Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4](Cl)[C:5](=[O:7])[CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)[C:5](=[O:7])[CH3:6]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloro-3-oxobutyric acid methyl ester (3.5 g) and 4-chlorobenzenethiol (4.1 g) in dichloromethane (60 mL) at 0° C. was added triethylamine (4.0 mL). The mixture was warmed to room temperature and then stirred at this temperature for 3 days. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 by volume) to afford title compound as a waxy solid, 7.2 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:36])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][O:16][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:11]([CH2:13][O:14][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Compound XIII-1 (280 mg, 54.6%) was obtained in the same manner as that in Reference Example 2, by using trans-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (156 mg, 0.674 mmol) obtained by using the method described in WO2006/100036 and oleic acid (Tokyo Chemical Industry Co., Ltd.; 419 mg, 1.48 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:13](Cl)(Cl)=[S:14].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][N:6]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)c1ccc(N=C=S)cn1
Yield: 19.1 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of i5.9 g (0.096 mole of 5-amino-2-diethylaminopyridine with 22.2 g (0.193 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 50 ml of water and 150 ml of chloroform yielded 3.8 g of (2-diethylaminopyridin-5-yl) isothiocyanate as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)=[O:29])[CH3:32]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (104.9 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) under N2 and ethyl chloroformate (34.5 mg, 0.32 mmol) was added dropwise. The solution was stirred at room temperature overnight, and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=18 cm, V=5 ml). A yellow resin was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)#[CH:49]>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.[Cu]I>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C@H:12]2[O:11][C:10](=[O:21])[NH:9][C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:49]#[C:48][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)c2)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
A suspension of (+)-(4R,5R)-4-(3-bromophenyl)-5-(3-methoxyphenyl)oxazolidin-2-one (2.4 g, 6.89 mmol) in triethylamine (24 mL, 172 mmol) was purged with nitrogen for 1 h (volume dropped by ca. 5 mL). The reaction was treated with triphenylphosphine (0.152 g, 0.579 mmol) and ethynylbenzene (0.776 mL, 7.07 mmol), and purged 10 minutes longer. To this was added PdCl2(PPh3)2 (0.034 g, 0.048 mmol) and copper(I) iodide (7.88 mg, 0.041 mmol). After purging 10 min longer, the reaction was warmed to a vigorous reflux. The reaction was heated at reflux overnight. In the morning, the reaction was cooled to room temperature, diluted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->40% EtOAc/Hex) gave 2.2 g (80%) as a colorless foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.56 (m, 4H), 7.36-7.45 (m, 4H), 7.34 (m, 1H), 7.30 (m, 1H), 6.92-6.98 (m, 1H), 6.85-6.90 (m, 2H), 5.93 (bs, 1H), 5.31 (d, J=7.3, 1H), 4.78 (d, J=7.3, 1H), 3.84 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 158.6, 138.92, 138.85, 132.3, 131.8, 130.2, 129.6, 129.4, 128.7, 128.5, 126.4, 124.6, 122.9, 118.1, 115.0, 111.2, 90.6, 88.6, 85.9, 64.6, 55.5. Mass spec.: 370.18 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:33]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[S:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=2)=[CH:17][CH:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NCc3ccccc3)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 200 mg) in DCM (6 ml) was added triethyl amine (0.417 ml, 5.0 equiv.) and benzyl bromide (308 mg, 3.0 eq) and the reaction mixture was stirred for 2 days at RT. The solvent was evaporated and the residue was purified by column chromatography using 1% ethylacetate in chloroform to give the title compound. Yield: 50 mg (20%). 1H NMR (CDCl3; 300 MHz): δ 7.87 (s, 1H), 7.66 (d, 1H), 7.44 (d, 2H), 7.38 (m, 5H), 7.32 (m, 1H), 6.68 (d, 2H), 4.74 (m, 1H), 4.40 (s, 2H), 3.79 (s, 3H), 2.34 (m, 1H), 1.05 (t, 6H); MS (ESI) m/z 424.2 [M+H]+, 446.1 [M+Na]+.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:2][CH:7]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C1=C(c2ccccn2)c2ccccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 10 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 0.12 ml of bromine were added. The mixture was stirred at room temperature for 1 hour, then at 35° C. for 1 hour and finally at 65° C. for 1 hour. After cooling the mixture was washed with sodium bicarbonate solution, the aqueous washings were extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 230 mg of 6-bromo-3,4-dihydro-2,2-dimethyl)-4-(2-pyridyl)-2H-1-benzopyran of melting point 134°-136° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:6][CH2:7][CH2:8][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:4].[CH2:47](Br)[CH2:48][CH2:49][CH3:50]>CN(C=O)C>[CH2:47]([N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]/[CH:12]=[CH:11]/[CH2:10][N:9]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:8][CH2:7][CH2:6][N:5]([CH2:3][CH3:4])[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCBr
Reactant: CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.059 g (1.47 mmol) of sodium hydride dispersion (approx. 60%) is added, with stirring, to a solution of 0.46 g (0.73 retool) of (E)-1-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 5a) in 6 ml of DMF. The mixture is stirred for 5 min. at room temperature; 0.159 ml (1.47 mmol) of butyl bromide is added, and the reaction mixture is stirred for a further 15 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the title compound, Rf value=0.56 (silica gel/ethyl acetate:hexane (1:1)).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 21.6 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 160 cc. of DMF, 19.0 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CC#N>[CH3:13][S:14]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-chloro-1-propanol (283 g, 2.99 mol) and triethylamine (629 mL, 4.5 mol) in CH3CN (3500 mL) at 10° C. was added dropwise methanesulfonyl chloride (518 g, 4.52 mol). The resulting reaction mixture was stirred overnight at room temperature, filtered and concentrated in vacuo to an oil. The oil was dissolved in CH2Cl2 and purified by filtration through silica gel. The appropriate fractions were combined and concentrated in vacuo to give the title compound 335 g (65%). TLC (Rf: 0.3; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 2.96 (s, 3H, CH3) 3.59 (t, 2H, CH2), 4.28 (t, 2H, CH2). 13C NMR (CDCl3) δ31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH2:1]1[C:4]2([CH2:7][N:6]([C:22]([C:21]3[CH:25]=[CH:26][N:27]=[CH:28][C:20]=3[NH:19][C:17]([C:15]3[C:14]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)=[CH:13][CH:12]=[C:11]([CH:8]4[CH2:10][CH2:9]4)[N:16]=3)=[O:18])=[O:23])[CH2:5]2)[CH2:3][O:2]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: C1NCC12COC2
Product: O=C(Nc1cnccc1C(=O)N1CC2(COC2)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 9 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-oxa-6-aza-spiro[3.3]heptane with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (9%) as amorphous off-white solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH:26]=O.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:19][C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:5])=[O:4]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (90 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 90 mg (70% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (mixture of isomers).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(F)c1
Temperature: 23 °C
Yield: 85.3 %

Procedure:
Potassium t-butoxide (7.40 g, 0.066 mol) was added to a stirred solution of 3-fluoro-phenol (3.78 g, 0.034 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (6.50 g, 86%) as a yellow oil.
Reaction SMILES: C(N(CC)CCC1C=CC([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)=CC=1)C.Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:37](=[O:39])[CH3:38]>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][C:37](=[O:39])[CH3:38])=[C:29]([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)[CH:34]=1
Reactant: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Product: CC(=O)Nc1ccc(F)cc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example YY), the tricyclic bromide (300 mg, 1.13 mmol) and N-(2-bromo-4-fluoro-phenyl)-acetamide (276 mg, 1.19 mmol) were coupled to yield N-[4-fluoro-2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 83 mg (22%) as a beige solid: m.p. 260-261° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ1.97 (s, 3H), 2.66 (m, 2H), 3.33 (m, 2H), 7.25 (m, 3H), 7.56 (dd, J=7.5, 0.6 Hz, 1H), 7.70 (dd, J=7.2, 0.6 Hz, 1H), 7.76 (m, 1H), 8.04 (br t, 1H), 11.50 (br s, 1 H). MS (FAB, MH+): 338. Anal. (C16H19FN3O2.0.16 H2O) C, H, N.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[C:21]([NH:35][CH2:36][CH2:37][CH3:38])=[N:22][C:23]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[N:24][CH:25]=2)=[O:19])[CH2:13]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:36]([NH:35][C:21]1[C:20]([C:18]([NH:17][CH:14]2[CH2:15][CH2:16][NH:12][CH2:13]2)=[O:19])=[CH:25][N:24]=[C:23]([NH:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[N:22]=1)[CH2:37][CH3:38]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NC1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a suspension of 10% palladium-carbon (12 mg) in methanol (1 mL), a solution of ammonium formate (64 mg) and N-(1-benzylpyrrolidin-3-yl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (E9, 117 mg) in methanol (4 mL) was added at room temperature, and the mixture was stirred for 5 hours and 30 minutes under reflux by heating. The reaction mixture was cooled to room temperature, and then methanol was added to the mixture. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)-N-(pyrrolidin-3-yl)pyrimidine-5-carboxamide (E10, 85 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH2:6][C:7](=O)[CH2:8][CH3:9].[NH2:11][C:12]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[CH:20][C:13]=1[C:14](OC(C)C)=[O:15].Cl>C1(C)C(C)=CC=CC=1.CO>[CH2:8]([C:7]1[NH:11][C:12]2[C:13]([C:14](=[O:15])[C:6]=1[CH3:5])=[CH:20][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=1)=[C:22]([CH3:24])[CH:23]=2)[CH3:9]
Reactant: CCC(=O)CC
Reactant: Cc1cc(N)c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Temperature: 25 °C
Yield: 83 %

Procedure:
Aluminum chloride (30.0 g) and 125 ml of xylene were added into a 1000-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and Dean-Stark device under a nitrogen gas stream. 3-Pentanone (58.1 g) was added dropwise thereto with stirring at 10° C. or below. Subsequently, 60.55 g of isopropyl 2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate dissolved in 250 ml of xylene was added dropwise thereto at room temperature, and the mixture was heated under reflux for 6 hr. A mixture composed of 5.0 g of aluminum chloride, 65 ml of xylene, and 9.69 g of 3-pentanone was added into the reaction solution, and the mixture was further heated under reflux for 18 hr. After the completion of the reaction, the reaction solution was allowed to cool at room temperature. The reaction solution was added little by little to 150 ml of a 5% aqueous hydrochloric acid solution prepared in a separate 1000-ml glass flask. Further, 150 ml of methanol was added thereto, and the mixture was heated under reflux for about one hr. The reaction mixture was allowed to cool at room temperature and was collected on a suction filter. The reaction mixture was washed with an aqueous methanol solution and was dried to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one as a light brown solid (51.33 g, yield: 90.7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([N:9]([CH:23]1[CH2:25][CH2:24]1)[C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:6](=O)[CH3:7])[CH3:2].FC(F)(F)C([O-])=O.[NH4+:34]>CO>[CH2:1]([O:3][C:4]([C:5]1[N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:34][C:6]=1[CH3:7])=[O:26])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(C)=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: CCOC(=O)c1c(C)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Yield: 70.6 %

Procedure:
To 0.15 g (0.4 mmol) of 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-butyric acid ethyl ester in 5 ml of MeOH was added 0.2 g (1.5 mmol) of ammonium trifluoroacetate. The MeOH was evaporated and the residue heated to 110° C. for 4 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 3:7 to 1:1] afforded 0.1 g (73%) of the title compound as a colorless solid. MS: 355.2 (MH+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:35]2[C:43]3[C:38](=[C:39]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][CH:42]=3)[CH:37]=[N:36]2)([CH2:33][CH3:34])[CH2:31][OH:32])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:35]2[C:43]3[C:38](=[C:39]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][CH:42]=3)[CH:37]=[N:36]2)([CH2:33][CH3:34])[CH:31]=[O:32])=[CH:26][CH:25]=1
Reactant: CCC(CO)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Dess-Martin periodinane (8.12 g, 19.15 mmol) in DCM (90 mL) at 0° C. was added a solution of tert-butyl 1-[2-(4-chlorophenyl)-1-hydroxybutan-2-yl]-1H-indazol-4-ylcarbamate (3.18 g, 7.67 mmol) in DCM (20 mL). The mixture was allowed to stir at rt for 2 hours. Then it was filtered and the filtrate was concentrated in vacuo to afford the crude product. The product was purified via column chromatography (0-10% EtOAc/hexanes) to provide the desired product.