Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:37][C:38]1[C:39]([N:46]2[C:50]3=[N:51][CH:52]=[N:53][C:54](Cl)=[C:49]3[CH:48]=[N:47]2)=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:54]1[N:53]=[CH:52][N:51]=[C:50]2[N:46]([C:39]3[C:40]([C:41]#[N:42])=[CH:43][CH:44]=[CH:45][C:38]=3[Cl:37])[N:47]=[CH:48][C:49]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
60% Sodium hydride (95 mg, 2.38 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (540 mg, 1.08 mmol) in anhydrous THF (15 mL), at 0° C., under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (314 mg, 1.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and was then stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in isohexane. Fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (466 mg, 57.2%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, d), 3.83-3.66 (4H, m), 4.11-4.04 (1H, m), 4.20-4.12 (1H, m), 6.00 (1H, s), 7.44-7.31 (6H, m), 7.60 (4H, m), 7.87 (2H, m), 8.03 (1H, t), 8.22-8.13 (2H, m), 8.39 (1H, d), 8.62 (1H, d), 8.68 (1H, d), 11.23 (1H, s). m/z (ES+) (M+H)+=752; HPLC tR=3.89 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:25][CH3:24])[C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1
Reactant: CCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Yield: 67.6 %

Procedure:
4-Chloro-2-(2-ethoxy-3-formylphenoxy)benzonitrile (0.55 g, 1.8 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (55 mL) for 3 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. Fumaric acid (0.21 g, 1.8 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated overnight with ethyl acetate, collected by filtration, and dried to give 4-chloro-2-[2-ethoxy-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (527 mg, 67%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)=[O:4].[N:16]([O-])=O.[Na+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([OH:30])=[O:29].[OH-]>Cl.O.[OH-].[Na+].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]=[N:16][C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: O=C(O)Cc1ccccc1O
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(N=Nc2ccc(O)c(CC(=O)O)c2)cc(C(=O)OC)c1
Temperature: 80 °C

Procedure:
20.9 g of dimethyl-5-amino-benzene-1,3-dicarboxylate was dissolved in 20 ml of concentrated hydrochloric acid in 200 ml of ice water. The solution was diazotized with 7 g of sodium nitrite dissolved in 30 ml of water. 30.4 g of 2-hydroxy-phenylacetic acid was dissolved in 200 ml of water and 24 g of sodium hydroxide. The solution was cooled with 100 g of ice. To this hydroxide solution was then added the diazonium salt solution, all at once, and with vigorous stirring. After 30 seconds the solution was acidified with acetic acid and the precipitate was filtered off. The precipitate was leached with an about 25% ethanol solution which was then diluted with water until a state of weak opalescence was reached. The solution was treated with active carbon and evaporated down to half its volume. Sodium hydrogen carbonate was added until the solution was clear, whereupon the solution was heated (80° C.) and acidified with hydrochloric acid. The solution was cooled, the crystals were filtered off and dried.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29](C([O-])=O)[N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCN1CCCN(C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
To a solution of 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (2 mL) was added HCl as a 4.0 M solution in 1,4 dioxane (8 mL) and the reaction was stirred at RT for 5 h. The volatiles were removed in vacuo and the crude product was washed with hexane and dried under vacuum to yield 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-amine (0.063 g, 0.105 mmole, 26% over 2 steps.). MS 600.4 (M+1). HPLC retention time 5.01 mins.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:18](=[O:19])[O:17][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)CC)(=O)[CH2:27]C>>[C:16]([NH:15][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[O:19])[CH2:26][CH3:27])(=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C1OC(c2ccccc2)N=C1CCCCNC(=O)c1ccccc1
Product: CCC(=O)C(CCCCNC(=O)c1ccccc1)NC(=O)c1ccccc1

Procedure:
Reaction of 4-(4-benzamidobutyl)-2-phenyl-5-oxazolone according to the procedure of Example 1 (ii) but using propionic anhydride in place of acetic anhydride yields 4,8-dibenzamidooctan-3-one which on hydrolysis according to the procedure of Example 1 (iii) gives 4,8-diaminooctan-3-one. Reaction of this product with potassium thiocyanate according to the procedure of Example 1 (iv) gives the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>O1CCOCC1.C(OCC)C>[ClH:30].[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
N-t-butyloxycarbonyl-L-valyl-L-proline benzylester (16.32 g, 40 mmole) was dissolved in 4N hydrochloric acid in dioxane (100 ml) solution, and the solution was stirred for 1 hour at room temperature. The solvent was distilled off and the residue thus obtained was powdered in diethyl ether to give L-valyl-L-proline benzylester hydrochloride (yield 10.31 g, 75.6%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[C:16]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][CH3:16])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C)s1

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3 -methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1 H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18][CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:38])[F:37])=[N:31]4)[C:27]([F:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:43])=[CH:9][C:10]([CH3:42])=[C:11]([CH:13]([S:18]([CH:19]([C:24]3[CH:29]=[C:28]([N:30]4[C:34]([NH2:35])=[N:33][C:32]([C:36]([F:39])([F:37])[F:38])=[N:31]4)[C:27]([F:40])=[CH:26][C:25]=3[CH3:41])[C:20]([F:21])([F:22])[F:23])=[O:56])[C:14]([F:17])([F:16])[F:15])[CH:12]=2)[N:5]=[C:4]([C:44]([F:47])([F:46])[F:45])[N:3]=1
Reactant: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1C(SC(c1cc(-n2nc(C(F)(F)F)nc2N)c(F)cc1C)C(F)(F)F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1C(S(=O)C(c1cc(-n2nc(C(F)(F)F)nc2N)c(F)cc1C)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
1.9 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfide was dissolved in 100 ml of chloroform, and 1.0 g of m-chloroperbenzoic acid was added at 0° C., followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent ethyl acetate:hexane:triethylamine=50:50:1) to obtain 1.8 g of [5-(5-amino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfoxide as pale yellow crystals (melting point 236 to 238° C.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:16][C:15]1[C:10]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1CNCC(C)N1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(c2ncccc2Cl)CC(C)N1
Yield: 64.4 %

Procedure:
2,6-dimethylpiperazine (291 mg, 2.55 mmol) and 2,3-dichloropyridine (377.4 mg, 2.55 mmol) were charged to a microwave vial, dissolved in DMF (0.25 mL) and added with diisopropylethylamine (1.11 mL, 6.38 mmol). The reaction mixture was irradiated at 165° C. for 30 minutes. The reaction was complete as determined by TLC. After solvent removal the crud product was purified via flush column chromatography to afford 1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine in 64.4% yield (370 mg).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11](O[C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[NH3:16]>>[CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:16][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: N
Product: O=C1NC(=O)c2cccc3cccc1c23

Procedure:
U.S. Pat. No. 3,812,130 describes reacting solid 1,8-naphthalic anhydride with gaseous ammonia to produce 1,8 naphthalimide. The product is isolated directly by evaporating off the water. Although this procedure minimizes waste water, it still requires a pressure vessel and has the disadvantage of not allowing for any water soluble impurities or unreacted starting material to be removed after the reaction. Thus, a potentially impure product is produced.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:24][C:23]2=[O:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-[N-(ethoxycarbonyl)amino]phenyl]piperidin-3-ol (600 mg, 1.1 mmol) in 10 ml of dimethylsulfoxide (DMSOI), was added 0.46 ml of triethylamine (3.3 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.51 g, 3.3 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 320 mg of the titled compound as white color.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][CH:40]=1)[CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate (0.114 g, 0.5 mmol). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellowish brown solid (0.2 g, 93%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.64 (d, 2H, J=13.6 Hz), 2.41-2.49 (m, 2H), 3.48 (br, 2H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 4.59-4.64 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.17 (t, 2H, J=8 Hz), 7.54-7.60 (m, 2H), 7.89-7.92 (m, 2H); MS for C27H33N3O5 m/z 480.08 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(O)(C(F)(F)F)=O.C1C(=O)N(I)C(=O)C1>C(#N)C>[O:9]1[C:5]2[CH:4]=[C:3]([S:11][C:12]3[NH:13][C:14]4[C:19]([N:20]=3)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=4)[CH:2]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Agent: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncnc2[nH]c(Sc3ccc4c(c3)OCC4)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-amine (S6-4) To a solution of S6-3 (40 mg, 0.14 mmol) in 6 mL of acetonitrile was added TFA (40 μL) and NIS (63 mg, 0.28 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (CH2Cl2:MeOH, 100:0 to 90:10) to afford S6-4 (48 mg, 53%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, 1H), 4.65 (t, J=8.8 Hz, 2H), 3.28 (t, J=8.7 Hz, 2H); MS (ESI) m/z 412.0 (M+H)+.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.FC(F)(F)C([O-])=O.[C:22]([C:25]1[C:26]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:27][N:28]([C:30]2([CH2:36][C:37]#[N:38])[CH2:35][CH2:34][NH2+:33][CH2:32][CH2:31]2)[CH:29]=1)(=[O:24])[NH2:23].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:33]2[CH2:34][CH2:35][C:30]([N:28]3[CH:29]=[C:25]([C:22]([NH2:23])=[O:24])[C:26]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[N:27]3)([CH2:36][C:37]#[N:38])[CH2:31][CH2:32]2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Biphenyl-4-carbaldehyde (12 mg, 0.070 mmol) was treated with a solution of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-2) (20 mg, 0.050 mmol) and TFA (0.020 mL, 0.23 mmol) in DMF (0.65 mL). The resulting solution was then treated with MP-(OAc)3BH (80 mg, 0.16 mmol). The resulting mixture was shaken at ambient temperature for 16 hours on an orbital shaker. The mixture was then filtered through a 0.45 micron fit and the fit was washed with DMSO (1.0 mL). The filtrate was then purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #21-1.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:20].O>C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
TPP (4.45 g, 9.34 mmol) was added to a 0° C. solution of alcohol 6 (2.00 g, 7.78 mmol) in dry CH2Cl2 (50 mL). After 10 min, CBr4 (3.10 g, 9.34 mmol) was added and the stirring was continued at 0° C. After 2 h, water (20 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 30-35% ethyl acetate/hexane to afford 7 (2.20 g, 91%). TLC:EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (400 MHz, 45/55 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H, rotamers), 3.46 and 3.36 (t, J=5.8 Hz, rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H, rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, rotamers) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH2:8]O.S(Cl)([Cl:12])=O>ClCCl>[ClH:1].[Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[CH2:8][Cl:12]
Reactant: Cn1cnc(CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: Cn1cnc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (5-chloro-1-methyl-1H-imidazol-4-yl)methanol (397 mg, 2.7 mmol) in anhydrous dichloromethane (20 mL) was added thionyl chloride (1 mL). The mixture was stirred at room temperature for 2 hours. Dichloromethane was evaporated and then co-evaporated with toluene (2×10 mL). The residue was dried in vacuo, affording 5-chloro-4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (550 mg, 99% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]([C:18](O)=[O:19])[CH2:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:30][C:31]1[CH:37]=[CH:36][C:34](N)=[CH:33][CH:32]=1)[CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(P(=O)(OCC)OCC)#[N:39].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH3:22][N:23]([CH2:30][C:31]1[CH:37]=[CH:36][CH:34]=[CH:33][C:32]=1[C:14]1([C:18]([NH2:39])=[O:19])[CH2:13][C:12]2[CH:21]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[O:17][CH2:16][CH2:15]1)[CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)CC(C(=O)O)CCO3)cc1
Reactant: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)CC(C(N)=O)(c2ccccc2CN(C)C2CCOCC2)CCO3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxylic acid (141 mg) and 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (110 mg) in DMF (4 ml) were added under ice cooling diethyl cyanophosphonate (0.08 ml) and triethylamine (0.08 ml). After being stirred at 0° C. for 30 minutes and at room temperature for 8 hours, an aqueous solution of sodium bicarbonate was added into the reaction mixture under ice cooling. The resulting mixture was extracted with ethyl acetate, and the extract was washed with an aqueous saturated solution of sodium chloride. The extract was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/hexane=4/1) and further to recrystallization from ethyl acetate/hexane to obtain N-[4-[(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)phenyl]-7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxamide (compound 25) (43 mg) as colorless crystals.