Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[NH2:66][CH:67]([CH:87]1[CH2:92][CH2:91][CH2:90][CH2:89][CH2:88]1)[C:68]([N:70]1[CH2:74][CH2:73][CH2:72][C@H:71]1[C:75]1[N:76]=[N:77][N:78]([CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[N:79]=1)=[O:69]>CC(N(C)C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:12])[NH:66][CH:67]([CH:87]1[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92]1)[C:68]([N:70]1[CH2:74][CH2:73][CH2:72][C@H:71]1[C:75]1[N:76]=[N:77][N:78]([CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[N:79]=1)=[O:69])[CH2:13][CH3:14])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl-methyl-amino)-butyric acid (53.0 mg, 0.24 mmol) in DMA (2 mL) is added HBTU (125.0 mg, 0.33 mmol), HOBt (44.6 mg, 0.33 mmol) and diisopropylethylamine (192 uL, 1.1 mmol). The mixture is stirred at room temperature for 5 minutes. A solution of compound F in DCM (2 mL) is added to the above mixture at 0° C. The reaction mixture is stirred at room temperature for 1 hour and concentrated under vacuum. The residue is diluted with EtOAc. The organic is washed with brine, citric acid (5%), brine, NaHCO3(Sat.) and brine. The organic layer is then dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=554.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 50.0 g of 3,4-dichloroacetophenone and 75 ml of N,N-dimethylformamide dimethyl acetal was heated under reflux for 6 hours, then allowed to cool for 16 hours. The crystalline precipitate was collected by filtration, washed with hexane and dried. The addition of hexane to the above filtrate precipitated some additional product which was collected by filtration. The precipitates were combined, washed with hexane and dried in vacuo to give 55.0 g of 3',4'-dichloro-3-dimethylaminoacrylophenone as bright yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:27]=[CH:26][NH:25][C:24]=1[CH2:28]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:28][C:24]2[NH:25][CH:26]=[CH:27][C:23]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(Nc1ccc(F)cc1)C(=O)O
Reactant: OCc1[nH]ccc1Cc1ccccc1
Product: CC(C)C(Nc1ccc(F)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
The acid 2-(4-fluorophenylamino)-3-methylbutanoic acid is reacted with 3-benzylpyrrolylmethyl alcohol using the procedure of Example 3 to give 3-benzylpyrrolylmethyl 2-(4-fluorophenylamino)-3-methylbutanoate.
Reaction SMILES: [OH-].[Li+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCOC1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCOC1CCN(Cc2ccccc2)CC1
Yield: 28.3 %

Procedure:
Lithium hydroxide (7.21 ml of a 1N aqueous solution) was added to a solution of methyl 3-[(1-benzyl-4-piperidyl)oxy]propanoate (1.00 g) [see Preparation 34) in methanol (43.3 ml). The reaction mixture was stirred for 36 hours at room temperature after which time the methanol was evaporated under reduced pressure. The crude product was dissolved in a small amount of water and purified on a Dowex 50WX8-200 (trade mark) ion-exchange resin eluting with 0:100 changing to 50:50 (in 10% increments), by volume, water: 0.88 aqueous ammonia solution. The aqueous eluted solution was concentrated under reduced pressure and the residue was frozen and lyophilised to afford 3-[(1-benzyl-4-piperidyl)oxy]propanoic acid (269 mg) as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[CH2:27][CH:28]1[CH2:30][CH2:29]1)(=[O:25])[NH2:26]
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-2-amino-3-cyclopropylpropanamide hydrochloride (Example 97 a) as starting materials. MS (EI): m/e=382.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)NN2CCN(C)CC2)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(NC(=O)c2ccc(C(=O)NN)s2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
Methyl 5-(4-methylpiperazin-1-ylcarbamoyl)thiophene-2-carboxylate (218 mg, 0.77 mmol) in ethanol (60 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature, and the solvent was evaporated at 40° C. mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 142 mg of the desired product (yield 65%).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[C:47](=[O:51])[NH:46][CH2:45]3)O1>C(#N)C.O>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[C:47](=[O:51])[NH:46][CH2:45]3)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CNC4=O)cc2)CCOCC1
Temperature: 90 °C
Yield: 60.9 %

Procedure:
A mixture of (S)-tert-butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 260 mg), potassium acetate (153 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (162 mg) in acetonitrile (10 mL) and water (5 mL) under a nitrogen atmosphere, was treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) and the mixture stirred and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The products were extracted into ethyl acetate (2×100 mL) and the combined extracts dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccccc1OCc1cccc(OCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.7 %

Procedure:
A solution of 215 mg of 1-[(2-chlorophenoxy)methyl]-3-[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]benzene, as prepared in the preceding step, in methylene chloride (2 mL) was treated with 1.5 mL of 4N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to provide 183 mg of the title compound as a colorless powder after repeated concentrations from diethyl ether/hexane/methanol. 1H-NMR (300 MHz, DMSO-d6) δ 8.51 (br s, 2H), 7.45 (dd, 1H, J=1.3, 7.9 Hz), 7.27-7.35 (m, 2H), 7.21 (d, 1H), 6.90-7.05 (m, 4H), 5.18 (s, 2H), 3.87 (d, 2H), 2.90 (t, 2H, J=10 Hz), 2.05 (m, 1H), 1.91 (d, 2H, J=13.8 Hz), and 1.5-1.54 (m, 2H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H22ClNO2 : 332.1 (M+H). Found: 332.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) and TBTU (177 mg, 0.55 mmol) in DMF (2.5 mL) was added DIPEA (428 μL, 2.50 mmol). Then 4-aminotetrahydropyran (56 mg, 0.55 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane, then 5% methanol in dichloromethane) afforded the title compound (43 mg, 22%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])[NH:6][C:5]3=[O:11])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
4-Methyl-2-oxindole was condensed with 1H-indole-5-carbaldehyde using method B to give 3-(1H-indol-5-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a white solid which was reduced using method C to give 20 mg (40%) of 3-(1H-indol-5-ylmethyl)-4-methyl-1,3-dihydroindol-2-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:13][C:14]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[CH:20]=[C:19]([F:30])[C:15]=3[C:16]([OH:18])=[O:17])=O)=[CH:9][C:4]=2[O:3][CH2:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[O:17][C:16](=[O:18])[C:15]4[C:19]([F:30])=[CH:20][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:22][C:14]=4[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN1CCN(c2cc(F)c(C(=O)O)c(NC(=O)Cc3ccc4c(c3)OCO4)c2)CC1
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2cc(F)c3c(=O)oc(Cc4ccc5c(c4)OCO5)nc3c2)CC1
Temperature: 130 °C

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][C:6]#[N:7].[H-].C([Al+]CC(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C@H:30](N)[CH3:31])[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][NH:7][C@@H:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)[CH3:31]
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: Cc1ccccc1C=CC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2ccccc2C)c1

Procedure:
In a similar fashion, 2-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate mine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(2-methylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12C, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 4), 266 (15), 176 (18), 146 (62), 135 (58), 131 (100), 115 (23), 105 (19), 91 (38), 77 (17).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[CH2:12][NH:11][CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(O)C>O.C(O)(C)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH3:4])[CH:7]=3)[CH2:12]2)[N:22]=[CH:21][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1cc(Cl)ncn1)CC2

Procedure:
Sodium hydroxide solution (80 ml, IN) was added to a suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in water (20 ml) followed by 4,6-dichloropyrimidine (5.95 g) and the mixture was heated on a steam bath for 5 hours. The solvent was evaporated in vacuo to give a brown oil which solidified on standing. Re-crystallization from aqueous ethanol followed by isopropanol gave 4-chloro-6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)pyrimidine (6.0 g). An analytical sample re-crystallized from isopropanol, m.p. 88°-89°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]3[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCn3c2nc2cccnc23)cc1
Reaction time: 24 h
Yield: 79 %

Procedure:
A mixture of 1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridine (1.7 g) and 10% palladium on carbon (50% wet, 1.0 g) in MeOH (150 mL) was hydrogenated under balloon pressure at room temperature for 1 day. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][N:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:30][C:27]([C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)([OH:28])[CH3:29])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(C2(C)CO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) was dissolved in DMF (3 mL), sodium hydride (106 mg, 2.65 mmol) was added and stirred for 15 min. at RT. 2-Methyl-5-(2-methyl-oxiranyl)-pyridine (263 mg, 1.76 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 3 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (2×60 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 200 mg of 1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-(6-methyl-pyridin-3-yl)-propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.5 (d, 1H), 8.3 (s, 1H), 7.79 (d, 1H), 7.22 (s, 1H), 6.82 (s, 2H), 5.03 (t, 1H), 4.38 (dd, 2H), 3.8 (m, 1H), 3.66 (m, 2H), 3.46 (m, 2H), 3.2 (m, 2H), 2.7 (m, 1H), 2.67 (s, 3H), 2.36 (s, 3H), 2.22 (m, 2H), 1.77 (s, 3H). Separation by chiral HPLC provided enantiomers II-128a-b.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26]C1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC=C(OC)N=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([O:26][CH3:25])[N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: COc1cccc(Br)n1
Product: COc1cccc(-c2ccc(-c3nc4ccccc4o3)cc2OC)n1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-6-methoxypyridine (65 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(6-methoxypyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.96–7.95 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 1H), 7.67–7.60 (m, 3H), 7.39–7.36 (m, 2H), 7.14–7.12 (m, 1H), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 333 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)(=O)[CH3:8].[BH4-].[Na+]>[OH-].[Na+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:15][C:12]1[S:11][C:10]([CH:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH3:8])=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(Br)s1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CC(c1ccc(Br)s1)N1CCOCC1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
To a solution of morpholine (1.20 mmol) in titanium (IV) isopropoxide (1.95 mmol) was added 2-acetyl-5-bromothiophene (1.20 mmol). The reaction was heated in a microwave at 150° C. for 5 minutes. Sodium borohydride (1.95 mmol) was added and the reaction stirred at RT for 16 h. The reaction was diluted with sodium hydroxide solution (2N, 10 ml) and the solids formed removed by filtration. The filtrate was extracted with ethylacetate (3×20 ml), the combined organics were washed with brine and dried over magnesium sulphate. The product was purified by flash chromatography (silica gel, 10-20% ethylacetate in iso-hexane) to, give the title product as a brown oil: m/z=276 (100%, M+H), 278 (100%, M+H) in MS ES+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:13]2([CH3:21])[CH3:20])[NH:4][N:3]=1.[CH3:29]C1C2C(C(O)=O)=CC(C3C=CC(OC4CCCCO4)=CC=3)=NC=2N(C2CCCCO2)N=1.C(N1CC(CC)(C)NCC1(C)C)C1C=CC=CC=1>>[CH2:20]([C:13]1([CH3:21])[CH2:14][NH:15][C:16]([CH3:18])([CH3:19])[CH2:17][N:12]1[CH2:11][C:9]1[CH:8]=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)[N:6]=[C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]=12)[CH3:29]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Agent: CCC1(C)CN(Cc2ccccc2)C(C)(C)CN1
Product: CCC1(C)CNC(C)(C)CN1Cc1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12

Procedure:
4-[4-(2-ethyl-2,5,5-trimethyl-piperazin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol was synthesized in analogy to Example 49 (4-[3-Methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol) starting from 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 1-benzyl-5-ethyl-2,2,5-trimethyl-piperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH3:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]2[CH2:29][CH2:30][N:31]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:32][CH2:33]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: C[C@@H](c1ccc(F)cc1)N1CCNCC1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
(6-Chloropyrimidin-4-yl)-quinolin-7-yl-amine, Example 4(c), (59 mg, 0.23 mmol) was reacted with 1-[(1S)-1-(4-fluorophenyl)ethyl]piperazine (57 mg, 0.27 mmol, prepared from (1S)-1-(4-fluorophenyl)ethylamine (SynQuest) according steps (a) and (b) of Example 4) under the conditions of Example 4(d) to give the title compound. M.p.: 206-207° C. MS (ESI, pos. ion.) m/z: 429 (M+1).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26]
Reactant: CCCCCCC(=N)N
Reactant: Cc1ccc(N=C=S)c(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccc(C)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1 and using 2.3 g. sodium in 250 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 16 g. 2-chloro-4-methylphenyl isothiocyanate (b.p. 80°-82° C./0.3 mm.; prepared from 2-chloro-4-methylaniline) in 100 ml. dry acetone there was obtained 1-(2-chloro-4-methylphenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 78°-80° C. (from benzene-n-pentane); hydrochloride (23 g.), m.p. 138°-140° C. (from isopropyl alcohol).