Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:1][CH:2]([CH3:22])[CH:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][S:19][CH2:20][CH2:21]3)=[CH:11][C:8]=2[C:9]=1[CH3:10])[OH:4]
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
2-Methyl-1-[3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl]propan-1-one (849 mg) synthesized above was dissolved in methanol (3 mL)-tetrahydrofuran (15 mL), and sodium tetrahydroborate (90%) (202 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-85:15, v/v) to give the title compound (621 mg, 73%) as a colorless oil.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@H:34]12>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:11][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@@H:34]4[CH2:13]3)=[CH:18][C:19]=2[N:20]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (R)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as white solid (90 mg, 61%).
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[NH2:33][CH:34]([CH3:44])[CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][OH:43])[CH:39]=[CH:40][CH:41]=1>>[OH:43][CH2:42][C:38]1[CH:37]=[C:36]([CH2:35][CH:34]([NH:33][C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:32])[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:25]=[C:17]34)[CH:13]=[CH:12][N:11]=2)[CH3:44])[CH:41]=[CH:40][CH:39]=1
Reactant: CC(N)Cc1cccc(CO)c1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Product: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2cc(-c2ccccc2)cc3=O)n1

Procedure:
Following the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl -1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.29 g, 0.83 mmol) was displaced with [3-(2-amino-propyl)-phenyl]-methanol (0.3 g, 1.66 mmol) to give the title compound as a light yellow solid. MS m/e 468 (M+H)+.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:10]=[C:9]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:8]=1)=O.CO.Cl>C1COCC1.O1CCOCC1>[OH:4][CH2:5][C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:10]=[C:9]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:8]=1
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(CO)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A 2M solution of lithium borohydride in THF (22.4 ml, 44.8 mmol) was added to a mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (4.0 mg, 8.96 mmol) in anhydrous THF (200 ml). The reaction mixture was stirred at ambient temperature for 3 hours and then heated at reflux for 1 hour. The mixture allowed to cool and methanol was added until effervescence ceased, a 4M solution hydrogen chloride in dioxane (30 ml) was then added and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation, the residue was dissolved in water and the resulting solution adjusted to pH 9 by careful addition of 10M aqueous sodium hydroxide solution. The aqueous mixture was extracted with DCM and purification by chromatography on silica gel, eluting with DCM/methanol (100:0 increasing in polarity to 90:10) to give the title compound (3.4 g, 91%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:3])[CH3:2]
Reactant: Nc1ccc(O)c2ncccc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(O)c3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-8-quinolinol (67 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during 40 hours and the final product was collected by filtration and washed with diethylether to yield the title compound (100 mg, 90% yield).
Reaction SMILES: C([O:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[C:27](=[O:36])[CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.[Pd]>[O:29]([CH2:28][C:27]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]1[C:19]1[O:18][N:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:37])=[O:8])=[CH:11][CH:12]=2)[N:20]=1)=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Reaction time: 0.5 h

Procedure:
4 mmol of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid benzyl ester were dissolved in MeOH and treated with Pd/C and flushed with hydrogen (3 bar) and stirred for 30 min. The catalyst was filtered off and the solvent evaporated. After extraction from ethylacetate/water the resulting oil was purified via preperative HPLC. The corresponding alkylesters were treated with aq. 2N NaOH or LiOH in methanol at room temperature. The allylester can be cleaved using Pd(Ph3)4 as catalyst and morpholine as a nucleophile.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>CN(C=O)C>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:2]/[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5]1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of benzyl 3-acetylpiperidine-1-carboxylate (15 g, 54.53 mmol, 1.00 equiv, 95%) in DMF (100 mL). To the mixture was added DMF-DMA (17 g, 141.43 mmol, 2.50 equiv, 99%). The resulting solution was allowed to reflux for about 6 hours. The mixture was then cooled down to room temperature and concentrated on a rotary evaporator affording crude (E)-benzyl 3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate as brown oil (19 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.8 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.8 g (12.8 mM) of 2-amino-5-nitropyridine in 20 ml of anhydrous DMF was stirred at 25° C. for 2 days. The reaction mixture was filtered and the collected solid washed successively with cold DMF, ethyl acetate, and ether to give 1.0 g of the above urea as yellow solid, m.p. 225°-227° C. (dec.).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C(=O)(O)[O-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:18]3[C:17]([F:16])=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[N:25]4)=[CH:20][CH:19]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 75 °C

Procedure:
A stirred solution of 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (40 mg, 0.1 mmol), 8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline (52 mg, 0.15 mmol) and cesium carbonate (50 mg, 0.15 mmol) in dimethoxyethane (DME) (1.67 mL) and H2O (0.33 mL) was degassed for 10 minutes using N2. Tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) was added, and the reaction was heated to 75° C. and maintained at this temperature for 16 hours. After cooling, the reaction mixture was poured into saturated sodium bicarbonate (NaHCO3) solution (50 ml) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (2×50 ml), dried over magnesium sulfate (MgSO4), filtered and concentrated. The material was purified by chromatography on silica gel [eluting with 100% DCM→0.4% MeOH in DCM] resulting in the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 2.06-1.99 (m, 1H), 2.10-2.20 (m, 1H), 2.42-2.52 (m, 2H), 2.62-2.71 (m, 2H), 4.14-4.21 (m, 1H), 7.45-7.56 (m, 3H), 7.74 (d, J=8.6 Hz, 1H), 7.79 (dd, J=6.3 Hz, 6.3 Hz, 1H), 7.87 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.21 (d, J=6.8 Hz, 2H), 8.27 (d, J=7.6 Hz, 1H); MS (ES+): m/z 411.00 (100) [MH+], HPLC: tR=3.53 min (MicromassZQ, polar—5 min).
Reaction SMILES: [C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10])#[N:2].C(Cl)(=[O:24])C1C=CN=CC=1.FC1C=C(C=CC=1)C(Cl)=O.ClC1C=CC=C(C(OO)=O)C=1>C(OCC)(=O)C>[C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[NH+:8]([O-:24])[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10])#[N:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: N#Cc1[nH]cnc1NC(=O)c1ccncc1
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: N#Cc1[nH]cnc1[NH+]([O-])C(=O)c1ccncc1

Procedure:
To a stirred suspension of N-(5-cyano-1H-imidazol-4-yl)-4-pyridinecarboxamide (0.53 g, 0.0025 mole), which can be made by the procedure of Example 1 substituting isonicotinoyl chloride for the 3-fluorobenzoyl chloride, in 20 ml of ethyl acetate was added 3-chloroperbenzoic acid (0.65 g, 0.003 mole). The mixture was heated at reflux for 15 hours, cooled and the solid product collected by filtration. The solid was washed with ethyl acetate and dried under reduced pressure to give N-(5-cyano-1H-imidazol-4-yl)-4-pyridinecarboxamide N-oxide (0.52 g; mp, 290°).
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH3:14]>>[C:1]12([NH:11][C:12]([NH2:14])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: N
Product: NC(=S)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-adamantyl isothiocyanate (4.83 g, 25.0 mmol, Aldrich) and ammonia (0.5 M solution in 1,4-dioxane, 100 mL, 50 mmol) was stirred at ambient temperature for 48 h. The solvents were removed in vacuo to give the title compound as a white solid. MS m/z: 211.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Br:13].C([O-])([O-])=[O:15].[Ca+2]>O1CCOCC1.O>[OH:15][CH2:2][C:3]1[C:8]([Br:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Br:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)c(CO)c(Br)c1

Procedure:
A mixture of 1-bromomethyl-2,6-dibromo-4-nitrobenzene (4.45 g, 1 eq.) and CaCO3 (5.7 g, 5 eq.) in 1,4-dioxane (20 mL) and water (20 mL) was heated to and maintained at reflux overnight. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrousmgSO4, filtered and concentrated. The product was purified by silica gel chromatography (eluted with 4:1 hexanes:ethyl acetate) to give 1-Hydroxymethyl-2,6-dibromo-4-nitrobenzene. 1H NMR (500 MHz, CDCl3) δ CHCl3: 2.28 (1H, broad t), 5.05(2H, m), 8.397(2H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]([F:20])([F:19])[CH3:18].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][C:17]([F:20])([F:19])[CH3:18])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(F)(F)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)(F)F)nc1Cl
Yield: 94.3 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-(2,2-difluoropropoxy)piperidine-1-carboxylate obtained in Example (128d) (0.68 g, 2.3 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.41 g, 2 mmol), WSC hydrochloride (0.77 g, 4 mmol), HOBt (0.41 g, 3 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.85 g of the title compound as a colorless solid (94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:15])([CH2:18][CH:17]=[CH2:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reaction time: 40 h
Yield: 77 %

Procedure:
To the solution of ethyl 2-(3,4-dichlorophenyl)-2-oxoacetate (100 g, 3.8 mol) in CH2Cl2 was added allyltributyltin (1.2 equivalents) and TiCl4 (1.2 equivalents) at 0° C. and mixture was stirred for 40 hours at 0° C. to room temperature. Purification by chromatography on silica gel provided title compound (90 g, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:28].[Na+]>C1COCC1.CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
A solution of the fluorobenzoate (46, 27 mg, 0.051 mmol) in THF (2 mL) and MeOH (2 mL) was treated with 1M NaOH (0.2 mL, 0.2 mmol) and allowed to stand at ambient temperature for 7 h. After the solvent was evaporated, the residue was treated with CHCl3 (40 mL) and 10% Na2CO3 solution (30 mL); we then separated the layers, dried the organic layer over MgSO4, and filtered and evaporated it under reduced pressure. Purified on 2 g of Merck grade 60 flash silica gel using MeOH/CHCl3 (5:95) afforded 13 mg (60%) of 25-fluoro-3β-ol (47), mp 196°-198° C. EIMS (m/z): 428 (M+H), 413 (M-M3). 1H NMR: δ3.70 (m, 1H), 1.49 (s, 3H), 1.27 (s, 3H), 1.09 (s, 3H), 1.02 (d, 3H, J=6.4 Hz), 0.81 (s, 3H).
Reaction SMILES: [CH:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCC(C)S(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)C(C)CC)n1

Procedure:
A mixture of 5.76 g. 3-sec.butylsulphinyl-1,2,4-triazole, 5.31 g. diallylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 5 ml. dry triethylamine was kept under anhydrous conditions at room temperature for 72 hours. The reaction mixture was filtered and the filtrate evaporated under reduced pressure at room temperature to give a residual oil which was dissolved in methylene dichloride. The resulting solution was washed with water, dried over anhydrous sodium sulphate and distilled under reduced pressure at room temperature to give 1-diallylcarbamoyl-3-sec.butylsulphinyl-1,2,4-triazole as a residual oil, nD25 1.5268, for which a satisfactory elemental analysis was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.C([O:21][CH2:22][CH3:23])(=O)C>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:5]3[CH:4]=[C:23]([CH:9]=[CH:8][CH:6]=3)[CH:22]=[O:21])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mg of 3-formylbenzenelboronic acid and 55 mg of Bis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na2CO3 and 0.6 mL of acetonitrile was heated to 100° C. in the microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (60 mL), and then washed with H2O (40 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by ISCO CombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH2:12])[CH:8]=1)([CH3:6])[CH2:4][F:5].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 75.5 %

Procedure:
Using the procedure described in Example 161C, using 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-amine (0.287 g, 1.6 mmol), phenyl chloroformate (0.313 g, 2 mmol) were reacted in the presence of K2CO3 (0.345 g, 2.5 mmol) in THF (15 mL), and purified by silica gel chromatography (using 5-25% EtOAc/hexane as eluants) to afford phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as a solid (0.358 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.17 (br, 1H), 7.42 (m, 2H), 7.26 (m, 1H), 7.20 (m, 2H), 6.81 (s, 1H), 4.67 (q, 2H), 4.51 (q, 2H), 1.42 (s, 3H); LC-MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>O1CCOCC1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g (1.7 mmol) of 2-tributylstannyl)-furan in 5 mL of dioxane was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to reflux for 16 hours, cooled to ambient temperature and diluted with 5 mL of ethyl ether. The mixture was washed once with 5 mL of saturated aqueous potassium fluoride, the organic layer was separated and the aqueous portion was extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded a yellow oil which was recrystallized from ethyl ether/hexane to afford 0.2 g (51%) of the title compound.