Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:22]([C:20]3[C:19]4[O:18][C:17]([CH3:26])([CH3:27])[CH2:16][C:15]=4[C:12]4[N:13]([CH3:14])[C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:28])=[N:10][C:11]=4[CH:21]=3)=[O:24])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C2CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(C4CC4)cc3)c3c(c21)CC(C)(C)O3
Yield: 35.2 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 4-cyclopropylaniline (Intermediate-50, 0.047 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.63 (m, 2H), 0.91 (d, J=6.6 Hz, 2H), 1.60 (s, 6H), 1.89 (m, 1H), 3.48 (s, 2H), 3.59 (s, 3H), 7.05 (d, J=7.8 Hz, 2H), 7.26 (s, 1H), 7.54 (d, J=8.1 Hz, 2H), 8.46 (s, 2H), 9.61 (br s, 1H), 10.88 (br s, 1H); MS [M−H]−: 520.06.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH2:38])[C:19]3=[O:39])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([C:46]([NH:59][C:60]2[S:61][CH:62]=[C:63](/[C:65](=[N:69]/[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])/[C:66](O)=[O:67])[N:64]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O1CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:66](=[O:67])/[C:65](/[C:63]2[N:64]=[C:60]([NH:59][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:61][CH:62]=2)=[N:69]\[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])[C:19]3=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Reactant: COC(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The product obtained in Step 2 (3.25 g) and 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetic acid (5.64 g) were dissolved in dichloromethane (93 ml) and tetrahydrofuran (93 ml) under a nitrogen stream, and the solution was cooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to this solution by small portions, and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.5 g of the objective compound as yellow crystals.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)=[CH:12][CH:11]=1.N>O.C(O)C>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(I)cc1
Yield: 41.6 %

Procedure:
A solution of sodium dithionite (85%, 19.7 g, 96 mmol) in water (100 ml) was added to a suspension of N-(4-iodophenyl)-2-nitroaniline (8 g, 24 mmol) in ethanol (400 ml). The resulting mixture was heated under reflux for 45 min, cooled, treated with dilute aqueous ammonia (300 ml) and concentrated under reduced pressure. The resulting white slurry was treated with dilute aqueous ammonia (200 ml), filtered, the collected solid washed with water (100 ml) and dried to give N-(4-iodophenyl)-2-aminoaniline (3.1 g, 43%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromothiophenol (10 g) in acetone (250 mL) was added potassium carbonate (14.6 g) and iodomethane (4.28 mL). The heterogenous mixture was refluxed for 4 hrs., cooled to room temperature, filtered, and concentrated under reduced pressure. Ether (200 mL) was added, and the mixture was filtered again and finally evaporated to dryness to yield the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[Br:10][C:11]1[N:16]=[C:15]([C:17]2[C:25]3[C:20](=[N:21][C:22](Cl)=[N:23][CH:24]=3)[NH:19][N:18]=2)[CH:14]=[CH:13][CH:12]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1.O>CN(C=O)C>[Br:10][C:11]1[N:16]=[C:15]([C:17]2[C:25]3[C:20](=[N:21][C:22]([NH:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[N:23][CH:24]=3)[N:19]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[N:18]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: NCCN1CCOCC1
Reactant: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
SEM-Cl (5.15 g, 30.9 mmol) was added dropwise to a solution of 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 30 supra) (8.0 g, 25.8 mmol) and TEA (10.4 g, 103 mmol) in DMF (170 mL). The reaction was stirred at room temperature for 40 minutes. Then 2-morpholinoethanamine (4.03 g, 30.9 mmol) was added dropwise to the above solution. The mixture was heated at 55° C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate. Ethyl acetate solution was evaporated and purified by chromatography (silica gel, dichloromethane:MeOH, 50:1) to afford [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine as yellow solid. (Yield 5.6 g, 41%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4].[CH:13]([N:16]([CH:19](C)C)[CH2:17]C)(C)C.C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:19][N:16]([CH:17]=[N:30][C:31]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=1)=[S:32])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C=NC(=S)Nc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 7.47 g (36 mmol) 3-Methylsulfonyl aniline hydrochloride and 6.15 ml diisopropylethylamine in 75 ml THF was added 5.87 g (36 mmol) benzoyl isothiocyanate dropwise and allowed to stir at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was treated with diethyl ether. The precipitate was filtered off, dried and dissolved in 100 ml THF and 130 ml methanol. 18 g (130 mmol) potassium carbonate in 45 ml water was added and the mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and diluted with water. The precipitate was filtered off, washed with diethyl ether/ethanol and dried. The crude solid was dissolved in 50 ml dimethylformamide dimethyl acteal and heated for 3 h to 90° C. The precipitate was filtered off, washed with THF and dried to obtain 9.3 g (90%) of the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.[C:20](O)(C(F)(F)F)=[O:21]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:20]=[O:21]
Reactant: Oc1c(F)cccc1F
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A stirring solution of 2,6-difluorophenol (2 g, 15.4 mmol) and hexamethylenetetramine (2.16 g, 15.4 mmol) in TFA (16 mL) was heated at reflux under argon overnight. On cooling to room temperature the solvent was evaporated in vacuum and the crude residue was taken up in DCM (35 mL). The mixture was washed with an aqueous solution of NaHCO3 (sat.) and the separated aqueous layer acidified to pH 1 with concentrated HCl. The aqueous layer was extracted with DCM (2×25 mL), the combined organic fractions dried (MgSO4) and evaporated in vacuum to afford desired product as a cream solid (1.76 g, 73%). Rf=0.39 (SiO2; cyclohexane/EtOAc (6/4); UV) 1H NMR (300 MHz; CDCl3) δ: 6.38 (br, 1H); 7.50 (d, 2H, J=6.6 Hz); 9.82 (s, 1H). 13C NMR (75 MHz; CDCl3) δ: 113.2 (dd, JCF=13.8 Hz and 7.8 Hz); 128.2 (t, JCF=6.0 Hz); 139.0 (t, JCF=16.1 Hz); 151.9 (dd, JCF=246.9 Hz and 5.3 Hz); 189.1. 19F NMR (282 MHz; CDCl3) δ: −52.2
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCCCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 2,5,6-trichloronicotinonitrile (Method 44, 1.0 g, 4.8 mmol) and DIEA (0.81 g, 6.2 mmol) in n-BuOH (5 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (2.3 g, 19.3 mmol). The reaction was heated to 60° C. for 2 hours, at which point the reaction was cooled to room temperature and concentrated. The resulting residue was diluted with 10 ml ACN, and stored at 0° C. for 1 hour. The solids that formed were then filtered, washed with cold ACN, dried and collected to give the title compound (0.62 g, 43%). MS: Calcd.: 294. Found: [M+H]+ 295.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:30]>C(#N)C>[Br-:27].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])=[O:30])([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)C(C(=O)OC(c1cccc(F)c1)c1cccc(F)c1)C2)c1ccccc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (90 mg, 0.25 mmol, prepared as in example 4) and 2-bromo-1-(2-fluorophenyl)ethanone (65.6 mg, 0.30 mmol) were dissolved in acetonitrile (4 ml) and stirred at room temperature overnight. Acetonitrile was evaporated, and the residue was triturated with Et2O and filtered to obtain 3-((bis(3-fluorophenyl)methoxy)-carbonyl)-1-(2-(2-fluorophenyl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (51.3 mg, racemic mixture).
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)#N.[OH-:13].[Na+].[OH2:15]>>[C:4]1([CH2:3][C:1]([OH:15])=[O:13])[O:5][CH:6]=[C:12]2[CH:11]=[CH:10][CH:9]=[CH:7][C:8]=12
Reactant: O
Reactant: N#CCc1cc2ccccc2o1
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)Cc1occ2ccccc12
Temperature: 25 °C

Procedure:
7. The crude cyanomethylbenzofuran, compound 6, was stirred for 6 hours in boiling water (1,000 ml) containing sodium hydroxide (80 g), cooled to 25° C., then washed with methylene chloride (250 ml, then 2×100 ml). The pH was brought to 2.0 with 6 N HCl. The precipitate was extracted with methylene chloride (200 ml, then 100 ml, then 50 ml), dried over magnesium sulfate and the solvent evaporated. The yield was approximately 72 g.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[F:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:43]([C:41]3[CH:40]=[CH:39][C:38]([F:46])=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[N:42]=3)=[O:44])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.7 mg, 0.018 mmol), HATU (15.0 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 1 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18, 30×10 mm 5 μm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the sub-title compound as a colorless gum (4.0 mg, 42%). LCMS calc. for C32H35F3N5O5 (M+H)+: m/z=626.3. Found: 626.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(O)[CH2:41][CH2:40]C[CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:41][CH2:40]2)=[CH:18][CH:17]=1
Reactant: OC1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCCCC4)cc3)c2cc1OC
Yield: 92.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][S:29]([C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[F:21])(=[O:31])=[O:30]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(F)cc2F)c1

Procedure:
Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonyl chloride.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16](O)=O)=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C([O:46][C:47](=[O:57])CCSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:16][C:47]([OH:57])=[O:46])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCC2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclopentyl-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 89 %

Procedure:
6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved in 80 ml of carbon tetrachloride, and a solution in which 3.80 g (21.1 mmol) of bromine was dissolved in 10 ml of carbon tetrachloride was dropped into the reaction solution by a dropping funnel. After the dropping, stirring was conducted for 1 hour at room temperature. After reaction, a sodium thiosulfate water solution was added and the reaction was stopped. An organic layer was washed with an NaOH water solution and a saturated saline and dried with magnesium sulfate. After the natural filtration, it was concentrated, dissolved in toluene, and filtered through florisil, Celite (registered trademark), and alumina. The filtrate was concentrated and recrystallized by dichloromethane and hexane. Then, 7.0 g of a light-yellow solid of 9-bromo-10-phenylanthracene, which was the intended object, was obtained with a yield of 89% (synthetic scheme of (b-4)).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2].[CH3:20][O:21][C:22](=[O:32])[C@@H:23]([NH2:31])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:31][C@H:23]([C:22]([O:21][CH3:20])=[O:32])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 46.7 %

Procedure:
To a solution of 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.3 g, 4.96 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.2 g, 5.45 mmol) and N,N′-diisopropylethylamine (1.71 mL, 9.91 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.62 g, 9.91 mmol) and acetic acid (0.47 mL, 7.49 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5-methoxy-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 45.5%) as an oil.
Reaction SMILES: [NH2:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([Cl:14])[CH:7]=[CH:8][C:9]=2[NH2:13])[NH:4][CH2:3]1.ClCCl.C1C[O:21][CH2:20][CH2:19]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:20]([NH:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([Cl:14])[CH:7]=[CH:8][C:9]=2[NH2:13])[NH:4][CH2:3]1)(=[O:21])[CH3:19]
Reactant: C1CCOC1
Reactant: Nc1ccc(Cl)c2c1C(=O)C(N)CN2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1CNc2c(Cl)ccc(N)c2C1=O

Procedure:
260 mg of the compound prepared in (3) above was dissolved into a mixed solvent of 5 ml of dichloromethane and 5 ml of THF. To this solution were added 0.16 ml of pyridine and 0.13 ml of acetic anhydride while stirring under ice cooling, and the mixture was stirred for 20 minutes. The reaction product was concentrated, and after the addition of chloroform, the residue was washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated and the residue was charged into ether and petroleum ether in to produce 287 mg powder of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:16]CN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(Cl)Cl>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CC1Cc2ccccc2NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(2-Oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid (2.73 mmol), EDCl (3.27 mmol) and DIEA (3.27 mmol) are dissolved in 10 mL MeOH. About 2 mL of CH2Cl2 is also added to help dissolving the solid. The reaction mixture is stirred at room temperature for 2 hours before removal of the solvent under reduced pressure. The residue is purified by silica gel chromatography (hexane/EtOAc) to give (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as a white solid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 7.88 (br, 1H), 7.18 (m, 2H), 7.00 (td, 1H), 6.75 (d, 1H), 3.73 (s, 3H), 3.13-2.98 (m, 3H), 2.89 (m, 1H), 2.51 (dd, 1H). MS: (ES+): 220.2 [M+1].