Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (150 mg, 0.797 mmol) was taken up in DMA (4 mL) and K2CO3 (331 mg, 2.392 mmol) was added, followed by drop wise addition of MeI (0.060 mL, 0.957 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated solution of NaHCO3 and Na2S2O3, and then diluted with EtOAc. The organic layer was washed with saturated NaHCO3, then brine, and dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH:30]([OH:35])[C:31](=N)OC>C(O)C.O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:31]([CH:30]([C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[OH:35])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 14 h
Yield: 84.6 %

Procedure:
To a stirred solution of tert-butyl {3-[(2,6-diaminophenyl)amino]propyl}carbamate (5.47 g, 19.5 mmol) in ethanol (39 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.80 g, 19.5 mmol) at room temperature. After 14 h, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound as a colorless solid (7.67 g, 16.5 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]([C:7]([C:9]2[NH:13][N:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([O:40][CH2:41]OCC)[CH3:39]>C(Cl)Cl>[CH2:38]([O:40][CH2:41][N:12]1[N:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])=[N:13]1)[CH3:39]
Reactant: CCOCOCC
Reactant: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCOCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (210 mg) and p-toluenesulfonic acid monohydrate (62 mg) were suspended in methylene chloride (5 ml) under an argon atmosphere. Diethoxymethane (0.5 ml) was added to the suspension. The mixture was stirred at 80° C. for 2 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (242 mg, 99%) as a yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC.[Li+].[Cl-]>C1(C)C=CC=CC=1.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>[CH:12]([C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc(F)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)c(C#N)c1C
Temperature: 105 °C

Procedure:
A mixture of 3-bromo-6-fluoro-2-methylbenzonitrile (8.8 g, 41 mmol), tributyl(vinyl)tin (14.3 g, 45.2 mmol), LiCl (5.20 g, 123 mmol) and Pd(PPh3)4 (2.3 g, 2.0 mmol) in toluene (200 mL) was heated at 100-110° C. under N2 overnight. The mixture was concentrated and the residue was purified by column chromatography to obtain 3-ethenyl-6-fluoro-2-methylbenzonitrile.
Reaction SMILES: Br[CH:2]([CH:13]([CH3:15])[CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.C(O)C.[C:19]([NH2:22])(=[S:21])[CH3:20]>C(OC(=O)C)C>[CH:13]([C:2]1[S:21][C:19]([CH3:20])=[N:22][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:15])[CH3:14]
Reactant: CC(N)=S
Reactant: COc1ccc(C(=O)C(Br)C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nc(C)sc2C(C)C)cc1
Reaction time: 22 h
Yield: 51 %

Procedure:
While 77.0 g of 2-bromo-1-(4-methoxy-phenyl)-3-methyl-butan-1-one (4) prepared in Example 2 were added to 200 ml of ethanol and stirred, 42.7 g of thioacetamide were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 22 hr. After the reaction was completed, the resultant reaction mixture was added with 300 ml of ethylacetate, and then washed with a saturated aqueous solution of potassium carbonate. The ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, thus obtaining 35.8 g (yield: 51.0%) of a title compound as brown liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:23].[SH:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1.[OH-].[Na+]>C(O)C.O>[CH3:23][C:7]1[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(SCCCSc2nc3ccccc3[nH]2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 83 %

Procedure:
2-{[[4-(3-Chloropropylthio)-3-methyl-2-pyridinyl]methyl]thio}-1 H-benzimidazole (1 mmol) is stirred at 60° C. for 20 h with 2-mercapto-1 H-benzimidazole (1.05 mmol) and 1N sodium hydroxide solution (3 ml) in 10 ml of ethanol and subsequently diluted with a further 10 ml of water. The mixture is allowed to cool, and the precipitated solid is filtered off, washed with ethanol/water 1/1 and dried in vacuo at 50° C. The title compound is obtained as a gray powder; m.p. 85°-87° C.; yield: 83% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a stirred solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran of Example 6(a) (32 kg, 213 moles) in DMF (192 L) was added potassium carbonate (31.0 kg, 224 moles). After stirring for 5 min. at room temperature, benzyl bromide (145.2 kg, 264 moles) was added and the resulting mixture was stirred for 2 hours at room temperature. The mixture was poured into water (651 L), stirred for 30 minutes and the product collected by centrifugation. The crude solid was washed with water (580 L), 80% ethanol (100 L) and dried under vacuum to afford the desired product (49.1 kg; 95%) which was used without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(OCC3CO3)ccc2c2oc3ccccc3c12
Temperature: 55 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
In N,N-dimethylformamide was dissolved 10.0 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one, and to the solution were added 28.0 g of epibromohydrin and 5.5 g of potassium carbonate. The mixture was stirred at 55° C. for 3 hours. Into the reaction mixture was poured water, and precipitates were collected by filtration, washed with water, and dried to obtain 11.8 g of 3-(2,3-epoxypropoxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05 mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400 g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.260 g (35%) as an orange foam. mp 99-103° C. (dec). FDMS m/e=401 (M+ of free base). α[D]589=+5.1 (c=0.98, dimethylsulfoxide).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3].[CH3:14][OH:15]>C1COCC1>[CH3:14][O:15][C:2]([C:4]1[CH:5]=[C:6]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
To a solution of 3-chlorocarbonylbenzenesulfonyl chloride (5.0 g, 21 mmol) in THF (100 ml) was added methanol 1.7 ml (42 mmol) and the mixture was stirred at room temperature for 13 hours. After the reaction was completed, the resultant was concentrated under reduced pressure to give 5.14 g (21 mmol) of the titled compound as a pale purple solid. Yield: 100%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1)=[O:14]>CN(C)C=O>[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20][O:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:18][CH:19]=1)=[O:14]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(I)cc2)o1
Temperature: 5 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of 4-iodophenol (10.08 g, 45.8 mmol) in N,N-dimethylformamide (30 mL) was added to a ice-bath cooled suspension of sodium hydride (60%; 1.65 g, 41.2 mmol) in N,N-dimethylformamide (30 mL). The ice bath was removed and the mixtrue was stirred for 1 h. The mixture was cooled again to ˜5° C. and a solution of 5-(chloro-methyl)-furan-2-carboxylic acid methyl ester (4.00 g, 22.9 mmol) in N,N-dimethylformamide (60 mL) was added. The reaction mixture was stirred overnight at room temperature, then the solvents were evaporated under reduced pressure and water was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed twice with 1 M NaOH, and once each with water and brine. The organic solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 65 L purification system, eluting with 3% methylene chloride/toluene to give 5-(4-iodo-phenoxymethyl)-furan-2-carboxylic acid methyl ester (2.3 g, 28%) as a white solid, along with some mixed fractions.
Reaction SMILES: [B-]C#N.[Na+].[F:5][C:6]1([F:26])[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:10][CH2:9][NH:8][CH2:7]1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C>CO>[F:26][C:6]1([F:5])[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:24])([F:25])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:10][CH2:9][N:8]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:7]1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC1(F)CNCCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC(F)(F)C2)cc1
Temperature: 21 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
Sodium cyanotrihydroborate (58.5 mg, 0.93 mmol) was added to a stirred mixture of 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.62 mmol), 4-fluorobenzaldehyde (93 mg, 0.75 mmol) and acetic acid (71.1 μl, 1.24 mmol) in methanol (10 mL) at room temperature. The resulting mixture was stirred at 21° C. for 20 hours. The reaction mixture was concentrated to dryness, diluted with methanol and a few drops of 7M ammonia in methanol were added. The mixture was concentrated to dryness, the residue was diluted with DCM and the salts were filtered off. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% acetonitrile in DCM. Product-containing fractions were concentrated to give to give 6-[6,6-difluoro-4-(4-fluorobenzyl)-1,4-diazepan-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (154 mg, 55%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]1[N+:9]([O-:11])=[O:10])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([N:3]1[C:7]([CH:8]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][N:5]=[C:4]1[N+:9]([O-:11])=[O:10])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCn1c(C)cnc1[N+](=O)[O-]
Product: CCn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]

Procedure:
By reacting 0.33 g. of 1-ethyl-5-methyl-2-nitroimidazole with benzaldehyde according to the procedure of Example 55, 0.030 g. of 1-ethyl-2-nitro-5-styrylimidazole is obtained, m.p. 154°-156° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[OH:13])=[N+]=[N-].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.[Pd]>[C:14]([NH:1][CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[OH:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@H]1CC[C@H](O)[C@@H](CN=[N+]=[N-])O1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](O)[C@@H](CNC(C)=O)O1
Reaction time: 5 h

Procedure:
Methyl 6-azido-2,3,6-trideoxy-α-D-erythro-hexopyranoside (3.0 g, 16 mmol) in methanol (100 ml) containing acetic anhydride (2 ml) was hydrogenated over 10% palladium-on-charcoal (0.4 g) at room temperature under a pressure of 2.5 atms. for 5 h. The catalyst was filtered off and the filtrate was evaporated to dryness giving a syrupy residue which crystallized upon treatement with ether to yield 3.18 g, 98%. The product was recrystallized from chloroform-ether to give pure methyl 6-acetamido-2,3,6-trideoxy-α-D-erythro-hexopyranoside. M.p.: 117°-118°. [α]546121 -13° (c 1, chloroform).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C)=NSC=2C=1O)=O)CCC.P(Br)(Br)([Br:41])=O>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([Br:41])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2snc(C)c2c1O
Agent: CCCCOC(=O)c1nc(O)c2c(C)nsc2c1O
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Temperature: 120 °C
Reaction time: 0.58 h

Procedure:
To a solution of the mixture of 4,7-dihydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 4,7-dihydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (6.67 mmol) obtained as described above in dichloroethane (33.3 mL) was added POBr3 (8.0 mmol). The reaction mixture was stirred at 120° C. in a microwave oven for 35 min. After cooling to r.t., the mixture was partitioned between CH2Cl2 and sat. NaHCO3, then filtered and the organic layer of the filtrate was washed with brine before it was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester (850 mg) as a white solid: MS (m/z) 342.9 (M−1), 345.0 (M−1), and 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (473 mg) as a white solid: MS (m/z) 342.9 (M−1), 345.0 (M−1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH:44]([CH2:45][OH:46])[CH2:43][CH:42]2[CH:40]1[CH2:41]2)=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH:44]([CH2:45][O:46][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH:42]2[CH:40]1[CH2:41]2)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(COc2cccnc2)CC2CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To an ice cold solution of triphenylphosphine (1.66 grams, 6.4 mmol) in dry tetrahydrofuran (7 mL) was added diethyl azodicarboxylate (1.0 mL, 6.4 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C. and a solution of 3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (obtained in step (vii) of preparation 1) (0.9 grams, 4.2 mmol) in dry tetrahydrofuran (7 mL) was added followed by a solution of 3-hydroxypyridine (0.6 grams, 6.4 mmol) in dry tetrahydrofuran (14 mL). The reaction mixture was gradually warmed to room temperature and stirred for 0.16 hours. The volatiles were evaporated under reduced pressure and crude obtained was purified by flash column chromatography using 230-400 mesh silica gel to obtain title compound 0.83 grams as gummy liquid. Yield: 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[C:18](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:13][CH:12]([NH2:28])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH:12]([NH:28][C:36](=[O:38])[CH3:37])[CH2:11][CH2:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(N)CCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1cccc2nc3n(c12)CC(NC(C)=O)CCN3c1ccc(Cl)cc1Cl
Yield: 41.5 %

Procedure:
To a mixture of 1-(2,4-dichlorophenyl)-N7,N7-diethyl-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-4,7-diamine (59.5 mg, 0.142 mmol) and triethylamine (0.0396 mL, 0.284 mmol) in tetrahydrofuran (1.4 mL) was added acetic anhydride (0.161 mL, 0.170 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 1 hr, aqueous sodium bicarbonate was added and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give a solid, which was recrystallized from ethyl acetate to afford the title compound as a colorless solid (27.1 mg, 0.0589 mmol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[Li].C1C=CC=CC=1.[C:17]([CH2:21][CH2:22][C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:23]([CH2:22][CH2:21][C:17]([O:19][CH3:20])=[O:18])=[O:24]
Reactant: COC(=O)CCC(=O)Cl
Reactant: [Li]c1c(F)cccc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CCC(=O)c1c(F)cccc1OC

Procedure:
A cold solution of 2-fluoro-6-methoxylithiobenzene in ether was added to a cold dilute benzene solution of β-carbomethoxypropionyl chloride and the resulting complex was decomposed with ammonium chloride solution to give methyl 3-(2-fluoro-6-methoxybenzoyl)propionate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: COC(=O)CCCBr
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: COC(=O)CCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 63 %

Procedure:
Obtained in 63% yield by an analogous method to Example 19, preparation of starting materials, starting from 4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol and methyl 4-bromobutanoate.
Reaction SMILES: [CH2:1]([N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH:5]([NH2:8])[CH2:6][NH2:7])[CH3:2].[C:15](O)(=O)C.C(N)=N>C(O)C>[N:7]1[CH2:6][CH:5]([CH2:4][N:3]([CH2:1][CH3:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:8][CH:15]=1
Reactant: CCN(CC(N)CN)c1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: CCN(CC1CN=CN1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a solution of rac-N1-ethyl-N1-phenyl-propane-1,2,3-triamine (0.19 g, 1.0 mmol) in ethanol (5 ml) was added formamidine acetate (0.11 g, 1.08 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield an off-white amorphous solid (0.042 g, 21%); MS (ISP): 204.1 ((M+H)+).