Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[N:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH:31]([N:34]([CH:37](C)C)CC)(C)[CH3:32].C(Cl)(Cl)=[O:41].C1(C)C=CC=CC=1>ClCCl>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([NH:34][CH2:31][CH3:32])=[O:41])[C:3]4[N:4]([CH:28]=[CH:29][N:30]=4)[N:5]=3)[C:9]=2[CH3:27])=[O:26])=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)nn2ccnc12
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of N-[3-(8-amino-imidazo[1,2-b]pyridazin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (0.019 g, 0.047 mmol) and diisopropylethylamine (0.021 mL, 0.12 mmol) in 1 mL of dichloromethane at 0-5° C. was added a 20% phosgene in toluene solution (0.030 mL, 0.057 mmol) all at once. The cloudy yellow solution was stirred for 10 min., then ethylamine gas was bubbled in via a Pasteur pipette for 2 min. Silica gel (3 g) was added, and the mixture was concentrated to a pale yellow powder. Column chromatography (66%->100% EtOAc/hexanes) afforded 0.013 g (58%) of 4-tert-butyl-N-{3-[8-(3-ethyl-ureido)-imidazo[1,2-b]pyridazin-6-yl]-2-methyl-phenyl}-benzamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)amide as a yellow solid (93.2 mg, 79%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([CH3:23])=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:24])[C:4]=1[CH2:25][CH2:26][C:27](O)=[O:28])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:61]([CH2:63][NH2:64])[OH:62]>C(Cl)Cl.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([CH3:23])=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:24])[C:4]=1[CH2:25][CH2:26][C:27]([NH:64][CH2:63][CH2:61][OH:62])=[O:28])[CH3:2]
Reactant: NCCO
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)NCCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (42 mg, 100 μmol) and DIPEA (39 mg, 300 μmol) in DCM (2 mL), TBTU (32 mg, 100 μmol) followed by ethanolamine (18 mg, 300 μmol) is added. The mixture is stirred at 0° C. for 16 h before it is diluted with EA, washed with 1 N aq. NaOH solution, dried over Na2SO4 and filtered. The solvent is evaporated and the residue is dried under HV to give 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-N-(2-hydroxy-ethyl)-propionamide (39 mg) as a beige solid; LC-MS: tR=1.10 min, [M+1]=456.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:15][C:16]([NH2:18])=[O:17])=[CH:5][CH:4]=1
Reactant: NC(=O)CI
Reactant: COc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccn(CC(N)=O)c2c1

Procedure:
Intermediate C12 was prepared as described for Intermediate C2 using 6-methoxyindole (489 mg, 3.32 mmol), sodium hydride (160 mg, 3.98 mmol) and iodoacetamide (615 mg, 3.32 mmol) in DMF (50 mL). Two recrystallizations from ethyl acatete yielded intermediate C12 as a whte solid (252 mg, 37%). m.p. 210.1–211.0° C. 1H NMR (200 MHz, DMSO-D6) δ 7.48 (br s, 1H), 7.41 (d, 8.6 Hz, 1H), 7.25 (br s, 1H), 7.16 (d, 3.2 Hz, 1H), 6.91 (d, 2.0 Hz, 1H), 6.69 (dd, 6.4 Hz, 2.2 Hz, 1H), 6.35 (d, 0.8 Hz, 1H), 4.74 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16]([CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])=O.[NH2:25]/[C:26](/[CH3:34])=[CH:27]\[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(O)(=O)C>CC(O)C>[CH3:34][C:26]1[NH:25][C:16]([CH3:15])=[C:18]([C:19](=[O:20])[C:21]([F:24])([F:23])[F:22])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:27]=1[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)C(F)(F)F)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 143.3 mg (0.93 mmol) of 1,1,1-trifluoroacetylacetone, 76.09 mg (0.53 mmol) of isopropyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 95:5). 15 mg (6.2% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-:20].[Na+].C1(C)[C:23](C)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:2]([C:11]3[CH:10]=[CH:5][C:4]([N:12]4[CH2:23][CH2:24][CH:25]([OH:20])[CH2:26][CH2:27]4)=[N:3][CH:2]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:19]
Reactant: [OH-]
Reactant: Cc1ccccc1C
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: [Na+]
Product: CCN1CCN(c2nc(-c3ccc(N4CCC(O)CC4)nc3)cc3ccccc23)CC1

Procedure:
3-Bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.16 g) and {2-[4-(t-butyldimethyloxy)piperidin-1-yl]pyridin-5-yl}tributylstannum (1.37 g) was reacted in the presence of tetrakistriphenylphosphine dichloride (0.30 g) in xylene (30 ml) at 140° C. for 5 hr. The reaction solution was concentrated. A 2N aqueous solution of hydrochloric acid was added to the resulting residue, and then reacted at 50° C. for 1 hr. The reaction solution was basified with a 2N aqueous solution of sodium hydroxide, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.26 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(O)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=O>O>[CH3:27][O:26][C:23]1[C:22]2[C:32](=[O:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[CH2:29][O:28][C:21]=2[C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(OC)c(OCc2ccccc2C(=O)O)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c2c1OCc1ccccc1C2=O
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To 50 g of phosphorus pentoxide is slowly added 30 ml of ethanol at room temperature and the mixture is further stirred with heating at 100° C. for 1 hour. Thereto 10 g of 2-[(2,5-dimethyoxyphenyloxy)methyl]benzoic acid is added and the mixture is stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture is added with 300 ml of water and extracted with toluene. After the extract is successively washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure to give 7 g of 1,4-dimethoxy-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 270(M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14]>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][N:15]([CH2:19][CH3:20])[CH2:16][CH3:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Product: CCOC(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
The title compound was prepared by alkylation of ethyl-4-hydroxybenzoate with diethylchloroethylamine using methods analogous to those described in Example 2(i).
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:15]([CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[OH:20])([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:20][CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-2-amino 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:16].[CH2:17](B1OC(C)(C)C(C)(C)O1)[CH:18]=[CH2:19]>CO>[CH2:17]([C:12]1([NH2:16])[CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]1)[CH:18]=[CH2:19]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: N
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Solvent: CO
Product: C=CCC1(N)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g (4.38 mmol) of 4-(tert-butyldimethylsilyloxy)cyclohexanone in 6.2 mL (43.8 mmol) of 7N ammonia in methanol, previously stirred for 15 min at room temperature, were added dropwise 3.5 mL (7.0 mmol) of a 2M solution of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane in methanol. The reaction mixture was stirred for 16 h at room temperature. The volatiles were removed in vacuo and the residue could be purified by silica gel chromatography using dichloromethane/methanol/NH3 aq. as eluent. Rt=1.19 min (Method C). Detected mass: 270.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])O.[Na+].[Br:19]Br>CO>[Br:19][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([F:12])([F:13])[F:1]
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl.C(OCC)C>[CH3:17][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([C:28]2[CH:27]=[C:26]([F:25])[CH:34]=[C:33]([F:35])[CH:32]=2)=[O:30])=[CH:7][CH:6]=1)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(NC(=O)c2cc(F)cc(F)c2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a 0° C. solution of [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (21.5 g, 0.0838 mol) and triethylamine (9.75 g, 13.4 mL, 0.0964 mol) in CH2Cl2 (86 mL) was added 3,5-difluorobenzoyl chloride (16.3 g, 0.0922 mol) dropwise over 30 min. After the addition was complete, the reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was washed with deionized water (2×100 mL) and 0.1 N HCl (2×100 mL). The organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K2CO3 (100 mL), 0.1 N HCl (100 mL), dried (MgSO4, 3 g), filtered and co-evaporated with EtOAc to afford an oil. This oil was diluted with diethyl ether (125 mL), which induced crystallization. The solids were collected by filtration, washed with diethyl ether (2×20 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (31.8 g, 95.7%) as a white crystalline powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH2:3]1.CC(C1C=C(C(C)C)C(S([N:37]=[N+:38]=[N-:39])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:37]([CH:3]1[C:4](=[O:21])[N:5]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[C:2]1=[O:1])=[N+:38]=[N-:39]
Reactant: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Temperature: -30 °C

Procedure:
For this substrate General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at −78° C., and following addition of the KN(TMS)2 solution, this suspension was allowed to warm to −30° C., during which the suspension became a solution, and was re-cooled to −78° C. Upon re-cooling to −78° C. a precipitate began to form, therefore the reaction flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to −50° C.; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to −20° C. whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then, treated as described in the general procedure. 3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystalization from hot to −23° C. CHCl3/EtOAc/EtOH (5:5:1) and isolated as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:21]1[CH:22]=[C:17]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][N:13]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CCN1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 90 °C
Yield: 44 %

Procedure:
A solution of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (185 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77.7 mg, 0.13 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was triturated with methanol and dichloromethane and filtered, washed with ether and dried to give 6-chloro-4-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one (138 mg, 44%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.Cl[CH:11]([CH:17]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:1]=2)[CH:4]=1)#[N:9]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: N#Cc1ccc(N)nc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(C#N)cn12

Procedure:
2-Amino-5-cyanopyridine (15.5 g, 152 mmol) was dissolved in ethanol (500 mL) in 2 L round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 730 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture was heated at reflux for 10 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica-gel chromatography to give ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (13.9 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:27])=O>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]1)[C:5]([Cl:27])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 34e (166 mg, 0.39 mmol) in THF (4 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, warmed to room temperature, and stirred for 18 h. The solvents were removed under reduced pressure. The resultant residue, compound 34f, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[CH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH2:20])[CH:17]=2)[CH2:12][CH2:11][CH:10]1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25].[OH:30]O.[OH-].[Na+]>C1COCC1.O>[CH2:24]([O:23][C:22](=[O:26])[NH:21][CH:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][CH:14]=2)[CH:9]1[CH2:8][C:7]1[CH:27]=[CH:28][CH:29]=[C:5]([Cl:4])[CH:6]=1)[CH3:25]
Reactant: C=Cc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
BH3.DMS (1 M in THF, 0.838 ml, 0.838 mmol) was added a solution of ethyl 1-(3-chlorobenzyl)-7-vinyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.55 g, 4.19 mmol) in 20 ml dry THF. The reaction was stirred at 60° C. for 1 h and cooled to room temperature. Some water was added to destroy the excess of borane complex and the resulting mixture refluxed for 1 h with 30% H2O2 (8.56 ml, 84 mmol) and 2N NaOH (9.74 ml, 19.49 mmol). The reaction mixture was extracted with CH2Cl2, washed with water and brine, dried, filtered and the solvent evaporated to obtain a pale brown solid (1.7 g), which was purified by chromatography to afford 854 mg of product as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH2:23]([Br:25])[CH3:24]>>[Br-:25].[CH2:1]([N+:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCCN(CC)CCCCc1ccc(OC)cc1
Reactant: CCBr
Product: CCCCCCC[N+](CC)(CC)CCCCc1ccc(OC)cc1
Product: [Br-]

Procedure:
24 Grams of N-ethyl-N-n-heptyl-4-(4-methoxyphenyl) butylamine was placed in a 500 ml. round bottom flask and 200 ml. ethyl bromide was added. The mixture was refluxed for 31/2 days. Thin layer chromatography indicated very little secondary amine left. The excess ethyl bromide was evaporated in vacuo leaving an oil, N,N-diethyl-N-n-heptyl-4(4-methoxyphenyl)butylammonium bromide which next was converted to the hydroxide form as follows: Using 350 ml. BIO-RAD, hydroxide form, 100-200 mesh 1.2 meq./ml. resin in a water packed column the oil was taken up in water and flushed over the column. 800 Milliters was collected off the column. This was partly acidified from pH 12.4 to pH 10 with 15 g. of p-toluenesulfonic acid in water. The solution tended to oil on acidification. This suspension was passed over a column of 300 ml. of resin which had been converted to the tosylate form by washing with 1 l. of 0.4 N p-toluenesulfonic acid solution. A total of 4 l. eluate was collected. Lyophilization of the eluate of 11/2 days left a residue which was taken up in hot ethyl acetate, filtered and evaporated in vacuo. 44 Grams of oil was left which solidified on standing. The material was recrystallized from 300 ml. ethyl acetate to form 36.76 g. N,N-dimethyl-N-n-heptyl-4(4-methoxyphenyl)butylammonium p-toluenesulfonate. M.P. 65°-67° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(N-t-butoxycarbonylamino)nicotinic acid (2.72 g, 11.4 mmol), TFA (10 mL), and CH2Cl2 (20 ml) is stirred at room temperature for 12 h. The volatiles are removed under reduced pressure, and the resulting crude 4-amino nicotinic acid is used directly in the next reaction,