Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])=[C:4]([O:19][CH3:20])[CH:3]=1.C(O)CC#C.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)#[CH:27]>>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]#[C:26][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:3][C:4]=1[O:19][CH3:20]
Reactant: C#Cc1ccccn1
Reactant: COc1cc(Br)ccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: C#CCCO
Product: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F

Procedure:
According to the procedure of example 11(a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (0.29 mmol; 100 mg) and 3-butyn-1-ol by 2-ethynylpyridine (0.73 mmol; 73 μL), the title compound was prepared as a yellow solid (81%; 87 mg) after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[NH:38])=[CH:35][CH:34]=3)[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21](OCCO)[C:20]=3[F:31])=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1.COC(=O)N=C(SC)C(C1C(F)=C2C(=C(OC)C=1)[O:67][CH2:66][CH2:65][CH2:64]2)=NC1C=CC(C2N=C(C)ON=2)=CC=1.[F:77][C:78]([F:83])([F:82])[C:79]([OH:81])=[O:80].COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1>C(O)(=O)C>[F:77][C:78]([F:83])([F:82])[C:79]([OH:81])=[O:80].[NH2:5][C:6]1[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:32][C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[NH:38])=[CH:35][CH:34]=3)[C:19]3[C:20]([F:31])=[C:21]4[C:22](=[C:23]([O:25][CH3:26])[CH:24]=3)[O:67][CH2:66][CH2:65][CH2:64]4)=[N:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c(F)c2c1OCCC2

Procedure:
The same procedure was carried out as in Examples (200b) to (200c), except that [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)) and 0.1% trifluoroacetic acid were used instead of respectively the (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester in Example (200b) and 0.1% acetic acid in Example (200c), to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:21]([O:22][CH3:23])[CH3:20])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1.0 g, 4.0 mmol) in dichloromethane (10 mL) were added N,O-dimethyl hydroxylamine hydrochloride (0.77 g, 8.0 mmol), EDCl (1.2 g, 6.0 mmol), HOBt (0.05 g, 0.4 mmol), Et3N (0.8 g, 8.0 mmol) and the contents were stirred at ambient temperature. After 2 hr, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-tert-butyl(2-(methoxy(methyl)amino)-2-oxo-1-phenylethyl)carbamate. 1H NMR (300 MHz, CDCl3) δ 7.39-7.29 (m, 5H), 5.77 (bs, 1H), 5.73 (bs, 1H), 3.47 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:11]C)[CH2:9][CH3:10])C.[N+:13]([C:16]1[CH:25]=C2[C:19]([CH2:20][CH2:21][CH2:22]C2O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O1CCCC1>[CH3:11][N:8]([CH3:6])[CH:9]1[C:10]2[C:19](=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:25]=2)[CH2:20][CH2:21][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
With cooling with ice, 0.16 mL of methanesulfonyl chloride and 0.29 mL of triethylamine were added to a tetrahydrofuran (5 mL) solution of 200 mg of 7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol obtained according to the method described in WO2004/087124, and stirred for 1 hour. The insoluble matter was removed through filtration through Celite, the solvent was evaporated away from the filtrate, the residue was dissolved in 3 mL of N,N-dimethylformamide, then 1.55 mL of 2 M dimethylamine/tetrahydrofuran solution was added to it, and stirred overnight at 60° C. After left cooled, water was added to the reaction solution, and then diluted with ethyl acetate. The organic layer was washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 100 mg of the entitled compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:36][O:37][C:38](Cl)=[O:39]>ClCCl>[CH2:12]([C:9]1[N:7]2[N:8]=[C:3]([CH2:2][NH:1][C:38]([O:37][CH3:36])=[O:39])[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:6]2=[CH:11][CH:10]=1)[CH3:13]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCc1c(CNC(=O)OC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methyl chloridocarbonate (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
Reaction SMILES: Br[CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[C:14]([OH:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([S:21][CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5])(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)/C(=C/c1ccccc1)CBr
Reactant: OC(=S)c1ccccc1
Product: O=C(O)/C(=C/c1ccccc1)CSC(=O)c1ccccc1
Yield: 67 %

Procedure:
The (Z)-2-bromomethyl-3-phenylpropenoic acid described in Example 1 (step A) is reacted with thiobenzoic acid according to the experimental procedure described in Example 1 (step B). Yield=67% (recrystallized in ether) m.p. 160° C. 1H NMR CDCl3 /TMS): 8.15 to 7.80 (m, 3H); 7.70 to 7.20 (m, 8H); 4.20 (s, 2H)
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]Br>C(Cl)(Cl)(Cl)Cl.[W]>[Br:23][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][C:17]=1[F:22]
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Yield: 81.8 %

Procedure:
A solution of 1.08 g (3.36 mmol) of N-t-butyl-3'-fiuoro-4'-methyl-2-biphenylsulfonamide (from Step E) in 20 in mL of CCl4 was stirred at reflux under irradiation from a 100-watt tungsten lamp as a solution of 3.5 mmol of bromine in approximately 13 mL of CCl4 was added dropwise over 1.5 hour. After being stirred at reflux overnight, the solution was cooled and concentrated. The residue was crystallized from EtOAc-hexane to give 1.10 g of the title compound as an off-white solid, mp 138°-140° C. (estimated purity 87%, containing minor unbrominated and dibrominated contaminants by TLC); mass spectrum (FAB) m/e 400, 402 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH:19]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]1[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:20]2[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1CCCCN1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as a solid (mp=114-118° C.). The reaction was monitored by tlc (Rf=0.71 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH2:40])[CH3:39].CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH:40][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2)[CH3:39]
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Reactant: C[C@H](N)Cc1cc(F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H](Cc1cc(F)ccc1Cl)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 36.1 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silica gel, DCM:MeOH 9:1) to give 2-(4-((1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (25 mg, 36%) as pale yellow oil. ESI-MS: m/z (MH+) 549.5. 1H NMR (300 MHz, CD3OD): δ 8.0 (d, J=60.6 Hz, 1H), 7.67 (d, J=52.5 Hz, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 6.89 (m, 1H), 6.09 (m, 1H), 4.66 (m, 2H), 3.98 (m, 2H), 3.68 (m, 1H), 3.30 (m, 2H), 3.15 (m, 6H), 2.02 (m, 4H), 1.43 (d, J=6.60 Hz, 3H).
Reaction SMILES: [C:1]1([C:7](=[N:17][OH:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:24](=O)=[O:25]>C1COCC1.CCCCCC>[OH:25][C:24]1[O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1
Reactant: CSc1ccc(CC(=NO)c2ccccc2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(-c2c(-c3ccccc3)noc2O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a stirred solution of 1-phenyl-2-(4-methylsulfanylphenyl) ethanone oxime (2.0 g) in dry THF (20 mL), was added a solution of n-butyl lithium (0.98 M. 25 mL) in hexane at −70° C. over a period of 30 minutes. The reaction mixture was warmed to 20° C. over a period of 2 h. To this was added solid CO2 (25 g) and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with cold 1N HCl (20 mL) and extracted with ethyl acetate (3×50 mL). The organic extract was washed with water (100 mL); brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed over silicagel using 10% ethyl acetate in petroleum ether as eluent, yielding 1.2 g of pure product as a thick liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][S:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]3)[CH:13]=[CH:12][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc3nc(SC)sc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (500 mg, 2.2 mmol) from Example 36 and methyl 4-imidazole carboxylate (400 mg, 3.3 mmol) in DMF (15 mL) was added K2CO3 (0.9 g, 6.5 mmol). After the mixture was stirred for 3 h at rt, it was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2% MeOH in CH2Cl2 to afford methyl 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate (130 mg, 19%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J=0.9 Hz, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.93 (d, J=0.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.7, 8.3 Hz, 1H), 5.35 (s, 2H), 3.72 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 322 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27](Cl)=[O:28])=[CH:20]2)[CH3:16]>C(Cl)Cl>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:28])=[CH:20]2)[CH3:16]
Reactant: COC(=O)CN
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc2nnc(C(=O)NCC(=O)OC)cc2c1
Reaction time: 5 h

Procedure:
A mixture of glycine methyl ester hydrochloride (2.5 g.) and triethylamine (2.6 ml.) in dry methylene chloride (10 ml.) was added to a solution of 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.) in dry methylene chloride (10 ml.). The resulting solution was kept at room temperature for 5 hours, diluted with methylene chloride (80 ml.) and washed successively with N-hydrochloric acid, water, 10% w/v sodium bicarbonate solution, and water and then dried (MgSO4). The solvent was evaporated and the solid residue was crystallized from aqueous ethanol to give 6-ethyl-N-(methoxycarbonylmethyl)-cinnolin-3-yl carboxamide, m.p. 135°-137° C.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([NH:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(C2(N)CCCC2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2(NC(=O)C(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-(p-methylphenyl)cyclopentylamine (8.8 g) and triethylamine (6.1 g), and trimethylacetyl chloride (6.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 10.8 g of N-[1-(p-methylphenyl)cyclopentyl]trimethylacetamide. M.P., 166°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH2:18]([SH:20])[CH3:19].[Na]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[S:20][CH2:18][CH3:19]
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: CCS
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]

Procedure:
A solution of 7-Chloro-1,4-dihydro-6-fluoro-5-nitroquinoxaline-2,3-dione (0.100 g, 0.385 mmol) and ethanethiol, sodium salt (0.130 g, 1.55 mmol) in DMSO (1.0 mL) was stirred at room temperature for 24 h. The resulting solution was diluted with water (5 mL) and acidified with concd HCl (4-5 drops) to pH 5. The precipitated solid was collected by filtration under vacuum, washed with water (10 mL), and dried under vacuum to obtain 0.098 g (84%) pure (HPLC) title compound as a yellow powder; mp darkens at 323° C.; 1H NMR (DMSO-d6) δ 1.04 (t, 3H, J=7.2 Hz), 2.82 (q, 2H, J=7.5 Hz), 7.34 (s, 1H), 12.20 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[CH3:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16]>>[CH3:14][N:15]([CH:17]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH3:18])[CH3:16]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN(C)CCCl
Agent: Cl
Product: CC(N(C)C)n1ccc2cc([N+](=O)[O-])ccc21
Yield: 76.9 %

Procedure:
Prepared according to the method of Example 15a) from 5-nitroindole (0.217 g) and dimethylaminoethyl chloride hydrochloride (0.21 g) to leave sub-title compound as an orange/brown solid (0.24 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:32][CH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: NCc1cccnc1C1CCNC1
Product: NCc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 3.0 mmol) and 2-(3-pyrrolidinyl)-3-pyridinemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.09 g, 86%) as an off-white solid, mp 246°-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])=[N:7][N:6]=[CH:5]2
Reactant: CN(C)CCN
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-dimethylethane-1,2-diamine (0.20 mL, 1.81 mmol) was added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3x with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 295(M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[S:32])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2NC1=S

Procedure:
730.6 mg (1.696 mmol) of 2-methyl-3-oxo-6-[2-(3-chlorobenzyl-tert-butyloxycarbonylamino)-ethyl]-3,4-dihydro-2H-1,4-benzoxazine is mixed in 8 ml of pyridine with 201.1 mg (0.607 mmol) of phosphorus pentasulfide, and then it is refluxed for four hours. The solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The yield is 439.3 mg (58%).
Reaction SMILES: S(=O)(O)O.[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:11]([N:14]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC1CCCCC1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CN(Cc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of cyclohexanecarboxaldehyde bisulfite adduct (5.0 mmol) and Et3 N (5.5 mmol) in dichloroethane (20 mL) was stirred at room temperature for 15 min. The suspension was treated with N-methylbenzylamine (5.5 mmol) and was stirred for 45 min. NaBH(OAc)3 (7.0 mmol) was added portion-wise over approximately 30 min. After 16 h, the reaction mixture was diluted with EtOAc (80 mL), and was washed with 1 N NaOH (25 mL) followed by brine (25 mL). The organic layer was dried (MgSO4) and concentrated to yield benzyl-cyclohexylmethyl-methyl-amine as an oil. The crude material was purified by the General Purification Method as described above.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:11].O>C1COCC1>[CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C=NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)NCc1ccccc1
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
96.3 g (366 mmoles) of benzylisothiocyanate were dissolved in 100 ml o THF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution. After 0.5 hour at 40-45° C., 300 ml of water were added and the THF removed in vacuo. The gummy suspension is treated with 200 ml of ether, the crystals collected and washed with water and ether. Suspension in 30 ml of methylenechloride and collection gave 65.77 g (64.2%) of benzyl-2-thiourea with mp 144-5° C.