Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:18][C:19]1C(N)=NC2(C3C(=CC=C(N)C=3)OCC2)N=1.C(I)C.CC([O-])(C)C.[K+]>CC1OCCC1.[Cl-].[Na+].O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCI
Solvent: O
Solvent: CC1CCCO1
Product: CCOC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one as a 2:1 mixture of isomers (Intermediate 5 Step 2, 10.4 g, 34.1 mmol) and ethyl iodide (3.6 mL, 44.3 mmol) were dissolved in 2-MeTHF (100 mL) under N2. KOt-Bu (7.65 g, 68.2 mmol) was added portionwise to the reaction mixture, keeping the internal temperature below 30° C. The solution was stirred at r.t. overnight. Water (40 mL) and brine (25 mL) were added and the mixture was further stirred for 5 min. The mixture was diluted with brine and 2-Me-THF until two layers formed. The phases were separated. Activated charcoal was added to the organic layer which was then stirred for 10 min. Diatomaceous earth was added and the mixture was further stirred for 5 min. The mixture was filtered through a plug of silica gel and diatomaceous earth, which was rinsed with heptane/EtOAc 7:3. The filtrate was concentrated. The filtration sequence was repeated, affording 4.0 g (36% yield) of the title compound (as a 2:1 mixture of isomers): 1H NMR (300 MHz, CDCl3) ppm 1.22 (t, 3 H), 1.32-1.45 (m, 2 H), 1.45-1.52 (m, 2 H), 1.77 (dt, 2 H), 2.07-2.16 (m, 2 H), 2.98 (s, 2 H), 3.30-3.40 (m, 1 H), 3.57 (q, 2 H), 7.34 (d, 1 H), 7.69 (dd, 1 H), 7.87 (d, 1 H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C@H:13]([NH:17]C(OC(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[F:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C@H:13]([NH2:17])[CH2:12][CH2:11][CH2:10]3)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(COS(C)(=O)=O)ccc21
Reactant: FC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N[C@@H]1CCCc2cc(CN3CCC(F)CC3)ccc21

Procedure:
A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (2.0 g, 5.633 mmol, 1.0 eq.), 4-fluoropiperidine.HCl (0.78 g, 5.633 mmol, 1.0 eq.) and K2CO3 (2.33 g, 16.9 mmol, 3.0 eq.) in THF (25 ml) was heated at reflux for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml), washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 40% ethyl acetate/hexanes) to yield the title compound as a light yellow solid. Yield: 60% (1.22 g, 3.37 mmol) 2. TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (325 mg, 0.898 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 4 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was employed in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)glycine (4.0 g, 23 mmol), N,O-dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and N,N-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2Cl2 (100 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0° C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCl (1 M, 2×40 mL) followed by a saturated aqueous solution of NaHCO3 (2×40 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90%). 1H-NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]([C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[CH2:36][CH2:37][C@H:38]1[O:43][CH2:42][C@@H:41]([CH2:44][O:45][C:46](=[O:53])[NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])[N:40](C(OC(C)(C)C)=O)[CH2:39]1)=[O:27])[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C@@H:10]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[CH2:36][CH2:37][C@H:38]2[O:43][CH2:42][C@@H:41]([CH2:44][O:45][C:46](=[O:53])[NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])[NH:40][CH2:39]2)=[O:27])[NH2:9])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
4M HCl (44.5 mL, 178 mmol) in dioxane was added to a solution of tert-Butyl (2R,5S)-2-[2-(2-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenyl)ethyl]-5-({[(2,2,2-trifluoroethyl)carbamoyl]oxy}methyl)morpholine-4-carboxylate (7.46 g, 8.89 mmol) in Dioxane (89 mL) at 0° C. and then the reaction was stirred at rt for 4 hours. The solvent was removed in vacuo and ether was added to the residue to afford a white ppt. The ppt was triturated with ether (×3) and the residing white solid dried under high vacuum to afford the title compound (5.84 g, 8.21 mmol, 92% yield) as a white powder, MS (ESI): m/z=639.5 (MH+); 100% pure by LCMS.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.S(=O)=O.[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>>[Br:1][C:19]1[CH:20]=[CH:21][C:16]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: CC(C)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S=O
Product: CC(C)Cc1ccc(Br)cc1
Reaction time: 1.08 h
Yield: 2 %

Procedure:
To a mixture of 1.78 g (10 milliMoles) of N-bromosuccinimide in 20 ml of liquid sulfur dioxide at -30° C. is added 1.57 ml (10.0 mMoles) of isobutylbenzene. The mixture is stirred at -30° to -18° for 65 minutes, then worked up as above. Assay gives only 2% p-bromoisobutylbenzene and 88% recovered starting isobutylbenzene, indicating that the reaction with NBS is very slow at this temperature.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:69][N:70]1[CH2:75][CH2:74][S:73][CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:68][N:58]([C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:69][N:70]3[CH2:71][CH2:72][S:73][CH2:74][CH2:75]3)[CH2:45][N:46]=1)=[CH:57]2)[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:60])=[O:61]
Reactant: CN(c1cccc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.33 h
Yield: 5.3 %

Procedure:
To a solution of triphenylphosphine oxide (0.79 g) in dichloromethane (5 mL) was slowly added trifluoromethanesulfonic anhydride (0.38 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.67 g) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4). The obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (29 mg, yield: 5%) as colorless crystals. MS: 488 (MH+). melting point 142-144° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].C=O.C(C(/C=C\C(O)=O)=O)C(CC(O)=O)=[O:25].ClC(Cl)(Cl)C(C1C=CC(Cl)=CC=1)C1C=CC(Cl)=CC=1>>[CH3:6][C:2]([CH:3]=[O:5])=[O:25].[NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)/C=C\C(=O)CC(=O)CC(=O)O
Agent: C=O
Agent: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Product: CC(=O)C=O

Procedure:
Glutathione functions as a co-enzyme for formaldehyde dehydrogenase, maleylacetoacetate isomerase, glyoxalase, prostaglandin endoperoxidase isomerases, and dichlorodiphenyltrichloroethane dehydrochlorinase and similar enzymes. In the glyoxalase reaction, the hemimercaptal formed nonenzymatically by reaction of methylglyoxal and glutathione (GSH) is converted by glyoxalase I to S-lactyl-Glutathione, which is split by glyoxalase II to D-lactate and Glutathione. In the formaldehyde dehydrogenase reaction, S-formyl Glutathione is formed (Glutathione+HCHO+NAD+) and hydrolyzed to formate and Glutathione.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH2:20][CH2:19]1)([OH:4])=[O:3].[CH3:33]O>>[CH3:33][O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH2:22][CH2:23]1)=[O:4]
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1
Agent: Cl
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCO5)CC3)c2c1

Procedure:
HCl gas is passed into a boiling solution of 2.5 g of 1-[4-(5-carboxyindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine in 50 ml of absolute methanol for 2 hours. The mixture is then boiled for a further hour, worked up in the customary manner and gives 1-[4-(5-methoxycarbonylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)piperazine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.Cl.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.[Na+].[I-]>C(#N)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[S:8][CH2:7]3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1N(CCCCBr)CSC12CCCC2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1N(CCCCN2CCN(c3nsc4ccccc34)CC2)CSC12CCCC2
Yield: 33.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.33 g), K2 CO3 (7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65° C. for 14.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.25 g of crystals, m.p. 200°-203° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccc(F)cc5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 286. NMR (DMSO): 2.55-2.58 (4H, m), 2.98-3.03 (4H, m), 3.73-3.77 (4H, m), 3.88 (2H, s), 3.90-3.94 (4H, m), 7.06 (2H, br. s), 7.32 (1H, s), 7.50-7.55 (211, t), 7.80-7.84 (2H, m), 9.10 (2H, s). MS (ESI+): MH+ 570.23 (100%)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:22]1([C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:20][CH:19]=2)=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(OC[C@H]2CCCN2)nc1
Reaction time: 2 h

Procedure:
To a solution of product from step 3 (100 mg, 0.26 mmol) was treated with 5 ml of 4 N HCl in dioxane and stirred for 2 h. The solvent was removed in vacuo, triturated with ether to give the title compound as the hydrochloride salt (35 mg, 42%) MS; m/z 283 (M+H) 99%; 1H NMR (DMSO-d6, 400 MHz) δ 1.78-2.22 (4H, m), 3.20 (2H, m), 3.98 (1H, m), 4.45-4.65 (2H, m), 7.05 (1H, d, J=8.8 Hz), 7.60 (2H, m), 7.69-7.76 (3H, m), 8.14 (1H, dd, J1=2.8 Hz, J2=8.8 Hz), 8.56 (1H, dd, J1=0.8 Hz, J2=2.4 Hz), 9.2 (1NH, s)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH3:29][C:30]([S@:33]([NH2:35])=[O:34])([CH3:32])[CH3:31].[BH4-].[Na+].CO>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([NH:35][S@@:33]([C:30]([CH3:32])([CH3:31])[CH3:29])=[O:34])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
1-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanone (0.577 g, 2.49 mmol) was added to a solution of (R)-(+)-2-methyl-2-propanesulfinamide (0.150 g, 1.24 mmol), titanium (iv) ethoxide (0.510 mL, 2.48 mmol) in THF (5 mL). The reaction mixture was heated to 70° C. for 23 h, At which time was cooled to −50° C. To the reaction mixture was added a suspension of sodium borohydride (0.187 g, 4.95 mmol) in 0.5 mL of THF also at −50° C., allowed to stir for 18 h at −50° C. The reaction mixture was warmed to 0° C. and MeOH was added dropwise until gas evolution was no longer observed. The crude reaction mixture was poured into an equal volume of brine while being stirred rapidly. The resulting suspension was filtered through a plug of celite, the cake rinsed with EtOAc and MeOH. The filtrate was reduced in vacuo, the residue diluted with EtOAc, extracted with brine and dried over MgSO4. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (R)-N-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide. MS (ESI) m/z: calculated: 493.2; Observed: 494.0 (M++1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6](OC)=[O:7].O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[CH2:3][CH:2]([OH:1])[CH2:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: NN
Reactant: COC(=O)C(CC1CO1)c1ccccc1C(F)(F)F
Solvent: O
Solvent: CCO
Product: NN1CC(O)CC(c2ccccc2C(F)(F)F)C1=O

Procedure:
Methyl 3-oxiranyl-2-(2-trifluoromethylphenyl)propionate (2.61 g) was dissolved in ethanol (20 mL). Hydrazine monohydrate (2.3 mL) was added at room temperature, and the mixture was reacted for 24 hours. Concentration under reduced pressure gave an oil which was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride four times. After drying over magnesium sulfate, concentration under reduced pressure gave the title compound (1.8 g) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)=[CH:2]1>C(O)C.[Pd]>[S:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH2:2]1
Reactant: Nc1ccc(C2=CSCC2)cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CCSC2)cn1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-(4,5-dihydrothiophen-3-yl)pyridin-2-amine(0.78 g, 4.38 mmol) was dissolved in ethanol(30 mL), to it was added Pd—C (Deggussa, 10%, 0.233 g) and the mixture was stirred under H2 balloon overnight. The reaction was not complete by LCMS. The Pd—C catalyst was removed by filtering through a Celite pad, and to the filtrate was added new Pd—C catalyst (0.24 g), and the mixture was stirred under H2 balloon under same condition for another 6 h. The reaction mixture was filtered off through Celite pad, and the filtrate was concentrated under reduced pressure yielding 5-(tetrahydrothiophen-3-yl)pyridin-2-amine (0.661 g, 84%) as colorless oil. LCMS (m/z): 181.2 (MH+), 0.39 min.
Reaction SMILES: [OH-].[NH4+].[OH:3][C:4]1[NH:9][C:8](=S)[NH:7][C:6](=[O:11])[C:5]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].N1C=CC=NC=1.Cl>[Ni].O>[OH:3][CH:4]1[CH:5]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[C:6](=[O:11])[N:7]=[CH:8][NH:9]1
Reactant: O=C(Nc1ccccc1)c1c(O)[nH]c(=S)[nH]c1=O
Agent: [Ni]
Agent: Cl
Agent: [NH4+]
Solvent: c1cncnc1
Solvent: O
Product: O=C1N=CNC(O)C1C(=O)Nc1ccccc1
Reaction time: 4 h

Procedure:
To concentrated aqueous ammonium hydroxide (400 ml) and water (400 ml) was added 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidinecarboxamide (13.2 g) (prepared as described in Example 1 of the aforesaid copending application Ser. No. 699,776). The pyrimidine dissolved. To this solution was added a slurry of Raney Nickel in water (50 g). The suspension was gently refluxed with stirring for four hours. It was cooled and the solids, which consisted of product and inorganics, were treated with dilute hydrochloric acid, the mixture filtered and the solids extracted with 2-Normal sodium hydroxide solution and filtered. The filtrate was then acidified with dilute hydrochloric acid, the resulting precipitate redissolved in aqueous ammonium hydroxide, purified with activated charcoal and celite, and reprecipitated with dilute acid. The solid was collected, washed with water and dried. Yield 5.8 g, melting point 200°-208°. Mass spectrum 231, calculated 231; Nuclear Magnetic Resonance (DMSO), 6.8-7.7 δ (aromatic peaks); 8.28 δ (2-hydrogen atom); 11.8 δ (exchangeable protons).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:12](=[O:28])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]1=[O:27].[BH4-].[Na+]>CO>[OH:28][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][C:15]1=[O:27]
Reactant: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-Butyl 4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]-3-oxopiperazine-1-carboxylate (160 mg, 0.41 mmol) in MeOH (10 ml) was added NaBH4 (31 mg, 0.82 mmol). The reaction was allowed to stir at RT for 2 hours. TLC showed clean conversion. The reaction was quenched by addition of water. The crude material was diluted with EtOAc, washed with water, dried over sodium sulfate, and concentrated to give the title compound. LC-MS (IE, m/z): 391 [M+1]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1C=CN=CC=1.N1CCCC1.C1(C)C=CC=CC=1>O>[CH3:2][CH:3]1[CH2:13][CH2:12][N:1]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: Cc1ccncc1
Reactant: c1cc(N2CCCC2)ccn1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCN(c2ccncc2)CC1

Procedure:
The exact procedure of Example 5 for the preparation of 4-pyrrolidinopyridine was followed substituting 12.4 g (0.125 mole) of 4-methylpyridine in 18.6 ml of water for the aqueous pyrrolidine solution. After concentration of the toluene extracts, a quantitative yield of the title compound product was obtained as a reasonably pure oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[N:19]1([C:25]2[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][N:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:31](=[O:32])[C:29]3[CH:28]=[CH:27][N:26]=[C:25]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH:30]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccnc(N4CCOCC4)c3)CC2)ccc1Cl
Yield: 34 %

Procedure:
The title compound (16 mg, 34%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2-(4-morpholinyl)-4-pyridinecarboxylic acid. MS: 459.4 (MH+)