Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]3[CH:23]=[CH:24][S:25][C:15]=23)[CH2:9][CH2:8]1)(=O)=O.[C-:26]#[N:27].[Na+]>CS(C)=O.CCOC(C)=O>[N+:20]([C:19]1[C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][C:26]#[N:27])[CH2:8][CH2:9]2)=[C:15]2[S:25][CH:24]=[CH:23][C:16]2=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl methanesulfonate (0.20 g, 0.52 mmol) and sodium cyanide (0.057 g, 1.2 mmol) in dimethyl sulfoxide (2 mL) was stirred at 90° C. for 4 h. After diluting with EtOAc, the resulting mixture was washed with sat. NaHCO3 solution, water and brine, then concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C15H17N4O2S (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@H:31]([OH:34])[CH2:32][O:33][C@H:27]34)=[N:22][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][S:17](=[O:21])(=[O:20])[CH2:18][CH:19]=2)=[CH:10][CH:9]=1.[H][H]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@H:31]([OH:34])[CH2:32][O:33][C@H:27]34)=[N:22][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=S1(=O)CC=C(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: O=S1(=O)CCC(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1

Procedure:
Placed 4-(4-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (5 mg, 0.010 mmol) under nitrogen in methanol (1.0 ml). A few drops of DCM were added to dissolve the solid. Then 10% Pd(C) (10 mg, 9.92 μmol) was added and a slight vacuum was pulled followed by the introduction of hydrogen gas (3×). The reaction mixture was stirred under 1 atmosphere of hydrogen gas at room temperature for 1.5 hours, then filtered and concentrated under reduced pressure. The resulting residue was chromatographed using a 20 g silica gel cartridge eluted with 0-10% methanol in DCM over 10 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C23H24ClN3O6S 505.09 observed m/e: 505.98 (M+H)+ (Rt 2.58/4 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (325 mg, 1.0 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (88 mg, 1.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (630 mg, 10.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (200 mg, Yield 48.9%). 1H NMR (CD3OD, 400 MHz): δ 8.44 (brs, 1H), 7.32-7.20 (m, 3H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 7.08-7.00 (m, 1H), 6.86-6.77 (m, 1H), 4.39 (s, 2H), 4.35-4.25 (m, 1H), 4.03-3.89 (m, 2H), 3.63-3.40 (m, 7H), 3.31-3.07 (m, 4H), 2.06-1.92 (m, 2H), 1.55-1.40 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])=[N:6]1)[CH3:4].[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=3[CH3:19])=[N:6]2)[CH3:4])=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: Cc1c(-c2ccn([C@H](C)CN)n2)ccc(C#N)c1Cl
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3C)n2)[nH]n1
Yield: 18.5 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.09 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (202 mg, 1.31 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 83 mg (19%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.52-2.58 (m, 6H), 3.79 (dd, 1H), 3.91 (dd, 1H), 4.60-4.71 (m, 1H), 6.92 (d, 1H), 7.25 (s, 1H), 7.27-7.29 (m, 1H), 7.52 (d, 1H), 7.54-7.60 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28]OS(C)(=O)=O)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:34].[Li+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][Br:34])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(COS(C)(=O)=O)cc3)c2CC1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CBr)cc3)c2CC1
Reaction time: 8 h

Procedure:
Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-(4-methanesulfonyloxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous acetone (3 mL), treat with anhydrous lithium bromide (335 mg, 3.89 mmol) and continue stirring overnight. Add water, extract the reaction mixture three times with ethyl ether, wash with brine, dry over anhydrous MgSO4, and concentrate in vacuo to obtain the desired intermediate that was used without purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Br:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Br:21])[CH:20]=2)[C:16]#[N:17])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Yield: 58.9 %

Procedure:
3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (2.04 g, 5.35 mmol) dissolved in THF (30 mL) was treated successively with triphenylphosphine (2.10 g, 8.02 mmol) and water (0.482 g, 26.7 mmol) at 25° C. for 16 h with stirring. The reaction mixture was concentrated to dryness and purified on silica gel (eluted successively with EtOAc (to remove triphylphosphine oxide) followed by a gradient of 100% EtOAc to 10% CH3OH/DCM) to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (1.12 g, 3.15 mmol, 58.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (t, 1H), 7.46-7.57 (m, 4H), 3.77 (s, 2H), 1.91 (br. s., 2H). LC-MS (ES+) m/z 354.92, 356.91, 358.88 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4ccccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), and 2-hydroxynaphthalene (40 mg, 0.28 mmol) in DMF (1.5 ml) containing potassium carbonate (48 mg, 0.35 mmol) was stirred at 100° C. for 3.5 hours. After cooling, methylene chloride (4.5 ml) was added and the mixture was poured onto a column of silica (SiO2 Isolute®) and eluted with, successively, methylene chloride, methylene chloride/methanol (9/1), methylene chloride/methanol/3M ammonia in methanol (75/20/5). The fractions containing the product were evaporated under vacuum. The residues was triturated with ether, filtered and dried under vacuum to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline (80 mg, 83%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:26])=[O:2])[C:13](=[O:25])[CH:14]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a stirred solution of (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (450 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (134 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (320 mg, 74%) as a off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH2:21][CH2:22][CH3:23])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.730 g (4.748 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-propyl-1,2,4-triazin-5-ol were admixed with 23 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 330 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the mixture was concentrated on a rotary evaporator, the residue was stirred with 200 ml of water and filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 1.360 g (60% of theory) of the target compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].O>CS(C)=O>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][N:4]([C:5]2[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=2)[C:1](=[O:3])[CH3:2])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: CC(=O)Nc1ccc(C(=O)C(C)CC(=O)O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(C(=O)C(C)CC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
30.0 g (120 mmol) of 3-(4-acetamidobenzoyl)-butyric acid are added to a suspension of 7.6 g (253 mmol) of sodium hydride (80%) in 150 ml of dimethyl sulphoxide and the mixture is stirred for 30 minutes at 60° C. After the addition of 33.2 g (120 mmol) of N-(3-bromopropyl)-phthalimide, stirring is continued at 80° C. for 6 hours. After cooling, the reaction mixture is poured out on 200 ml of iced water and extracted with 3×100 ml of dichloromethane. The extracts are discarded. The aqueous phase is then adjusted to pH 6.5 with 2N hydrochloric acid and again extracted with 3×100 ml of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum. The oil obtained as residue crystallizes when triturated with 20 ml of ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][C:17]([O:19][CH3:20])=[CH:16][CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(=O)Nc2cccc(Br)c2C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c2c1
Yield: 68.4 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide (596 mg, 1.78 mmol) and triphosgene (633 mg, 2.13 mmol) in THF (30 mL) was stirred at room temperature for 2 h. The mixture was treated with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The resulting mixture was extracted twice with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc -hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione as a white solid (440 mg, 68% yield). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: O[CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[NH:9]=[N+:10]=[N-:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:9]([CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=N
Reactant: O=C1CC[C@H](CO)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To (R)-5-(hydroxymethyl)pyrrolidin-2-one (660 mg, 5.73 mmol), hydrogen azide (10.8 mL, 8.60 mmol, 0.8 M in toluene), and PPh3 (2.25 g, 8.60 mmol) in THF was added DIAD dropwise. The mixture was stirred at rt for 1 h. LCMS indicated the completion of the reaction. The mixture was partially concentrated, filtered, and purified by RP-HPLC to give (R)-5-(azidomethyl)pyrrolidin-2-one (730 mg, 87%, 90% pure). LRMS (M+H+) m/z 141.1.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C.[OH-].[NH4+:11]>>[NH2:11][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCC(=O)O
Reactant: [NH4+]
Agent: C
Agent: [OH-]
Product: CCCC(N)CC(=O)O
Temperature: 150 °C

Procedure:
A mixture of 2 hexanoic acid (7.0 g, 0.06 mole) and concentrated aqueous ammonium hydroxide (70 ml) is heated for 24 hours in an autoclave at 150° C. The cooled mixture is treated with carbon black and filtered. After evaporation of the solvent, the crude product is recrystallized from ethanol to give the title compound m.p. 203° C. (Compound 1.21, Table 1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34](=[C:41]1/[CH2:42][N:43]([C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:45][CH:46]/1O)/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:67]([OH:70])(=[S:69])[CH3:68]>O1CCCC1.C1(C)C=CC=CC=1>[C:67]([S:69][CH:46]1[CH2:45][CH2:44][N:43]([C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:42]/[C:41]/1=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:70])[CH3:68]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of triphenylphosphine (6.39 g) in tetrahydrofuran (100 ml) was added a solution of diisopropyl azodicarboxylate in toluene (13.11 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, to the reaction mixture was added dropwise a solution of (E)-3-benzylidene-1-(triphenylmethyl)piperidin-4-ol (5.26 g) and thioacetic acid (1.74 ml) in tetrahydrofuran (50 ml) at the same temperature, and the resulting mixture was furthermore stirred at room temperature for 2.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:23) as the eluent to afford (E)-4-(acetylsulfanyl)-3-benzylidene-1-(triphenylmethyl)piperidine (containing impurities) as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:25][CH:22]4[CH2:24][CH2:23]4)[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H]1c2nncn2-c2cnc(NC3CC3)nc2N1C1CCCC1

Procedure:
(R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.23 mmol), cyclopropylamine (0.5 ml, 7.18 mmol), DIPEA (0.16 ml, 0.918 mmol) in nBuOH (2 ml) were heated in a sealed tube in the microwave at 140° C. for 90 minutes. The reaction mixture was concentrated in vacuo, and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 □M, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as an off-white powder. The free base was generated using a bicarbonate resin, and was freeze-dried to give the title compound as a colourless solid (25.6 mg, 34% yield)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH-].[Na+].[N:14]#[C:15]Cl>C(Cl)Cl.O>[NH:1]([CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[C:15]#[N:14]
Reactant: N#CCl
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(NC#N)CC(C)(C)N1

Procedure:
156 g (1 mole) of 4-amino-2,2,6,6-tetramethyl piperidine were dissolved in 500 ml of methylene chloride, 40 g (1 mole) of sodium hydroxide in 500 ml of water were introduced and 51 ml of cyanogen chloride were added dropwise at 0° to 5° C. The mixture was then stirred until it reached room temperature, after which 4-cyanamido-2,2,6,6-tetramethyl piperidine melting at 240° C was filtered off in a yield of 166 g (corresponding to 91.5% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH:64]1[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][CH:64]([OH:63])[CH2:65]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: OC1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(O)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-hydroxy-piperidine in DMSO at ambient temperature.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.9 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.07 (d, J=6.6 Hz, 3H), 3.98 (s, 3H), 6.47 (q, J=6.6 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 7.49 (d, J=9.9 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.02 (s, 1H), 8.10 (d, J=9.6 Hz, 1H). MS (ES+): m/z 377.04 (100) [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).