Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](=[O:20])([O-])[O-].[Cs+].[Cs+]>>[CH2:9]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:20][C:17]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1
Agent: [Cs+]
Product: Brc1ccc(Oc2ccc(Br)cc2Cc2ccccc2)c(Cc2ccccc2)c1
Yield: 84.7 %

Procedure:
The title compound (6.22 g, 82%) was prepared from 4-bromophenol (5.0 g, 28.9 mmol), benzyl bromide (3.44 ml, 28.9 mmol) and cesium carbonate (10.36 g, 31.8 mmol) in a similar manner to Intermediate 76. 1H NMR (CDCl3) δ 7.50-7.30 (7H, m), 6.86 (2H, d, J 8.8 Hz) and 5.05 (2H, s).
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22]Br)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22][C:28]2[CH:27]=[C:26]([NH2:25])[CH:31]=[CH:30][N:29]=2)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCc1cc(N)ccn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(2-benzylsulfonylhydrazino)-1-(3-bromopropyl)-6-methylpyrazinone, the product of Example 32, (0.174 g, 0.42 mmol) in dioxane (15 mL), are added 4-aminopyridine (0.048 g, 0.51 mmol) and 2,6-lutidine (0.099 mL, 0.85 mmol). The resulting mixture is stirred at 90° C. for about 15 hours and then is concentrated under reduced pressure. The crude residue is purified by RP-HPLC using acetonitrile/water/trifluoroacetic acid as eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[Si]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:27]1[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=1)=[CH:11]2
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.10 g, 0.37 mmol) with 4-tert-butyldimethylsilyloxyphenylboronic acid (0.13 g, 0.52 mmol) according to Method A to yield 0.036 g (33%) of a white solid: mp 254-256° C.; 1H NMR (DMSO-d6): δ 6.90 (2H, d, J=8.64 Hz), 7.43 (1H, d, J=8.95 Hz), 7.72 (2H, d, J=8.64 Hz), 7.99 (1H, d, J=8.97 Hz), 8.38 (1H, d, J=1.95 Hz), 8.47 (1H, d, J=1.92 Hz), 9.73 (1H, s), 11.08 (1H, s); MS (ESI) m/z 294/296 (M−H)−.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]=[C:18]([CH2:22][OH:23])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]2[C:18]([CH2:22][OH:23])([CH2:2]2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC1=CCCN(Cc2ccccc2)C1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ClCCl
Solvent: ICI
Product: OCC12CC1CCN(Cc1ccccc1)C2
Reaction time: 0.25 h

Procedure:
To a solution of ZnEt2 (17.3 ml, 1.0 M) in CH2Cl2 (20 ml) at 0° C. was added CH2I2 (1.4 ml) (CAUTION: exothermic!). After stirring for 15 min, a solution of 172 (352 mg, 1.73 mmol) in CH2Cl2 (2 ml) was added. The mixture was stirred from 0° C. to room temperature overnight. 5% HCl was added to bring the mixture to a homogeneous solution. (white solid dissolved). The two layers were separated. Aqueous layer was neutralized with 2N KOH to pH=10-12, extracted with CH2Cl2 (twice). The combined organic solution was dried (K2CO3/NaSO4), filtered and concentrated. The LRMS of the crude mixture showed that the ratio of 173 to 172 was about 1:1. The product was not isolated from the starting material due to their similar polarities. LRMS (calculated for C14H19NO) 217, found 217.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([CH3:43])=[CH:37]2>CC(N(C)C)=O>[F:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([O:33][C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[NH:39][C:38]([CH3:43])=[CH:37]5)=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A solution of 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (240 mg, 0.63 mmol) in DMA (5 ml) was treated with potassium carbonate (96 mg, 0.69 mmol) and 5-hydroxy-2-methylindole (102 mg, 0.69 mmol), (WO 00/47212, Example 48), and stirred at 85° C. for 4 hours. The mixture was cooled and the solvent evaporated under vacuum to give a residue which was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8). Evaporation of the relevant fractions gave an oil which crystallised on trituration with ether to give 7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (150 mg, 48%).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[OH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[OH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH:30][CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:25][CH2:24]1
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Reactant: NC[C@H]1CC[C@H](O)CC1
Reactant: C=O
Product: O=C1Nc2cccnc2N(CC#CCNC[C@H]2CC[C@H](O)CC2)c2ccccc21
Yield: 31 %

Procedure:
Prepared analogously to Example lb) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and trans-(4-hydroxy-cyclohexyl)methylamine in a yield of 31% of theory. Colourless crystals, m.p. 183°-184° C. (after recrystallisation from ethyl acetate and methanol).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.[NH2:13][NH2:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=2[C:1](=[O:6])[NH:14][NH:13]1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 100 °C

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (3.5 g, 23 mmol), hydrazine hydrate (2.0 mL), sodium acetate (15.4 g, 188 mmol) in 100 mL of acetic acid is heated at 100° C. overnight. Upon cooling, a white solid is formed and collected by filtration. The solid is washed with water and dried to give 2,3,5,6,7,8-hexahydro-phthalazine-1,4-dione. The solid is taken up in 15 mL of POCl3. The resultant mixture is heated at reflux overnight. After cooled, the excess POCl3 is removed under reduced pressure. Crushed ice is added to the residue followed by careful addition of solid Na2CO3 to pH 9. The product is extracted with EtOAc twice. The combined extract is washed with brine, dried and concentrated. The residue is purified by flash silica gel column (Hexanes/EtOAc 4:1) to give 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine as a white solid. 1H NMR: (CDCl3) 2.74 (m, 4H), 1.87 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH2:20]([O:22][C:23]([CH2:25]I)=[O:24])[CH3:21]>>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Reactant: CCOC(=O)CI
Product: CCOC(=O)CN1CCc2c(sc(N)c2C(=O)c2ccc(Cl)cc2)C1
Yield: 70 %

Procedure:
The same procedure as Example 17 was used except an equivalent amount of 2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno[2,3-c]pyridine was used in place of 2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), and an equivalent amount of ethoxycarbonylmethyl iodide was used in place of methyl iodide (3 mmol). (m.p. 105-106° C.; 70% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)[C:8]([C:26]([NH2:28])=[O:27])=[CH:7][N:6]=1.C1COCC1.CO.[H][H]>[C].[Pd].CN(C=O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]([C:26]([NH2:28])=[O:27])=[CH:7][N:6]=1
Reactant: [H][H]
Reactant: NCCNc1ncc(C(N)=O)c(Nc2cccc(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCCNc1ncc(C(N)=O)c(Nc2cccc(O)c2)n1
Yield: 32.8 %

Procedure:
A 100 mg portion of 10% palladium-carbon powder was added to a mixture of 869 mg of 2-(2-aminoethylamino)-4-(3-benzyloxyanilino)pyrimidine-5-carboxamide with THF, methanol and DMF, followed by stirring at room temperature for 3 days in an atmosphere of hydrogen under ordinary pressure. The reaction mixture was filtered, and the filtrate was concentrated under a reduced pressure. By Ad:. recrystallizing the resulting residue from an ethyl acetate-methanol mixed solvent, 217 mg of 2-(2-aminoethylamino)-4-(3-hydroxyanilino)pyrimidine-5-carboxamide was obtained (light brown solid).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([O:12][Si:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][Si:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:30][CH:31]=1)=[S:2]
Reactant: CC(C)(C)[Si](OC(=O)c1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(=O)c1ccc(OC(=S)Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 40.7 ml of thiophosgene in 300 ml of dry diethyl ether at -78° C. was added dropwise a solution of 20 g of diphenyl-(2-methylprop-2-yl)silyl 4-hydroxybenzoate and 8.5 ml of triethylamine. After having been stirred for a further 30 minutes at -78° C. and 90 minutes at room temperature, the mixture was partitioned between diethyl ether and water. The organic layer was washed with water and brine, was dried over calcium chloride, and then evaporated in vacuo to afford 25.9 g of an orange oil. Crromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded 16.8 g of the title compound.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[CH3:30].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([F:20])=[C:22]([CH3:30])[CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(F)c(C)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-3-methyl-benzoic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as light brown powder. MS: m/e=417(M+H+).
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=2)[O:8][N:7]=1.[CH3:31][NH2:32].O>O1CCOCC1>[CH3:31][NH:32][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH:16]=2)[O:8][N:7]=1
Reactant: CN
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Temperature: 120 °C
Yield: 66 %

Procedure:
To a solution of 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (330 mg, 0.79 mmol) in 1,4-dioxane (4 mL) was added 40 wt % solution of methylamine in H2O (2.7 mL, 31.6 mmol). The mixture was heated at 120° C. for 12 h, cooled, and concentrated. The residue was dissolved in water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 2:1 to give N-methyl-3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionamide (217 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (40.2 g, 165 mmol) in CH2Cl2 (500 mL) and AcOH (60 mL) was added dihydro-2H-pyran-4-one (17.3 g, 173 mmol) and sodium triacetoxyborohydride (73.6 g, 330 mmol). The reaction mixture was stirred at RT for 20 hours. Then saturated NaHCO3 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was concentrated in vacuo. The residue was triturated with ethyl ether, and resultant precipitate was collected to afford the titled compound as a white solid (39.1 g, 72%). 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.01 (s, 1H), 6.98 (s, 1H), 5.00 (d, J=7.6 Hz, 1H), 3.84-3.87 (m, 2H), 3.79 (s, 3H), 3.54-3.56 (m, 1H), 3.43 (m, 2H), 2.14 (s, 3H), 1.81-1.84 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:44](=[O:45])[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]3=[O:46])[CH:29]=[CH:30][CH:31]=2)O1>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:30]3[CH:29]=[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]4[C:37](=[O:46])[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:44]4=[O:45])[CH:27]=[CH:26][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2cccc(CCCCN3C(=O)c4ccccc4C3=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 10 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1), 2-(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)isoindoline-1,3-dione (C13b), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 75° C. and isolated as a dark orange solid (5.48 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.13-8.04 (m, 2H), 7.96-7.89 (m, 2H), 7.88-7.77 (m, 4H), 7.67-7.57 (m, 2H), 7.45-7.38 (m, 1H), 7.31 (dt, J=7.7, 1.5 Hz, 1H), 3.69-3.53 (m, 2H), 2.70 (t, J=6.8 Hz, 2H), 1.64 (dq, J=6.6, 3.1 Hz, 4H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 507 ([M+H]+).
Reaction SMILES: C([OH:4])C#C.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.N1C=C[CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:12][CH2:16][C:17]#[CH:18])=[O:4]
Reactant: C#CCO
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccncc1
Agent: Cl
Solvent: c1ccccc1
Product: C#CCOC(=O)CCCCCBr
Reaction time: 8 h

Procedure:
Propargyl alcohol (0.5 mL, 3.41 mmol, 1 eq.) was dissolved in 10 mL of dry pyridine and 10 mL of dry benzene under argon and this solution was cooled in an ice bath. 6-bromohexanoyl chloride (0.612 mL, 4.1 mmol, 1.2 eq.) dissolved in 10 mL of dry benzene under argon was then added dropwise to the propargyl alcohol solution and stirred overnight. The solution was acidified with 1M HCl, then extracted twice with CH2Cl2. The organic layers were twice washed with 1M NaOH, once washed with brine, and dried over Na2SO4. The solvent was removed on a rotary evaporator to yield a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=2)[CH2:9][CH2:8]1)=[O:5]>[O-2].[Mn+4].[O-2].C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:12]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](CNc2ccc(CO)cn2)CC1)c1cc(C(F)(F)F)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-2-Chloro-N-{4-[(5-hydroxymethyl-pyridin-2-ylamino)-methyl]-cyclohexyl}-5-trifluoromethyl-benzamide (Example 19.20) (100 mg, 0.23 mmol) is placed in a flask with DCM (10 mL) and manganese (IV) oxide (297 mg, 3.4 mmol). The reaction mixture is stirred at RT for 4 hours and manganese (IV) oxide is removed by filtration. The solvent was removed in vacuo to afford the title compound; NMR (400 MHz, DMSO-d6) δ 9.66 (1H, s), 8.49 (2H, m), 7.77 (5H, m), 6.58 (1H, d), 3.70 (1H, m), 3.23 (2H, m), 1.93 (2H, m), 1.81 (2H, m),1.53 (1H, m), 1.23 (2H, m), 1.09 (2H, m).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[N:45]1([CH2:50][CH2:51][O:52][C:53]2[CH:59]=CC(N)=[CH:55][CH:54]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1.N[C:61]1C=CC=C[CH:62]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:30]=[CH:59][C:53]([O:52][CH2:51][CH2:50][N:45]6[CH2:49][CH2:48][CH2:47][CH2:46]6)=[CH:54][CH:55]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:61][CH2:62]1)[CH2:5][O:12][CH2:9]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN5CCCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(2-(pyrrolidin-1-yl)ethoxy)aniline as the aniline component. (50%, MS=583.5 (M+H))
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:16]([OH:18])=O)([O-:3])=[O:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([NH2:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:30]([N:36]2[C:16](=[O:18])[C:5]3[C:6](=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C(=O)O
Solvent: Cc1ccccc1
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 48.8 %

Procedure:
A mixture of 3,4-dinitrophthalic acid (4.63 g, 18.1 mmol) and 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)eth-2-ylamine (4.94 g, 18.1 g) in toluene (70 mL) was heated to reflux for 15 hours. The water was removed by a Dean-Stark trap. To the reaction mixture was added ethyl acetate (150 mL). The organic layer was extracted with water, sodium hydrogen carbonate (sat), brine (100 mL each), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (300 mL) to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione as an orange solid (4.35 g, 49% yield): mp, 122.0-124.0° C.; 1H NMR (CDCl3) δ1.47 (t, J=6.9 Hz, 3H, CH3), 2.93 (s, 3H, CH3), 3.65 (dd, J=3.9, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.56 (dd, J=11.4, 14.1 Hz, 1H, CHH), 5.90 (dd, J=3.9, 11.1 Hz, 1H, NCH), 6.84 (d, J=8.0 Hz, 1H, Ar), 7.07-7.11 (m, 2H, Ar), 8.16 (d, J=8.2 Hz, 1H, Ar), 8.60 (d, J=7.9 Hz, 1H, Ar); 13C NMR (CDCl3) δ14.66, 41.66, 49.57, 53.38, 55.98, 64.61, 111.61, 112.42, 120.64, 123.93, 126.18, 127.85, 131.93, 136.74, 138.10, 142.45, 148.77, 150.17, 161.57, 163.47; Anal Calcd for C20H19N3O10S+0.1 ethyl acetate: C, 48.78; H, 3.97; N, 8.37. Found: C, 48.50; H, 3.77; N, 8.07. (HNMR showed the sample contained ˜10% eq of ethyl acetate).
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:28]([CH3:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH:54]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH3:51])[CH2:38][CH2:37]4)=[C:28]([CH3:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)CC=O
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1OCCCN1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E70.2 (100 mg, 0.16 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.068 ml, 0.48 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.031 ml, 0.24 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.24 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (98 mg, 96%).