Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[NH:14][C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[CH3:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1>CN(C=O)C>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2/[N:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:17])[N:14]([CH2:46][C:44]3[N:45]=[C:41]([CH3:40])[S:42][CH:43]=3)[C:15]/2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nc(CCl)cs1
Reactant: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2\C(=O)N(Cc3csc(C)n3)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl E-4-[[2-butyl-5-[[3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.66 g, 1.5 mmol) in DMF (10 mL) is added K2CO3 (3.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-chloromethylthiazole hydrochloride (0.28 g, 1.5 mmol) is added. The mixture is stirred for 16 hours and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. The mixture is filtered and allowed to stand in which time the product crystallizes. Petroleum ether is added to complete crystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.B(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].C(Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([O:10][CH2:11][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:4]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: BrCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1,3-Dimethoxy-5-bromobenzene (14.5 g, 66.7 mmol) was dissolved in 40 mL CH2Cl2 and cooled to 0° C. BBr3 (100 mL, 1.0 M in CH2Cl2, 100 mmol) was added and the solution was stirred for 12 h at room temperature. The reaction was carefully quenched with MeOH and then concentrated to dryness. The resulting syrup was redissolved in EtOAc and was washed with H2O (3×25 mL). The organic phase was then dried over Na2SO4, filtered and concentrated to dryness. The residue was then dissolved in DMF (50 mL) and K2CO3 (20.2 g, 146.7 mmol) was added, followed by benzyl bromide (BnBr, 17.4 mL, 146.7 mmol). The reaction mixture was stirred for 3 h after which TLC analysis (60% EtOAc/hexanes) indicated that the reaction was complete. The reaction mixture was then diluted in EtOAc and washed with water (3×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated to yield the crude product. The product was crystallized from isopropanol to yield 1,3-bis-Benzyloxy-5-bromobenzene 22 (21 g, 57 mmol, 85° A) yield) as a white powder. 1H NMR (CD2Cl2) δ 7.3-7.5 (m, 10H), 6.71 (s, 2H), 6.60 (s, 1H), 5.05 (s, 4H); 13C NMR (CD2Cl2) δ 161.2, 137.2, 128.9, 128.4, 127.8, 123.1, 111.0, 101.5, 70.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[N:7]=1
Reactant: CCOCCn1nc(C(=O)OC)c2nc(Cl)nc(Cl)c21
Reactant: Cc1ccnc(N)c1
Solvent: CS(C)=O
Product: CCOCCn1nc(C(=O)OC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The dichloro compound of Step 6 (1.98 g, 6.20 mmol) was dissolved in dimethyl sulphoxide (10 mL) and the solution treated with 2-amino-4-methylpyridine (1.34 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane (300 mL) and water (500 mL) and the dichloromethane layer separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 98:2. The crude product was triturated with ether (50 mL), filtered and concentrated in vacuo to yield the title product, 1.2 g.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.CO>[OH:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCO
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethylene glycol (22 g, 207.5 mmol) in CH2Cl2 (100 ml) was added triethylamine (10.5 g, 103.75 mmol). 9.89 (51.8 mmol) Toluene-4-sulfonyl chloride was added in one portion. The solution was stirred at room temperature for 1 hour. TLC was performed in 5% MeOH in DCM. After ½ hour a TLC showed formation of product. After 1 hour and 15 minutes the reaction mixture was washed with 0.1 M KHSO3 and 5% NaHCO3. The organic phase was dried with Na2SO3 and evaporated under reduced pressure. The crude reaction mixture was trapped on silica and purified by flash chromatography on a CombiFlash companion instrument (330 g column) using Hexane/EtOAc 50/50. Structure confirmed NMR.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26]C)OC)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1.[F-].[K+].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O>[C:8]([C:7]1[C:2]([N:36]2[CH2:37][CH2:38][C:31]3([CH2:30][N:29]([CH3:28])[CH2:33][CH2:32]3)[CH2:34][CH2:35]2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[O:26])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Reactant: CN1CCC2(CCNCC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC2(CCN(c3cc(NC(=O)N4CCCc5ccc(C=O)nc54)ncc3C#N)CC2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 40 mg, 0.103 mmol) and 2-methyl-2,8-diazaspiro[4.5]decane (31.8 mg, 0.206 mmol) were dissolved in DMF (1 ml) under argon. The mixture was stirred at 100° C. for 2 h. KF (12.0 mg, 0.206 mmol) and K2CO3 (42.8 mg, 0.309 mmol) were added to the reaction mixture and it was stirred at 100° C. for 3 h. Subsequently, the reaction mixture was cooled to room temperature, treated with conc. HCl (200 μl) and stirred for 30 min. The reaction mixture was diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by supercritical fluid chromatography (SFC 1, diethylaminopropyl stationary phase, DEAP column) to give the title compound as a white solid.
Reaction SMILES: C[O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2CC2C=CC(OC)=CC=2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[NH:23]2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1CCCCCCCCCC[C@@H]2C[C@H](C[C@](O)([C@@H]3CSC(=O)N3)O2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,14R,16R)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadecan-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[C:24]3[C:19](=[CH:20][C:21]([I:25])=[CH:22][CH:23]=3)[C:18](=[O:26])[C:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:16]2)[CH2:9]1)=O)(C)(C)C.Cl>ClCCl>[I:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:15]([CH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH:16]=[C:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]2=[O:26]
Reactant: CCOC(=O)c1cn(C[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cn(C[C@@H]2CCCNC2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.4 %

Procedure:
To a solution of (S)-ethyl 1-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 112, 2.47 g, 4.57 mmol, 1 equiv.) in dichloromethane (18 mL) was added 4 N hydrogen chloride (4.57 mL, 18.28 mmol, 4 equiv.). This was stirred at room temperature for 12 h. The precipitate was washed with diethyl ether and dried to provide (R)-ethyl 6-iodo-4-oxo-1-(piperidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (2.1 g, >99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1.[Cl:17]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:17])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccc(Cl)o2)c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a stirred solution of 2.03 g (8.73 mmol) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidine-5-carbonitrile in 12 ml DMF was added 1.22 g (9.16 mmol) N-chlorosuccinimide and stirring continued at 50° C. for 2 hours. The reaction mixture was then poured into 500 ml ice-water and the resulting precipitate collected by filtration and washed with water and then ether to afford 2.19 g (94%) 2-amino-4-(5-chloro-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light brown crystalline solid. EI-MS m/e (%): 268 (M{37Cl}+, 22), 267 ([M{37Cl}-H]+, 42), 266 (M{35Cl}+, 64), 265 ([M{35Cl}-H]+, 100), 231 ([M—Cl]+, 37).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][S:5][C:6]=1[C:7](OCC)=[O:8].C(O)(=O)C.[CH:29](N)=[NH:30]>C(O)C>[O:8]=[C:7]1[NH:30][CH:29]=[N:1][C:2]2[C:3]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)=[CH:4][S:5][C:6]1=2
Reactant: N=CN
Reactant: CCOC(=O)c1scc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2csc3c(=O)[nH]cnc23)CC1
Yield: 21.4 %

Procedure:
tert-Butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (307 mg, 0.87 mmol) was dissolved in ethanol (8 mL), and then formamidine acetate (542 mg, 5.20 mmol) was added, followed by heating under reflux for 36 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (62.5 mg, 21.5%) as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]([CH2:39][OH:40])[CH2:35][CH2:36][CH2:37][NH2:38])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][CH2:37][CH2:36][CH2:35][C@H:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:41])[CH2:39][OH:40])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCN
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.155 g (0.42 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.12 g (0.55 mmol) of tert-butyl[(1S)-4-amino-1-(hydroxymethyl)butyl]carbamate (Example 247A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.105 g (0.55 mmol) of EDC and 0.017 g (0.13 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]([CH3:32])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-])=O)[CH:25]=2)[N:20]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1>C(O)C.O=[Pt]=O>[NH2:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH2:18][N:17]([CH3:32])[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH:28]=[CH:27]2
Reactant: CN(Cc1ccc2cc([N+](=O)[O-])ccc2n1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(Cc1ccc2cc(N)ccc2n1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Reaction time: 6 h
Yield: 89 %

Procedure:
N-[4-[2-Hydroxy-3-[methyl[(6-nitro-2-quinolinyl)methyl]amino]propoxy]phenyl]methanesulfonamide (1.20 g, 2.61 mmol) and PtO2 (0.120 g, 10% by wt.) were suspended in ethanol (100 mL) and the flask was charged with H2 (1 atm). After stirring for 6 hours, the mixture was filtered through a pad of solka floc and the filtrate was concentrated in vacuo to afford 1.00 g of product as a pale oil which was used directly in the next step.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17]Br>>[CH:1]1[C:13]2[CH:12]([CH2:17][CH2:16][Br:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: BrCCBr
Product: BrCCC1c2ccccc2-c2ccccc21

Procedure:
reacting fluorenyllithium with 1,2-dibromoethane to produce 1-(9-fluorenyl)-2-bromoethane,
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH:16]=[CH:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]Cl)=[CH:25][CH:24]=1)([OH:22])=[O:21]>N1C=CC=CC=1>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:1][C:2]2[C:12]3[NH:11][CH:10]([O:13][CH3:14])[CH:9]4[CH2:15][C:16]([CH:15]=[CH:9][C:10]([NH2:11])=[O:13])=[CH:17][N:8]4[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][C:3]=2[CH3:19])=[CH:25][CH:24]=1)([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(CCCl)cc1
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2C=CCC12
Solvent: c1ccncc1
Product: COC1Nc2c(ccc(C)c2OCCc2ccc(C(=O)O)cc2)C(=O)N2C=C(C=CC(N)=O)CC12
Reaction time: 12 h

Procedure:
In 120 ml of pyridine were reacted 300 mg of 5,10,11,11a-tetrahydro-9-hydroxy-11-methoxy-8-methyl-5-oxo-1H-pyrrolo-[2,1-C][1,4]benzodiazepine and 1 g of 1-(4-carboxyphenyl)-2-chloroethane, for 12 hr at 50° C. After completion of the reaction, purification and recrystallization were conducted in the same manner as in Example 14 to obtain a light yellow crystal of 5,10,11,11a-tetrahydro-9-[2-(4-carboxyphenyl)-ethoxy]-11-methoxy-8-methyl-5-oxo-1H-pyrrolo-[2,1-C][1,4]benzodiazepine-2-acrylamide having a melting point of 193° to 195° C. Further, this product was converted to a corresponding sodium salt in the same manner as in Example 14. The yield of the sodium salt was 350 mg.
Reaction SMILES: [Na].N.[Si:3]([O:10][CH2:11][C@H:12]1[CH2:16][N:15]([C@@H](C2C=CC=CC=2)C)[C:14](=[O:25])[CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C>[Si:3]([O:10][CH2:11][C@H:12]1[CH2:16][NH:15][C:14](=[O:25])[CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CO[Si](C)(C)C(C)(C)C)CC1=O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Under a nitrogen gas atmosphere, metallic sodium (920 mg, 40.0 mmol) was added to liquid ammonia (about 30 ml) at −78° C. over a period of 5 minutes, and the mixture was further stirred at the same temperature for 15 minutes. To the reaction solution, a solution of (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (Heterocycles, 2003, vol. 60, No. 11, pages 2485-2498, or synthesized with reference to JP09136886; 3.34 g, 10.0 mmol) in tetrahydrofuran (10 ml)/tert-butyl alcohol (1 ml) was added over a period of 5 minutes and the mixture was stirred for about 1 hour. Ammonium chloride (3.21 g) was added thereto, and ammonia was evaporated by gradually raising the temperature to room temperature when the color of the reaction solution changed from dark blue to colorless. Water was added to dissolve the insoluble material and the resultant was extracted with a mixed solution of chloroform-methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to yield 2.29 g (100%) of the title compound in the form of a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[Cl-].[Mg+2].[Cl-].C=O.C(N(CC)CC)C.[C:22]([O-])([O-])=[O:23].[Cs+].[Cs+].CI.B(Cl)(Cl)Cl.B(Br)(Br)Br>C(#N)C.CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:22]=[O:23])=[C:4]([OH:8])[C:3]=1[OH:9]
Reactant: Oc1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: BrB(Br)Br
Agent: C=O
Agent: ClB(Cl)Cl
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(F)c(O)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 3-fluoro-benzene-1,2-diol (20 g, 156 mmol) in anhydrous acetonitrile (400 mL) was added magnesium chloride (37.1 g, 312 mmol), paraformaldehyde (31.6 g) and triethylamine (134 mL, 975 mmol). The reaction mixture was heated at 80° C. for 8 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The solid was treated with cold 2 N HCl and the aqueous layer was extracted with EtOAc. The organic layer was concentrated in vacuo yielding 20.4 g of crude. After a second run 40.8 g of crude was dissolved in DMF (1 L), cooled to 0° C., added to Cs2CO3 (340 g, 1.04 mol) portion-wise. Then methyl iodide (330 mL, 5.28 mol) was added. After warming to room temperature and stirring overnight the solution was filtered, ethyl acetate was added and the organic layer was washed with water (3×). After concentration in vacuo the product was purified by Biotage silica gel chromatography (2% to 3% to 10% to 20% EtOAc/hexanes) resulting in 14.8 g of dimethoxy compound. This material was dissolved in DCM and cooled to −30° C. and BCl3 (1 M in DCM, 134 mL, 0.1343 mol) was added to the solution at −30° C. After overnight at room temperature, the solution was cooled to −70° C. and BBr3 (1 M in DCM, 67.25 mL, 0.067 mol) was added. After overnight warming to room temperature, the solution was cooled in an ice bath and slowly ice water was added. The DCM layer was separated and the aqueous layer was extracted with DCM (2×). The combined organic layer was extracted with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. After triturating the residue obtained with hexanes/DCM (6:4) the 5.60 g (11% yield) of the title compound obtained was a brownish pink solid. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.36 (s, 1H), 9.83 (s, 1H), 7.16-7.13 (m, 1H), 6.82-6.78 (m, 1H), 5.48 (brs, 1H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −119.03-−119.08 (m, 1F).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[Na]>C(O)C>[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na]
Solvent: CCO
Product: COC(=O)c1ccccc1-c1ccc(C=O)cc1

Procedure:
2-Nitropropane (7.7 ml) and compound C (20.0 g) were added to a solution of sodium (1.52 ) in ethanol (80 ml) and the solution was heated under reflux for 5 hours. Volatile material was removed by evaporation and the residue was partitioned between ether (300 ml) and water (300 ml). The organic phase was separated, washed with saturated sodium chloride solution and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with a mixture of ethyl acetate and hexane (1:9 v/v gradually changing to 1:1 v/v), to give methyl 4'-formylbiphenyl-2-carboxylate (D) (10.2 g) as a waxy solid; NMR (d6 -DMSO): 3.6(s,3H), 7.45-7.6(m,4H), 7.7(d of t, 1H), 7.85(d of d, 1H), 7.95(d,2H), 10.05(s,1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH:3]=1.O1CCCC1.[BH4-].[Li+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(=O)=O.CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([CH:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[OH:19])[CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: OC(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanone (11.81 g, 26.08 mmol) in tetrahydrofuran (300 mL, 4000 mmol) was added lithium tetrahydroborate (52.17 mmol, 52.17 mmol) in tetrahydrofuran (26 mL, 320 mmol) under argon. The mixture was stirred at rt for 3 h and then cooled down in dry ice-acetone bath. Acetic acid (7.1 mL, 120 mmol) was added. The mixture was stirred for 5 min and saturated aqueous sodium bicarbonate solution was added, followed by EtOAc. The organic layer was separated and washed with brine, then dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography to afford (5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanol as a white powder (11.2, 94.2%). LCMS: (FA) ES+ 454.0, 456.0