Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (175 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg). The crude product was used for next step without further purification. MS (ES): C28H31N3O3S requires 489. found 490.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=5)=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][N:12]=3)[NH:7][C:6]=2[C:33]=1[F:34].FC1C=CC2N=C(NC3C=CC(OC4C(C5C=CN=C(S(C)(=O)=O)N=5)=CC=CN=4)=CN=3)[NH:41][C:40]=2C=1F.C1COCC1>CN.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH3:40])[N:25]=5)=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][N:12]=3)[NH:7][C:6]=2[C:33]=1[F:34]
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Reactant: CS(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Agent: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nc4ccc(F)c(F)c4[nH]3)nc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The mixture of 6,7-difluoro-N-(5-(3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine and 6,7-difluoro-N-(5-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine (0.140 g, 0.28 mmol) in methylamine, 2.0 M solution in THF (2.1 ml, 4.2 mmol) was heated in a sealed tube to 70° C. After 4 h, the reaction was partitioned between EtOAc and 1 N NaOH, and the aqueous suspension was extracted 1×EtOAc, 3× dichloromethane, and the suspension was then filtered and rinsed with methanol. The solid material was combined with the combined organic layers adsorbed onto 2 g silica gel and purified with silica gel chromatography, eluting with 0-75% MC-90/10 MC/MeOH to give a white solid. The solid was sonicated in methanol and filtered, rinsing with Et2O. The resulting material was dried in vacuo to give 6,7-difluoro-N-(5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-yl)-1H-benzo[d]imidazol-2-amine as a white solid. MS m/z=447 [M+H]+. Calc'd for C22H16F2N8O: 446.4.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>ClCCl.C(OCC)C>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Reaction was carried out in two separate batches, employing 5 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid in each batch. To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5 g, 32 mmol) in anhydrous dichloromethane (20 mL) at 0° C. (under an argon atmosphere), was added dropwise a solution of (trimethylsilyl)diazomethane (18 mL of a 2M solution in diethyl ether, 35 mmol) (gas evolution observed). The resulting yellow solution was allowed to warm to rt and stirred for a further 48 h. An additional 5 mL of 2M (trimethylsilyl)diazomethane solution (10 mmol) was added, and stirring continued for a further 5 h whereupon a further 6 mL of 2 M (trimethylsilyl)diazomethane solution (12 mmol) was added. After stirring for a further 15 h, the reaction mixture was concentrated in vacuo (keeping bath temperature below 30° C.). The resulting oil was redissolved in diethyl ether (200 mL), washed with saturated sodium hydrogencarbonate solution (100 mL), separated, and dried over MgSO4. Filtration followed by concentration in vacuo (keeping bath temperature below 30° C.) gave crude product. Crude product from both batches were combined to afford crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (7.69 g) as a yellow oil which was taken on without further purification. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:33]=O>CO.[Pd]>[CH3:33][N:8]1[CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]([NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])[C:2](=[O:1])[CH:6]2[CH2:7]1
Reactant: C=O
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CN(C)CCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O

Procedure:
A solution of 0.361 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide (prepared as described in Example 63) in 10 ml of methanol was treated with 1 ml of 40% aqueous formaldehyde solution and then hydrogenated for 1 hour in the presence of 0.03 g of 10% palladium-on-carbon. The catalyst was removed by filtration and evaporation gave 0.395 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-7-methyl-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a clear oil.
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[NH2:14][C:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH2:18][C:17](=[O:28])[CH:16]=1>C(#N)C>[CH3:12][C:7]1([CH3:11])[O:6][C:5](=[O:13])[C:4](=[CH:3][NH:14][C:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH2:18][C:17](=[O:28])[CH:16]=2)[C:9](=[O:10])[O:8]1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Solvent: CC#N
Product: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3Cl)C2)C(=O)O1
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.5 %

Procedure:
To a solution of 5-methoxymethylene-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.7 g) in acetonitrile (15 ml) was added 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g), and the mixture was stirred at room temperature for 13 hours. Precipitated crystals were filtered and washed with acetonitrile to give colorless crystals of 2,2-dimethyl-5-[(3-oxo-5-(2-chlorophenyl)-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.7 g).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:18]([N:22]1[C:8]([NH2:9])=[CH:7][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.5 %

Procedure:
A solution of pivaloylacetonitrile (300 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 days, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, ethyl acetate to 20% methanol in ethyl acetate) to afford the product as an off-white solid (123 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([O:34]C)([O:32]C)=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([O:22]CC[Si](C)(C)C)=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([OH:34])([OH:32])=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)P(=O)(O)O
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was added trimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at ambient temperature. The reaction was allowed to proceed for 16 hours before it was concentrated to dryness. The residue was resuspended in a solution of DMF: H2O (8:2, 1 mL) and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49 (m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4, 12, 23 Hz), 3.38 (3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; 31p (121.4 MHz, CDCl3) δ 19.5 ppm; MS (m/z) 415.2 [M+H]+, 437.2 [M+Na]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16].[OH-].[K+].O1CCOCC1>CCOCC>[CH2:5]([O:4][C:2]([O:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC(=NO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#CC(=NOC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A solution of benzyl chloroformate (5.1 g.) in ether (40 ml.) was added to a solution of 2-hydroxyimino-2-phenylacetonitrile (4.4 g.) in a mixture of a 1N potassium hydroxide aqueous solution (30 ml.) and dioxane (10 ml.) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 4 hours at room temperature. The ether layer was separated from the reaction mixture and the aqueous layer was further extracted with ether. Both ether layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off and to the residue was added n-hexane. The precipitated crystals were collected by filtration to give 2-benzyloxycarbonyloxyimino-2-phenylacetonitrile (5.2 g.), mp 73° to 75° C.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2ccc(N3CCC(O)CC3)cc2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol. LCMS calculated for C27H31N4O3(M+H)+: m/z=459.2. Found 459.3.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CN(C=O)C.Cl[C:27]1[N:31]([CH3:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=1>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)=[CH:14][CH:13]=2)[N:4]=1)[CH3:2]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a mixture of 4-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (120 mg), sodium hydride (60% in oil, 21.0 mg) and DMF (5.0 ml) was added 2-chloro-1-methyl-1H-benzimidazole (84 mg), and the mixture was stirred under microwave irradiation at 180° C. for 1 hr. The reaction mixture was diluted with methanol, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:11])[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: COc1cccc(N=C=O)c1
Solvent: O
Product: COc1cccc(NC(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)c1

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-methoxyphenyl)urea was prepared from 3-methoxyphenyl isocyanate (15 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (26 mg, 53 μmol, 46%). LC/ESI-MS: m/z=503 [M+H]+; m/z=501 [M−H]−; Rt=3.12 min.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C(#N)C>[C:14]12([NH:24][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:12]#[N:13])=[O:4])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.20 mmol) in acetonitrile (3 mL) at room temperature under nitrogen was added 1-adamantanamine (0.06 g, 0.408 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 312 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([Cl:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
4-(benzyloxy)-4-oxobutanoic acid (6.16 g, 1 eq, from Example 1a) was dissolved in toluene (20 mL) and placed in a 300 mL round bottom flask, fitted with a condenser. While the reaction was stirred under inert atmosphere, thionyl chloride (5.30 g, 1.5 eq) was added. A few drops of DMF were also added and tire reaction mixture was heated to 35° C. for 45 minutes and then to 60° C. for 2 hours. The solution was concentrated to 6.71 g of brownish oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CCCCCC)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCCCCC)c1
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A mixture of 11.64 g of 3-(2-hexyl-4-tetradecylphenoxy)-1,2-propanediol, 12.32 g of trityl chloride and 40 ml of pyridine was stirred for 24 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, water, dried and the solvents evaporated under reduced pressure. The residue was coevaporated with toluene, giving 14.6 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH3:15][CH2:16][O:17][P:18](Cl)([O:20][CH2:21][CH3:22])=[O:19].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:15][CH2:16][O:17][P:18]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOP(=O)(Cl)OCC
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (20 ml) was added chlorodiethylphosphate (1.45 ml, 0.01 mole). After stirring for 4 hours at 25° C. additional chlorodiethylphosphate (1.5 ml) was added and the reaction mixture was stirred at 25° C. for 18 hours then poured into ice water and excess hydrochloric acid to give 1.15 g of diethyl(2-sulfamoyl-6-benzothiazolyl)phosphate m.p. 142°-144° C. after recrystallization from ethylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.[C:17](=[N:23][Si](C)(C)C)=[N:18][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]/[C:5]/2=[N:23]\[C:17]#[N:18]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC2(CCOC2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCOC2)Oc2ccc(Br)cc21
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (206 mg, 0.731 mmol) in anhydrous DCM (6 mL) was added TiCl4(281 mg, 1.48 mmol) dropwise within 15 minutes at room temperature and resulting mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (300 mg, 1.61 mmol). The resulting mixture was stirred for another 18 hours after addition. The reaction mixture was poured into water-ice and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give crude product (225 mg, 100%), which was used in the next step without further purification.
Reaction SMILES: Cl.[S:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[CH2:32]([O:31][CH2:30][C@H:12]([NH:11][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][S:2][CH2:3]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CN1CCSC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCSC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 22.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(thiazolidin-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 235, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(thiazolidin-3-yl)acetamido)propanamide (9.3 mg, 22.8%). MS (EI) for C27H28FN3O4S. found 510.5 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:40])[CH:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][NH:35][CH2:36]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:35]5[CH2:36][CH:37]6[CH:32]([N:31]([CH3:40])[CH3:30])[CH:33]([CH2:39][CH2:38]6)[CH2:34]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:27])[CH3:28])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CN(C)C1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)C5N(C)C)cn3)nc2n1C1CCCC1
Yield: 14 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine following amide formation method 3 which gave 7-cyclopentyl-2-(5-(8-(dimethylamino)-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (12 mg) 14% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H) 8.76 (s, 1H) 8.55 (d, J=9.60 Hz, 1H) 8.44 (d, J=2.02 Hz, 1H) 7.78 (dd, J=8.59, 2.02 Hz, 1H) 6.48 (s, 1H) 4.87-4.73 (m, 1H) 4.31 (br. s., 1H) 3.75 (br. s., 1H) 3.35 (m, 2H) 3.16 (s, 6H) 2.68-2.51 (m, 2H) 2.30 (s, 7H) 2.16-1.97 (m, 6H) 1.86-1.66 (m, 6H). HR-MS (m/z MH+) 531.32 RT 2.67 min