Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:33])[CH2:21][N:22]([CH:30]([CH3:32])[CH3:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1.[CH3:34][C@H:35]1[C:43]2[C:42]([C:44]3[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=3)=[N:41][CH:40]=[N:39][C:38]=2[CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([O:33][C:47]2[CH:48]=[CH:49][C:44]([C:42]3[C:43]4[CH:35]([CH3:34])[CH2:36][CH2:37][C:38]=4[N:39]=[CH:40][N:41]=3)=[CH:45][CH:46]=2)[CH2:21][N:22]([CH:30]([CH3:31])[CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:16][CH:15]=1
Reactant: CC(C)N(CC(O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(O)cc3)c21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1CCc2ncnc(-c3ccc(O[C@@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
Diethyl azodicarboxylate (0.166 mL, 1.05 mmol) was added slowly to a solution of tert-butyl 2-(4-chlorophenyl)-2-hydroxyethyl(isopropyl)carbamate (265 mg, 0.843 mmol), (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenol (159 mg, 0.703 mmol), and triphenylphosphine (276 mg, 1.05 mmol) in tetrahydrofuran (7.0 mL) at −30° C. (bath). The mixture was allowed to warm up to room temperature and stirred overnight. Most of the starting material remained. Triphenylphosphine (276 mg, 1.05 mmol) was added. The contents were cooled at −30° C. Diethyl azodicarboxylate (0.166 mL, 1.05 mmol) was added. The mixture was stirred at room temperature for 4 hours. tert-Butyl 2-(4-chlorophenyl)-2-hydroxyethyl(isopropyl)carbamate (265 mg, 0.843 mmol) was added. The mixture was stirred at room temperature overnight. EtOAC (10 mL) and water (10 mL) were added. The organic layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic solutions were dried (Na2SO4). The crude was purified by flash chromatography to give (R)-tert-butyl 2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate (26 mg, 7%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:10](O)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].B.C1COCC1>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccnc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOc1cccnc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 124.6 %

Procedure:
To a solution of 3-ethoxypicolinic acid (0.202 g, 1.21 mmol) in dry THF (1 mL) was added BH3.THF (1.0 M in THF, 5.0 mL, 5.0 mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The mixture was then quenched with methanol (20 mL), stirred at reflux for 4 hours and concentrated under reduced pressure. The resultant crude product was dissolved in methanol (3×15 mL) and concentrated to give the desired crude alcohol (0.231 g) as an orange solid. 1H NMR (CDCl3): δ1.46 (t, 3H, J=7.0 Hz), 4.07 (q, 2H, J=7.0 Hz), 4.74 (s, 2H), 7.09-7.20 (m, 2H), 8.14 (d, 1H, J=4.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C:5]1([CH2:3][OH:2])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(OC2CCCCO2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(OC2CCCCO2)CC1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
1-(Tetrahydro-pyran-2-yloxy)-cyclopropanecarboxylic acid methyl ester (3.50 g, 17.50 mmol) was dissolved in diethyl ether (85 mL) and a 2.0 M solution of lithium aluminum hydride in diethyl ether (8.75 mL, 17.50 mmol) was added. Upon complete addition, the reaction was refluxed under nitrogen for 1 h. Upon cooling to 25° C., the excess lithium aluminum hydride was hydrolyzed by the addition of ice chips. The organic layer was seated, washed with water (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to afford [1-(tetrahydro-pyran-2-yloxy)-cyclopropyl]-methanol (2.81 g, 93%) as a clear, thick oil: H1-NMR (400 MHz, CDCl3) δ 0.5-1.0 (4H, m), 1.40-2.0 (6H, m), 3.0-3.2 (2H, m), 3.3-4.3 (2H, m), 4.5-4.7 (1H, m), 4.75-5.0 (1H, m).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[NH2:14])(C(C)(C)C)(C)C.[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:14][C@H:10]2[C@@H:9]([OH:8])[CH2:13][O:12][CH2:11]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H]2COC[C@@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
The title compound is prepared by essentially following the procedure as described in Example 1 using (3R,4R)-4-(tert-butyl(dimethyl)silyl)oxytetrahydrofuran-3-amine (Preparation 36) and 2-chloro-4-fluoro-3-methyl-benzonitrile. The crude product is purified on silica gel using 40-70% EtOAc/hexanes. The isolated product is dissolved in THF to make a 0.5 M solution. TBAF (2.0 mL, 2 mmol, 1 M solution in THF) is added and stirred at room temperature for 16 h. The solution is concentrated in vacuo, EtOAc is added, and the solution is washed with water (2×). The organic portion is dried over magnesium sulfate, filtered, and concentrated. The residue is purified by reverse phase chromatography on silica-bound C18 using 15-95% acetonitrile/water+0.1% formic acid. Fractions containing the title compound are concentrated in vacuo to remove acetonitrile, then extracted with EtOAc. The organics are dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (134 mg, 19%). 1H-NMR (400 MHz, DMSO-d6) δ 7.53 (d, J=8.7 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.60-5.56 (m, 1H), 5.53 (d, J=4.9 Hz, 1H), 4.33-4.29 (m, 1H), 4.05-3.99 (m, 2H), 3.92 (dd, J=4.6, 9.6 Hz, 1H), 3.63 (dd, J=2.4, 9.5 Hz, 1H), 3.53-3.50 (m, 1H), 2.19 (s, 3H). LC-ES/MS m/z 253 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cn[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 11 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 15 min (×3). The solution was concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in cyclohexane, to give the title compound (10.7 mg). LCMS (A) m/z: 419 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a suspension of K2CO3 (0.654 g, 4.74 mmol) in DMF (6 mL) is added 2-benzyloxy-4-fluoro-1-nitrobenzene (0.90 g, 3.64 mmol), followed by phenol (0.343 g, 3.64 mmol). The mixture is stirred at 100° C. for 48 h. The mixture is allowed to cool to ambient temperature, then poured into water and extracted into EtOAc. The organic phase is washed with water (2×), saturated NaCl (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford 2-benzyloxy-4-phenoxy-1-nitrobenzene as a pale-yellow solid: mp=96-98° C.; 1H NMR (CDCl3) δ 7.87 (d, J=9.09 Hz, 1H), 7.36-7.23 (m, 7H), 7.20-7.15 (m, 1H), 6.95 (dd, J=8.59, 1.01 Hz, 1H), 6.58 (d, J=2.27 Hz, 1H), 6.46-6.43 (m, 1H), 5.08 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1)=[O:3].[OH-].[Na+].O.Cl[C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>C1(C)C(C)=CC=CC=1>[C:2]([C:4]1[CH:5]=[C:6]([I:11])[C:7]2[O:10][C:16]([CH3:20])([CH3:19])[CH:17]=[CH:18][C:8]=2[CH:9]=1)(=[O:3])[CH3:1]
Reactant: C#CC(C)(C)Cl
Reactant: CC(=O)c1ccc(O)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)c1cc(I)c2c(c1)C=CC(C)(C)O2
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 4-hydroxy-3-iodoacetophenone (5.24 g), 40% sodium hydroxide solution (4.8 ml), water (19 ml), xylene (11 ml) and 3-chloro-3-methylbut-1-yne (4.1 g) was heated to 90° C. for 3 hrs. The mixture was cooled and extracted with ether, and the ether extracts were washed with 2N sodium hydroxide solution, water and brine and dried over anhydrous sodium sulphate. The ethereal solution was filtered and evaporated, and the xylene solution that remained was refluxed for 16 hrs. The solution was evaporated and the residue chromatographed on silica gel using 10% ethyl acetate in hexane to give 6-acetyl-8-iodo-2,2-dimethyl-2H-1-benzopyran as a colourless solid (3.07 g), m.p. 102° C.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([NH:39][C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:48])[CH2:45][CH2:44]1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Butyllithium (1.6 M in hexane, 5.0 ml, 8.00 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (3.21 g, 8.00 mmol) in THF (25 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.30 g, 5.72 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 1 h and at room temperature overnight. Water was added and the product extracted with CH2Cl2. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave trans-2-(4-tert-Butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (1.10 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:18][C:19]([CH3:34])([CH3:33])[CH2:20][CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:16]=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl>O1CCCC1>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:18][C:19]([CH3:33])([CH3:34])[CH2:20][CH2:21][O:22][Si:23]([CH:24]([CH3:25])[CH3:26])([CH:27]([CH3:28])[CH3:29])[CH:30]([CH3:32])[CH3:31])[C@@H:16]([OH:17])[CH2:5][CH2:4][CH:3]=[CH2:2])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CCCBr
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCC[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C

Procedure:
The Grignard reagent is prepared from 3.70 ml of 4-bromo-1-butene and 880 mg of magnesium powder in 50 ml of tetrahydrofuran at 55° C. This solution is then added dropwise to a solution of 3.0 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexanal (Example 1g)) in 25 ml of tetrahydrofuran at 5°-10° C. 1 h after the end of the addition, the mixture is poured onto a 0.1N hydrochloric acid solution, extracted with methylene chloride and concentrated. The crude product contains the two 5(S):5(R) diastereomers in a ratio of about 5:1. The title compound (non-polar diastereomer) is obtained by purification over 250 g of silica gel (mobile phase E): Rf (E)=0.30.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2
Reactant: OCc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(CO)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 29.3 %

Procedure:
281 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 120 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[N:56]1([C:62]2[N:67]=[CH:66][C:65]([NH2:68])=[CH:64][N:63]=2)[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:68][C:65]2[CH:66]=[N:67][C:62]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[N:63][CH:64]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(N2CCOCC2)nc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cnc(N3CCOCC3)nc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.9 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.314 mmol) and stirred for 20 min under argon. 2-MORPHOLIN-4-YLPYRIMIDIN-5-AMINE (23.4 mg, 0.130 mmol, Atlantic Research) was added. After stirred 2.5 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After dried over Na2SO4, the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(2-morpholinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide (78.4 mg., 97.2%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 629.19. found: 629.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[CH:10]([CH:12]=[CH2:13])=[O:11].CC1C=C(C)C=C(C)N=1>S(=O)(=O)(O)O>[C:1]([O:5][CH:6]([O:9][C:10](=[O:11])[CH2:12][CH3:13])[CH:7]=[CH2:8])(=[O:4])[CH2:2][CH3:3]
Reactant: C=CC=O
Reactant: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CC(OC(=O)CC)OC(=O)CC
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
To a solution of 345 g (2.65 mols) propionic anhydride and 1.05 g concentrated sulfuric acid maintained at 45°-50°C. was added dropwise 140 g (2.5 mols) acrolein over a period of 15 minutes. The reaction mixture was stirred for an additional 10 minutes. A 2.6 g-sample of 2,4,6-trimethylpyridine was then added and the reaction mixture stirred at about 25°C. for about 17 hours. The reaction mixture was then distilled through a short column to give 268 g of the product as a slightly yellow liquid, b.p. 96°-101°C. (0.25 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]([C:20]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:23]=3[N:22]([CH3:29])[CH:21]=2)=[O:19])[CH:15]=[N:16][CH:17]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH3:29])[CH:21]=3)=[O:19])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)c2cncc(NC(=O)Nc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1-chloro-4-isocyanatobenzene (24 mg, 0.15 mmol) was added to (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (30 mg, 0.12 mmol) (Preparation 232) in pyridine (1.0 mL). The mixture was stirred at room temperature overnight then evaporated in vacuo to yield the product as a crude residue. The crude residue was purified by preparative HPLC to afford the title compound in 49% yield, 24 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:7]
Reactant: CN1CCNCC1
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
2-Methoxy-3-nitro-benzoic acid (1.20 g, 6.09 mmol), 1-Methylpiperazine (1.01 mL, 9.13 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1750 mg, 9.13 mmol, 1-hydroxybenzotriazole hydrate (1.45 g, 9.13 mmole) and N,N-Dimethylformamide (40.4 mL) were combined into a vial and stirred at room temperature for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with saturated NaHCO3 and filtered off resulting ppt. The solid was filtered and washed with water. The solid was dried under vacuum overnight to give (2-Methoxy-3-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid (0.70 g, 44%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].[N+](C1C=CC([O:29][C:30](=O)[O:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)=CC=1)([O-])=O.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][N:15]([C:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)=[O:29])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CCNC2
Reactant: COc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)N2CCc3sc(C(=O)Nc4ccccc4N)cc3C2)cc1OC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (1.0 eq) obtained in step VIII of example 203 in DMF was treated with Carbonic acid 3,4-dimethoxy-phenyl ester 4-nitro-phenyl ester (1.0 eq) in presence of base like Et3N and stirred at 50° C. for 8 h Reaction was then quenched with water and extracted with ethyl acetate and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CCOCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of a solution of 4-fluorophenyl-magnesium bromide in ether (2 M, 12.5 mL, 25 mmol) and anhydrous tetrahydrofuran (25 mL) was stirred at ambient temperature under a nitrogen atmosphere. A solution of 1-benzyl-4-formylmethylpiperidine (3.6 g, 16.6 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise. The reaction mixture was stirred for 19 hours, then it was poured onto a saturated ammonium chloride solution, mixed and extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate:hexanes:1:1) gave the product, a pale yellow solid (Rf =0.08, 2.7 g):mp=84°-86° C.; 1H-NMR:7.4-7.25(m,7H), 7.0(t,2H,J=8), 4.7(dd,1H,J=8,6), 3.45(s,2H), 2.9-2.75(m,2H), 2.1-1.2(m,10H); HR-MS:Calcd for C20H24FNO:313.1842; Found:313.1862.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:13][S:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[N:8]=1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Reactant: CC(C)(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1ncc2ccnc(NCC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
To a solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33, 1 g, 4.72 mmol) in NMP (15 mL) was added neopentylamine (5.5 mL, 4.72 mmol). The reaction mixture was heated to 80° C. for 20 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 mL) and EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane give the title compound (915 mg, 74%).