Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[N:50]=[CH:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[CH:45][NH:46]2>>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:42]1[C:43]3[CH:44]=[CH:45][NH:46][C:47]=3[CH:48]=[CH:49][N:50]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Brc1nccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3nccc4[nH]ccc34)nc21

Procedure:
2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (150 mg) was reacted with 4-bromo-5-azaindole via General Procedure G to afford 119 (20 mg) following reverse phase purification. MS (Q1) 491.2 (M)+. 1H NMR (400 MHz, MeOD) δ 8.31 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 4.39 (s, 4H), 4.03-3.69 (m, 10H), 3.31 (d, 5H), 3.01 (d, 2H), 2.10 (t, 2H), 2.03 (s, 2H), 1.75 (d, 2H), 1.53-1.22 (m, 4H), 1.13 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]1=[O:23].C[Si](C)(C)[O-].[K+].Cl>C1COCC1>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:7]2[CH2:8][CH2:9][C@H:5]([O:4][C:3]3[CH:24]=[CH:25][C:26]([C:28]([OH:30])=[O:29])=[CH:27][C:2]=3[F:1])[C:6]2=[O:23])[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(C(=O)O)cc3F)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (900 mg, 2.06 mmol) was dissolved in THF (20 mL) and potassium trimethylsilanolate (529 mg, 4.12 mmol) was added and the reaction stirred at ambient temperature. After 2 hours, additional potassium trimethylsilanolate (529 mg, 4.12 mmol) was added and stirred for 3 hours, the reaction was poured into 1N HCl and extracted with EtOAc, dried over Na2SO4, filtered and concentrated to afford (S)-4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (834 mg, 1.97 mmol, 95.7% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 73 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 73%). 1H NMR (200 MHz, CDCl3): δ 2.35 (s, 3H), 2.98-3.03 (m, 4H), 3.73-3.78 (m, 3H), 4.10-4.14 (m, 4H), 7.02-7.17 (m, 2H), 7.19-7.29 (m, 2H), 7.36 (s, 1H), 7.48-7.60 (m, 1H), 7.67-7.74 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:38][CH2:39][O:40][CH3:41])[CH2:9][CH2:10][N:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[C:19]2=[O:37])[S:12]([CH3:15])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:38][CH2:39][O:40][CH3:41])[CH2:9][CH2:10][N:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][C:27]([OH:29])=[O:28])[C:19]2=[O:37])[S:12]([CH3:15])(=[O:13])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(CCN(c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O)S(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COCCN(CCN(c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O)S(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of benzyl 2-(5-(N-(2-(tert-butoxycarbonyl(2-methoxyethyl)-amino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.166 g, 0.282 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH was hydrogenated in a Parr apparatus at 30 psi for 3 hours. The catalyst was filtered off and the filtrate was evaporated to dryness affording 2-(5-(N-(2-(tert-butoxycarbonyl(2-methoxyethyl)amino)ethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.138 g, 0.276 mmol, 98% yield, MS/ESI+ 522.0 [MNa]+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[CH3:16]I>C(#N)C.[Ag]=O>[CH3:16][O:1][CH2:2][C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CI
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@@H](C)NC(=O)OCc1ccccc1
Yield: 71.5 %

Procedure:
To a solution of benzyl [(1R)-2-hydroxy-1-methylethyl]carbamate (0.5 g, 2.38 mmol) in acetonitrile (20 mL), silver oxide (3.8 g, 13.09 mmol) is added followed by the addition of methyl iodide (1.94 mL, 23.8 mmol). The resultant mixture was stirred overnight at room temperature. The insoluble salt was filtered off and the filtrate was concentrated. The residue was flashed using silica and Ethyl acetate/hexanes system as eluent to give the desired product as clear oil (0.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([N:18]1[C:26]2[C:21](=[CH:22][C:23]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)=O.[OH-].[Na+]>ClCCl>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)CC1
Reaction time: 0.75 h

Procedure:
tert-butyl-1-piperazinecarboxylate (5.94 g, 31.9 mmol, 2.00 equiv) was added to a solution of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (1-6, 5.00 g, 15.9 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 45 minutes. The brown-colored reaction mixture was concentrated and the resulting tan-colored solid dried in vacuo. A solution of the solid in a mixture of 1,4-dioxane (100 mL) and methanol (30 mL) was treated with aqueous 1N NaOH solution (47.9 mL, 47.9 mmol, 3.00 equiv), and the resulting mixture was stirred for 1 hour. The mixture was concentrated, and the resulting solid suspended in diethyl ether (130 mL) and filtered. The filtered solid was then partitioned between aqueous saturated sodium chloride solution (150 mL) and ethyl acetate (4×85 mL). The organic layer was dried over sodium sulfate and concentrated to provide the tert-butyl 4-(2,3-dihydro-1H-indol-5-ylsulfonyl)piperazine-1-carboxylate (2-1) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.41 (m, 2H), 6.57 (d, 1H, J=8.9 Hz), 3.69 (t, 2H, J=8.6 Hz), 3.50 (t, 2H, J=4.9 Hz), 3.09 (t, 2H, J=8.6 Hz), 2.93 (t, 2H, J=4.9 Hz) 1.42 (s, 9H).
Reaction SMILES: [Cl:1][CH:2]([C:6](=[O:8])[CH3:7])[C:3]([NH2:5])=[O:4].[C:9](Cl)(=[O:11])[CH3:10]>C(OC(=O)C)(=O)C>[C:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[C:6](=[O:8])[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)C(Cl)C(N)=O
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)C(Cl)C(C)=O

Procedure:
A solution of 2-chloro-3-oxobutyramide (1 g) in acetic anhydride (5 ml) containing acetyl chloride (1 ml) was heated in a 100° oil bath for 2 hours. Excess reagent was evaporated under reduced pressure and the residue was vacuum distilled in a kugelrohr apparatus. The distilled product crystallized to give a colorless solid with mp 54°-8°; ir (Nujol) 3200 and 1700 cm-1 (broad); nmr (CDCl2) 2.28 (CH3), 2.47 (CH3), 5.53 (CH), and 9.7 ppm (NH), (a weaker set of singlets corresponding to the enol appears at 2.23, 2.52, and 8.7 ppm); mass spectrum m/e 43 (100%), 93, 135, and 177 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5].[Br:11]Br>CO.C(O)(=O)C>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cccc(C)c1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Br)cc(C)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To an ice-water cooled solution of 2-methoxy-6-methylaniline (10 g, 72.9 mmol) in 30 mL of methanol and 10 mL of acetic acid was added dropwise bromine (3.75 mL, 72.9 mmol). The reaction mixture was allowed to stand for overnight. The solvent was removed under reduced pressure and the residue was suspended in 60 mL of 1N NaOH and extracted with ethyl acetate and dried over sodium sulfate and evaporated to dryness to give reddish crude product, which was recrystallized from hexane to give pure product (14.3 g, 91%).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[S].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.Cl>C(O)C.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]2[S:10][C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:24][C:16]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Agent: [S]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium sulfide nonahydrate (875 mg, 3.78 mmol) and sulfur (120 mg, 3.78 mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4-methylbenzamide (1 g, 3.44 mmol) in ethanol (20 mL) at 85° C. The solution was stirred at 85° C. for 3 h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v to afford 400 mg (43%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([SH:27])[CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:29])[C:16]([C:17]2[CH:18]=[C:19]([S:27][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)=[O:28])=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: O=C(O)CCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SCCCCC(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.263 g, 584 μmol, example 310, intermediate a) in acetonitrile (4 mL) were added 5-bromopentanoic acid (132 mg, 730 μmol) and DIPEA (189 mg, 255 μL, 1.46 mmol) and the clear, light yellow solution was stirred at room temperature for 2.25 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 50:50). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.119 g, 74%). MS (ESI): m/z=551.16 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O.Cl.[NH2:18][C:19]1([C:22](OCC)=[O:23])[CH2:21][CH2:20]1>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:3]3[C:4]([CH3:7])=[N:5][S:6][C:2]=3[NH:1][C:22](=[O:23])[C:19]3([CH2:21][CH2:20]3)[N:18]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1(N)CC1
Reactant: Cc1nsc(N)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Temperature: 170 °C
Yield: 14.7 %

Procedure:
A mixture of (5-amino-3-methylisothiazol-4-yl)(4-chlorophenyl)methanone (0.19 g, 0.75 mmol) and ethyl 1-aminocyclopropanecarboxylate hydrochloride (0.19 g, 1.13 mmol) in pyridine (1 mL) was heated at 170° C. for 18 h. The reaction mixture was then evaporated, extracted with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc/hexane 0:10 to 5:5) to give 4′-(4-chlorophenyl)-3′-methylspiro[cyclopropane-1,6′-isothiazolo[5,4-e][1,4]diazepin]-7′(8′H)-one (35 mg).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:16]=[CH:17][C:18]=1[B:19]1[O:23]C(C)(C)C(C)(C)[O:20]1>CC(C)=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:16]=[CH:17][C:18]=1[B:19]([OH:20])[OH:23]
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.5 %

Procedure:
Sodium periodate (1.967 g, 9.20 mmol) and ammonium acetate (0.709 g, 9.20 mmol) were added to a stirred solution of methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 2-7; 0.952 g, 3.07 mmol) in acetone (20 mL) and water (10 mL). The resulting suspension was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×250 mL). The organic extracts were combined washed with saturated brine (100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-4-(2-methoxy-2-oxoethyl)phenylboronic acid (0.656 g, 94%) as a cream oil which solidified on standing, and was used without further purification.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2F)C1
Yield: 98.4 %

Procedure:
The title compound (D127) (95 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 2,4-Difluorophenol (0.032 ml, 0.338 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:21]#[N:22])[CH2:17][CH2:16]1.S([O-])(O)(=O)=O.[Na+]>C(OCC)C.C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:15]2([OH:14])[CH2:20][CH2:19][C:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:21]#[N:22])[CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: Brc1cccc(Br)c1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(O)(c2cccc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
8.00 g of 1,3-dibromobenzene were dissolved in 200 ml of dry diethyl ether and 22.61 ml of an n-butyllithium solution (1.5 M in n-hexane) were added dropwise between 0° C. and 5° C. The reaction mixture was stirred for 5 min at 0° C. Subsequently a solution of 6.76 g of 4-oxo-1-phenylcyclohexanecarbonitrile in 70 ml of dry THF was injected at −70° C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min at room temperature. The reaction mixture was then poured onto 200 ml of a saturated aqueous sodium hydrogensulfate solution, and the phases were separated and the aqueous phase extracted with 200 ml of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was stirred with 70 ml of HEP. 7.50 g of the title compound were obtained as a resinous, partially crystallizing solid.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH2:12](I)[CH2:13][CH3:14].Cl>O.CO>[CH2:12]([S:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=1)[CH2:13][CH3:14]
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCSc1nc(O)cc(O)n1
Temperature: 32.5 °C
Yield: 61.9 %

Procedure:
2-Thiobarbituric acid (100 g) was added to water (250 ml) under stirring. A solution of sodium hydroxide pellets or flakes (63.13 g) in water (147.35 ml) was added to the resulting mixture over a period of 15 to 20 minutes at 20-25° C. The resulting mass was stirred for 40 minutes at 20-25° C., followed by the addition of water (200 ml). The reaction temperature was raised to 30-35° C., followed by the addition of methanol (200 ml) and propyl iodide (123.36 g) under stirring at 30-35° C. The resulting reaction mixture was stirred for 30 hours at 30-35° C. The reaction was monitored by thin layer chromatography. After completion of reaction, the pH of the reaction mixture was then adjusted to less than 2.0 by the addition of dilute hydrochloric acid (prepared by mixing of 60 ml of concentrated hydrochloric acid with 140 ml of water). The resulting slurry was stirred for 15 hours and the product was isolated by filtration and washed successively with water (4×200 ml). The wet cake was slurried in cyclohexane (500 ml) at boiling temperature for 30 minutes, followed by cooling to 25-30° C. The product was isolated by filtration and washed with cyclohexane (200 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 80 g of 2-propylthio-pyrimidine-4,6-diol as a white powder (Yield: 61.9%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][NH:22][CH3:23]>CC(O)C>[NH2:17][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:22]([CH3:23])[CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])[N:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccnc(Cl)n2)n1
Reactant: CNCCN(C)C
Solvent: CC(C)O
Product: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2N)n1
Yield: 98.6 %

Procedure:
A solution of Intermediate 140a (250 mg, 0.99 mmol) and N,N,N′-trimethylethylenediamine (0.32 mL, 2.48 mmol) in IPA (2.5 mL) was heated to 120° C. for 10 mins under microwave irradiation. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (0.31 g, quant.) as a golden oil that was used in the next step without purification. LCMS (Method 3): Rt 2.51 min, m/z 318.3 [MH+].
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(C)cc2c(=O)cc(-c3ccncc3)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)O)c2oc(-c3ccncc3)cc(=O)c2c1
Yield: 86.2 %

Procedure:
A mixture of 8-acetyl-6-methyl-2-(4-pyridinyl)-4H-1-benzopyran-4-one (4.6 g, 16.5 mmol) in methanol (100 ml) was treated with sodium borohydride (1.22 g, 33 mmol) and heated to reflux overnight. Upon cooling water (2 ml) was added and the solution concentrated to near-dryness in vacuo. Water (100 ml) was added and a precipitate formed which was filtered yielding a tan/orange solid (4.0 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting Materials: 4-fluoro-2-methoxy-1-nitrobenzene and 1-methyl-4-(piperidin-4-yl)piperazine.
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([CH2:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[F:13])([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2cc(F)ccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added a crystal of iodine followed by 0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction was initiated with a high intensity heat gun, then 2-(bromomethyl)-1,4-difluorobenzene (5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added at such a rate that a gentle reflux was maintained. After addition was complete the reaction mixture was kept on stirring at reflux for 100 min, cooled to room temperature. To this reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.25 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was complete a white cake was formed which was left overnight at room temperature. The cake was hydrolized by treatment with aqueous ammonium chloride (NH4Cl) solution, extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.1% ammonium hydroxide, NH4OH) to give intermediate compound 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containing large amount of impurities. To a suspension of sodium hydride (NaH) (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was slowly added a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was complete, the reaction mixture was kept on stirring at 110° C. (in a preheated oil bath), after 5 minutes dimethylformamide (9 mL) was added and stirring was continued at reflux for 2 h. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.1% ammonium hydroxide, NH4OH) to give the subtitled compound (190 mg).