Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:41](=[O:42])[CH2:40][Cl:39])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Temperature: 4 °C
Reaction time: 25 h
Yield: 95.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (1.1 g, 2.5 mmol; prepared as described in Example 31-starting materials) was dissolved in a mixture methylene chloride (20 ml) and diisopropylethylamine (1.0 ml) under a nitrogen atmosphere. The solution was cooled in an ice/water bath to 4° C. and chloroacetyl chloride (0.2 ml, 2.63 mmole) was added. The reaction mixture was stirred cold for two 25 hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (1.14 g, 94.9%); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[O:8])(=[O:3])[NH2:2].[OH-].[Na+].O>C(O)C>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[N:13]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH3:23])[NH:9][C:7]2=[O:8])(=[O:3])[NH2:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccccc1-c1nc2c(C(N)=O)cccc2c(=O)[nH]1
Yield: 77.6 %

Procedure:
A stirred mixture of 3-carbamoyl-2-(2-ethoxybenzamido)benzamide (Preparation 18; 1 g, 0.003 mol) sodium hydroxide (0.61 g, 0.015 mol), water (30 ml) and ethanol (7 ml) was heated under reflux for 1 hour. The cool solution was washed with dichloromethane (3×30 ml), acidified to pH 1 with 2N hydrochloric acid and the resulting precipitate collected by filtration. The solid was suspended in saturated aqueous sodium carbonate solution (60 ml) and this suspension extracted with dichloromethane-methanol (98:2, 3×100 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue triturated with diethyl ether (50 ml) to give the title compound as a white solid (0.72 g, 78%), m.p. 252-254° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH3:33])[N:7]=3)[CH:17]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CNc1nccc(-c2sc(C(C)C)nc2-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol), methylamine (2.0 M in THF, 2.0 mL, 4.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (100 mg, 0.21 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H); m/z (ESI): 485.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1cnc2ccnn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: c1ccc(-c2nn3c(c2-c2cnc4ccnn4c2)CCC3)nc1
Yield: 26.2 %

Procedure:
To a microwave tube, add 6-bromo-pyrazolo[1,5-a]pyrimidine (0.175 g, 0.884 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (0.25 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol), 2M aqueous potassium carbonate (0.5 mL, 1.0 mmol) and dimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwave reactor set at 110° C., 50 Watts, 10 min with external cooling. Dilute the reaction mixture with diethyl ether (250 mL) and extract the product into 0.1M aqueous hydrochloric acid (450 mL). Make the aqueous solution basic by adding 5M aqueous sodium hydroxide (25 mL) and extract with dichloromethane (300 mL). Filter the organic layer and concentrate under reduced pressure. Recrystallize the resulting solid from ethyl acetate, filter, rinse with ethyl acetate, and dry at 100° C. under vacuum to obtain 70 mg (26%) of the title compound as a tan solid. MS (electrospray, m/z) 302.9 (M+1).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][OH:14])[CH2:8][CH3:9])=[CH:3][CH:2]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][O:14][C:22]2[CH:54]=[CH:53][C:25]([CH2:26][CH:27]3[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]3=[O:52])=[CH:24][CH:23]=2)[CH2:8][CH3:9])=[CH:5][CH:6]=1
Reactant: CCC(=NOCCO)c1ccc(-c2ccccc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 539 mg of 2-[1-(4-biphenylyl)propylideneaminooxy]ethanol (prepared as described in Preparation 38), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.09 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: C(O)(=O)C.Cl.Cl.[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>CC(C)=O>[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[O:21])[N:7]([C@@H:8]3[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]3)[C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1
Reactant: N[C@@H]1CCCNC1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(=O)N([C@@H]1CCCNC1)C2=O
Temperature: 27.5 °C

Procedure:
In a clean round bottom flask, 100 ml acetic acid, 50 gms 3-(R)-aminopiperidine dihydrochloride & 56.5 gms of 4-methylphthalic anhydride were charged. The reaction mass was refluxed & then cooled to 25-30° C. Acetone was added to the reaction mass & obtained solid was filtered. Acetone was added to the solid obtained & refluxed to get uniform slurry. The reaction mass was cooled to 25-30° C. & filtered. Wet wt 70 gms. In another round bottom flask, methylene dichloride, wet cake and water were charged. The reaction mass was basified & layers were separated. The organic layer was washed with water & concentrated upto half volume. Diisopropyl ether was added to the reaction mass to obtain the product. Dry wt 40 gms, HPLC purity=85%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[C:36]1([CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:42]([S:43]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)(=[O:45])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(S(=O)(=O)Cc6ccccc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and phenylmethanesulfonyl chloride. LCMS (M+H)+: m/z=639.2.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:32]N1C(=O)CCC1=O.CCOC(C)=O>ClCCl>[Br:32][C:8]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[NH:6][C:7]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2sccc2c1Br
Temperature: 23 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.06 g, 0.31 mmol) in dichloromethane (1 mL) was added TBAF (1M THF, 0.46 mL) followed by N-bromosuccinimide (NBS) (0.07 g, 0.4 mmol). The resulting mixture was allowed to stir at 23° C. for 16 h at which time the entire reaction mixture was placed on a silica gel column. Flash column chromatography (20% EtOAc in hexanes) affords one major peak containing a mixture of 4-bromo and 2,4-dibromo products. Separation of the desired product from the byproduct by RP-HPLC (10-100% gradient 0.1% formic acid in H2O to CH3CN over 10 min) afforded ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.03 g, 35% yield).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].I[CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].O>CN(C)C=O>[S:1]([CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]#[N:3]
Reactant: O=C1N[C@H](CI)[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
1.5 g of potassium thiocyanate were added at 75° C. with stirring to a mixture of 1.78 g of the product of Step A in 5 ml of dimethylformamide and the mixture was stirred for 31/2 hours and was poured into water. The mixture was vacuum filtered and the product was washed with water and dried. The product was empasted with hot isopropyl ether, vacuum filtered and dried to obtain 1.25 g of racemate of cis 4-thiocyanatomethyl-3-phthalimido-2-oxo-azetidine.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[C:50]([CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:55]1[CH2:56][CH2:57][CH:52]([C:50]([C:42]2[N:41]([CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=2)=[O:51])[CH2:53][CH2:54]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: O=C(c1nc2ccccc2n1Cc1ccccn1)C1CCNCC1
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(F)cc1
Agent: I
Product: COc1ccc(C2C=NN=N2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccccn2)CC1)c1ccc(F)cc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-fluorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide and 4-(1-(pyrid-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[N:11][OH:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C:9](=[N:11][OH:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[S:6]3(=[O:18])=[O:17])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Cn1ccc2c1C(=NO)CN(CCCCl)S2(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1ccc2c1C(=NO)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 87.3 %

Procedure:
A suspension of 116 mg (0.4 mmol) of Compound 19, 108 mg (0.6 mmol) of 1-(4-fluorophenyl)piperazine, 134 mg (1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml of acetonitrile was refluxed for 23 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/methylene chloride=1/20), whereby-152 mg of the title compound were obtained (yield: 87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16](=O)[CH3:17]>>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)[CH3:17]
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: CC=O
Product: CCN1CCCC2(C1)C(=O)Nc1ccccc12

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and acetaldehyde (5 equivalents). Yield: 45 mg (26%). 13C NMR of the HCl-salt (CD3OD): δ 9.6, 19.8, 31.3, 46.3, 54.2, 54.3, 55.1, 111.5, 123.9, 124.4, 130.4, 131.3, 142.6, 182.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.CO.[CH3:18][CH2:19]O>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: O=C(O)c1cncc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cncc(O)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 5-hydroxynicotinic acid (25 g, 0.1797 mol, Combi Blocks) in EtOH (500 mL) was added a catalytic amount of conc. H2SO4. The resulting reaction mixture was stirred for 12 h at 110° C. After completion of the reaction (monitored by TLC, 10% MeOH in CHCl3), EtOH was removed under reduced pressure and the reaction mixture was quenched with sat'd NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ: 11.00 (br.s., 1H), 8.74 (s, 1H), 8.42 (d, J=2.1 Hz, 1H), 7.90 (t, J=3.9 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J=6.9 Hz, 3H). MS (ESI, positive ion) m/z: 168 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:22][CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:22]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:23]
Reactant: CCI
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
A solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.200 g, 0.749 mmol), iodoethane (0.182 mL, 2.25 mmol) and N,N-dimethylformamide (10 mL) under nitrogen balloon was put on an ice water bath. Sodium hydride (0.090 g, 2.25 mmol) was added and the mixture was stirred under nitrogen balloon at 0° C. for 15 minutes. The reaction was then stirred at room temperature for 2 hours. Water was added to quench the excess sodium hydride and the mixture was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was solidified by adding isopropylether. The precipitate was filtered and dried under reduced pressure to give 2-ethoxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.131 g, 59% yield). ES(−)MS m/z=294 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J=6.9 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 4.95 (s, 2H), 6.56 (dd, J=8.6, 1.9 Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 7.08 (dd, J=8.1, 1.6 Hz, 1H), 7.14 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 9.19 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.F[B-](F)(F)F.[N:23]#[O+:24]>C(#N)C>[C:1]([O:5][C:6](=[O:11])[N:7]([N:23]=[O:24])[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#[O+]
Reactant: CC(C)(C)OC(=O)NC1CC1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(N=O)C1CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 26.4 %

Procedure:
A solution of cyclopropyl-carbamic acid tert-butyl ester (4.8 g, 30.5 mmol) and pyridine (5.9 mL, 73 mmol) in acetonitrile (75 mL) was cooled to approximately −25° C. in a carbon tetrachloride/dry ice bath. Nitrosonium tetrafluoroborate (4.7 g, 40.2 mmol) was added over a period of 20 min. The cooling bath was removed and the reaction mixture was stirred in an ice-bath at 0° C. for 2.5 h. Water (100 mL) and ethyl acetate (500 mL) were added and the organic layer was washed with water (100 mL), 2 M aqueous HCl (50 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and purified in two batches using an ISCO 120 g column, eluting with 10-30% ethyl acetate, to give N-nitroso-N-cyclopropyl-carbamic acid tert-butyl ester (1.5 g, 26%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CCOCC.CCOC(C)=O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]1[CH:16]=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1)(=[O:4])=[O:5]
Reactant: Clc1ncccn1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C)S(=O)(=O)n1ccnc1-c1ccnc(Cl)n1
Reaction time: 1 h
Yield: 4.5 %

Procedure:
N-BuLi [2.5M in hexane] (4 ml, 10 mmol) added at −78° C. to a solution of N,N-dimethyl imidazole-1-sulphonamide (1.75 g, 10 mmol) in dry ether (60 ml), stirred 1 hour, anion transferred to a suspension of 2-chloropyrimidine (1.48 g, 10 mmol) in ether (80 ml) keeping the temperature -30° C., temperature brought to 0° C. and held for 30 min. Reaction quenched with AcOH (0.64 ml) and water (0.1 ml), to the reaction was added THF (2 ml) then DDQ (2.27 g) in THF (10 ml) and stirred 0/N. Reaction diluted with EtOAc, solid filtered off and filtrate washed with water (3×) then ice cold 0.5% NaOH, organic layer dried over MgSO4, filtered and concentrated under reduced pressure, residue was purified by column chromatography to give the product (130 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[C:15](=O)[C:14]2[C:13]([C:24](OCC)=[O:25])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:30][NH:31][C:24](=[O:25])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1nccn1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
A mixture of ethyl 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (3 mL) was stirred at room temperature for 3.5 h. Evaporated the solvent and methanol (1 mL) was added, filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (45 mg, yield 41%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.46 (s, 3H), 3.49 (s, 3H), 4.78-4.81 (d, J=12.0 Hz, 1H), 5.08-5.11 (d, J=12.0 Hz, 1H), 6.69 (s, 1H), 6.76-6.79 (m, 3H), 6.99-7.02 (d, J=7.6 Hz, 1H), 7.42-7.49 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([NH:26][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:27]=[CH:28][CH:29]=2)[CH:22]=1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Reactant: Cc1cn(-c2cccc(N)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccccc34)c2)cn1
Reaction time: 40 h
Yield: 37 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (106 mg) and 3-(4-methylimidazol-1-yl)aniline (87 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 40 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4-methylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (68 mg, 37.0%).