Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[C:33]2[CH2:40][CH2:41][CH2:42][NH2:43])#[N:29].C(N(CC)CC)C>CS(C)=O>[CH3:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:28]#[N:29])=[CH:38][CH:37]=2)[C:33]([CH2:40][CH2:41][CH2:42][NH:43][CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)=[CH:34]1
Reactant: Cn1cc(CCCN)c2cc(C#N)ccc21
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCCc1cn(C)c2ccc(C#N)cc12)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.1 mmol), 3-(5-cyano-1-methyl-indol-3-yl)propylamine (0.33 g, 1,4 mmol) and triethylamine (0.23 mL, 2.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen for 16 hours. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.2 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 148° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([C:33](=[N:35]O)[NH2:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cccc(F)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55 mg (58% of theory)
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1C=CC=CC=1>CCOCC>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NCc1ccncc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc2c(c1)Oc1ccccc1C2NCc1ccncc1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.0 g. of 4-aminomethylpyridine in 100 ml. of benzene is refluxed for 24 hours. The reaction mixture is stripped of solvent and the residue dissolved in ether. The ether solution is washed with cold 5% sodium carbonate and water and dried over potassium carbonate and chromatographed with alumina and eluting with ether/hexane. The eluate is extracted with ether/acetone and concentrated in vacuo to give 4-pyridylmethyl-9-xanthylamine having a m.p. of 83°-85° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][C:27]=1[Cl:37].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:37][C:27]1[CH:28]=[C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:31][C:26]=1[NH:25][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)c2nn(C)c3ccccc23)c(Cl)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To 1-methylindazole-3-carboxylic acid (600 mg, 3.41 mmol) and DMF (27.0 μl, 0.34 mmol) was added methylene chloride (20 ml). Under stirring at room temperature, oxalyl chloride (0.36 ml, 4.09 mmol) was added dropwise to the resulting mixture. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 50 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (5 ml). The resulting solution was added to a solution of methyl 4-amino-3-chlorophenylacetate (680 mg, 3.41 mmol) and triethylamine (1.42 ml, 10.2 mmol) in methylene chloride (5 ml) under stirring at room temperature. The reaction mixture was heated under reflux at room temperature for 7 hours. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, methyl (3-chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.08 g, 89%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)benzenesulfonamide (1.744 g) in DMF (30 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 311 mg) and the mixture stirred at 20° for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.15 ml) was added and the mixture was stirred for a further 2 h at 20°. Phosphate buffer solution (pH 6.5, 50 ml) and water (50 ml) were added and the mixture was extracted with EtOAc (2×50 ml). The combined extracts were washed with water (2×100 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (3:7) gave the title compound (1.917 g). LCMS RT=3.83 min, ES+ve 417 (MNH4)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Reactant: OB(O)c1ccncc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2ccncc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and 4-pyridineboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.62 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.85 (dd, J=8.68, 4.28 Hz, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.24 (dd, J=11.25, 4.16 Hz, 2H) 3.40-3.53 (m, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.45 (d, J=5.87 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.65 (d, J=5.14 Hz, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:23])[CH:17]([NH:18][C:19](=[S:22])[CH2:20][CH3:21])[C@H:4]2[S:3]1.C(O)(=O)C>[Zn].CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:23])[CH:17]([NH:18][C:19](=[S:22])[CH2:20][CH3:21])[C@H:4]2[S:3]1
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12
Reaction time: 1 h
Yield: 88.1 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate (0.48 g), glacial acetic acid (0.48 ml) and zinc powder (0.48 g) were added to anhydrous dimethylformamide (5 ml), and the mixture was stirred for 1 hour under ice-cooling. After the reaction, zinc powder was filtered off. The filtrate was poured into a mixture of 3% hydrochloric acid (10 ml) and ethyl acetate (10 ml), and the ethyl acetate layer was separated. The aqueous layer was further extracted three times with ethyl acetate (10 ml). The ethyl acetate layer was combined. The combined extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The obtained residue was crystallized by adding ether and the crystals were collected by filtration and washed with ether to give 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid (0.29 g), mp 181° to 183° C. (dec.).
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=3[O:28]C)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CO>ClCCl>[C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=3[OH:28])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COc1ccc(OC)c(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1cc(O)ccc1O)c1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
5-Adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4-dihydroxybenzamide (0.27 g) is dissolved in dichloromethane (3 mL). After adding BBr3 (1.7 mL in CH2Cl2 1.0 M solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 mL) is added and extraction is carried out using water and dichloromethane. The organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography to obtain 0.02 g of the target compound as white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCC(CC)CO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCC(CC)COC(=O)c1ccccc1

Procedure:
Using a method similar to the procedure carried out in Example 1, 12 mol of 2-ethylhexanol were reacted with 8 mol of benzoic acid and tetrabutyl titanate. Distillation gave 2-ethylhexyl benzoate with purity of 99.7% determined by gas chromatography.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)C.[OH-].[K+].Cl>C(O)C>[C:28]([C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:11][CH2:10]3)[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: CCOC(=O)CC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(-c2nc(N3CCC(CC(=O)O)CC3)cc3cccnc23)c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
{1-[8-(3-Cyano-phenyl)-[1,7]naphthyridin-6-yl]-piperidin-4-yl}-acetic acid ethyl ester (250 mg, 0.62 mmol) is dissolved in ethanol (5 ml) with 2M KOH (aq., 0.95 ml, 1.86 mmol) and the mixture stirred at 45° C. for 0.5 hours. After cooling, the pH of the mixture is adjusted to pH 3 by the dropwise addition of concentrated HCl. After stirring for 0.5 hours, the resultant solid is filtered and washed with water to yield the desired product. M.p. 178-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].C(N(CC)CC)C.Cl[CH:31]([C:36]([CH3:38])=[O:37])[C:32]([O:34][CH3:35])=[O:33].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH:31]([C:36](=[O:37])[CH3:38])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
10.0 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol was dissolved in 30 ml of N,N-dimethylformamide, to this was added 5.0 ml of triethylamine, then 5.0 g of methyl 2-chloroacetoacetate was added to the resulted mixture at room temperature with stirring. Then, stirring was continued for 10 minutes at room temperature and for 1 hour at 60° C. 2.0 ml of triethylamine and 2.0 g of methyl 2-chloroacetoacetate were added to this solution, then, the mixture was further stirred for 1 hour at 60° C. The reaction solution was stirred overnight at room temperature, then, the reaction solution was poured into ice water and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.86 g methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxobutyrate.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH2:49][CH2:50][CH3:51])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: CCCOC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added propyl chloroformate (4.3 μL, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C21H29N4O3S (M+H)+: m/z=417.2. Found: 417.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[CH:18]=[CH:17][C:16]=1B(O)O.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.C(O)C>[CH:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[CH:18]=[CH:17][C:16]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1ccc2oc3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccc(-c3ccc4oc5ccccc5c4c3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.8 %

Procedure:
Into a 300-mL three-neck flask were put 2.3 g (9.4 mmol) of 3-bromo-9H-carbazole, 2.0 g (9.4 mmol) of dibenzofuran-2-boronic acid, and 0.42 g (1.4 mmol) of tris(2-methylphenyl)phosphine. To the mixture were added 30 mL of ethanol, 50 mL of toluene, and 10 mL (2.0 mol/L) of an aqueous solution of potassium carbonate. This mixture was stirred to be degassed while the pressure was reduced. To this mixture was added 63 mg (0.28 mmol) of palladium(II) acetate. This mixture was stirred at 90° C. for 5 hours, cooled to room temperature, and then left for 15 hours; accordingly, a brown solid was precipitated. The precipitated solid was subjected to suction filtration and then collected. The collected solid was dissolved in about 30 mL of hot toluene, and this solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The resulting filtrate was concentrated to give a white solid. This solid was recrystallized with toluene/hexane to give 0.87 g of white powder in 27% yield. The synthesis scheme of Step 3 is shown in (a-3).
Reaction SMILES: CCN(CC)CC.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[Cl:18].[NH2:19][C:20]1[C:40]([CH:41]2[CH2:43][CH2:42]2)=[CH:39][C:23]2[C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1.CCOC(C)=O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:19][C:20]2[C:40]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][C:23]3[C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)=[CH:11][C:10]=1[Cl:18]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N)c(C3CC3)cc12
Reactant: OB(O)c1ccc(Br)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(Nc3ccc(Br)c(Cl)c3)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
NEt3 (0.490 mL, 3.51 mmol) was added to a suspension of (4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) and the resulting solution was added dropwise to mixture of ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (500 mg, 1.405 mmol), copper(II) acetate (281 mg, 1.546 mmol), 3A molecular sieves (1 g) and NEt3 (0.490 mL, 3.51 mmol) in DCM (7 mL) stirring vigorously at RT open to the air in a flask equipped with a drying tube. After stirring for 4 h at RT, another solution of NEt3 (0.490 mL, 3.51 mmol) and (4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) was added dropwise to the reaction mixture, followed by more copper(II) acetate (281 mg, 1.546 mmol). The reaction mixture was stirred for 3 d and more solution of NEt3 (0.490 mL, 3.51 mmol) and (4-bromo-3-chlorophenyl)boronic acid (364 mg, 1.546 mmol) in DCM (7 mL) was added dropwise with further addition of copper(II) acetate (281 mg, 1.546 mmol). After 2 h, EtOAc was added followed by Celite. The mixture was stirred for 30 min then filtered through a pad of Celite and the brown solution was concentrated to dryness. EtOAc was added followed by water. The organic layer was separated, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on silica gel (hex/EtOAc) to give ethyl 6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (685 mg, 1.231 mmol, 88% yield) as an orange foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (s, 1H), 7.98-8.07 (m, 2H), 7.58-7.65 (m, 3H), 7.49-7.56 (m, 2H), 7.11 (d, 1H), 6.87 (dd, 1H), 4.36 (q, 2H), 1.95-2.12 (m, 1H), 1.36 (t, 3H), 0.93-1.05 (m, 2H), 0.57-0.71 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=C(B(O)O)C=CC=1>>[Cl:21][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1NCCc2c(-c3cccc(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-chlorophenylboronic acid (130 mg, 0.83 mmol) were coupled to yield 2-(3-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 151 mg (67%), as a shiny pale-yellow solid. mp 147-149° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.06 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.46 (m, 1H), 7.58 (m, 4H), 7.70 (m, 2H), 7.64 (m, 1H), 8.11 (br t, 1H), 11.68 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.9 H2O) C, H, N.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:17][CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:19][C:18]#[CH:17]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: C#CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A suspension of NaH (60%, 8.50 g, 213 mmol) in 200 mL of DMF was added tert-butyl ethyl malonate (36.3 g, 193 mmol) drop-wise at 25° C. The mixture was stirred for 1 hour and 4-iodobut-1-yne (38.2 g, 212.2 g) was added drop-wise. The resulting suspension was stirred overnight and diluted with 1 L of ether, and washed with water (3×200 mL), brine, dried over anhydrous Na2SO4 and concentrated to afford tert-butyl ethyl but-3-yn-1-ylpropanedioate, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N:26]=[C:27]=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:27]([NH:26][C:19]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=3[O:17][CH3:16])=[O:28])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Reactant: COc1ccc(OC)c(N=C=O)c1
Product: COc1ccc(OC)c(NC(=O)Nc2cc(Nc3cccc(Cl)c3)ncn2)c1

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,5-dimethoxyphenyl isocyanate.