Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][C@@H:20]1[CH2:33][C@@H:23]2[O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][C@@H:22]2[C@H:21]1/[CH:34]=[CH:35]/[C@@H:36]([O:49]C1CCCCO1)[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=1>CO>[OH:19][C@@H:20]1[CH2:33][C@@H:23]2[O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][C@@H:22]2[C@H:21]1/[CH:34]=[CH:35]/[C@@H:36]([OH:49])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: CO
Solvent: O
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) was add to a stirred solution of (8aR,9R,10R,11 aS,Z)-10-((tetrahydro-2H-pyran-2-yl)oxy)-9-((3R,E)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (14.0 g, 23.0 mmol) in methanol (150 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (200 mL), and the methanol was removed under reduced pressure. The residue was extracted with ethyl acetate (200 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 15.0 g of the crude product. The crude product was subjected to further purification by flash column chromatography to obtain 8.2 g of the title compound as a solid. DSC analysis showed that the solid contained two crystalline forms (mp 92˜97° C. and mp 113˜118° C.) The solid was recrystallized from a mixture of hexane and ethyl acetate to give 7.3 g of title compound as a single crystalline form (mp 113˜118° C.). The x-ray powder diffraction pattern of crystalline title compound (mp 115˜120° C.) has characteristic peaks expressed in degrees 2θ at approximately 10.7, 12.1, 13.4, 14.5, 14.8, 16.0, 16.6, 17.7, 18.4, 18.5, 19.4, 20.5, 21.0, 22.0, 22.4, 23.3, 24.6, 24.7, 25.1, 28.9, 29.9, 37.9, 44.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:24]1
Reactant: CC1CNCC1CN
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)CC1CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.21 g) and DBU (0.26 g) was refluxed for an hour and then stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.45 g) as pale yellow powder, mp 228°-232° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([I:11])[S:10][C:3]=23)=[CH:21][CH:20]=1
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccnc3cc(I)sc23)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 32 %

Procedure:
Related methodology was described in WO 2005/121125. A stirred mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (1.48 g, 5.00 mmol, prepared according to Ragan, J. A. Org. Proc. Res. 2003, 7, 676), cesium carbonate (2.44 g, 7.50 mmol), and DMF (50 mL) was heated to 135° C. under nitrogen with an attached reflux condenser. Next a solution of 6-chloropyridin-3-ol (0.972 g, 7.50 mmol) in DMF (20 mL) was added dropwise by syringe (2 mL approx every 5 min over a period of 50 minutes). The reaction was heated for 4 hours more after addition was complete. The reaction was left stirring at room temperature for 18 hours for convenience. The dark mixture was partitioned between EtOAc (100 mL) and water (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (50 mL). The combined organic phases were washed with water (3×200 mL), brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by Biotage Flash 40M, eluting with 20% EtOAc/hexanes (1 L) followed by 1:1 EtOAc/hexanes (1 L). The product was obtained as a beige solid (628 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 7.43 (d, J=9 Hz, 1H), 6.54 (d, J=6 Hz, 1H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCOCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[C:1]([Br:5])[Br:2])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL methylene chloride was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL methylene chloride in a 1-L rb flask with ice bath cooling over 1.75 h. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formylpiperidine (from Step B2 above) in 100 mL methylene chloride was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL methylene chloride and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes until the total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% sodium bicarbonate, 300 mL water (2×), and 150 mL brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 53.5 g crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0˜15% ethyl acetate in hexanes) gave 21.595 g title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[C:40]([O:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45](=[O:49])[CH2:46][N:47]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CC(=O)OC(C)(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added sarcosine tert butyl ester hydrochloride (84 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 577 (M+H).
Reaction SMILES: [Mg].II.Cl[CH2:5][CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10].BrCCBr.[CH2:16]=[O:17].S(=O)(=O)(O)O>O1CCCC1>[CH3:11][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][CH2:16][OH:17]
Reactant: C=O
Reactant: CCCCC(C)CCl
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCC(C)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium turnings (2.0 g, 82.3 mmol) are etched with iodine, and 1 ml of a solution of 96% 1-chloro-2-methylhexane (11 g, 78.5 mmol) in tetrahydrofuran (10 ml) is added at 60° C. The reaction is started by the addition of 1,2-dibromoethane (0.2 ml), then the rest of the solution of 1-chloro-2-methylhexane is added dropwise. After dilution with tetrahydrofuran (15 ml) the mixture is stirred under reflux for 2.5 h. Gaseous formaldehyde is passed through the solution, whose temperature is kept at from 40° C. to 50° C. The mixture is stirred for a further 1 h at room temperature, then 30% sulfuric acid (10 ml) is added to hydrolyze the Grignard compound. The mixture is steam distilled and the distillate is extracted several times with ether. The extract is washed with sodium chloride solution, dried over sodium sulfate, and evaporated down.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)=[CH:4][CH:5]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: C=Cc1ccncc1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC1CCN(CCc2ccncc2)CC1)c1ccccc1

Procedure:
A mixture of 4-vinylpyridine (578 mg.), 4-benzamidopiperidine (1.02 g.), acetic acid (330 mg.) and methanol (5 ml.) was refluxed for 8 hours, cooled, and evaporated. The residue in water was basified with potassium carbonate and the resulting solid was collected. Recrystallisation from aqueous ethanol gave the product (1.24 g.) m.p. 193°-5° C. (Found: C, 73.3; H, 7.4; N, 13.3. C19H23N3O requires C, 73.75; H, 7.4; N, 13.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:18][C:19]1[N:20]=[C:21]([CH2:25][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3cccc(C)n3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[S:23])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 79.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-n-propylphenyl)-1H-pyrazol-3-yl]ethanone (0.157 mmol, 40.5 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.157 mmol, 33.1 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (56.2 mg, yield 79%).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Br:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1>CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:5][C:3](=[O:4])[CH:2]([C:6]3[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=3)[C:20]=2[CH:21]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CO
Product: CC(C)c1ccc(C2C(=O)Oc3ccc(Br)cc32)cc1
Yield: 30 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 4-bromophenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 30%. Melting point: 157-158° C. (methanol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)ccc2Cl)n1
Temperature: 150 °C
Yield: 42 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2,5-dichlorobenzoyl chloride (0.111 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.031 g (42% yield) of pure product: MS (ES) m/z 479 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cccnc1Oc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccnc1Oc1ccc(C#N)cc1
Yield: 32.2 %

Procedure:
A solution of 2-(4-Cyano-phenoxy)-nicotinic acid ethyl ester (0.90 grams, 2.44 mmole) in methanol (10 ml) and potassium carbonate (1.01 grams, 7.33 mmole) was refluxed for 20 minutes. The mixture was diluted with 100 ml water, acidified to pH 1 and filtered to give a solid (0.200 g). MW 254; MS (m/e) 254 (M+).
Reaction SMILES: CN(C)CC[N:5]1[C:13]2[CH:12]=[CH:11][C:10](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:9]3[C:25](=[O:32])[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:31]=4[C:7]([C:8]=23)=[N:6]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>N1C=CC=CC=1>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:10]1[CH:11]=[CH:12][C:13]2[NH:5][N:6]=[C:7]3[C:31]4[CH:30]=[N:29][CH:28]=[CH:27][C:26]=4[C:25](=[O:32])[C:9]=1[C:8]=23
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCN(C)C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1ccncc1-3
Reaction time: 1 h

Procedure:
A solution of 2-[2-(dimethylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6 (2H)-one of Example 2 (0.463 g) and 2-(dimethylamino)ethylamine (0.80 mL) in dry pyridine (4.63 mL) is heated at 80° C. for 1 h, 30' under a nitrogen blanket. The solution is then concentrated to dryness and the dark residue obtained is partitioned between brine (30 mL) and ethyl acetate (4×25 mL). The combined organic solutions are dried over Na2SO4 and concentrated to about 3 mL. After addition of n-hexane (12 mL) and stirring for one hour the precipitate is collected by suction and dried at 40° C. under vacuum to give 2-[2-(dimethylamino)ethyl)]5-[[2-(dimethylamino) ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.23 g).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12][N:13]2[CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:23].CO>CN1C(=O)CCC1>[CH:16]1([N:13]2[C:14]3[C:9](=[CH:8][C:7]([F:23])=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:15]=3)[C:10](=[O:22])[C:11]([C:19]([OH:21])=[O:20])=[CH:12]2)[CH2:17][CH2:18]1
Reactant: NCCO
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(O)c1cn(C2CC2)c2cc(NCCO)c(F)cc2c1=O
Temperature: 105 °C
Reaction time: 22 h

Procedure:
To a solution of ethanolamine (55.5 ml) in N-methyl pyrrolidinone (500 ml) at 95° C., 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105° C. and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60° C. and poured into MeOH (800 ml). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 29A and Intermediate 29B (49 g ) in a 1:1 ratio.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[C:3]([C:4](=[O:6])[CH3:11])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: C[Mg]Br
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloronicotinic acid (B-1) (7.88 g, 50.0 mmol) in THF (100 mL) was added methyl magnesium bromide (42 mL, 3-Methyl ether solution) dropwise under 0° C. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 0.5 h and then at room temperature overnight. The reaction mixture was added into ice/water (150 mL), and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound 1-(2-chloropyridin-3-yl)ethanone (B-2). MS (m/z): 156 (M+1)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13].O.CN(C)[CH:24]=[O:25]>>[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[C:17]([CH:24]=[O:25])=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(-n2[nH]c(C)c(C=O)c2=O)cc1C
Temperature: 100 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20° C. After the addition, the mixture was heated at 100° C. for 2 h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18 h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. 1H NMR (300 MHz, d6-DMSO) δ 9.63 (s, 1H), 7.47 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 2.23 (d, J=8.2 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[N+](C1C=CC=CC=1S([N:20]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1)(=O)=O)([O-])=O.C([BH3-])#N.[Na+]>>[N:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[CH:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=Cc1cc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1ccc(CNCc2ccc(CN(Cc3cc[nH]n3)C3CCCc4cccnc43)cc2)nc1
Yield: 64.3 %

Procedure:
Using general procedure A: Reaction of 3-pyrazolecarboxaldehyde (85 mg, 0.88 mmol) and N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (320 mg, 0.589 mmol) with sodium cyanoborohydride (55 mg, 0.883 mmol) followed by purification of the crude material by column chromatography on silica gel (5% methanol in dichloromethane), gave the desired product (166 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O.O>[CH3:34][O:33][C:31](=[O:32])[CH2:30][N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 2.0 g (6.4 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.9 g (8 mmol) of potassium t-butoxide in 30 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 0.7 ml (7.5 mmol) of methyl bromoacetate was added. The mixture was stirred for 5 min, diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography gave a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH:36]=[CH:35][C:33]([NH2:34])=[N:32][C:30]1=[O:31]>>[O:31]=[C:30]1[N:32]=[C:33]([NH:34][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH:35]=[CH:36][NH:29]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4cc[nH]c(=O)n4)s3)c2cc1OC
Yield: 11 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and cytosine (11.1 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (2-oxo-1,2-dihydro-pyrimidin-4-yl)-amide (5.6 mg, 11.0%) as a white solid. MS m/z 509 (M+1).