Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([OH:10])[C:4](OC(C)C)=[O:5].[NH3:18]>CO>[NH2:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([OH:10])[C:4]([NH2:18])=[O:5]
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)C(O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (200 mg, Reference compound No. 4-1) in methanol (3 ml) is saturated with an ammonia gas, and the solution is sealed and stirred overnight. The reaction solution is concentrated under reduced pressure to give the titled reference compound (162 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl.CO>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
A solution of 95.0 mg (0.210 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with MeOH (1 drop) and TFA (1 mL). The mixture was stirred at RT for 2 days, and the solvents were evaporated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 25% EtOAc-hexane and RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 36.0 mg (39%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 9.02 (dd, 1H, J=8.4, 1.6 Hz), 8.44 (dd, 1H, J=5.2, 1.6 Hz), 8.06 (s, 1H), 7.76-7.71 (m, 1H), 6.22 (sept, 1H, J=2.0 Hz), 2.50-2.43 (m, 2H), 2.18-2.13 (m, 2H), 1.65 (t, 2H, J=6.4 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C18H19N5O, 322.1 (M+H), found 322.1.
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:20]([O:22]C)=[O:21])(=O)C.O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[OH:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1O
Temperature: 60 °C
Yield: 48.3 %

Procedure:
Dissolve 3-[(2-acetoxyphenacyl)amino]-2-carbmethoxy-6-chloroindole (800 mg, 2.15 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydrate (932 mg, 8.5 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water, acidify and separate the organic phase. Dry, precipitate with hexane and filter the solid to give the title compound (358 mg, 50%); mp 198°-200° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6](N)[C:5]=2[CH:4]=1.C(=O)([O-])[O-:19].[K+].[K+]>O.C(O)C>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=[O:19])[C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1NC2=O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene-10-ylamine hydrochloride (U.S. Pat. No. 5,229,382) (50 g, 0.19 mol) and solid potassium carbonate (182 g, 1.32 mol) in a mixture of water (1 L) and ethanol (450 mL) and heat at 85° C. for 48 h. Cool to room temperature, and place in ice bath for 2 h. The desired material precipitates out as a yellow solid. Collect solid by filtration, wash with cold water, air-dry for a few minutes and place in the vacuum oven at 45° C. for 48 h to obtain 41.9 g of the title compound, which can be used directly on the next step without further purification: mass spectrum (APCI): m/z=231.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15]Cl)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2(CCCN3CCC(c4csc5cc(F)ccc45)CC3)OCCO2)cc1
Yield: 29 %

Procedure:
A mixture of 1.5 g of 2-(4-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane, 1.5 g of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride, 3.3 ml of diisopropylethylamine and 2.5 ml of methanol was stirred with heating under reflux for 25 hours. The reaction mixture was separated with chloroform and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with chloroform. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230-to 400-mesh, eluent: hexane-ethyl acetate=1:2) to obtain 0.71 g of 2-(4-fluorophenyl)-2-[3-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]propyl]-1,3-dioxolane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: C=CCNCC=O
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[N+:23]([CH3:26])([O-:25])=[O:24].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:7](/[CH:8]=[CH:26]/[N+:23]([O-:25])=[O:24])=[C:6]([F:5])[CH:13]=2)=[N:17][CH:18]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccc(F)cn2)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To an acetic acid (20.0 mL) solution of 2-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-benzaldehyde (901 mg, 3.62 mmol) described in Manufacturing Example 96-1-1 were added nitromethane (1.10 g, 18.1 mmol) and ammonium acetate (558 mg, 7.24 mmol) under nitrogen atmosphere, which was stirred for 2 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.00 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[N:4][CH:3]=1.[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.O1CCCC1>[C:7]1([NH:13][C:14]([NH:1][C:2]2[S:6][N:5]=[N:4][CH:3]=2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cnns1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1cnns1
Reaction time: 8 h

Procedure:
Combine 10.1 g (0.1 mole) 5-amino-1,2,3-thiadiazole, 75 ml of tetrahydrofurane and 11.5 ml (0.106 mole) of phenyl isocyanate. Further add 0.1 ml of triethylamine as catalyst. After standing overnight, the first crystals will have precipitated. The solvent is removed by evaporation under vacuum, and the residue is recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OCF
Temperature: 75 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A mixture of 43.9 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 16.5 mg of (3R)-3-ethynyl-3-quinuclidinol, 11.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.9 mg of cuprous iodide, 42 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 1 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, and then the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 33 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[C:10]2[CH:16]=[CH:15][N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1.C1COCC1.CO.[Li+].[OH-]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
tert-Butyl 4-(5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.100 g, 0.186 mmol) was placed in 1:1 THF:MeOH (6 mL). LiOH (0.621 mL, 1.86 mmol) was then added, and the reaction was stirred at 50° C. for 1 hour. The reaction was then poured into water and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give the crude product tert-butyl 4-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.066 g, 89.3% yield) that was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[OH-].[NH4+:15]>C(#N)C>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:15])=[O:9])[C:3]1=[O:13]
Reactant: [NH4+]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.50 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetate are treated with 11.5 ml of approximately 25% ammonium hydroxide solution, whereupon the mixture is stirred at room temperature for 1 hour. The mixture is treated with acetonitrile and evaporated. The residue is treated five times with acetonitrile and in each case again evaporated. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 163°-164° after recrystallization from methanol/diethyl ether (1:2).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH2:4][CH2:5][CH3:6]>>[I-:2].[CH2:3]([S:7][C:8]1[C:9]([C:13]2[CH2:14][N:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCSc1nsnc1-c1cccnc1
Reactant: CI
Product: CCCCSc1nsnc1C1=CC=CN(C)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(4-butylthio-1,2,5-thiadiazol-3-yl)pyridine (0.6 g, 2.3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:21][N:22]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[C:23]1=[O:41].[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:30]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[C:23](=[O:41])[N:22]([CH3:21])[CH:31]=2)=[N:3][C:4]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[N:5][CH:6]=1
Reactant: CS(N)(=O)=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2c(c1=O)CCCC2

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting product was treated with MeSO2NH2 in a manner similar to Example 163, step 5 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (s, 1H), 7.46 (s, 1H), 7.25-7.20 (m, 1H), 6.90-6.84 (m, 2H), 3.34 (s, 3H), 2.80 (s, 3H), 2.41-2.29 (m, 4H), 1.60-1.48 (m, 4H). LCMS: 463.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 ml (0.013 mole) of 40% aqueous monomethylamine. After stirring for 16 h the reaction mixture was diluted with 100 ml of water and the solid which precipitated was collected by filtration (2.4 g). Recrystallization from benzene/ligroin yielded 2.2 g of white crystals, mp 160°-161°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[NH:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cn[nH]c5)nn34)ccnc2c1

Procedure:
A 48 mL sealed tube was charged with N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.150 g, 0.439 mmol), 1H-pyrazol-4-ylboronic acid (0.0737 g, 0.658 mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, then placed in a 90° C. oil bath for 5 hours. The mixture was concentrated and the black solid was triturated with water to remove K2CO3, then purified by column chromatography using a 40 g RediSep column, eluting with 30-70% (90:10:1 DCM:MeOH:NH4OH solution) in DCM over 40 minutes. Pure fractions were collected to give N-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si](C#N)(C)(C)C.[N:25]1([C:30](N2C=CN=C2)=[O:31])C=CN=[CH:26]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:26][NH:25][C:30]3=[O:31])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccccc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (1.46 g, 10 mmol), benzaldehyde (1.06 g, 10 mmol), TMSCN (1.25 mL, 10 mmol), PdC (10%, 0.05 g). di-(imidazol-1-yl)methanone (1.73, 12 mmol), as described in method 2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.O.CO>C(OCC)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH2:34])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:39][CH:38]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(OCc2cccc(C#N)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(OCc2cccc(CN)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 66.6 %

Procedure:
To a suspension of LiAlH4 (238 mg, 6.28 mmol) in diethyl ether (30 mL), which was stirred and cooled with ice, was added dropwise a solution of 3-(4,4′-dimethoxytrityloxymethyl)benzonitrile (4) (0.86 g, 1.98 mmol) in diethyl ether (90 mL). The mixture was stirred for 16 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, to the mixture were added water (1.2 mL) and MeOH (7.2 mL) and stirred for additional 30 minutes. Then, a formed salt was removed by suction filtration. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:1) to give 3-(4,4′-dimethoxytrityloxymethyl)benzylamine (5) (0.58 g, 69%) as a colorless oil.
Reaction SMILES: [Na].[CH2:2](O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1.C(#N)C(C)=C>ClCCl.CCCCCC>[NH2:5][C:6]1[CH:10]([CH3:2])[CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1
Reactant: CCO
Reactant: NC1=NN(c2ccc(Cl)cn2)CC1
Agent: C=C(C)C#N
Agent: [Na]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1CN(c2ccc(Cl)cn2)N=C1N

Procedure:
As for Example 4 a 0.2 g. amount of sodium metal is dissolved in 50 ml. of absolute ethanol, then 5.0 g. of 5-chloro-2-hydrazinopyridine (Example 3) is added, followed by 4.8 g. of methacrylonitrile. The reaction mixture is refluxed for 18 hours. The solvent is removed in vacuo and water is added to give a gum which solidifies. The solid is collected by filtration, and washed with water. The solid is dissolved in dichloromethane, dried over magnesium sulfate and filtered through anhydrous magnesium silicate. The filtrate is evaporated and the residue is triturated with hexane to give a brown solid. The solid is dissolved in dichloromethane and hexane is added while concentrating to separate a solid. The mixture is cooled and filtered to give 3.4 g. of a gray solid. The desired product is recrystallized from dichloromethane-hexane to give a white solid, m.p. 159°-160° C.
Reaction SMILES: [CH2:1]([Cl:3])Cl.[CH2:4]([Li])[CH2:5][CH2:6]C.[C:9]12([OH:20])[CH2:17][CH:13]([C:14]1([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]2([OH:19])[CH3:18].COCCC[B:26]([O-:28])[O-:27]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[C:9]12([OH:20])[CH2:17][CH:13]([C:14]1([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]2([OH:19])[CH3:18].[Cl:3][C@@H:1]([B:26]([O-:28])[O-:27])[CH2:4][CH2:5][CH2:6][O:20][CH3:9]
Reactant: [Li]CCCC
Reactant: COCCCB([O-])[O-]
Reactant: ClCCl
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCC[C@@H](Cl)B([O-])[O-]
Temperature: -100 °C
Reaction time: 0.25 h

Procedure:
The desired (+)-pinanediol-(S)-1-chloro-4-methoxy-butane-1-boronate is prepared according to the procedure given in Organometallics 3, 1284 (1984). Therefore methylenechloride (2.2 ml) in THF is cooled to -100° C. and n-butyllithium (13.8 ml 1.6M solution, 22.0 mMol) is added over 20 min. After 15 min at -100° C., a solution of (+)-pinanediol-3-methoxy-propane-1-boronate (5.04 g, 20 mMol) in THF is added followed by anhydrous ZnCl2 (1.42 g, 10.0 mMol). After additional 15 min at -100° C. the reaction mixture is warmed to room temperature and stirred for 2 hr at this temperature. The solvent is removed in vacuo, the residue is diluted with ether and washed with water. The organic layer is dried over Na2SO4 and is concentrated to give an oil which is purified by flash chromatography (9:1 hexane/EtOAc) to give the desired (+)-pinanediol-(S)-1-chloro-4-methoxy-butane-1-boronate as a colourless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]([OH:12])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.Cl.[CH3:47][C:48]1([CH3:55])[CH2:52][CH2:51][CH2:50][CH:49]1[NH:53][NH2:54]>CC(N(C)C)=O.O>[CH3:47][C:48]1([CH3:55])[CH2:52][CH2:51][CH2:50][CH:49]1[NH:53][NH:54][C:10](=[O:12])[C:3]1[C:2]([I:1])=[CH:7][CH:6]=[N:5][C:4]=1[O:8][CH3:9]
Reactant: CC1(C)CCCC1NN
Reactant: COc1nccc(I)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1nccc(I)c1C(=O)NNC1CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a mixture of 4-iodo-2-methoxy-3-pyridinecarboxylic acid (2.8 g) and triethylamine (4.5 g) in DMA (40 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and (2,2-dimethylcyclopentyl)hydrazine trihydrochloride (2.8 g) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and added to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.0 g).