Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[C:6]1[O:16]C.I[Si](C)(C)C>C(#N)C>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: COC(=O)C1(CCC(C)(C)C)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)C1(CCC(C)(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of Example 8B (0.31g, 0.98 mmol) in acetonitrile (0.2 mL) was added iodotrimethylsilane (TMSI) (1 mL, 6.86 mmol). The reaction solution was stirred at room temperature for 4 h. The solution was concentrated in vacuo. Column chromatography on silica (50% ethyl acetate/hexane) afforded the title compound as a white solid (0.28g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([C:28]([F:36])([F:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS([Cl:44])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:44])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([C:28]([F:36])([F:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(C(F)(F)c4ccccc4)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(C(F)(F)c4ccccc4)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
The title compound was prepared following methods similar to those described in Preparation 351 starting from (2R,5R)-4-{2-[6-(difluoro-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.37 g, 2.5 mmol), methanesulfonyl chloride (234 μL, 3.0 mmol) and TEA (582 μL, 4.0 mmol) to give the title compound (1.0 g) as a pale yellow gum. MS: [M+H]+=563.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[CH:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][N:16]=[N+:17]=[N-:18])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:19])[CH2:15][N:16]1[CH:10]=[C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:18]=[N:17]1)[CH3:12]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)nc1C
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2C)nn1

Procedure:
The title compound was prepared as described in Example 413, Step 2 using 6-chloro-3-ethynyl-2-methylpyridine (250 mg, 1.65 mmol) and ethylazidoacetate (0.93 ml, 1.65 mmol) as starting materials
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(SCc3ccccc3)c2n1
Product: c1ccc(CSc2ncnc3c(N4CCSCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 162°-164° C.) and piperazine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:30])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[N:14]=1.[OH-].[Na+]>CO.O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:30])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[N:14]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3cc4ccccc4s3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)O)cc1
Reaction time: 13 h
Yield: 97.9 %

Procedure:
Methyl 3-[4-[2-(2-(benzothiophen-2-yl)-5-methyl-4-oxazolyl)ethoxy]phenyl]propionate (1.90 g, 4.51 mmol) obtained in Example 13 was dissolved in methanol (20 ml) and tetrahydrofuran (30 ml), and 2.5N aqueous sodium hydroxide solution (2.2 ml, 5.5 mmol) was added at room temperature, which was followed by stirring for 13 hr. Then, the solvent was evaporated and water was added to the obtained residue. 1N Hydrochloric acid was added to acidify the solution and the precipitated white solid was collected by filtration, washed with water and dried to give the title compound (1.80 g, yield 98%) as a white solid.
Reaction SMILES: O.[ClH:2].[CH2:3]([S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[N:27]=[C:26]([NH:28]C(=O)C)[CH:25]=[CH:24][CH:23]=3)[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[ClH:2].[CH2:3]([S:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][CH:23]=3)[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1cccc(-c2nc(-c3ccc(SCc4ccccc4)cc3)no2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2nc(-c3ccc(SCc4ccccc4)cc3)no2)n1
Temperature: 25 °C

Procedure:
Water (50 ml) and concentrated hydrochloric acid (50 ml) are added to N-(6-{3-[4-(benzylthio)phenyl]-1,2,4-oxadiazol-5-yl}pyridin-2-yl)acetamide (40.55 g) in ethanol (150 ml). The reaction mixture is heated under reflux until the starting material has reacted completely (about 3 h) and subsequently cooled to room temperature. The solid is collected by filtration, washed three times with ethanol and dried in a vacuum oven at 80° C. 36.60 g (92% of theory) of product are obtained as a solid.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1)=O.B.O1CCCC1>O1CCCC1>[NH2:1][CH2:2][CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: NC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Agent: B
Solvent: C1CCOC1
Product: NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 80 °C
Yield: 89.8 %

Procedure:
To a solution of 4-aminocarbonyl-1-(1-naphthylsulfonyl)piperidine (10.6 g, 33.3 mmol) in tetrahydrofuran (200 mL) stirring under argon at room temperature, was added borane-tetrahydrofuran complex (1.5 M in tetrahydrofuran, 67 mL, 100 mmol). The resulting solution was heated to 80° C. for 6 h before the solvent was evaporated under vacuum. The residue was dissolved in 1.0 M aqueous hydrochloric acid (100 mL), and this was washed with diethyl ether (100 mL twice). The aqueous layer was basified to pH 10 with 50% aqueous sodium hydroxide and extracted with dichloromethane (50 mL three times). The combined dichloromethane extracts were dried (anhydrous sodium sulfate) and evaporated under vacuum to obtain 4-aminomethyl-1-(1-naphthylsulfonyl)piperidine (9.1 g, 90% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([CH3:15])=[O:24])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2c(c1)CN(C(C)=O)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2ccc(S(C)=O)cc2C1
Temperature: 25 °C

Procedure:
A solution of N-acetyl-7-methylthio-1,2,3,4-tetrahydroisoquinoline, (2 gm., 0.009 m.) in 20 ml. of chloroform was cooled to -20° C. and treated with (1.6 gm., 0.009 m.) m-chloroperbenzoic acid. The reaction mixture was allowed to warm to 25° C. and was washed with 10% aqueous sodium carbonate, dried over sodium sulfate and evaporated to yield N-acetyl-7-methylsulfinyl-1,2,3,4-tetrahydroisoquinoline. This compound was hydrolyzed following the procedure set forth in Example 1 to yield 7-methylsulfinyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 200°-202° C. from ethanol-ethyl acetate.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([F:18])([F:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4,4-difluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.684 g, 2.47 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4,4-difluoropiperidine as a pale yellow oil (0.279 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 3.64-3.54 (m, 4 H); 3.30-3.25 (m, 1 H); 2.43-2.37 (m, 4 H); 2.06-1.93 (m, 5 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1cc(Br)ccc1N
Product: Cc1cc(Br)ccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 41.4 %

Procedure:
Using the procedure of example 1, 4-bromo-2-methylaniline (300 mg) was reacted with compound 1f (200 mg) to provide compound 41 (85 mg, 41%). 1H NMR (400 MHz, DMSO) δ 12.28 (br s, 1H), 8.75 (br s, 1H), 8.55 (d, J=7.8 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J=7.2 Hz, 1H), 8.26 (m, 1H), 7.52 (m, 2H), 7.40 (d, J=10.8 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.06 (dd, J=10.8 Hz, 6.0 Hz, 1H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13]CC2)CCCCC1.[CH2:16](O)C>>[CH3:16][N:7]([C:8]1[CH:13]=[CH:14][CH:15]=[CH:10][N:9]=1)[CH3:1]
Reactant: CCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN(C)c1ccccn1

Procedure:
Alternatively, a compound of the formula XXXII may be esterified by reaction with ethanol in the presence of dicyclohexylcarbodiimide and a catalyst such as dimethylaminopyridine to give a compound of the formula ##STR73##
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-].[K+].[CH2:12](O)[CH3:13]>Cl>[CH2:12]([O:6][CH:4]1[NH:5][C:1](=[O:7])[CH2:2][CH2:3]1)[CH3:13]
Reactant: CCO
Reactant: O=C1CCC(=O)N1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Product: CCOC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
At 0° C., 9.91 g of succinimide were initially charged in 415 ml of ethanol and admixed, a little at a time, with a total of 5.53 g of sodium borohydride. At this temperature, every 15 minutes 2 to 3 drops of 2N ethanolic hydrogen chloride were added dropwise over a period of 4½ hours. The mixture was subsequently acidified to pH 3 using more acid. The mixture was stirred at 0° C. for one hour and then neutralized with 1% strength ethanolic potassium hydroxide solution, stirred for a further 15 minutes and concentrated. The residue was taken up in water and extracted three times with dichloromethane. Drying over sodium sulphate and concentration gave 7.16 g (55% of theory) of γ-ethoxy-γ-butyrolactam.
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)(O)[C:12]#[N:13].C(N(CC)CC)C>O1CCCC1>[C:3]1([C@@H:2]([OH:9])[CH2:1][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC[C@H](O)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 40.0 g of (R)-styrene oxide, 31.12 g of acetone cyanohydrin, 36.96 g of triethylamine, and 150 ml of tetrahydrofuran was heated at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo, diluted with 200 ml of 2N potassium hydroxide, and extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate, and concentrated in vacuo providing 34.3 g of the title intermediate.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[F:6][C:7]1([F:58])[CH2:12][CH2:11][CH:10]([C:13]2[C:22]3[C@@H:21](O)[CH2:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]=3[N:16]=[C:15]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([CH2:44][OH:45])([CH3:43])[CH2:41][OH:42])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)[C:14]=2[C@@H:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:9][CH2:8]1>COC(C)(C)C>[CH3:1][S:2]([O:5][C@H:21]1[CH2:20][C:19]([CH3:24])([CH3:25])[CH2:18][C:17]2[N:16]=[C:15]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]4[N:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([CH2:41][OH:42])([CH3:43])[CH2:44][OH:45])=[CH:34][N:33]=4)[CH2:30][CH2:31]3)[C:14]([C@@H:46]([F:57])[C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:55])([F:54])[F:56])=[CH:49][CH:48]=3)=[C:13]([CH:10]3[CH2:11][CH2:12][C:7]([F:6])([F:58])[CH2:8][CH2:9]3)[C:22]1=2)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(C)(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: CS(=O)(=O)O
Solvent: COC(C)(C)C
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(C)(CO)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](OS(C)(=O)=O)C1
Yield: 50.7 %

Procedure:
Reactions similar to those of Example 3 were performed except for using 4.5 μl (0.069 mmol) of methanesulfonic acid instead of 47% hydrobromic acid salt and using 2.5 ml of tert-butyl methyl ether instead of methyl ethyl ketone, and from 51.8 mg (0.069 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 19, 29 mg of the title compound was obtained as a white powder (yield: 50%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1.[ClH:39].CCOCC>C(O)C>[ClH:39].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of (S)-N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.360 g, 0.656 mmol) in ethanol (25 mL) was added an aqueous 6N solution of HCl (2 mL). The reaction was heated at 80° C. for 2 hours, then cooled to ambient temperature, stirred for 30 minutes, then cooled to 0° C. Ether (25 mL) was slowly added to initiate precipitation/crystallization. The reaction was stirred 30 minutes, then filtered. The solids were washed with ether several times, then hexanes, and dried overnight under vacuum at 50° C. to afford (S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.205 g, 0.406 mmol, 61.9% yield) as a light yellow powder/fine crystals. Mass Spectrum (apci) m/z=469.2 (M+H—HCl).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[CH2:16]([NH:23][C:24]([O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:24](=[O:25])[NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:28][CH:29]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(OC(=O)NCc2ccccc2)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(OC(=O)NCc3ccccc3)cc2)C(=O)OC1=O

Procedure:
To a boiling solution of 2.1 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol is added 2.4 g. (0.01 m.) of p-(N-benzylcarbamoyloxy)aniline and the resulting mixture is refluxed for one hour. The cooled reaction mixture is filtered and the solid is recrystallized to furnish 5-acetyl-3-[1-(p-N-benzylcarbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: Cc1ccccc1B(O)O
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-methylphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H22NO3 (M+H): 348.1594. Found 348.1603
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:4]([CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(CNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g, 29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K2CO3 (4.121 g, 29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68 h. The solids were removed by filtration and the solution was concentrated in vacuo. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title compound of Preparation 10 (5.637 g). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[O:5][C:6]1[C:7](=[O:45])[N:8]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][C:22]([NH:26]CC4C=CC(OC)=CC=4)=[CH:23][CH:24]=3)[N:19](CC3C=CC(OC)=CC=3)[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[NH2:26][C:22]1[N:21]=[C:20]2[NH:19][N:18]=[C:17]([CH2:16][N:8]3[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:6]([O:5][C:4]4[CH:46]=[C:47]([Cl:49])[CH:48]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:45])[C:25]2=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(Cl)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(Cn3ccc(C(F)(F)F)c(Oc4cc(Cl)cc(Cl)c4)c3=O)n[nH]c2n1
Reaction time: 4 h

Procedure:
3-(3,5-dichlorophenoxy)-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridine-3-yl}methyl)-4-(trifluoromethyl)pyridine-2(1H)-one (0.900 g, 12.7 mmol) dissolved in TFA (10 mL) was placed in an oil bath at 75° C. After 4 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with 50% aqueous sodium carbonate (50 mL). The aqueous was back extracted with ethyl acetate (100 mL) and the combined organic extracts were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting solid was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 12.60 (s, 1H), 8.00-7.90 (m, 1H), 7.65-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.12-7.00 (m, 2H), 6.65-6.55 (m, 1H), 6.42-6.25 (m, 3H), 5.40-5.30 (s, 2H). LRMS (M+1)=469.77.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[OH-].[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(O)(=O)C>[CH:20](=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c3ccccc3c(=Cc3ccccc3)c2n2ccnc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
A suspension of 5.75 g of 5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one, 10 g of sodium hydroxide pellets and 125 mg of tetrabutylammonium bromide in 200 ml of dimethyl sulphoxide is stirred at a temperature in the region of 20° C. 3.18 g of benzaldehyde are then added and the stirring is continued for 18 hours at a temperature in the region of 20° C. The reaction mixture is poured into a mixture of water and ice (250 ml) and acidified with 100 ml of acetic acid. The solid formed is filtered off and the crude product is purified by two successive chromatographies on a column of silica with a mixture of dichloromethane and methanol (90/10 by volume). 0.13 g of 10-benzylidene-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is thus obtained, in the form of a yellow solid melting above 260° C. (Analysis % calculated C: 77.16, H: 4.21, N: 13.50, O: 5.14, % found C: 76.7, H: 3.7, N: 13.2).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9]2)C=CC=CC=1.Cl.O1CCOCC1.[H][H]>CO>[NH:8]1[CH2:11][CH:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9]1
Reactant: [H][H]
Reactant: CS(=O)(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)NC1CNC1

Procedure:
A solution of N-[1-(diphenylmethyl)-3-azetidinyl]-methanesulfonamide (185 mg, 0.585 mmol) in MeOH (10 mL) was treated with 1 mL of 4.0 N HCl/dioxane and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite and used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:16][CH2:17]1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: Clc1cnccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)OCC(CN1CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Yield: 27.2 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (2.35 g, 10 mmole), 2-chloropyrazine (1.15 g, 10 mmole) and diisopropylethylamine (1.3 g, 10 mmole) were combined in 100 ml of 1-methyl-2-pyrrolidinone and heated under N2 at 100° C. for 24 hours. Upon cooling, the solvent was removed in vacuum and the residue filtered through 75 g of silica gel using chloroform as the eluent. The product-containing fractions were combined, the solvent evaporated and the residue was crystallized from methanol with addition of 4N isopropanolic HCl. A second recrystallization from methanol gave 850 mg of title compound, as the dihydrochloride salt, m.p. 248°-253° C.(d).