h

Procedure:
50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90° C. with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78°-90° C. under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile),
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[CH3:43][NH:44][CH3:45].O>CS(C)=O>[CH3:43][N:44]([CH3:45])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][N:35]=[CH:34]2
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN(C)C
Temperature: 85 °C

Procedure:
To an ice-cold solution of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.26 g, 0.55 mmol) in DMSO (3 mL) was bubbled dimethylamine for 3-4 minutes. The mixture was heated at 85° C. for 2 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[C:33](O)[CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][C:3]([CH3:14])([CH2:2][O:1][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:32]=1[N:31]=[C:30]([C:27]1[N:25]3[CH:26]=[C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=[CH:23][C:24]3=[N:29][N:28]=1)[CH:39]=[CH:38]2)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: Oc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(-c5ccccc5)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol.