Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=CC=3S[C:3]=12.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].Cl.N1C=CC=CC=1>CO>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:16][CH:15]=[CH:14][C:3]=12
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: N#Cc1cnc2ccccc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 530 mg (3.27 mmol) of 2,4-dichloroaniline and 112 mg of pyridine hydrochloride is heated until no 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile remained as measured by thin layer chromatography. The reaction mire is cooled to room temperature and the solid is treated with methanol and then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the solid is collected by filtration to give 225 mg (66%) of a yellow solid. An analytical sample is obtained by column chromatography, eluting with 6:1 hexane/ethyl acetate, to provide a fight yellow solid, mp 260–262° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: C1COCCN1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCOCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and morpholine are converted to the named compound.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([CH2:23][C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=[C:17]4N=N3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:30].[NH4+]>O>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]3[C:17]([OH:30])=[CH:22][C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Agent: [NH4+]
Solvent: O
Product: Oc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.83 h

Procedure:
A mixture of 3-[3-(5,6,7,8-tetrahydroquinol-8-yl)propyl]-6-(pyrid-3-ylmethyl)-3H-1,2,3-triazolo[5,4-b]pyridine (3.56 g) and polyphosphoric acid (17.5 g) were heated with stirring at 188°-197° C. for 50 minutes. Water (30 ml) was added to the hot residue and, after slight cooling, the solution was basified with aqueous ammonium hydroxide to pH 10 and then extracted with chloroform. The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo and the residue was chromatographed on silica eluted with 5% v/v methanol in chloroform to give the title compound as a brown gum (0.68 g). The aqueous portion after extraction, was concentrated to dryness, to give a paste, water (100 ml) was then added, the mixture was refluxed for 1 hour and a brown oil which formed was extracted with chloroform (3×100 ml). The extracts were dried, combined and concentrated to give a further quantity of the title compound as an oil (0.31 g). The two portions of the product were combined, converted to the trihydrochloride with ethanolic HCl and then recrystallised, first from isopropanol and then from isopropanol/methanol to give the title compound as a buff solid (0.5 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:8][C:9]([C:13]([NH2:15])=[O:14])=[N:10]2)=[CH:5][CH:4]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:17][CH:18]=1
Reactant: OB(O)c1cncnc1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cc3cncnc3)cc2n1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
Degassed DME (1237 μl)/Water (619 μl) was added to 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 100 mg, 0.278 mmol), pyrimidin-5-ylboronic acid (41.4 mg, 0.334 mmol), Pd(PPh3)4 (16.09 mg, 0.014 mmol), and Na2CO3 (62.0 mg, 0.585 mmol). The reaction was heated at 100° C. in the microwave for 10 minutes. The reaction was quenched with water and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The crude material was purified by flash column chromatography (12 g SiO2, 0-100% EtOAc/hexanes) to afford impure product. The material was purified further by reverse phase HPLC (20×150 mm, Waters Sunfire, Solvent A=0.1% TFA/H2O, Solvent B=0.1% TFA/MeCN, 20 ml/min) to afford, after basic workup, 4-(4-fluorophenyl)-7-(pyrimidin-5-ylmethyl)quinoline-2-carboxamide (6-3, 8.16 mg, 8.18% yield) as a white solid. 1H NMR (500 MHz, CDCl3): δ 9.14 (s, 1H); 8.68 (s, 2H); 8.23 (s, 1H); 8.05 (s, 1H); 7.97 (s, 1H); 7.93 (d, J=8.7 Hz, 1H); 7.50 (dd, J=8.5, 5.4 Hz, 2H); 7.42 (dd, J=8.7, 1.8 Hz, 1H); 7.24 (t, J=8.5 Hz, 2H); 5.64 (s, 1H); 4.22 (s, 2H). LRMS m/z (M+H)+ 359.2 found, 359.4 required.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:29]([O:31][CH3:32])=[O:30].Cl>N1C(C)=CC(C)=CC=1C>[CH3:32][O:31][C:29]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[CH:24][CH:25]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:30]
Reactant: C#Cc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: C#Cc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg of 1-(β-D-glucopyranosyloxy)-2-(4-ethynylbenzyl)-benzene in 0.5 ml of 2,4,6-collidine are combined with 0.026 ml of methyl chloroformate in the ice bath and then stirred for 16 hours at ambient temperature. 5 ml of 0.1 N hydrochloric acid are added to the reaction mixture which is then extracted with 10 ml of ethyl acetate. The organic phase is separated off, washed with saturated saline solution and evaporated down. The residue is stirred with 8 ml of diethyl ether/petroleum ether (1:1), the solid is suction filtered and dried at 40° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH:12]=[O:13])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[C:1]([NH:5][S:6]([C:9]1([CH2:12][OH:13])[CH2:10][CH2:11]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)C1(C=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)NS(=O)(=O)C1(CO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round-bottom flask equipped with a stir bar was charged with a solution of N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide (8.89 g, 43.3 mmol) in MeOH (110 mL). The solution was cooled to 0° C. and to the solution was added portionwise sodium borohydride (1.64 g, 43.3 mmol). The solution was stirred for 1 h. To the solution was added brine and the mixture was stirred for 15 min. The mixture was concentrated in vacuo to remove MeOH and the aqueous solution was then transferred to separatory funnel and was twice extracted with EtOAc. The combined organics were washed with sat. aq. NaCl; dried over MgSO4; filtered; and then concentrated in vacuo to afford N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide as a colorless, crystalline solid (8.66 g, 96%). 1H NMR (400 MHz, CDCl3) δ 4.35 (br. s., 1H), 3.86 (d, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 1H), 1.50-1.45 (m, 2H), 1.39 (s, 9H), 1.06-1.01 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]([C:11]([F:14])([F:12])[F:13])/[CH:9]=[CH:8]/[C:6]2[CH:7]=[CH:2][C:3]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Reaction SMILES: [OH:1][C:2](=[C:20]1[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])OC1=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:30](O)(C)(C)C>>[O:1]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][C:25]([O:24][C:23]([CH3:27])([CH3:28])[CH3:30])=[O:26]
Reactant: CCCCCCCCC=CCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)O
Product: CCCCCCCCC=CCCCCCCCC(=O)CC(=O)OC(C)(C)C

Procedure:
Starting from 5-(1-hydroxy-9-octadecenylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (18 g) and tert-butyl alcohol (200 ml), tert-butyl 3-oxo-11-eicosenoate (13 g) was obtained as an oil according to a similar manner to that of Preparation A-2 (2).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]([C:9]2[N:10]([CH2:25][C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[S:28][CH:27]=3)[N:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH2:21][CH:22]([CH3:24])[CH3:23])[N:6]([CH3:8])[CH:7]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(N(CC)CC)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([CH2:25][N:10]2[C:9]([C:5]3[N:6]([CH3:8])[CH:7]=[C:3]([NH:2][C:35](=[O:37])[CH3:36])[N:4]=3)=[C:17]3[C:12]([N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[N:11]2)=[CH:27]1
Reactant: CC(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(N)cn3C)n(Cc3csc4ccccc34)nc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cn(C)c(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2csc3ccccc23)n1

Procedure:
This compound was synthesized by the reaction of 3-(4-amino-1-methyl-1H-imidazol-2-yl)-2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione hydrochloride and acetyl chloride using triethylamine as a base. Mass: 506.09 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)=[C:9]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[CH:8]=1)=[O:5])[CH3:2].[OH-].[Li+]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)=[C:9]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(-c2cncc(C(=O)OCC)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(-c2cncc(C(=O)O)c2)cn1
Temperature: 45 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Ethyl 6′-{[(ethylamino)carbonyl]amino}-5″-fluoro-3,3′:4′,3″-terpyridine-5-carboxylate (Example 68, 0.19 g, 0.46 mmol) was added to a 25 mL round-bottomed flask with THF (3 mL) to give a white suspension. Lithium hydroxide (1.160 mL, 1.16 mmol) was added to the mixture, and the solution was stirred at 45° C. for 2 h. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and adjusted to pH˜4 by 2N HCl. The precipitate that formed was collected by filtration, washed with water, and dried to give the title compound as a white solid (154 mg). MS (ESP): 382 (MH+) for C19H16FN5O3; NMR: 1.08 (t, 3H), 3.13-3.24 (m, 2H), 7.63 (s, 1H) 7.64-7.68 (m, 1H) 7.69-7.77 (m, 1H), 7.93 (t, 1H), 8.19 (t, 1H), 8.36 (s, 1H), 8.45 (d, 1H), 8.55 (d, 1H), 8.90 (d, 1H), 9.45 (s, 1H).
Reaction SMILES: [C:1]([NH:5][NH2:6])(=O)[CH2:2][OH:3].[CH3:7][N:8]=[C:9]=[S:10].CO.[Na]>C(O)C>[OH:3][CH2:2][C:1]1[N:8]([CH3:7])[C:9]([SH:10])=[N:6][N:5]=1
Reactant: CN=C=S
Reactant: NNC(=O)CO
Agent: [Na]
Solvent: CO
Solvent: CCO
Product: Cn1c(S)nnc1CO
Yield: 35.9 %

Procedure:
A mixture of 9 g of glycolic acid hydrazide, 7.3 g of methyl isothiocyanate, 50 ml of methanol and 50 ml of ethanol was heated under reflux for 5 hours. Following the addition of 2.3 g of sodium metal, the mixture was further refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 ml of water and adjusted to pH 2.5 with phosphoric acid. The resultant crystals were collected by filtration and recrystallized from ethanol. By the above procedure there were obtained 5.2 g of the captioned compound. m.p. 199°-201° C.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11](F)=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1.[O-]C#[N:21].[K+].CN(C=O)C>O>[CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11]([NH2:21])=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: N#C[O-]
Reactant: Cc1cc2c(nc1F)C(=O)N(C(C)C1CC1)C2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(nc1N)C(=O)N(C(C)C1CC1)C2=O

Procedure:
6.3 g (0.0254 mol) of N-1-(cyclopropyl)ethyl-6-fluoro-5-methylpyridine-2,3-dicarboximide and 4.1 g (0.051 mol) of potassium cyanate were introduced into a mixture of 50 ml of DMF and 1 ml of water at 25° C. with stirring and then stirred at 125° C. for 30 minutes. After concentrating the reaction mixture under reduced pressure, the residue was stirred in succession with methyl tert-butyl ether and with water. Insoluble matter was filtered off with suction, washed with methyl tert-butyl ether and dried under reduced pressure. 3.5 g (56% of theory) of the title compound of m.p. 219°-220° C. were obtained. A further 1.6 g (=26% of theory) of the title compound of m.p. 201°-219° C. were obtained from the organic phase after washing with water and drying over magnesium sulfate (active compound Example 1.059).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[C:3]([NH2:12])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
The title compound was made using a procedure described in Collins, et. al., Tetrahedron, Vol. 48, No. 37, pp 7887-7898, 1992. To a solution of 1-fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.64 mL, 5.7 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH2Cl2 and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.
Reaction SMILES: [CH3:1][C:2]([OH:21])([CH2:4][CH2:5][NH:6][C:7]1[N:8]=[N:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH3:3].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:3][C:2]1([CH3:1])[O:21][C:23](=[O:25])[N:6]([C:7]2[N:8]=[N:9][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(O)CCNc1ccc(C#Cc2ccccc2)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC1(C)CCN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1

Procedure:
The title compound, a crystalline light yellow solid, MS: m/e=308.3 (M+H+), was prepared in accordance with the general method of Example 152, step 2 starting from 2-methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol (Example 153, step 1) and triphosgene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.[CH3:21][CH2:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][CH3:21])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC(CCC)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45; 45.7 mg) and 4-heptanone (24 μL) were dissolved and stirred in 3 mL of dichloroethane. After 15 min, 44.5 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred at 60° C. during the day and at room temperature over night during 3 d. During this period, an additional 109 μL of 4-heptanone and an additional 104 mg of sodium triacetoxyborohydride were added to drive the reaction to completion. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate was dried with magnesium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 11 mg of crystalline [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amine (5-6): ms (MH+)=389.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(F)(F)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(F)(F)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 5-(4-bromo-phenyl)-4-(1,1-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccc([N+](=O)[O-])cc3)c2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Yield: 90.7 %

Procedure:
3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 98, 70 mg) was dissolved in 25 mL of anhydrous EtOH and treated with 10% palladium on carbon (20 mg). The mixture was subjected to hydrogen for 4 h at 30 psi. The mixture was filtered through diatomaceous earth. The filtrate was concentrated and dried via vacuum line to afford 55 mg of 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate aniline was then dissolved in 1 mL of MeOH and treated with 5 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The resulting yellow semi-solid was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.007 g of the title compound as a light yellow solid. MS (ESI): exact mass calculated for C20H22N4, 318.18; found, m/z 319.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.34 (m, 1H), 6.94-6.90 (m, 2H), 6.68-6.65 (m, 2H), 5.23 (s, 2H), 3.11-3.06 (m, 4H), 2.99-2.96 (m, 2H), 2.91-2.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN(C)C=O>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[O:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nc5ccccc5s4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred mixture of 5.5 parts of 4-[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethylformamide were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at room temperature, 2.54 parts of 2-chlorobenzothiazole were added and the whole was further stirred for 3 hours. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.6 parts (61%) of N-[1-[2-(2-benzothiazolyloxy)ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 147.0° C. (compound 67).