Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])(=[O:22])[CH3:21]
Reactant: CC(=O)NCCN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: CC(=O)NCCn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
4.6 g (0.018 mol) of 6-phthalimido-2,5-hexanedione and 1.8 g (0.018 mol) of 2-(acetylamino)-ethylamine are stirred in 120 ml of acetic acid at 80° C. for 4 hours. Working up is carried out as described in Example 1:
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:17])=[C:9]([O:15]C)[C:10]([O:13]C)=[N:11][CH:12]=2)[CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:17])=[C:9]([OH:15])[C:10](=[O:13])[NH:11][CH:12]=2)[CH:2]=1
Reactant: COc1ncc(-c2cccc(-c3ccccc3)c2)c(F)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 5-(biphenyl-3-yl)-4-fluoro-2,3-dimethoxypyridine (15 mg, 0.048 mmol) in CH2Cl2 (1 mL) was added a methylene chloride solution of BBr3 (1 M, 0.97 mL). After 24 h of stirring at room temperature, the reaction mixture was concentrated and the resulting residue was stirred in 3 N aqueous HCl as a suspension for 1 h. Concentrated, triturated with MeOH and the precipitated solid was collected by filtration, washed with MeOH and dried in vacuo to afford 12 mg (88%) of 5-biphenyl-3-yl-4-fluoro-3-hydroxypyridin-2(1H)-one as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.12 (s, 1H), 9.45 (s, 1H), 7.77-7.69 (m, 3H), 7.66-7.64 (m, 1H), 7.54-7.37 (m, 5H), 7.23 (d, J=8.8 Hz, 1H). High resolution mass spec (FT/ICR) calc (M+H)+=282.0925 found 282.0921.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][O:2][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[N:9][NH:10]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C([O-])O
Reactant: Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Yield: 87 %

Procedure:
6-Carboxy-3-methyl-1H-indazole (359 mg, 2.11 mmol) was dissolved in methanol (50 ml), and concentrated sulfuric acid (0.1 ml) was added. The mixture was heated under reflux for 22 hr. After cooling, a saturated aqueous sodium hydrogencarbonate solution was added and the methanol was distilled away under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (340 mg, 87%) as brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23].CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:23][CH2:22][CH2:21][NH2:24])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(NC(=S)NCCN)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate (7.0 g) in CH2Cl2 (600 mL) is added dropwise over 45 minutes to ethylenediamine (8 mL) in solution in CH2Cl2 (200 mL). The mixture is stirred for 3 hours at room temperature. Ether (150 mL) is added to the suspension and the mixture is stirred for 10 minutes at room temperature. The solid is filtered. The filtrate is rotary evaporated, the residue diluted with CH2Cl2 and reprecipitated with ether to afford a second crop. The combined solids are dried overnight in vacuo to afford N-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].Br[C:10]1[CH:11]=[CH:12][C:13]2[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[CH:24]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:3]1([C:1]#[C:2][C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Temperature: 80 °C
Reaction time: 17 h
Yield: 69.2 %

Procedure:
A mixture of ethynylbenzene (511 mg, 5.00 mmol), methyl 7-bromo-2,3-dihydro-1-benzooxepine-4-carboxylate (708 mg, 2.50 mmol), dichlorobis(triphenylphosphine)palladium (176 mg, 0.25 mmol), copper iodide (48 mg, 0.25 mmol) and triethylamine (15 ml) was stirred at 80° C. for 17 hours. The reaction mixture was concentrated under reduced pressure and was mixed with ethyl acetate (70 ml), and the resulting mixture was washed successively with 1 N hydrochloric acid (5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 35 g, ethyl acetate/hexane=1/19). The objective fractions were concentrated under reduced pressure and were mixed with diisopropyl ether, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylate (525 mg, 1.73 mmol, 69%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH2:34](Br)[CH:35]=[CH2:36].Cl>CN(C)C=O.O>[CH2:36]([N:18]1[C:19]2[C:24](=[CH:23][C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])=[CH:21][CH:20]=2)[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:17]1)[CH:35]=[CH2:34]
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Sodium hydride (0.048 g of a 60% dispersion in oil) was added to a stirred solution of methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (0.5 g) in N,N-dimethylformamide (5 ml), under an atmosphere of nitrogen. After 0.5 hr, allyl bromide (0.14 g) was added and stirring continued for 3 hr. The solution was acidified with 1M hydrochloric acid (10 ml), diluted with water (20 ml), extracted with ethyl acetate (twice), and the organic phase was washed with water (4 times), brine, and dried (MgSO4). The solvent was evaporated to give an oil which was purified by flash chromatography, eluting with 2:1:1 hexane:methylene chloride:ethyl acetate, to give methyl E-4[1-allyl-5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl)-3-methoxybenzoate (0.36 g, 66%) as a white foam; partial NMR (250 MHz, DMSO-d6) 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2 H, CH2CH2CH3), 1.99(s, 3H, CCH3), 3.11(m, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.90(s, 3H, OCH3), 4.06(s, 2H, ArCH2Ar'), 4.77(br d, J=5.3 Hz, 2H, NCH2CH:C), 5.00-5.16(m, 2H, olefinic H), 6.0(m, 1H, olefinic H), 7.94(br t, 1H, NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:32])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A mixture of 0.37 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl) phenylamino)propyloxy)benzene, 0.1 ml of methyl iodide, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at 50° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of ethyl acetate. The combined ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.26 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methyl(4-(trifluoromethyl)phenyl)amino)propyloxy)benzene (68% yield), nD25.5 1.5593.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.O1CCOCC1>Cl>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(N)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-chloro-4-methoxy-2-nitrophenyl)-acetamide (2 g, 8.2 mmol) in 5 N HCl (20 mL) is added 1,4-dioxane (10 mL), and the mixture is stirred at 60° C. for 1.5 hours. The reaction mixture is concentrated and partitioned between EtOAc/2 N NaOH. The aqueous layers are washed with EtOAc (3X), brine, dried (MgSO4), adsorbed onto silica gel, and chromatographed (70% EtOAc/hexanes) to provide an orange powder.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)c2c(c1)CCCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Br)c2c(c1)CCCC2

Procedure:
5,6,7,8-tetrahydro-4-bromo-2-naphthol (7 g, 30.8 mmol; step c) in example 29) is dissolved in dry acetone (100 ml) and treated with K2CO3 (15 g, 0.11 mol) and methyliodide (7.25 ml, 0.13 mmol). The reaction mixture is kept at RT over night. After filtration and removal of the solvent the residue is purified over silica gel (methylene chloride/cyclohexane 1/1) affording the compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[S:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([N:18]1[CH2:19][CH2:20][S:16][C:17]1=[S:21])=[O:8])([O-:3])=[O:2]
Reactant: S=C1NCCS1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)N1CCSC1=S
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To 15 ml of dimethylformamide were dissolved 3,5-dinitrobenzoyl chloride (2.5 g) and 1,3-thiazolidine-2-thione (1.3 g). To the solution was added dropwise a solution of triethyl amine (1.2 g) and dimethylformamide (2 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 5 hours. The reaction mixture was filtered and the solvent was removed at a reduced pressure. To the residue was added water and the insolubles were filtered off. The filtrate was washed with cold methanol and then with ether to obtain crude crystals. Recrystallization from toluene gives 2.4 g of the desired compound as yellow needle crystals (yield 76.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Br[CH2:23][C:24]1[S:28][C:27]([C:29]#[N:30])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])[O:8][CH2:23][C:24]1[S:28][C:27]([C:29]#[N:30])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: N#Cc1ccc(CBr)s1
Product: N#Cc1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)s1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 5-bromomethyl-thiophene-2-carbonitrile [CAS 134135-41-4]. MS (ES+) m/e 414.2
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[NH:23][C:22](=O)[C:21]=2[CH:31]=1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[N:23]=[C:22]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:21]=2[CH:31]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cscc2Nc2ccc(F)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cscc3Nc3ccc(F)cc32)CC1

Procedure:
To a stirred mixture of 14.0 g. of N-methylpiperazine, 3.4 ml. of titanium tetrachloride and 6 ml. of anisole in 60 ml. of toluene is added a mixture of 6.7 g. of N-methylpiperazine and 5.6 g. of 7-fluoro-4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one in 6 ml. of toluene. The mixture is treated as described in Example 1, giving the desired product as a tan solid, m.p. 224°-227° C. (dec.).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[CH3:5][C:6]([CH3:32])([CH2:7][C:8]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:10])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)N2CCOCC2)cn1)c1ccccc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added morpholine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (117 mg, 63% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][CH:9]1[CH2:17][C:16]2[C:11](=[C:12]([CH3:20])[C:13]([CH3:19])=[C:14]([OH:18])[CH:15]=2)[NH:10]1>C(O)=O>[OH:18][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([CH3:20])[C:13]=1[CH3:19])[N:10]([CH:1]=[O:3])[CH:9]([CH3:8])[CH2:17]2
Reactant: Cc1c(O)cc2c(c1C)NC(C)C2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1c(O)cc2c(c1C)N(C=O)C(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
Acetic anhydride (0.76 mL, 8.1 mmol) was added to formic acid (4 mL), and the mixture was stirred at room temperature for 15 minutes. To this solution was added 2,3-dihydro-2,6,7-trimethyl-1H-indole-5-ol (0.71 g, 4.0 mmol), and the mixture was stirred at room temperature for 5 hours. Ice was added to the reaction mixture, and precipitated solid was filtered to obtain 0.40 g of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: COc1ccc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 49% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH:17]=[CH2:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1>[Pd].C(O)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][CH3:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C=Cc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Yield: 65.2 %

Procedure:
A solution of 3-amino-9-vinylbenzo[f]quinazolin-1(2H)-one (0.060 g, 0.25 mmol) and 10% palladium on carbon (0.10 g) (Aldrich) in ethanol (200 ml) was shaken under hydrogen (40 psi), for 1 hour and then filtered through celite and concentrated in vacuo. The residue was suspended in ethanol, filtered, and dried at 85° C. under reduced pressure to give 3-amino-9-ethylbenzo[f]-quinazolin-1(2H)-one (0.039 g) as a white solid. 1H NMR (DMSO-d6, 200 MHz) δ: 1.26 (t, J=7 Hz, 3H, CH3), 2.76 (q, J=7 Hz, 2H, CH2), 6.49 (br s, 2H, NH2), 7.21 (d, J=9 Hz, 1H, Ar), 7.31(dd, J=8, 2Hz, 1H, Ar), 7.77(d, J=8 Hz, 1H Ar), 7.96 (d, J=9 Hz, 1H, Ar), 9.47 (s, 1H, Ar), 11.08 (br s, 1H, NH). Mass spectrum (CI—CH4): 240 (M+1, 100%). Anal. Calculated for C14H13N3O.0.1H2O: C, 69.75; H, 5.52; N, 17.43. Found: C, 69.79; H, 5.53; N, 17.37.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:8])[CH2:15][S:12](=[O:14])(=[O:13])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CS(=O)(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (774 mg, 2.64 mmol) in anhydrous THF (10 mL) was added NaH (60% in mineral, 111 mg, 2.77 mmol). The mixture was stirred at room temperature for 5 hr. The reaction was monitored by LCMS for completion. H2O (1 mL) was added to quench the reaction followed by the addition of aqueous hydrochloric acid (1N, 50 mL) and EtOAc (50 mL). The organic layer was separated, and the water layer was extracted with 2×EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (689 mg, 100%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3cc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Yield: 88 %

Procedure:
The product of Example 432D (0.505 g, 0.927 mmol) was suspended in 1,4-dioxane (6 mL), treated with a solution of lithium hydroxide monohydrate (0.078 g, 1.85 mmol) in water (3 mL) at room temperature, then heated at 50° for one hour. The reaction was diluted with water (25 mL), adjusted to pH 1 with 1N aqueous HCl, and extracted with ethyl acetate (50 mL). The organic extract was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (0.433 g, 0.816 mmol, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.48 (s, 9 H) 2.98-3.23 (m, 1 H) 6.92 (d, J=8.09 Hz, 1 H) 7.36 (d, J=8.46 Hz, 2 H) 7.54 (d, J=8.82 Hz, 2 H) 7.59 (d, J=11.77 Hz, 1 H) 7.73 (d, J=8.09 Hz, 1 H) 7.89 (s, 1 H) 8.34-8.49 (m, 2 H) 9.61 (s, 1 H) 9.94 (s, 1 H). MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12]>C(O)=O>[CH:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: NC(CC(=O)O)c1ccccc1
Solvent: O=CO
Product: O=CNC(CC(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Formic acid (1.0 ml, 26.6 mmol) was added dropwise to 2.0 ml (21.4 mmol) of acetic anhydride in an ice bath. After that, the ice bath was removed, and the solution was stirred at 50° C. for 15 minutes. After allowing to stand for 15 minutes, the resulting solution was cooled again with an ice bath and was added dropwise to a solution of 586 mg (3.55 mmol) of (±)-3-amino-3-phenylpropanoic acid in 0.5 ml of formic acid previously cooled to a temperature not higher than 10° C. The mixture was stirred for 40 minutes as it was, and, when the solution became room temperature, it was stirred for 80 minutes more. The residue prepared by concentrating the reaction solution in vacuo was recrystallized from water to give 624 mg (3.23 mmol) of (±)-3-formylamino-3-phenylpropanoic acid in a yield of 91.0% (melting point: 127 to 128° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH2:10][CH3:11])([CH3:9])[O:8][C:4]=2[CH:3]=1.[C:14](Cl)(Cl)=[S:15].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:10]([C:7]1([CH3:9])[O:6][C:5]2[CH:12]=[CH:13][C:2]([N:1]=[C:14]=[S:15])=[CH:3][C:4]=2[O:8]1)[CH3:11]
Reactant: S=C(Cl)Cl
Reactant: CCC1(C)Oc2ccc(N)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)Oc2ccc(N=C=S)cc2O1
Yield: 94.5 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of 1.9 g (0.011 mole) of 5-amino-2-ethyl-2-methyl-1,3-benzodioxole with 2.4 g (0.021 mole) of thiophosgene and 6.2 g (0.045 mole) of potassium carbonate in 10 ml of water and 70 ml of chloroform yielded 2.3 g of (2-ethyl-2-methyl-1,3-benzodioxol-5-yl) isothiocyanate as an oil. The nmr spectrum was consistent with the proposed structure.