Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:26][N:27]([CH3:43])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41]>CC(C)=O>[CH3:43][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CN(C)CCCNC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)NCCCN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
Potassium carbonate (0.55 g) and 1-bromooctadecane (0.67 g) were added to a solution containing N-[3-(dimethylamino)propyl]-3-(2-hydroxyphenyl)propanamide (0.50 g) obtained in Example 1(1) in acetone (5 ml). After being stirred for 24 hours at 60° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 40 g, chloroform: methanol=10:1), thereby yielding the entitled compound (0.42 g) as white solid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]([OH:20])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1cc(=O)c2cc(C(C)CO)ccc2o1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(=O)c2cc(C(C)C(=O)O)ccc2o1

Procedure:
2-(2-Ethyl-4-oxo-4H-1-benzopyran-6-yl)propan-1-ol (3.0g; 0.0129 mol) was dissolved in acetone (20 ml) and Jones Reagent (Example 2) was slowly added until the solution attained a permanent brown colour. Water (100 ml) was added and the mixture was extracted with chloroform (4 × 70 ml). The combined chloroform phases were extracted with saturated sodium bicarbonate solution (4 × 30 ml). The aqueous phases were combined, washed with chloroform (100 ml) and then acidified with concentrated hydrochloric acid. The precipitated product was extracted with chloroform (3 × 100 ml) and the combined extracts dried over magnesium sulphate. After removing solvent, the product was recrystallised from benzene/hexane (1;1) to yield a pale yellow amorphous solid (1.4g) mp 128°-128.5°.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (5 mL), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (153 mg, 1.00 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The crude product was purified by applying onto a C18 Column (water/acetonitrile) to afford 150 mg (41%) of 148 as a white solid. LC-MS (ES, m/z): 355 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.97 (s, 1H), 7.69 (d, 1H), 7.48 (m, 5H), 7.25 (m, 2H), 7.11 (m, 2H), 6.58 (d, 1H), 5.65 (q, 1H), 1.71 (d, 3H)
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Temperature: 150 °C

Procedure:
In 20.8 ml of pyridine were dissolved 5.2 g (40 m mol) of 5-fluorouracil and 14 g (200 m mol) of 2,3-dihydrofuran. The solution were heated at about 150° C. in a closed tubular reactor under agitation for 6 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was passed through a column of silica gel. The column was eluated with chloroform and the effluent was concentrated to dryness under reduced pressure. The residue was washed with a small amount of petroleum ether to give the above-mentioned compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:32]2[CH:31]=[C:30](B(O)O)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.COC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:31]4[C:32]5[C:23]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=6[CH:30]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: COC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5c5ccccc45)cc3CC[C@@H]12
Yield: 30.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 9-phenanthreneboronic acid (173 mg, 0.78 mmol), triethylamine (0.2 mL, 1.3 mmol), and 2 mL of dimethyl ether, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 80 mg (30%) of the title compound as a white solid. mp 218°-220°. FDMS: m/e=405. α[D]589 =+63.01 (c=0.98, chloroform).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1.N1C=CC=CC=1>[C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5]
Reactant: CCC#CC(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC/C=C\C(=O)OCC
Yield: 98.5 %

Procedure:
To a slurry of Lindlar catalyst (0.844 g, 0.396 mmol) in THF (100 mL) and pyridine (10.00 mL) was added ethyl pent-2-ynoate (5.22 mL, 39.6 mmol). The reaction mixture was sparged with hydrogen for about 10 min and an atmosphere of hydrogen was maintained via balloon. After about 15 h the reaction mixture was filtered through a pad of Celite®, diluted with Et2O (30 mL) and washed with saturated aqueous CuSO4 (40 mL), followed by water (40 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd in vacuo to provide crude (Z)-ethyl pent-2-enoate (5 g, 98%). 1H NMR (DMSO-d6) δ 1.05 (t, 3H), 1.28 (t, 3H), 2.65 (m, 2H), 4.18 (q, 2H), 5.72 (m, 1H), 6.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (18-4, 0.10 g, 0.31 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by isonicotinoyl chloride hydrochloride (0.15 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-(4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (18, 0.070 g) as light yellow solids in 52% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=5.5 Hz, 2 H), 7.99 (dt, J=3.1, 1.5 Hz, 2 H), 7.92 (d, J=3.1 Hz, 1 H), 7.52 (dt, J=5.7, 3.2 Hz, 1 H), 7.20 (s, 1 H), 7.00 (d, J=8.8 Hz, 1 H), 6.81 (s, 2 H), 3.81 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64].Cl>ClCCl>[C:23]([O:22][C@@H:21]1[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[O:46][C@H:20]1[O:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:7][CH:6]=2)[NH:16][N:17]=1)(=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-hydroxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (1.6 g) in dichloromethane (20 mL) were added triethylamine (0.44 mL) and pivaloyl chloride (0.31 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.O[C@@H:11]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@H:11]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(O[C@@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 3-methoxyphenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 472.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH2:15])[S:7][C:6]=2[CH:16]=1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[N+:25]([O-:27])=[O:26])[S:7][C:6]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Yield: 77.7 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 6-bromo-2-aminobenzo[b]thiophene-3-carboxylate (8.8 g), 2,4-difluoronitrobenzene (5.6 g) and dimethyl sulfoxide (100 ml), ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (10 g) was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[OH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Yield: 99.9 %

Procedure:
Dissolve (R)-pyrrolidin-3-ol (0.08 mL, 1.00 mmol) and 4-fluorobenzonitrile (121 mg, 1.00 mmol) into 1 mL of DMSO. Add K2CO3 (276 mg, 2.00 mmol) and heat the mixture at 120° C. for 16 h. LC-MS analysis indicates the desired intermediate. Add 10 mL of H2O. Filter the precipitate and dry in a Buchner funnel for 1 h to give 188 mg of 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[NH:10][C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[N:13]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]>C1(C)C=CC=CC=1>[N+:28]([C:25]1[CH:24]=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=[CH:27][C:26]=1[N:10]1[C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[N:13]=[C:9]1[Br:8])([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1[nH]c(Br)nc1C(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)OC(C)C)nc(Br)n1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
4.2 ml of triethylamine was added dropwise to 5 g (0.02 mol) of isopropyl 2-bromo-5-methyl-4-imidazolecarboxylate, 3.9 g of 1-fluoro-2,4-dinitrobenzene and 200 ml of toluene, and the mixture was refluxed for 16 hours. The toluene solution was then washed with water, dried and concentrated. The residue was stirred with diethyl ether and the solid obtained in this manner was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[C:36]([NH:39][NH2:40])(=O)[CH3:37]>O1CCCC1.C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:36]([CH3:37])=[N:39][N:40]=[C:11]2[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(I)ccc2N1
Reactant: CC(=O)NN
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of 15.7 g (0.04 mol) of 5-(2-chlorophenyl)-7-iodo-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 350 ml of tetrahydrofuran was cooled to -30° C. potassium t-butoxide. 4.9 g (0.044 mol) was added and stirring under nitrogen was continued for 30 minutes at -10° to -5° C. Diethyl chlorophosphate, 6.6 ml, was then added and the mixture was stirred at this temperature for another 30 minutes. Following the addition of 3.4 g of acetyl hydrazine, stirring without cooling was continued for 1 hour and 150 ml of n-butanol was added. The tetrahydrofuran was distilled out of the reaction mixture over a period of 45 minutes. The residue was partitioned between water and toluene. The organic phase was washed with brine, dried over sodium sulfate and evaporated down to a small volume. The precipitated crystals were collected to leave 14 g of crude product which was purified by chromatography over 250 g of silica gel using 5% ethanol (V/V) in methylene chloride. The clean fractions were combined and evaporated. Crystallization from tetrahydrofuran/ethanol gave 8.5 g (49%) of 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with m.p. 290°-292° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 150 mg, 0.33 mmol) and 1-amino-2-methylpropan-2-ol (50 mg, 0.66 mmol) in DMF (2 mL) was added DIPEA (0.11 mL, 0.66 mmol, 2 eq) and HATU (188 mg, 0.50 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium carbonate solution (50 mL) and EtOAc (50 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with acetonitrile to afford the title compound (63 mg, 36%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.COC1C=CC=CC=1OC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COc1ccccc1OC
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a mixture of 313 mg (purity: 96.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.47 mmol) of 2-cyclopropyl-6-methylphenol were added 1,2-dimethoxybenzene (2.76 g) and 326 mg (5.53 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 189 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 38%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][S-:16].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:16][CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCCCBr)CCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CCCCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
To a solution of 1-(4-bromobutyl)cyclopentane carboxylic acid methyl ester (38 mmol, 10 g) in DMF (100 mL) was added sodium thiomethoxide (72.6 mmol, 5.09 g). After addition of sodium thiomethoxide, the reaction was exothermic and the mixture became a light brown cloudy solution. The mixture was stirred for 15 h at room temperature and was poured into water (200 mL). The organic compound was extracted with ether (2×150 mL). The combined extracts were washed with brine (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 4.43 g (51%) of a colorless oil. LR MS (C12H22O2S): 230 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:20][O:19][C:17]([C:15]1[O:16][C:12]([CH2:11][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1)=[O:18]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(C)cc(C)cc2C)o1

Procedure:
1,3,5-Trimethylbenzene (6.85 g, 57 mmol), methyl 5-chloromethyl-2-furanoate (2.48 g, 14.2 mmol) and aluminum trichloride (2.46 g, 18 mmol) were refluxed in dichloromethane (30 mL) for 4 h. The reaction was quenched with water, and the two layers were separated. The organic layer was concentrated and passed through a silica gel column. Hexane was used as the mobile phase to elute the product. The 5-(2,4,6-trimethylbenzyl)furan-2-carboxylic acid methyl ester was obtained as a yellow oil (86%).
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])([OH:3])=[O:2].Cl(O)(=O)(=O)=O.C(OCC)(=O)C.O.C(O[C:37]([CH3:40])([CH3:39])[CH3:38])(=O)C>>[C:37]([O:2][C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])=[O:3])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(F)c(C2CC2C(=O)OC(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
In 10 ml of tert-butyl acetate was dissolved 1.00 g of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate. To the resulting solution was added 0.2 ml of a 70% aqueous perchloric acid solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 40 ml of ethyl acetate and 20 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/1) to obtain 0.81 g (yield: 68.1%) of ethyl 4-(2-tert-butoxycarbonylcyclopropyl)-2,3,5trifluorobenzoate.