Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@H:12]3[O:13]C(=O)C3C=CC=CC=3)[CH:9]=[N:10][C:3]=12.[NH3:44]>CO>[NH2:44][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]3[OH:13])[CH:9]=[N:10][C:3]=12
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nncc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: N
Solvent: CO
Product: Nc1nncc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The compound from Step C (420 mg, 0.7 mmol) was added to a solution of ammonia in methanol and stirred in a steel bomb at 150° C. for 6 hours. The reaction mixture was evaporated to dryness to afford a brown oil which was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (50 mg) as a yellow powder.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([SH:10])=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1cccc2nccn12
Reaction time: 2 h

Procedure:
To a solution of 120.02 g (0.7991 mol) of imidazo-[1,2-a]pyridine-5-thiol and 134 ml (0.959 mol) of triethylamine in 500 ml of ethanol was added 88.6 ml (0.799 mol) of ethyl bromoacetate dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was then distilled off under reduced pressure and ethyl acetate was added to the residue. The resulting precipitate (for the most part, triethylamine hydrochloride) was filtered off and washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure to provide ethyl (imidazo[1,2-a]pyridin-5-ylthio)acetate as crude product. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1.CN(C=O)C.C(Cl)Cl>[NH:4]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][N:2]([CH3:3])[CH3:1])=[CH:21][CH:20]=2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCC(=O)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 9 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2.0M; 4 ml) was added to a solution of 4-anilino-5-bromo-2-[4-(3-chloropropionamido)anilino]pyrimidine (Method 37; 60 mg, 0.135 mmol) in DMF (0.2 ml). The solution was heated at 80° C. for 1 hour, diluted with DCM (4 ml) and loaded onto a Varian Mega Bond Elut column. Elution with 0-10% 2.0M methanolic ammonia solution in DCM gave the product (5.4 mg, 9%). MS (MH+): 455, 457; HPLC (RT): 2.70.
Reaction SMILES: CN(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=O.[OH-].[Na+].CO>CS(C)=O>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(ccn2C(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate (0.7 g, 2.2 mmol), sodium hydroxide (1M aqueous solution, 18 mL), methanol (5 mL), and dimethylsulfoxide (3 mL) was stirred at 100° C. overnight under argon. The reaction mixture was cooled, washed with diethyl ether (20 mL), acidified with 6M hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The ethyl acetate extract was washed with brine (20 mL), dried (Na2SO4) and concentrated to give 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.58 g, 2.0 mmol, 91% yield) as a syrup and used as such for the subsequent step without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].O=[C:10]([CH2:16][CH2:17][C:18](OCC)=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[O:19]=[C:18]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=[C:17]1[CH2:16][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCC(=O)C(=O)OCC
Reactant: Nc1ccccc1N
Product: CCOC(=O)CCc1nc2ccccc2[nH]c1=O
Yield: 72 %

Procedure:
The title compound was prepared from 1,2-phenylenediamine and diethyl 2-oxopentanedioate using methods as described in the literature for similar compounds (Weygand et al., 1962) in 72% yield.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][C:14](C)=[CH:13][C:12](=[O:17])[CH2:11]1)C1C=CC=CC=1.[CH3:18]COC(C)=O>[Pd]>[CH3:18][C:10]12[O:15][CH:14]([O:8][CH2:9]1)[CH2:13][C:12](=[O:17])[CH2:11]2
Reactant: CC1=CC(=O)CC(COCc2ccccc2)O1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC12COC(CC(=O)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of 4.4 g of the 6-Benzyloxy compound from Step 2 in EtOAc was hydrogenated with H2 and Pd/C (10%). After completion, the reaction was filtrated on a bed of celite and then evaporated to dryness. The cru syrup was then taken up in CH2Cl2 containing 1 g of camphor sulphonic acid. The reaction was stirred at r.t. overnight, filtered and evaporated. Purification by flash chromatography (30% Et2O/pentane) gave 780 mg of the title compound (30%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]
Reactant: OC[C@@H]1CCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and (S)-1-pyrrolidin-2-ylmethanol. Yield: 0.2 g (25% of theory); C14H20N2O5 (M=296.32); calc.: molecular ion peak (M+H)+: 297; found: molecular ion peak (M+H)+: 297; Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O:38][C:39](=[O:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47](O)[CH3:48])=[CH:43][CH:42]=1)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C@H:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C:39]([OH:50])=[O:38])=[CH:42][CH:43]=1)[CH3:48])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: Oc1ccccc1
Product: C[C@H](Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of example 69 using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol as the phenol and [4-(1-Hydroxy-ethyl)-phenyl]-acetic acid ethyl ester as the alcohol and isolated using chiral column chromatography. MS (ESI) m/z 540.
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([C:19]([F:22])([F:21])[F:20])=[CH:12][C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[C:13]2[CH:12]=[C:11]([C:19]([F:20])([F:21])[F:22])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: N#Cc1ccno1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(F)(F)F)sc1N
Product: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-5-trifluoromethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C([Li])CCC.C[OH:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:16][CH2:17][CH3:18])=[CH:22][C:21]([O:20][CH2:24][CH3:23])=[O:7])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CCCC(=O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCCC(=CC(=O)OCC)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A solution of butyllithium, 2.5M in hexanes (166 ml, 0.416 mol, Aldrich) was added dropwise over 0.5 hr, with rapid mechanical stirring, to a solution of triethyl phosphonoacetate (93.2 g, 0.416 mol, Aldrich) in tetrahydrofuran (700 ml, anhydrous, Aldrich) at <5° C. while blanketed with a nitrogen atmosphere. This solution was stirred for an additional 0.25 hr and cooled to -5° C. with a methanol:ice bath and a solution of 4'-fluorobutyrophenone (69 g, 0.416 mol, Aldrich) in tetrahydrofuran (150 ml) was then added in one portion. Stirring was continued for 18 hr without additional cooling. The solution was concentrated to a dark camel sludge by spin evaporation in vacuo and diluted to 600 ml with deionized water. The aqueous solution was extracted with dichloromethane (5×500 ml) and the dichloromethane was concentrated by spin evaporation in vacuo. Distillation at reduced pressure gave 58.5 g (60%) of ethyl 3-(4-fluorophenyl)hexenoate as a mixture of (E) and (Z) isomers (ratio 1:1) as clear liquid b.p. 140-150° C. at aspirator pressure:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:22]=[CH:21][C:10]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=4)=[N:12][S:13][C:9]=3[CH:8]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CNC1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 418 (MH+, 1Br).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Br:15]Br.C(Cl)(Cl)Cl>ClCCl>[Br:15][CH2:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: CC(=O)c1cc2cc(C#N)ccc2o1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc2oc(C(=O)CBr)cc2c1
Yield: 70.1 %

Procedure:
21.0 g of 2-acetyl-5-benzofurancarbonitrile was dissolved in 300 ml of dichloromethane. With stirring at a temperature of -10° C., 30 ml of dichloromethane solution containing 18.2 g of bromine was added dropwise to the above solution. After gradually warming up to ice-cold temperature, the resulting reaction solution was mixed with chloroform and washed with 10% sodium thiosulfate aqueous solution. After drying the organic layer and subsequent concentration to dryness, the resulting residue was recrystallized from a benzene/n-hexane mixture to obtain 21.0 g of 2-(2-bromo-1-oxoethyl)-5-benzofurancarbonitrile in the form of colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: OCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (300 g) and sodium hydrogen carbonate (42.9 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (126 g) was added thereto. Thereafter, the mixture was heated up to 50° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 457 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:65/35/5), and concentration was performed under reduced pressure to obtain 3-O-glyceryl ascorbic acid (296 g).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=3)[CH2:27][CH2:28]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(N2CCNCC2)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)nc1
Yield: 32.1 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (374 mg) described in Preparation Example 18 and 1-(5-methylpyridin-2-yl)piperazine (250 mg), the title compound (185 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20](=[O:23])[CH2:21]Br)([CH3:18])([CH3:17])[CH3:16]>C(#N)C>[C:15]([O:19][C:20](=[O:23])[CH2:21][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71 %

Procedure:
To a mixture of 2-nitroimidazole 1 (17.7 mmol, 1 equiv.) and anhydrous potassium carbonate (70.74 mmol, 4 equiv.) in 20 mL of acetonitrile is added dropwise a solution of tert-butylbromoacetate (17.7 mmol, 1 equiv.) in 10 ml of acetonitrile. The mixture is stirred one night at room temperature and concentrated under vacuum. The residue is purified by chromatography on silica gel using a mixture CH2Cl2/MeOH 95/5 as eluent to give the expected compound as white powder in 71% yield. mp 95-97° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (s, 9H), 4.99 (s, 2H), 7.06 (d, 1H, J=1.01 Hz), 7.17 (d, 1H, J=1.01 Hz). MS (ESI+/ESI−) m/z 226.15 [M−H]−, 262.13 [M+Cl]−, 250.20 [M+H]+
Reaction SMILES: [NH3:1].Cl[C:3](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=O>C1COCC1>[Cl:17][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:3]([NH2:1])[CH2:4][O:6][CH2:7][CH3:8])[CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: CCOC(=O)C(Cl)=NNc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCOCC(N)=NNc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
45.0 mL (60.2 mmol) aqueous ammonia solution (25%) was added over 20 minutes to a solution of 15.0 g (57.4 mmol) ethyl 2-chloro-2-(2-(3-chlorophenyl)hydrazono)acetate in 75 mL THF and stirred for 1 h. The resulting mixture was diluted and extracted with hexane and EtOAc (1:1 mixture). The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and used without further purification for the next synthesis step (yield: 12.0 g (92%)).
Reaction SMILES: [OH:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][C:2]2[C:15]3[C:6](=[C:7]([O:16][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:34][CH:33]=4)[C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][C:3]=2[O:17][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2Cc2c1ccc(O)c2O
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Product: O=C(Oc1ccc2c(OC(=O)c3ccc(OCc4ccccc4)cc3)c3ccccc3cc2c1OC(=O)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 18.7 %

Procedure:
Using 1,2-dihydroxy-10-anthrone (2.26 g) and 4-benzyloxybenzoyl chloride (8 g) obtained in Synthesis Example 1, (2), the reaction was carried out in the same manner as described in Synthesis Example 1, (3). The crude solid (3.5 g) was chromatographed on silica gel (Wakogel C-200, a trade name, mfd. by Wako Pure Chemical Industries, Ltd.) with n-hexane/methylene chloride [4/1→2/1→1/1 (v/v)] as eluent to give 1.6 g of 1,2,10-tris(4-benzyloxybenzoyloxy)anthracene as yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](S(C)=O)[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH2:43])=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH:43][C:22]1[N:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Solvent: C1COCCO1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(NCC4CCCN4C(=O)OC(C)(C)C)n3)s2)o1

Procedure:
This material is prepared from 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) and 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester by an analogous procedure to Example 42 but replacing DMF by dioxane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:38])([F:37])[F:27])=[CH:30][CH:31]=3)=[C:19]([CH:23]([CH3:24])[CH3:25])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.70 g (1.99 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 30 ml of tetrahydrofuran and cooled to −78° C. 5.25 ml (2.62 mmol) of a freshly prepared 0.5 M solution of [4-(trifluoromethyl)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is stirred briefly at −78° C. and then warmed to 0° C. After about 30 min, the mixture is hydrolyzed with sodium bicarbonate solution, diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified a little at a time by preparative HPLC (method 12). This gives 0.635 g (64% of theory) of the title compound.
Reaction SMILES: [C:1](CC[NH-])#N.[CH3:6][NH:7][C:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15])=[N:9][CH3:10]>>[NH:9]1[CH2:10][CH2:1][CH2:6][N:7]=[C:8]1[CH2:11][CH2:12][NH:13][C:14]([C:16]1[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)=[O:15]
Reactant: CN=C(CCNC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C)NC
Reactant: N#CCC[NH-]
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCC1=NCCCN1

Procedure:
Compound 274 was synthesized from cyanoethylamide 242 as described above for compound 270 using 1,3-propylamine (6 ml). ES MS: 364.37 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH:13]C(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]#[N:13])[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)(C)NC(=O)C1CCN(C(=O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC1CCN(C(=O)CCl)CC1
Temperature: 55 °C
Yield: 97 %

Procedure:
To a solution of 1-(2-chloroacetyl)-N-(1,1-dimethylethyl)-4-piperidinecarboxamide (26.1 g, 0.10 mol) in N,N-dimethylformamide (35 mL) was added phosphorus oxychloride (18.8 g, 0.123 mol) dropwise over 30 minutes while allowing the temperature of the reaction mixture to rise to 37° C. The reaction mixture was heated at 55° C. for 1 h and then was slowly added to water (about 150 g) cooled with ice to maintain a temperature of about 10° C. The pH of the reaction mixture was adjusted to 5.5 with 50% NaOH aqueous solution. The mixture was extracted with dichloromethane (4×100 mL), and the combined extract was concentrated under reduced pressure to give 18.1 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)C1CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CC2)nn1
Yield: 75 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using cyclopropanecarbonyl chloride instead of methoxyacetyl chloride, to the title compound (185 mg, 75%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)=[CH:5][N:4]=1.O1CCOCC1>Cl>[CH3:16][C:13]1[S:12][C:11]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)=[N:15][N:14]=1
Reactant: COc1ncc(-c2nnc(C)s2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nnc(-c2c[nH]c(=O)[nH]c2=O)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
2,4-bis(methyloxy)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine (Prep. 12, 311 mg, 1.305 mmol) was suspended in hydrochloric acid 4M in dioxane (4 ml, 16.00 mmol) and the mixture stirred at 90° C. for 4 h. Solvent was removed under reduced pressure, to give title compound (334 mg, 1.303 mmol). Crude was used in the following step without any further purification.