Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[O-]CC.[Na+]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:11]([C:10]#[N:14])[C:12]#[N:13]
Reactant: N#CCC#N
Reactant: c1ccc2scnc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)=C1Nc2ccccc2S1

Procedure:
In the first step, the benzothiazole 10 [L is a leaving group, as in Reaction Scheme 4] reacts with malononitrile in the presence of a strong base, such as sodium ethoxide in ethanol, to give the 2-[benzothiazol-2(3H)-ylidene]malononitrile 17. Reaction of this nitrile in suspension in a polar solvent with gaseous hydrogen chloride gives the 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetimidate 18, and reaction of the imidate with ammonia gives the corresponding 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine 19. Compound 19 is then reacted with a β-diketone or equivalent, such as 2,4-pentanedione or ethyl 3-oxo-4,4,4-trifluorobutyrate, to form the pyrimidine ring [substituents not shown] of the compound of formula 6, in the presence of a base such as sodium ethoxide in an aprotic solvent under strong (e.g. microwave) heating. Finally, the compound of formula 6 is hydrolyzed to a compound of formula 8, as in Reaction Scheme 1. If the order is reversed, so that the hydrolysis is performed before the coupling, the hydrolysis proceeds as in Reaction Scheme 1, and the coupling may take place under milder conditions.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(Cl)c4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.039 g, 49%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (E)-4-(4-amino-1H-indazol-1-yl)-4-(4-chlorophenyl)hex-2-enenitrile (130 mg) and NMM (117 mg) in DCM (5 mL) was added MsCl (53 mg), Then the mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: PE/EA=5/1) to afford the title compound as a pale yellow solid. LC/MS m/z=415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][N:17]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:18][N:17]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5nnc(C6CCN(C(=O)OC(C)(C)C)CC6)o5)ccc43)cc2OC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5nnc(C6CCNCC6)o5)ccc43)cc2OC)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a −20° C. solution of tert-butyl 4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (0.090 mg, 0.14 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at −20° C. After 1 h, the mixture was concentrated. The residue was purified by Prep-HPLC to afford 0.010 g (14%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.02-8.01 (m, 2H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.76-6.72 (m, 3H), 5.32 (s, 2H), 5.03 (s, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.31-3.29 (m, 2H), 3.23-3.21 (m, 1H), 2.92-2.88 (m, 2H), 2.23-2.21 (m, 2H), 2.02-1.98 (m, 2H) ppm; (M+1)=527.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)oc1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
At -78° C., to a stirred solution of commercial 2,3-dimethylfuran (50 g, 0.520 mol) in THF (2.6 L) was add dropwise 1.6M n-BuLi/hexanes (325 mL, 0.520 mol). After the addition was complete, the dry ice/acetone bath was removed and the reaction was stirred for 1 h. At -78° C., to the reaction was added dropwise commercial benzyl bromide (62 mL, 0.520 mol). After the addition was complete the reaction was stirred at -78° C. for 6 h, the dry ice/acetone bath was removed and the reaction was stirred for 7 days. The reaction was concentrated in vacuo and purified on silica gel eluting with hexane to give 75.70 g (78%) of the title compound as a clear oil; 1H NMR (DMSO-d6) δ 1.83 (s, 3 H), 2.08 (s, 3 H), 3.83 (s, 2 H), 5.83 (s, 1 H), 7.16-7.30 (m, 5 H). mass spectrum (EI), m/z 186 (M+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)c3cccnc3)sc2-c2ccncc2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.62 mmol) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol) in N,N-dimethylacetamide (5 mL) was added nicotinoyl chloride hydrochloride (0.43 g, 2.42 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.49 g, yield 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[N:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46]>CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:31][CH:30]=3)[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnn34)CC2)cc1
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
A solution of toluene-4-sulfonic acid 4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl ester (5.0 mg, 0.0088 mmol), N,N-dimethyl-1,2-ethanediamine (1 mL, 0.009 mol) in MeOH (1 mL) was heated in microwave reactor at 300 watt, 100° C. for 2 h. The solvent and excess amine were removed in vacuo, and the material was purified by silica gel chromatography, eluting with 5% (7N NH3 in MeOH) in DCM. HPLC: tR=1.99 min. (OpenLynx, polar—5 min). MS (ES+): m/z 486.19 (100) [MH+].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1ccc(CBr)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Cl)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 3 of Example 12, and 4-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[N:9]1([CH2:15][C:16]2[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.ClCCCN>C1C=CC=CC=1.CS(C)=O>[NH2:6][CH2:5][CH2:4][CH2:3][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Yield: 86 %

Procedure:
3-Chloropropylamine hydrochloride (VI) (0.2 mol, 39 g) was dissolved into 3N sodium hydroxide solution (containing 10% sodium chloride) and extracted with 300 ml of benzene. The benzene layer was dried over anhydrous magnesium sulfate. Separately, 3-piperidinomethylphenol (V) (0.2 mol, 38.2 g), sodium hydroxide (0.25 mol, 10 g), 100 ml of dimethylsulfoxide, and 70 ml of benzene were charged to a flask equipped with a water quantitative measurement tube, and heated at 130° C. for 3 hours while stirring to remove water produced by the tube, followed by continued stirring for 2 hours at 140°-150° C. To the resulting reaction mixture was dropwise added said benzene solution of 3-chloropropylamine at 150° C. while stirring over 4 hours. The reaction mixture was allowed to stand still to cool to room temperature to separate deposited sodium chloride by filtration. The filtrate was concentrated under reduced pressure and vacuum distilled to obtain 42.7 g of N-[3-(3-aminopropoxy)benzyl] piperidine (VII) (yield: 86.0%). m.p. 148°-151° C./0.25 mmHg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[C:24]#[N:25].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:24]#[N:25])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Reaction time: 3 h

Procedure:
Piperidin-4-ylmethyl-carbamic acid tert-butyl ester (4 g, 18.66 mmol) was suspended in 120 ml of acetonitrile. Dried potassium carbonate (2.837 g, 20.53 mmol) was added. A solution of bromoacetonitrile in (3.72 ml, 5 mmolar solution, 18.66 mmol) was added (argon atmosphere) and the mixture was stirred for 3 hours. After addition of aqueous FeSO4 solution and ethyl acetate, the separated solid was filtered and the organic layer separated, dried and evaporated.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH2:12]O)[CH:11]=1)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:25][CH2:12][C:10]1[CH:11]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[C:5]2[C:9]=1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=[CH:6]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CO)c21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (980 mg, 2.83 mmol) and carbon tetrabromide (1.41 g, 4.24 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (1.11 g, 4.24 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→8% EtOAc/Hex) to give 1.155 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.61 (d, J=1.2 Hz, 1H), 6.05 (s, 2H), 5.01 (s, 2H), 3.52 (m, 2H), 0.87 (m, 2H), −0.08 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 138.4, 135.1, 126.4, 125.7, 124.4 (q, J=33 Hz), 124.3 (q, J=273 Hz), 122.5, 120.1, 80.5, 66.6, 29.7, 17.9, −1.4.
Reaction SMILES: [N:1]1([C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:7][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C(=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)CN1CCCCC1
Yield: 2.6 %

Procedure:
A Following the procedure of example 42§A, but starting from 1-(3-{[4′-(2-piperidinocarbonylethen-1-yl)biphenyl-4-yl]oxy}propyl)piperidine (0.6 g) and lithium aluminum hydride (120 mg) in tetrahydrofuran (15 mL) affords 15 mg of 1-(3-{[4′-(3-piperidinoprop-1-en-1-yl)biphenyl-4-yl]oxy}propyl)piperidine as pale yellow crystals melting at 100-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([C:25]1([CH2:28][CH2:29][CH3:30])[CH2:27][O:26]1)[CH2:23][CH3:24]>CCO.O>[OH:26][C:25]([CH2:28][CH2:29][CH3:30])([CH2:22][CH2:23][CH3:24])[CH2:27][NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: CCCC1(CCC)CO1
Solvent: O
Solvent: CCO
Product: CCCC(O)(CCC)CNc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
To a stirred solution of 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione (0.50 g, 1.78 mmol) in EtOH:H2O (9:1), 2,2-dipropyloxirane (0.45 g, 3.57 mmol) was added and the reaction mixture was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2-(3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propyl)isoindoline-1,3-dione as a yellow semisolid. Yield (0.22 g, 30%); 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.81 (m, 4H), 6.92 (t, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.37 (d, J=7.6 Hz, 1H), 4.89 (bs, 1H), 4.16 (s, 1H), 3.59 (t, J=7.2 Hz, 2H), 2.87 (d, J=5.2, 2H), 2.46-2.50 (m, 2H), 1.83-1.90 (quintet, J=7.2 Hz, 2H), 1.42-1.38 (m, 4H), 1.28-1.24 (m, 4H), 0.84 (t, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8](O)=[O:9])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>CN(C)C=O>[C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8]([Cl:22])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OC(C)CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OC(C)CCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
46.5 g (0.29 mol) of 4-acetoxypentanoic acid are dissolved at room temperature in 230 ml of abs. toluene, and then 0.2 ml of abs. Dimethyl formamide is added. Then 32.6 ml (0.38 mol) of oxalyl chloride are added dropwise such that the evolution of gas remains under control. When the dropwise addition is complete, the reaction mixture is heated to 50° C. and stirred for 1 hour at this temperature. The orange-red reaction solution is concentrated by evaporation. Distillation of the residue gives 42.2 g of 4-acetoxypentanoic acid chloride as a colourless liquid of b.p.34 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:26])=O)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[NH2:34][CH2:35][C:36]([CH3:39])([OH:38])[CH3:37]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([NH:34][CH2:35][C:36]([OH:38])([CH3:39])[CH3:37])=[O:26])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1
Reactant: CC(C)(O)CN
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)NCC(C)(C)O)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and 1-amino-2-methyl-2-propanol (Tyger, Cat. No. A57123). LCMS (M+H)+: m/z=517.4.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CC(N)C1)(OC(C)(C)C)=O>>[NH:48]1[CH2:43][CH:44]([NH:49][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:47]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CC(C)(C)OC(=O)N1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc 3-amino azetidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.28 (m, 1 H) 1.33-1.46 (m, 2 H) 1.59-1.66 (m, 2 H) 1.75-1.87 (m, 4 H) 3.32 (s, 3 H) 3.67-3.80 (m, 4 H) 3.95 (s, 3 H) 4.07 (t, 2 H) 4.4-4.5 (m, 1 H) 4.65-4.83 (m, 1 H) 7.50 (d, J=8.3 Hz, 1 H) 7.54 (d, J=1.5 Hz, 1 H) 7.93 (s, 1 H) 8.21 (s, 1 H) 8.29 (d, J=8.1 Hz, 1 H) 8.81 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C25H31F2N7O3 516; found 516.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[NH:3]1
Reactant: O=c1[nH]c2nccnc2n1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2nccnc2n1C1CCNCC1
Yield: 124.4 %

Procedure:
2-Oxo-1-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazine (1.7 g, 5.5 mmol) was dissolved in methanol (100 mL) and hydrogenated over 20% palladium on carbon (0.5 g) at 55 psi hydrogen overnight. The catalyst was filtered and solvent evaporated to give the title compound (1.5 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14](N)=[C:9]3[C:8]([CH3:22])=[N:7]2)[CH2:2]1.N([O-])=[O:24].[Na+].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O.O>[O:1]1[CH2:5][CH2:4][CH:3]([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14](=[O:24])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:2]1
Reactant: O=N[O-]
Reactant: Cc1nn(C2CCOC2)c2nc(-c3ccncc3)nc(N)c12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1[nH]n(C2CCOC2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: -5 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution of 1-(3-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (1.08 g, 3.6 mmol) in 60% sulfuric acid (30 ml) at -10° C. was added sodium nitrite (5.6 g, 81.2 mmol) in water (8 ml). The reaction mixture was stirred at -5° C. for 2 hours, then at room temperature for 24 hours. The mixture was poured onto ice-water, neutralized with K2CO3 and the salts were collected by filtration. The aqueous filtrate was extracted with chloroform (6×100 ml) and the combined organic layers were concentrated in vacuo. The residue was dissolved in isopropanol, treated with Darco and concentrated in vacuo to afford 0.5 g (46%) of 1-(3-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one.1/4 hydrate as an off-white fluffy powder, m.p. 251° C. when dried at 90° C. for 24 hours in high vacuum.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[N:7][N:8]=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[N:7][N:8]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)N(CCSc1nnc(N)s1)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(CCSc1nnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole (2.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Tert-butylbenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.2 g of the aimed compound.