Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[CH3:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1cccc(Cn2ncc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
A solution of 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (1.00 g, 2.54 mmol) in MeOH (25 mL) was cooled to 0° C. Zinc dust (0.829 g, 12.7 mmol) was added and the mixture was stirred for 10 minutes. Saturated aqueous NH4Cl was added (25 mL) and the mixture was stirred vigorously for 2 hours at 0° C., then warmed to ambient temperature and stirred for an additional 2 hours. Additional saturated aqueous NH4Cl was added (12.5 mL) and the mixture was stirred at ambient temperature for an additional 2 hours. The mixture was diluted with MeOH and filtered. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The mixture was extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (2 to 20% IPA/CHC13) to afford 0.428 g (70%) of the product as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH:6]([OH:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1.[CH3:28][CH:29]1[CH2:35][C:34](=[O:36])[O:33][C:31](=[O:32])[CH2:30]1.[Li+].[OH-].C1COCC1.O>O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][CH:6]([OH:23])[CH2:5][O:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:34]([CH2:35][CH:29]([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[O:36])[CH2:13][CH2:12]1
Reactant: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC1CC(=O)OC(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol (75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225 uL 0.2M /NMP) to get a product containing both esther and amide. After evaporation of the mixture it was treated with 3 eq 0.5M LiOH in (THF/water 1:4) for two hours at 80° C. to hydrolyse the esther. The reaction mixture was diluted with more water (2 mL) and the desired product was extracted with 5×500 uL EtOAc which was evaporated to dryness.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH2:25]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (21.4 g) and 10% Pd—C (3.17 g) in EtOH (400 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The solid was washed with THF-hexane to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10.90 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23](C5CCN(C(OC(C)(C)C)=O)CC5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([CH:43]1[CH2:46][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]1)=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[NH:22][C:23]([CH:43]5[CH2:44][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46]5)=[N:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CN(C(=O)OC(C)(C)C)C2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 182.3, except tert-butyl 3-formylazetidine-1-carboxylate was used in place of tert-butyl 4-formylpiperidine-1-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C:19]4([CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)[O:18][C:17]3=[O:28])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][C:3]1=[O:29].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3]>C(O)(C)C>[OH:27][CH:24]1[CH2:23][CH2:22][C:19]2([O:18][C:17](=[O:28])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:29])[CH:4]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)[CH2:26][CH2:25]1
Reactant: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC(O)CC2)OC1=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-1-oxa-3-aza-spiro[5.5]undecane-2,9-dione (130 mg), aluminum triisopropoxide (100 mg), and isopropanol (2 mL) is stirred at 140° C. for 1 h. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to afford the title compound in a ca. 1:1 mixture of cis- and trans-isomer. Yield: 72% of theory; LC (method 2): tR=1.49 and 1.51 min; Mass spectrum (ESI+): m/z=397 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24](F)(F)[C:25]([F:28])([F:27])I.CN(C=O)C>C(OCC)(=O)C.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:25]([F:28])([F:27])[CH2:24][C:23]([F:32])([F:31])[F:22])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(C(F)(F)CC(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.06 g), copper powder (0.95 g), heptafluoro-1-iodopropane (2.96 g) and DMF (14 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and an insoluble matter was filtered with Celite and washed with ethyl acetate. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-pentafluoropropyl-3-trifluoromethyl-1H-pyrazole (0.80 g).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].CCOCC>C(#N)C.[Cu]I>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCCCCOCCCCCCBr
Reactant: Brc1cnccn1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CC#N
Product: BrCCCCCCOCCCCC#Cc1cnccn1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of bromopyrazine (1.64 g), 6-[(6-bromohexyl)oxy]-1-hexyne (2.69 g) N,N-dicyclohexylamine (1.88 g), BTPC (130 mg) and copper (I) iodide (13 mg) in acetonitrile (30 ml) was stirred at 22° under nitrogen for 1 h. Ether (150 ml) was added, the mixture filtered and evaporated in vacuo to an oil which was purified by FCC eluting with hexane-ether (3:2→1:1) followed by ether to give the title compound as a dark yellow oil (2.79 g), t.l.c. (ether) Rf 0.5.
Reaction SMILES: C([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[OH-].[Na+].O1CCCC1>CO>[CH2:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([OH:17])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined with aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis was complete. The mixture was then treated in a manner similar to preparation 104. Concentration of the filtrate netted 0.79 g (90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+ 206.3, 207.3.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[NH2:20][C:21]1[C:29]2[NH:28][CH:27]=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[NH:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:29]=2[N:28]=[CH:27]1
Reactant: Nc1cccc2nc[nH]c12
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2[nH]cnc12
Yield: 63.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 130 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 113 mg of 4-aminobenzimidazole hydrochloride and 127 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 80 μl of pyridine and 2.0 ml of N,N-dimethylformamide. 112 mg of N-(1H-benzimidazol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:13]1([N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C([O-])(=O)C.[K+].C(O)C>[C:13]1([N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NN(c2ccccc2)c2ccccc2)cc1

Procedure:
p-nitrobenzaldehyde and N,N-diphenylhydrazine hydrochloride were heated in the presence of potassium acetate as a catalyst in ethanol to obtain p-nitrobenzaldehyde-N,N-diphenylhydrazone.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:1]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=3)[N:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(NCc3cccs3)c2c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3cccs3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-thienylmethylamino]-6-dimethylaminoquinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.43 g of the title compound is obtained, m.p.: 171° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[CH2:17]([N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:19][N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)N1CCCN1C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thirty four grams of benz[cd]indol-2(1H)-one is added with stirring to 500 ml of dry dimethylformamide. Ten grams of 50% sodium hydride (in oil) is added in portions, the reaction is stirred at room temperature for 1 hour, and then on a steam bath for one hour. A deep red/brown solution results. One hundred twenty grams of 1,3-dibromopropane is added in one portion, the red color disappears and a white suspension appears. The mixture is stirred and heated on a steam bath for 16 hours, concentrated to dryness and the residue dissolved in 250 ml of dichloromethane. The solution is passed through hydrous magnesium silicate and rinsed with 100 ml of dichloromethane; on standing at room temperature crystals formed. The solution is cooled to 0° C., collected and washed with 100 ml of hexane. After numerous fractional crystallizations, 12.6 g of (Bs) 1,1'-(1,3-propanediyl)bisbenz[cd]indol-2(1H)-one, mp. 161°-162° C. and (Bt) 1.4 g of 1-(3 -bromopropyl)benz[cd]indol-2(1H)-one, mp. 74°-76° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH3:13])=[O:11].S(Cl)([Cl:16])=O>>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([Cl:16])=[O:8])=[CH:6][N:1]=1)([O:12][CH3:13])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Product: COC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
In step A, the carboxylic acid functionality of the appropriate 2,5-pyridinedicarboxylic acid, 2-methyl ester (1) (Nippon Kagaku Zasshi, 1967, 88, 563) is converted to its acid chloride using techniques and procedures well known and appreciated by one of ordinary skill in the art, using a reagent such as thionyl chloride, to provide the corresponding 6-carbomethoxynicotinoyl chloride (2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[C:16]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][CH:30]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(OC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Chlorobenzene (7 ml) was added to 4-chloro-6,7-dimethoxyquinazoline (2.5 g) and 4-hydroxyphenyl benzoate (4.78 g), and the mixture was stirred at 140° C. overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by filtration and was washed to give the title compound (3.49 g, yield 78%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:8]([S:12][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(C=O)c(Br)c1
Temperature: 50 °C

Procedure:
To 2-bromo-4-fluorobenzaldehyde (150 mg, 0.74 mmol) in methanol (2 mL) was added sodium thiomethoxide (80 mg, 1.1 mmol). The reaction mixture was heated to 50° C. for 1 hour. After cooling, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and used as such.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[S:9]1)=[O:7])C.Cl>O.CCO>[CH:21]1[C:11]2[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:8]([C:6]([OH:7])=[O:5])[S:9][C:10]=2[CH:24]=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: CCOC(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Yield: 83.8 %

Procedure:
A solution of KOH (1.64 g, 29 mmol) in water (6 ml) was added to 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid ethyl ester (2.26 g, 7 mmol) in EtOH (16 ml) and the mixture heated to reflux for 2 hr. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated to give 1.65 g (80%) of 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid as a yellow foam. 1H NMR (DMSO) δ 12.55 (1H, br s), 11.70 (1H, s), 7.74-7.82 (1H, m), 7.00-7.57 (7H, m), 5.17 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH:18]2[CH2:21][CH2:22][CH2:23][N:17]2[C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluorophenol (217 ul, 2.002 mmol), N-tert-butoxycarbonyl prolinol (403 mg, 2.002 mmol), and Ph3P (630 mg, 2.403 mmol) in THF (7 mL) was added DIAD (477 ul, 2.423 mmol) at room temp. The resulting mixture was stirred for 6 hr at room temp and then overnight at 70° C. The mixture was concentrated in vacuo and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 549.4 mg (73%) 1-bromo-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzene as an oil. 1H-NMR (400 MHz, CDCl3) δ1.46 (s, 9H), 1.85 (br m, 1H), 1.90-2.10 (br s, 3H), 3.30-3.47 (m, 2H), 3.85, 4.04 (br s each, 1H), 4.11-4.20 (m, 2H), 6.82-6.98 (m, 1H), 7.13-7.26 (m, 2H); MS (FAB) m/z 374 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNCCN(C)C
Product: CC1Cc2ccc(-c3ccnc(C(=O)N(C)CCN(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and N,N,N′-trimethylethylenediamine (Aldrich, Cat. No. 127124). LCMS (M+H)+: m/z=544.2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:7]1[C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:8]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
6-Bromo-4-fluoro-2-nitroaniline was prepared using an adaptation of the method of Mitchell et al., J. Org. Chem. 44: 4733 (1979). To a solution of 4-fluoro-2-nitroaniline (500 mg, 3.2 mmol) in dry DMF (16 mL) under N2 was added dropwise a solution of N-bromosuccinimide (570 mg, 3.2 mmol) in dry DMF (16 mL). The reaction was allowed to stir 24 h. The solution was then poured into 100 mL H2O and this aqueous phase extracted with 4×25 mL CH2Cl2. The combined organic phases were washed with 3×4 mL H2O and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a brown oil which crystallized on standing. 642 mg (85.4%). 1H NMR (CDCl3) δ 6.51 (br s, 2H NH2), 7.58 (dd, JH4-3 -3 Hz, JH4-F =6.5 Hz, H-4), 7.92 (dd, JH3-F =3 Hz, JH3-F =8.7 Hz, H-3).
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C.C1COCC1>[F:20][C:18]1[CH:19]=[CH:12][C:13]([C:14]#[N:15])=[C:16]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][S:2]2(=[O:8])=[O:1])[CH:17]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of 1,1-dioxo[1,2]thiazinane (8.84 g, 65.4 mmol) in DMF (20 mL) and THF (10 mL) was added portion-wise sodium hydride (1.65 g, 65.5 mmol, 95%). After stirring for 30 min, 2,4-difluorobenzonitrile (10.0 g, 72 mmol) was added and the mixture was stirred at 90° C. for 2.5 h. The mixture was cooled and concentrated and the residue was purified by flash chromatography eluting with 0%-10% EtOAc/hexane to give the title compound as white needles (1.37 g, 8% yield). 1H-NMR (500 MHz, CDCl3) δ: 7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4 Hz), 7.15-7.12 (1H, m), 3.72 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz), 2.40-2.35 (2H, m), 2.05-2.01 (2H, m). LCMS [M+H]+ calcd for C11H12N2FO2S: 255.06; found: 255.19.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([CH2:9][C:10]#[N:11])=[O:8])([O-:3])=[O:2].[C:15]1([N:21](C2C=CC=CC=2)[CH:22]=N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([C:9](=[CH:22][NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]#[N:11])=[O:8])([O-:3])=[O:2]
Reactant: N#CCC(=O)c1cccc([N+](=O)[O-])c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 2-(3-nitrobenzoyl)acetonitrile (13.75 g, 72.3 mmol) and N,N-diphenylformamidine (14.2 g, 72.3 mmol) in xylene (200 ml) was heated at reflux under nitrogen atmosphere. After 3 h, the reaction mixture was cooled to room temperature and diluted with xylenes to give 2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (15.7 g) as a yellow solid.