Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cccc(-c2cc3c(C=O)c[nH]c3cc2Cl)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)c1
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
To a solution of 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carbaldehyde (100 mg, 0.35 mmol) in ACN/t-butanol=1/1(4 mL) was added 2-methyl-2-butene (1 mL) at 0° C. and stirred 10 min. Then an aqueous solution of sodium chlorite (315 mg, 3.5 mmol) and sodium dihydrogen phosphate (480 mg, 3.5 mmol) in water (1 mL) was added to the system dropwise. The reaction was stirred at room temperature for 10 h. The reaction was quenched with sodium sulfite. The mixture was partitioned between DCM and water. The combined organics were dried and concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (40 mg, 38%) as a white solid. MS (AP−) 300.1 (M−1)−. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.33 (t, 1H), 7.01-6.97 (m, 2H), 6.93 (dd, 1H), 3.84 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH:8]=[CH:7][N:6]=1.Cl[CH:19]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([F:32])[CH:26]=1)[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:19]([C:20]2[O:24][CH:23]=[N:22][CH:21]=2)[N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=3)=[CH:12][C:13]2=[O:17])=[CH:26][C:27]=1[F:32]
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Reactant: Fc1cc(C(Cl)c2cnco2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
NaH (13.2 mg, 0.331 mmol; 60 wt % oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (65.9 mg, 0.301 mmol) in DMF (600 μL) at room temperature under nitrogen. After 30 minutes, the suspension had become a solution. A solution of 5-(chloro(4-chloro-3-fluorophenyl)methyl)oxazole (111 mg, 0.451 mmol) was then added as a solution in DMF (300 μL) dropwise by syringe. After stirring at room temperature overnight, TLC in ethyl acetate showed a new high rf spot, as well as a new mid rf spot (both bright blue under UV). The reaction was quenched with water (1 mL) and then partitioned between ethyl acetate (30 mL) and water with a little brine (30 mL). The organics were isolated and washed with water/brine (3×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated to an oil. The mixture was loaded onto a Biotage 12M column with 7/3 ethyl acetate/hexanes and eluted. Two main spots eluted and corresponding fractions were pooled and concentrated. The least polar fraction appears to be alkylated on the pyridone oxygen. The second eluting spot appears to be the desired N-alkylated pyridone, which was isolated as a foam, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (50 mg, 39%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2cc(-c3ccccc3)ccn2)CC1
Yield: 46.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (113 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (75.0 mg, 0.313 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 3 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 52.0 mg (46.0%) as solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:22]OC(OC)N(C)C.C(O)(=O)C.[C:34]1([NH:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:41]=[CH:22][C:8]=2[CH2:9][C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:11])=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CN1CCC(OC(=O)CCC(=O)c2ccc(Cl)cc2)CC1
Reactant: COC(OC)N(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)Cc2cnn(-c3ccccc3)c2-c2ccc(Cl)cc2)CC1

Procedure:
35.1 g of 1-methyl-4-piperidyl 3-p-chlorobenzoyl-4-dimethylamino-3-butenoate [obtainable by esterification of 3-p-chlorobenzoyl-propionic acid with 1-methyl-piperidin-4-ol to produce 1-methyl-4-piperidyl 3-p-chloro-benzoylpropionate and subsequent reaction of the latter with dimethylformamide dimethyl acetal in the presence of acetic acid at 120°] and 12 g of phenylhydrazine are warmed for 4 hours at 100°. The reaction mixture is subjected to the customary working up (benzene/water) and 1-methyl-4-piperidyl 5-p-chlorophenyl-1-phenyl-pyrazol-4-yl-acetate is obtained; m.p. 90°-93°. Hydrochloride, m.p. 234°-235°.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=2)=[N:5]1)[CH3:3].[H-].[Na+].[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1S(C)(=O)=O.O>CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[N:17][C:16]([O:19][C:24]3[N:23]([CH3:22])[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:15][CH:14]=2)=[N:5]1)[CH3:1]
Reactant: CC(C)n1nc(-c2ccc(O)nc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)nc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a stirred mixture of 5-[1-(1-Methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]pyridin-2-ol (76 mg) in DMF (4 mL) was added NaH (60% in oil, 12.6 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (76 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (23.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([N:21]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.O.NN>C(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)cc3)s2)cc1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
To a solution of Example 11C (770 mg, 1.69 mmol) in methylene chloride (20 mL) and ethanol (2 min) was added hydrazine monohydrate (540 μL, 11.1 mmol, 6.6 eq.) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated. The residue was dissolved in methylene chloride again, which was filtered and the filtrate was concentrated to give the title compound (615 mg), which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].O[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: OCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc(OCc3ccc(B(O)O)cc3)cc2s1
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 94.2 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (2) (150 mg, 0.85 mmol, 1.1 equiv.) and 4-(hydroxymethyl)benzeneboronic acid (5) (166 mg, 0.77 mmol, 1 equiv.) were dissolved in 15 mL dry dimethylformamide (DMF) prior to the addition of cesium carbonate (277 mg, 0.85 mmol, 1 equiv.). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with DI H2O. The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 EtOAc:methanol, dry loaded) to give 225 mg (94%) of the pure product. 1H NMR (400 MHz, d6-Acetone): δ 5.33 (2H, s), 7.23 (2H, s), 7.45 (1H, dd, J=9.0, 2.6 Hz), 7.52 (2H, d, J=8.0 Hz), 7.93 (3H, m), 8.16 (1H, d, J=8.8 Hz).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[C:1]1([S:7][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCCSc1ccccc1
Yield: 99.5 %

Procedure:
Thiophenol (3 g), potassium carbonate (5.64 g) and 1,6-dibromohexane (6.64 g) were reacted and treated in the same manner as in Preparation Example 99 to give 7.4 g of 6-phenylthiohexyl bromide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36](C=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][NH2:45].[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:46][NH:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCN
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COCCNCc1ccc(-n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.4 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 2-methoxyethylamine (0.018 g, 0.24 mmol), and sodium triacetoxyborohydride (0.106 g, 0.500 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 24 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 15.0-16.2 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.010 g, 0.016 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, d, J=4.0 Hz), 8.35-8.37 (2H, m), 8.16 (2H, d, J=8.0 Hz), 8.01 (1H, t, J=7.4 Hz), 7.90 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 7.45 (1H, s), 7.40 (1H, d, J=8.8 Hz), 3.96 (3H, s), 3.80 (2H, s), 3.42-3.45 (2H, m), 3.25 (2H, m), and 2.70-2.71 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.23 min. MS: MH+610.2.
Reaction SMILES: [N+](=[C:3]1[C:7](=[O:8])[CH2:6][O:5][C:4]1=[O:9])=[N-].[CH3:10][CH:11]([CH:13]1[CH2:15][CH2:14]1)[OH:12]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH:13]1([CH:11]([O:12][C:3]2[C:4](=[O:9])[O:5][CH2:6][C:7]=2[OH:8])[CH3:10])[CH2:15][CH2:14]1
Reactant: CC(O)C1CC1
Reactant: [N-]=[N+]=C1C(=O)COC1=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CC(OC1=C(O)COC1=O)C1CC1
Temperature: 130 °C

Procedure:
To the mixture of 3-diazo-2,4-(3H, 5H)-furandione (300 mg, 2.38 mmol; Example 207, Step 1) and α-methylcyclopropanemethanol (2.0 mL) was added rhodium acetate (30 mg). The mixture was heated at 130° C. for a period of 18 h. The excess of alcohol was evaporated under reduced pressure and the resulting crude mixture was purified by flash chromatography (10% to 20% MeOH in CH2Cl2) to provide 50 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C=O)cc1)c1ccc(C(C)C)cc1)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(CO)cc1)c1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
N-[(4-Formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was dissolved in a mixed solvent (10 mL) of ethanol: tetrahydrofuran (2:1), and sodium borohydride (0.15 g) was added under ice-cooling. The mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-{[4-(hydroxymethyl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.25 g). melting point: 143.2° C.
Reaction SMILES: [NH3:1].[OH2:2].[ClH:3].[NH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.NO>>[ClH:3].[OH:2][N:1]=[C:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: O=C1CCNCC1
Reactant: N
Reactant: O
Agent: Cl
Agent: NO
Product: ON=C1CCNCC1
Reaction time: 2 h

Procedure:
5.4 ml of 28% aqueous ammonia solution were added to a mixture of 3.0 g of 4-piperidone hydrochloride monohydrate and 1.63 g of hydroxylamine hydrochloride, and the resulting mixture was stirred for 2 hours at 80° to 90° C. After completion of the reaction, the solvent was distilled off and the crystalline residue was recrystallized from methanol, giving 1.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:36][O:37]CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:36][O:37][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1
Reactant: COCC(=O)NN
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: NNC(=O)CC1CCOC1
Product: COCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-methoxyacetohydrazide (compound 190.6) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 430 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([NH:19][CH:20]([C:22]1[N:23]=[CH:24][C:25]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:28][C:26]=2[N:27]=1)[CH3:21])[CH3:18].CCN(C(C)C)C(C)C.CCCCO>CCOC(C)=O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:19]([CH2:17][CH3:18])[CH:20]([C:22]4[N:23]=[CH:24][C:25]5[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:28][C:26]=5[N:27]=4)[CH3:21])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CCNC(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(c1nccc(Nc2cc(C3CC3)[nH]n2)n1)C(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 115 °C
Yield: 80 %

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (60 mg, 0.25 mmol), N-ethyl-1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanamine (367.0 mg, 1.14 mmol), DIPEA (1.3 mL) and n-BuOH (3.5 mL), sealed and heated at 115° C. for 96 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2chromatography to afford 103.9 mg (52.35%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-ethyl-N2-(1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethyl)pyrimidine-2,4-diamine as a racemic mixture. MS (ESI) m/z: 520.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:3][CH:4]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:35][CH:36]=1
Reactant: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 2 °C

Procedure:
2-[6-([2-(4-aminophenyl)ethyl]{2-[(4-aminophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (108.3 mg) was dissolved in DCM (5 ml) and cooled to 0-4° C. in an ice-bath. Hunig's Base (0.227 ml) was added followed by the dropwise addition of mesylchloride (0.051 ml). The reaction was maintained at 0-4° C. for 0.5 h and then allowed to warm slowly to room temperature. After 3 h the reaction mixture was evaporated to dryness and used crude in next step.
Reaction SMILES: C1(C)C=C[C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=CC=1.Br>C(O)(=O)C>[CH3:4][S:7]([N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCNCCNCC1
Yield: 62.5 %

Procedure:
A mixture of 1,4-bis-(p-toluenesulfonyl)-7-methanesulfonyl-1,4,7-triazacyclononane (38.8 g, 0.08 mol), 800 mL of glacial acetic acid and 150 mL of 48% hydrobromic acid was refluxed for 72 hours. The reaction solution was cooled to 25 C. and most of the solvents were removed under reduced pressure. Then 50 mL of 48% hydrobromic acid was added and the solvents were again evaporated. This procedure was repeated two more times to remove acetic acid. A mixture of 100 mL of absolute ethanol and 200 mL of diethyl ether was added and the solids were filtered. The solids were combined with sodium hydroxide pellets (18.0 g, 0.45 mol) in 250 mL of toluene and the mixture was refluxed for 15 hrs. The remaining solid was filtered and washed with 75 mL of hot toluene. The filtrate was concentrated to a volume of 60 mL and allowed to cool slowly to 25 C. The colorless crystals were filtered and dried to give 1-methanesulfonyl-1,4,7-triazacyclononane (11.1 g, 0.05 mol, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8](OC)=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH:24]([O-])([O-])OC.C([O-])(=O)C.[NH4+:33]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]2[C:6](=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:13]=[CH:24][NH:33][C:8]2=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1N
Reactant: COC([O-])[O-]
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
In a 100-mL volume stainless steel pressure-resistant vessel were placed 5.80 g (17.9 mmol) of methyl 5-methoxy-4-(3-morpholinopropoxy)anthranilate, 3.79 g (35.8 mmol) of methyl orthoformate, 2.56 g (33.2 mmol) of ammonium acetate, and 30 mL of methanol. The reaction was carried out at 115° C. for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then, the concentrate was recrystallized from 100 mL of methanol. The crystalline product was collected by filtration and dried under reduced pressure to give 4.97 g (isolated yield: 87%) of 6-methoxy-7-(3-morpholinopropoxy)-quinazolin-4-one as a white crystalline product.