Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH:34]=O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][OH:45])[CH2:39]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:38]4[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][OH:45])[CH2:39]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:36][CH:37]=1)=[O:11]
Reactant: OCC1CCCNC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC(CO)C5)c[nH]4)c3)cc2)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide (120 mg, 0.24 mmol) and 3-piperidinemethanol (56 mg, 0.49 mmol) in anhydrous DMF (10 ml) was added acetic acid (10 mg, 0.17 mmol). The mixture was stirred under nitrogen for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.5 ml, 0.5 mmol). The reaction mixture was stirred for another hour, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 10˜20% methanol/chloroform solution to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3-carboxamide as white solid. Yield: 58 mg, 40%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)CO>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=C1Nc2ccc(O)c(Cl)c2C1=O
Solvent: OCCO
Product: Oc1ccc(Cc2nnc3nc4[nH]c5ccc(O)c(Cl)c5c4nn23)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
According to a cyclization procedure for Example 30, 0.60 mmol of 4-chloro-5-hydroxy-1H-indole-2,3-dione (118.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (16 hr).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:27])=[C:14]([CH:26]=1)[C:15]([O:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]>C(OCC)(=O)C>[Cl:27][C:13]1[CH:12]=[CH:11][C:10]([N:9]=[C:2]=[O:1])=[CH:26][C:14]=1[C:15]([O:17][C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl

Procedure:
A solution of 40 g of diphosgene in 150 ml of ethyl acetate is heated to 65° C. while stirring. To this solution is added dropwise a solution of 40 g of ethyl 2-(5-amino-2-chloro-benzoyloxy)-2-methyl-propionate in 70 ml of ethyl acetate. After completion of the addition the reaction mixture is heated to reflux temperature for 3 hours. Thereafter, the solvent is distilled off. The residue is distilled in a bulb-tube at 200°-230° C. and 0.1 torr. In this manner there is obtained ethyl 2-(2-chloro-5-isocyanato-benzoyloxy)-2-methyl-propionate,
Reaction SMILES: C(OC([NH:11][CH:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH:12]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:13][CH2:14][C:15]([NH:17][C@@H:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:16]
Reactant: CCOC(=O)CC[C@@H](NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](NC(=O)CCC(N)C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of 3.12 g (5.9 mmol) of diethyl N-[4-(benzyloxycarbonylamino)-4-tert.-butoxycarbonylbutanoyl]-D-glutamate in 27 mL of anhydrous ethanol was added 0.66 g of 10% Pd/C. The reaction mixture was then stirred under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through Celite® and the filtrate was concentrated in vacuo to give 1.83 g (81%) of diethyl N-(4-amino-4-tert.-butoxycarbonylbutanoyl)-D-glutamate as a white gum. Mass Spectrum (FD+): M+1=389; IR (CHCl3, cm-1)=845, 1023, 1156, 1370, 1394, 1448, 1477, 1507, 1602, 1673, 1729, 2983, 3024, 3426, 3690; Anal. Calcd. for C18H32N2O7 : C, 55.66; H, 8.30; N, 7.21.; Found: C, 55.93; H, 8.01; N, 7.26; 1H NMR (300 MHz, CDCl3) δ1.22-1.30 (m, 6H), 1.45 (s, 9H), 1.75-1.84 (m, 2H), 1.96-2.02 (m, 2H), 2.14-2.22 (m, 2H), 2.32-2.43 (m, 4H), 4.09-4.22 (m, 5H), 4.58-4.60 (m, 1H), 6.96 (d, J=7.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=[O:15])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cn(C(C)C)c2cc(Br)ccc12
Reaction time: 3.5 h
Yield: 93.3 %

Procedure:
To a solution of 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (1.94 g) in N,N-dimethylformamide (97 ml) were added potassium carbonate (1.43 g) and iodomethane (0.514 ml) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 3.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1 to 5/1) to give methyl 6-bromo-1-isopropyl-1H-indole-3-carboxylate (1.9 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.[H-].[Na+]>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-Fluoronitrobenzene (2.82 g, 20 mmol) was mixed with (S)-3-hydroxy-N-Boc-pyrrolidine (3.74 g, 20 mmol) in dry THF (100 mL). Sodium hydride (1.69 g, 60% in mineral oil) was added under ice bath and the mixture was stirred for 1 hr. The ice bath was removed and the mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.2N hydrochloric acid. The organic layer was washed with water and brine, dried over sodium sulfate. Solvents were evaporated and the residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexanes, 5% to 60% linear gradient). The desired fraction was concentrated and recrystallized from petroleum ether and ether (3:1 ratio) to give a pale yellow solid as (S)-3-(4-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.33 g, 70.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([C:28]3C=CC=CC=3)=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C(C2C=CC(F)=CC=2)=C(N2C(C)=NN=N2)C=CC(O)CC(=O)CC([O-])=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([CH3:28])=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: Cc1nnnn1C(C=CC(O)CC(=O)CC(=O)[O-])=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1C
Yield: 63 %

Procedure:
The general procedure of Example 9 was repeated except that the ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(5-phenyl-1H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate utilized therein was replaced by 2.0 g of 9.9-bis(4-fluorophenyl)-5-hydroxy-8-(5-methyl-1H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate and there was thereby produced 1.25 g (63%) of the title compound after purification by silica gel column chromatography with ethyl acetate in hexanes as eluent.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:6][C:5](=[CH2:7])[CH2:4][O:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:6][C:5](=[CH2:7])[CH2:4][O:3]1
Reactant: C=C1COC(C)(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C1COC(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
At 0° C., to a solution of 2-methyl-4-methylene-2-tetrahydrofuroic acid, tert-butyl ester dissolved in 0.3 mL dichloromethane was added 461 mL of a 1:1 solution of trifluoroacetic acid and dichloromethane. After 20 min, the ice bath was removed and the reaction mixture allowed to stir at room temperature for 5 h. The excess trifluoroacetic acid was removed by a stream of nitrogen, and the residue coevaporated with dichloromethane 3 times. The crude product was chromatographed via silica gel (gradient elution 0-12% MeOH/CH2Cl2) to give 55 mg of the desired acid as a glass (77%). Mass Spectrum: EI m/e 142 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9]#[C:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.CC[N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9]#[C:10][C:11]([NH2:40])=[O:12])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC(C#CC(=O)O)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(C#CC(N)=O)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step B (40 mg, 0.071 mmol, enantiomer A) in DMF (5 mL) was added DIPEA (18 mg, 0.142 mmol), HATU (40 mg, 0.11 mmol), NH4Cl (38 mg, 0.71 mmol). The mixture was stirred at RT overnight. After removing the organic solvent, the residue was dissolved with H2O (20 mL), extracted with ethyl acetate, and washed with brine, dried over sodium sulfate, then filtered. The solvent was evaporated and the residue was purified by Prep-TLC (EA/PE=2:1) to obtain the title compound. LC/MS m/z=582.0 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH2:15][C:16]2[CH:29]=[CH:28][C:19]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1OC
Reaction time: 1 h

Procedure:
To 3,4-dimethoxyphenol (1.69 g, 11 mmol) in THF was added NaH (60% dispersion in oil, 1.2 eq., 0.53 g) and stirring continued for 1 hour. 4-Bromomethyl benzophenone (3.01 g, 11 mmol) was then added to the solution and stirring continued for a further 24 hours. The solution was concentrated in vacuo, diluted with DCM, washed with citric acid (10% aq.), NaOH (1N) dried and solvent removed under vacuum. The residue was then purified by column chromatography, eluting with petrol (40–60):EtOAc 9:1 yielding the product as a white solid (2.58 g, 68%) (Found: C, 75.73; H, 5.96. C22H20O4 requires C, 75.84; H, 5.79%), mp 74–75° C.; Rf=0.23 (Petrol:EtOAc 4:1); δH (250 MHz, CDCl3) 3.82 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 5.10 (2 H, s, CH2), 6.47 (1 H, dd, J 9, 1, ArH p- to OMe), 6.65 (1 H, d, J 1, ArH o- to 2 OR), 6.80 (1 H, d, J 9, ArH m- to 2 OR), 7.47–7.75 (5 H, m, ArH), 7.80–7.91 (4 H, m, ArH o- to C═O); δC (50.3 MHz, CDCl3) 55.8 (OCH3), 56.4 (OCH3), 69.9 (CH2O), 101.2 and 104.0 (ArCH o- to OCH2Ar), 111.7 (ArCH m- to OCH2Ar), 127.0, 128.3, 130.0 and 130.3 (ArCH o- and m- to C═O), 132.5 (ArCH p- to C═O), 137.0 and 137.5 (4° ArCC═O), 141.9 (ArCCH2O), 143.8 (4° ArCOCH2), 149.9 (4° ArCOMe p- to OCH2Ar), 153.0 (4° ArCOMe m- to OCH2Ar), 196.3 (C═O); m/z (APCl+) 349 ([M+H]+, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC)(C)C.C[C:47]([N:49](C)C)=O>[C-]#N.[C-]#N.[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:47]#[N:49])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(C(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: COC(C)(C)C
Product: COc1cc(C#N)cc(C(C)(C)C)c1
Temperature: 150 °C

Procedure:
A mixture of trifluoro-methanesulfonic acid 3-tert-butyl-5-methoxy-phenyl ester (60.67 g, 194 mmol), Zn(CN)2 (15.97 g, 136 mmol), PPh3 (8.15 g, 31.1 mmol) and Pd(OAc)2 (1.745 g, 7.77 mmol) in dimethyl acetamide (174 mL) was heated at 150° C. for 16 h. The cold reaction mixture was poured onto water and TBME. The mixture was filtered over Celite, separated and the organic phase was washed with 1M H2SO4, water and brine. The product was dried over MgSO4, evaporated and distilled at ˜5 mbar, bp 94-100° C. to provide the title compound as a colorless oil: TLC (AcOEt-hexane 1:9) Rf=0.35; LCMS RtH2=2.73 min; ESIMS [M+H]+=190; 1H NMR (400 MHz, CDCl3): δ 7.27 (s, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 3.82 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:5]2=O.O.[NH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:14]3[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)=[C:7]([CH3:13])[NH:27][N:26]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc2c(c1)OCCO2
Reactant: NN
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccc2c(c1)OCCO2
Yield: 63.7 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-hydroxy-2-methyl-chromen-4-one (0.2 g, 0.58 mmol), Hydrazine hydrate (5 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.08 g, 63.7%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18]>C(#N)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:29]([NH:28][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:17]([O:16][CH3:15])=[O:18])(=[O:27])=[O:26])=[O:30])[N:11]=1
Reactant: CN(C)c1nc(N)nc2nccnc12
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(N(C)C)c2nccnc2n1
Yield: 85.2 %

Procedure:
A mixture of 1.3 g (0.0068 mol) of 2-amino-4-dimethylaminopteridine and 1.7 g of 2-methoxycarbonylphenylsulfonyl isocyanate in 40 ml of acetonitrile was refluxed for 4 hours and the hot mixture was vacuum filtered to obtain 2.5 g (85% of theory) of N-(4-dimethylaminopteridin-2-yl)-N'-(2-methoxycarbonylphenylsulfonyl)-urea in the form of brownish crystals melting at 219° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Sn:5]([CH2:12][CH2:13][CH3:14])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(OCC)C>[Sn:5]([CH2:4][CH2:3][CH2:2][NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])([CH2:12][CH2:13][CH3:14])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8]
Reactant: CN(C)CCCN
Reactant: CCC[Sn](CCC)(CCC)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC[Sn](CCC)(CCC)CCCNCCCN(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Over a period of 0.5 hour 9.25 g (0.025 mol) of (3-bromopropyl) tripropyltin was added to 25 ml of 3-dimethylaminopropyl amine at room temperature. The mixture was stirred for 1 hour at 60° C. Under cooling 75 ml of diethylether and 60 ml of a 15% aqueous solution of sodium bicarbonate were added. After stirring for 0.5 hour the organic phase was separated, dried and evaporated in vacuo. Distillation gave 7.5 g (77%) of Pr3Sn(CH2)3NH(CH2)3NMe2 ; b.p. 113°-114° C./0.1 mm Hg, nD20 =1.4855.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][CH:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1cnc(N)o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cc(Br)cn(C)c2=O)o1
Temperature: 92 °C
Yield: 87.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-methyloxazol-2-amine (276 mg, 2.82 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (753 mg, 2.82 mmol), tris-(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol), XantPhos (324 mg, 0.56 mmol), Cs2CO3 (1.8 g, 5.64 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 92° C. for 3 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 262a as white solid (702 mg, 88%). MS-ESI: [M+H]+ 284.1.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH2:38][CH3:39])[CH2:28][CH2:27][C:26]([C:40]([OH:42])=O)=[CH:25][C:24]=3[CH:43]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH2:38][CH3:39])[CH2:28][CH2:27][C:26]([C:40]([NH:29][C:23]4[CH:24]=[CH:43][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:42])=[CH:25][C:24]=3[CH:43]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OCC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OCC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (138 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (103 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 63) (161 mg) as yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:49][CH:50]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Cl:57][C:53]1[CH:52]=[C:51]([C:48]2[O:47][C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:13]5=[CH:14][C:15]6[O:19][CH2:18][O:17][C:16]=6[CH:20]=[C:12]5[O:11][CH2:10]4)[C:2]3=[O:21])=[CH:50][CH:49]=2)[CH:56]=[CH:55][CH:54]=1
Reactant: ClCc1ccc(-c2cccc(Cl)c2)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(-c3cccc(Cl)c3)o2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-5-[3-chlorophenyl]furan to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (t, 1H), 7.46 (dt, 1H), 7.28 (d, 2H), 7.21-7.14 (m, 2H), 7.09-7.04 (m, 2H), 6.59 (d, 1H), 6.50 (s, 1H), 6.40 (d, 1H), 6.10 (s, 1H), 5.84 (dd, 2H), 4.98 (ABq, 2H), 4.80 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.5, 149.2, 148.9, 142.4, 141.7, 134.8, 132.1, 132.0, 130.1, 128.9, 127.5, 124.0, 123.7, 123.6, 121.7, 119.4, 110.8, 109.2, 106.9, 103.0, 101.5, 93.6, 80.4, 58.2, 37.3; MS (ES+) m/z 472.2 (M+1).