Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:5][CH:4]=1.NC1C=CC(C[OH:42])=CC=1.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.CS(C)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:5][CH:4]=1)=[O:42]
Reactant: Nc1ccc(CO)cc1
Reactant: NCc1ccc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (1 g, 2.7 mmol; prepared as described in Preparation 14), 4-aminobenzyl alcohol (498 mg, 4.05 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.41 mL, 8.1 mmol) in DCM (14 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with 100 mL of DCM and washed first with a 1:3 mixture of 1N HCl/water (100 mL), then brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (100 mL) and the solution was cooled to −5° C. DIPEA (1.1 mL, 6.33 mmol) and DMSO (1.5 mL, 21.1 mmol) were added to the solution, followed by sulfur trioxide pyridine complex (1 g, 6.33 mmol). The reaction mixture was stirred at 0° C. for 1 hour then washed with a saturated solution of sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to give 0.84 g of the title intermediate (66% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][O:37][NH2:38].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:38][O:37][CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CON
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NOC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A mixture of (3S)-4-(((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol), O-methylhydroxylamine hydrochloride (0.2 g, 2.25 mmol), EDC.HCl (1 g, 5.2 mmol), HOAt (1 g, 7.3 mmol) and TEA (1.45 g, 14.3 mmol) in DCM (30 mL) was stirred at 0 t for 1 hour. Then the mixture was warmed to 25° C. and stirred for another 10 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (0.4 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)(=[O:3])[CH3:2].[Se](=O)=[O:20]>O1CCOCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH:18]=[O:20])[CH:14]=[CH:13]2)(=[O:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CC(=O)OCCOc1cccc2ccc(C)nc12
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCCOc1cccc2ccc(C=O)nc12
Yield: 96.4 %

Procedure:
To a solution of 2-(2-methylquinolin-8-yloxy)ethyl acetate (0.29 g, 1.2 mmol) in dioxane (20 mL) and water (0.20 mL) was added selenium dioxide (0.16 g, 1.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.30 g, 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=2)=[O:19])[CH2:3][CH2:2]1.Br[CH2:32][CH2:33][F:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:34][CH2:33][CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]=2)=[O:19])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3CCNCC3)cc12
Reactant: FCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3CCN(CCF)CC3)cc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
The reaction mixture containing 0.27 g of 1-(6-(piperidin-4-yl)quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (0.650 mmol), 0.073 ml of 1-bromo-2-fluoroethane (0.975 mmol), 1.059 g of cesium carbonate (3.25 mmol) and 6.5 of dioxane was shaken in a flask at 60° C. for 4 h. Due to non complete reaction, additional 0.049 ml of 1-bromo-2-fluoroethane (0.650 mmol) were added and the reaction mixture was shaken at 60° C. for 18 h. Saturated sodium bicarbonate solution was added and the mixture extracted three times with ethyl acetate. The combined organic phases were washed once with brine, dried over sodiumsulfat and the solvent removed under reduced pressure. After purifying of the raw material (190 mg) by column chromatography (silica gel, DCM/MeOH 95:5) 90 mg of the desired product were obtained as beige powder (yield: 30%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]([CH3:20])[CH2:11]1
Reactant: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)N1CCC(CO)CC1C

Procedure:
The compound was prepared as described in Reference Compound 4, Step 4 starting from methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-methylpiperidine-1-carboxylate and TBAF (10.65 mL, 10.65 mmol, 1 M in THF). The residue was purified by column chromatography (Biotage 40%-90% gradient EtOAc in heptane, 340 snap column), which resulted in the title compound. 1H NMR (400 MHz, cdcl3) δ 0.95-1.42 (m, 3H), 1.68-1.95 (m, 3H), 3.08 (m, 1H), 3.39-3.53 (m, 2H), 3.61 (m, 1H), 3.68 (s, 3H), 3.71-3.87 (m, 1H), 3.87-4.08 (m, 1H), 4.30-4.62 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=O)[CH2:10]2)[CH:8]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:10]2)[CH:8]=1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1F)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 170.7 %

Procedure:
To a solution of 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (0.6 g) and aminoguanidine hydrochloride (0.233 g) in ethanol (10 ml) was added concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 2 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 171) (0.6 g) as colorless crystals.
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[C@H:8]([OH:19])[CH2:7]1)=O.C([O:25]C1C=C(C=CC=1)C=O)(C)C.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+]>C(O)C.CO.C(Cl)Cl>[NH2:5][CH:6]([C:14]1[CH:9]=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:17])[CH3:18])[CH:13]=1)[CH2:7][C:8]([OH:19])=[O:25]
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CC(C)Oc1cccc(C(N)CC(=O)O)c1
Yield: 62 %

Procedure:
Step AU (2). A solution of 3-isopropoxybenzaldehyde (77 g, 470 mmol), malonic acid (52 g, 496 mmol) and ammonium acetate (65 g, 844 mmol) in 1.0 L of ethanol was refluxed at 120° C. for 24 h. The solvent was evaporated in vacuo. The residue was purified using silica-gel column chromatography with (100% EtOAc, then 30% methanol/methylene chloride) to afford 65 g (62% yield) of 3-amino-3-(3-isopropoxyphenyl)propanoic acid as a white solid. LC-MS (M+H)+=224.14. 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.3 (d, 6H) 2.4-2.5 (m, 2H) 4.2-4.4 (m, 1H) 4.5-4.7 (m, 1H) 6.8-6.9 (m, 1H) 6.9-7.0 (m, 2H) 7.2-7.3 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:24][C:11]1[C:5]2[C:6]3[CH2:10][CH2:9][S:8][C:7]=3[C:2]([CH3:1])([CH3:25])[O:3][C:4]=2[CH:14]=[C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran with acetic anhydride, there is obtained 9-acetoxy-1,2-dihydro-4,4 -dimethyl-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1)#[N:16].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([C:15]#[N:16])[CH:22]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(C#N)c1
Reaction time: 16 h

Procedure:
A 1.5 g (20 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Example 1a) and 3.57 g (30 mmol) of 3-cyanophenol (Aldrich) were added to a complex of TPP and DEAD, (prepared as in Example 5b above, 30 mmol of each) in 100 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was extracted with hexane and chromatographed on silica gel, eluting with 100:0-85:15 hexane:ethyl acetate to give 2.71 g of the title compound. MS: 303 (M+H)+, 320 (M+NH4)+. NMR (CDCl3) δ: 1.48 (s, 9H), 1.84-2.05 (m, 4H), 3.35-3.45 (br, 2H), 3.75-3.95 (m, 1H), 4.05-4.18 (br, 2H), 7.25-7.40 (m, 4H).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=[O:10].C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[Cl:7][CH2:8][C:9]1([OH:10])[CH2:11][O:5][C:1]([CH:2]([CH3:4])[CH3:3])=[N:6]1
Reactant: O=C(CCl)CCl
Reactant: CC(C)C(N)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)C1=NC(O)(CCl)CO1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a solution of isobutyramide (9.876 g, 0.1122 mol) in acetone (130 mL) was added 1,3-dichloroacetone (10.0 g, 0.0748 mol), NaHCO3 (9.429 g, 0.1122 mol), and MgSO4 (18.01 g, 0.1496 mol). The mixture was heated at reflux under argon for 63 hrs, then cooled to room temperature, vacuum filtered, and concentrated in vacuo to a dark brown semi-solid. The residue was purified by SiO2 flash chromatography using a gradient of EtOAc/CH2Cl2 (5%, 10%, 20%, 40%) to obtain the desired product as an orange liquid (6.06 g, 0.0341 mol, 46%): 1H NMR (CDCl3) δ1.20-1.28 (m, 6H), 2.56-2.72 (m, 1H), 3.70 (s, 2H), 4.18 (d, J=9.6 Hz, 1H), 4.38 (d, J=9.6 Hz, 1H). Mass spectrum: (M+H)+ =178, 180.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:22][C:23]([OH:25])=O)[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.ON1C2C=CC=CC=2N=N1.CN(C)N1C=CC=CC1.[NH2:46][N:47]1[CH2:51][CH2:50][NH:49][C:48]1=[O:52].C1(N=C=NC2CCCCC2)CCCCC1.CN([Si](C)(C)C)C(=O)C(F)(F)F>CN(C)C=O.C(#N)C.ClCCl>[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:22][C:23]([NH:46][N:47]2[CH2:51][CH2:50][NH:49][C:48]2=[O:52])=[O:25])[N:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1
Reactant: O=C(O)Cc1cc(=O)c(O)cn1Cc1ccccc1
Reactant: NN1CCNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: CN(C)N1C=CC=CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Cc1cc(=O)c(O)cn1Cc1ccccc1)NN1CCNC1=O
Reaction time: 8 h

Procedure:
4.99 ml (35.83 mmol) of triethylamine was added to a suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2-pyridineacetic acid, 0.28 g (1.79 mmol) of N-hydroxybenzotriazole, 0.22 g (1.79 mmol) of N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.41 mmol) of dicyclohexylcarbodiimide in 115 ml of dry dimethylformamide. Stirring was continued overnight at room temperature. The precipitated dicyclohexylurea was filtered off, washed with dimethylformamide, and the filtrate was evaporated in vacuo to leave a residue, which became crystalline by stirring with 110 ml of dichloromethane. The precipitate was collected by suction and dried in vacuo. To a suspension of this crude material in 65 ml of dry acetonitrile, 14.0 ml (71.6 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added. After having been stirred for 30 minutes at room temperature, the undissolved dicyclohexylurea was filtered off and the filtrate was evaporated in vacuo. The oily residue was boiled in 70 ml of methanol for 15 minutes and cooled. The precipitate was collected by suction, washed successively with methanol, methanol/ether (1:1) and ether and dried in vacuo. Yield: 8.7 g; sint. 242° C., melting point 260°-265° C. dec.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[N:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[NH:25][C:21]=1[CH2:20][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: ClCc1nc2ccccc2[nH]1
Product: O=c1c2ccccc2nc(SCc2nc3ccccc3[nH]2)n1-c1ccccc1
Yield: 39.3 %

Procedure:
The title compound was prepared in a yield of 39.3%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and 2-chloromethylbenzimidazole in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][CH2:22][N:8]3[C:7](=[O:23])[C:6]=2[CH:24]=1.O[CH2:26][CH:27]1CC1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH:19]4[CH2:27][CH2:26]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][CH2:22][N:8]3[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Reaction time: 0.33 h

Procedure:
6.92 g (20 mmol) of ethyl (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 20 g of hydroxymethyl-cyclopropane and 1 g of tetraethyl orthotitanate are heated to 130° for 16 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 20 minutes, the chloroform phase is separated, washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 146°-148°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26]4)[CH2:22][CH2:21]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 42.7 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.420 g, 1.68 mmol) obtained in Example 19, step 2 and spiro[inden-1,4′-piperidine]hydrochloride (0.450 g, 2.02 mmol), the title compound (0.300 g, 43%) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCCl>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([Cl:3])=[O:15])[CH:6]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: O=S(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(Cl)CCc1cccnc1
Temperature: 25 °C

Procedure:
Add thionyl chloride (0.05 mL, 0.53 mmol) to a stirred suspension of 3-(3-pyridyl)propionic acid (80.2 mg, 0.53 mmol) and benzyltriethylammonium chloride (1 mg, 0.004 mmol) in 1,2-dichloroethane (20 mL) and heat to reflux for 2.5 hours. Cool the reaction mixture to room temperature and concentrate in vacuo. Azeotrope the residue with CCl4 and place under vacuum. Use the resulting acid chloride without further purification.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:29])([F:28])[C:11]([NH:13][C@@H:14]([CH3:27])[C@H:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:15]([OH:26])[C@@H:14]([NH:13][C:11](=[O:12])[C:10]([F:29])([F:28])[F:9])[CH3:27])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Benzyl bromide (22 mL) was added to a suspension of 2,2,2-trifluoro-N-[(1S,2R)-2-hydroxy-2-(4-hydroxy-3-nitrophenyl)-1-methylethyl]acetamide (55 g) and potassium carbonate (36.8 g) in N,N-dimethylformamide (529 mL) at room temperature with stirring, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated in vacuo, and ethyl acetate and water were added to the residue. The organic layer was separated, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (73 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([O:13][CH2:14][CH3:15])[O:10][C:9](=[O:16])[C:8]=2[C:17]=1[CH2:18][CH3:19])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([O:13][CH2:14][CH3:15])[O:10][C:9](=[O:16])[C:8]=2[C:17]=1[CH2:18][CH3:19]
Reactant: CCOc1nc2ccc([N+](=O)[O-])c(CC)c2c(=O)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1nc2ccc(N)c(CC)c2c(=O)o1
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 0.75 g (2.8 mmoles) 6-nitro-5-ethyl-2-ethoxy-3,1-benzoxazin-4-one in 35 mL ethyl acetate was transferred to a Parr bottle. 0.40 g (0.38 mmoles) of 10% Pd/C catalyst was added. The sample was hydrogenated on a Parr shaker at ambient temperature and 1 atm pressure for 3 hours. The catalyst was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo to produce a bright yellow solid. There was obtained 0.58 g (86% yield) of 6-amino-5-ethyl-2-ethoxy-3,1-benzoxazin-4-one. NMR(CDCl3): 1.22 (t,3H,J=7.5 Hz), 1.42(t,3H,J=7.2 Hz), 3.14(q,2H,J=7.5 Hz), 4.44(q,2H,J=7.2 Hz), 7.09(d,1H,J=8.7 Hz), 7.14(d,1H,J=8.7 Hz). MS(m/z): 234(M+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:48][C:39]([CH3:41])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH3:40])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Reaction time: 0.08 h
Yield: 97.2 %

Procedure:
3-Phenoxybenzoic acid (3.00 g, 14.0 mmol) was dissolved in DMF (45 mL), and the solution was added with EDCI (4.03 g, 21.0 mmol) and HOBT monohydrate (1.07 g, 7.00 mmol) under ice-cooling, followed by stirring at the same temperature for 5 minutes. Then, the mixture was added with cumylamine (4.03 mL, 28.0 mmol) and stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using hexane to obtain 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.51 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=O.[OH-].[K+].O1CCO[CH2:18][CH2:17]1>>[N:1]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=2)[CH:12]=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: Nc1c(C=O)ccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: c1ccc2c(c1)ccc1cccnc12

Procedure:
23.8 g of 2-bromobiphenyl was converted to the Grignard form in THF using 3.4 g of metal magnesium, then this reacted with 18.0 g of 9-fluorenone at from room temperature to 50° C. and, by treatment in the normal way, 9-(2-biphenyl)-9-fluorenol was obtained. This was heated in acetic acid to which a small amount of hydrochloric acid had been added, so that water was eliminated and, by treatment in the usual way, 9,9′-spirobifluorene (18.5 g) was obtained. Next, Connecting Unit 1 (15.8 g) was reacted with 8.6 g of acetyl chloride and 14.7 g of aluminium chloride at 50° C. in 1,2-dichloroethane and, by treatment in the normal way, 2,2′-diacetyl-9,9′-spirobifluorene (11.2 g) was obtained. This diacetyl compound (2.3 g) was reacted with 2.0 g of 1-amino-2-naphthalenecarbaldehyde and 1.6 g of potassium hydroxide at 60° C. in dioxane and, by treatment in the normal way, there was obtained BQ-1 (1.5 g) shown below. 1H-NMR (CDCl3, ppm): 9.4 (d, 2H), 8.6 (d.d, 2H), 8.1 (d, 2H), 8.0 (t, 4H), 7.8 (d, 2H), 7.8-7.6 (m, 12H), 7.4 (t, 2H), 7.2 (t, 2H), 6.8 (d, 2H).