Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([NH:38][CH2:37][CH2:36][C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCCc1ccncc1
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)CC3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(C(=O)NCCc4ccncc4)CC3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylic acid (50 mg, 0.12 mmol), 2-(pyridin-4-yl)ethanamine (22 mg, 0.18 mmol), EDCI (69 mg, 0.36 mmol) and 1-methyl-1H-imidazole (50 mg, 0.60 mmol) in 25 mL of DCM was stirred at room temperature for 16 hours. Excess of DCM was removed under reduced pressure and the residue was washed with H2O (30 mL) and EtOAc (20 mL) dried under reduced pressure to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)piperidine-4-carboxamide (30 mg, 48%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 8.44-8.42 (m, 2H), 7.61 (d, 1H, J=2.4 Hz), 7.31-7.18 (m, 3H), 6.95 (d, 1H, J=8.7 Hz), 4.82-4.77 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.47 (t, 2H, J=6.9 Hz), 2.95-2.92 (m, 2H), 2.86 (t, 2H, J=6.9 Hz), 2.44 (brs, 1H), 1.74-1.62 (m, 4H). LC-MS: 520 [M+H]+, 260 [M/2+H]+, 518 [M−H]−, tR=1.29 min. HPLC: 97.06% at 214 nm, 97.32% at 254 nm, tR=3.47 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4](=[O:12])[C:3]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(Cl)c2ccccc2[nH]c1=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(NCc2ccc(OC)cc2)c2ccccc2[nH]c1=O
Temperature: 90 °C

Procedure:
Methyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 69) (0.928 g, 3.91 mmol) was dissolved in DMF (6 mL), and 4-methoxybenzylamine (1.14 mL, 8.78 mmol) was added. The reaction was heated at 90° C. for 30 minutes, then cooled to room temperature and poured into a stirred mixture of 50 mL hexanes and 100 mL ice water. The resultant precipitate was collected by filtration and further chromatographed on silica gel (0% to 20% MeOH in dichloromethane) to give methyl 4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxylate as an off white solid (0.841 g, 64%). MS 339 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: CC(C)(CO)CCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-2,2-dimethyl-1-pentanol (78 g, 0.35 mol) and p-toluenesulfonic acid (0.42 g) in dichloromethane (0.5 L) was added 3,4-dihydro-2H-pyran (45 mL) slowly at 0° C. The reaction mixture was stirred at rt overnight, or until no more starting material was evidenced by TLC. The mixture was filtered through aluminum oxide and was washed with dichloromethane (300 mL). The filtrate was evaporated under vacuum to produce 5-bromo-1-(tetrahydropyranyloxy)-2,2-dimethylpentane (101 g, 94.7% yield) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 4.48-4.52 (m, 1H), 3.90-3.75 (m, 1H ), 3.50-3.35 (m, 4H), 2.95 (d, J=12 Hz, 1H), 1.90-1.20 (m, 10H), 0.90 (s, 6H). 13C NMR (75 MHz, CDCl3=77.0 ppm/TMS): δ (ppm) 99.2, 76.3, 62.0, 38.0, 34.9, 34.2, 30.7, 28.0, 25.7, 24.8, 24.7, 19.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1Cl
Yield: 68.7 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 393.1 [(M+H)+]; mp 190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][N:18]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][N:18]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: O=Cc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
7-Chlorothieno[3,2-b]pyridine (6) (4.02 g, 23.70 mmol) was dissolved in THF (150 mL) to give a colorless solution. The solution was cooled to −40° C. in an acetonitrile/dry ice bath. n-BuLi (9.95 mL, 24.88 mmol, 2.5M in hexanes) was added dropwise. The dark mixture was then stirred for 15 min followed by an addition of zinc chloride (24.88 mL, 24.88 mmol, 1M in ether). The mixture was warmed to 0° C., then tetrakistriphenylphosphine palladium (1.095 g, 0.948 mmol) was added. The mixture was then stirred for 10 min and 6-bromonicotinaldehyde (7) (4.41 g, 23.70 mmol) was added. The mixture was heated to reflux and a precipitate formed rapidly. After 3 h, the reaction mixture was cooled down to r.t., quenched with 2 mL NH4Cl and left overnight. The solid was isolated by suction filtration, rinsed with small amount of THF and triturated with a mixture of water (200 mL) and EtOAc (100 mL) followed by an additional trituration with acetic acid (1×100 mL), to afford intermediate 50 (4.95 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.39 (dd, J=2.1, 8.4 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H). MS (m/z): 275.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv), and piperidine (78 mg). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane and the resulting mixture was washed with saturated aqueous ammonium chloride, water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (20/1) gave 28.5 mg (17%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+, H-NMR (300 MHz, CDCl3, ppm): δ 8.54 (s, 1H); δ7.68 (d, 2H); δ7.20 (d, 2H); δ7.16 (d, 2H); δ6.95 (m, 1H); δ6.55 (d, 1H); δ5.52 (s, 2H); δ6.98 (m, 1H); δ4.76 (m, 1H); δ4.34 (m, 1H); δ3.82 (m, 1H); δ3.23 (m, 1H); δ2.01˜δ2.42 (m, 4H); δ1.88 (m, 1H); δ0.85˜δ1.21 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cncn2)cc1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
1,2,4-Triazole (0.82 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.01 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.59 g, 73%).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=O)[CH2:6][CH3:7].O.[NH2:17]N>CCO>[CH2:6]([C:5]1[NH:17][N:2]=[CH:3][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CCC(=O)C(=CN(C)C)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1[nH]ncc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 1-(dimethylamino)-2-phenylpent-1-en-3-one (3.32 g, 16.33 mmol) in EtOH (80.0 mL) was added hydrazine hydrate (1.58 mL, 32.66 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to give a solid. The solid was re-crystallized, using 20% ethanol in water to give the title compound as a white solid (2.81 g). LCMS m/z=173 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=7.58 Hz, 3H), 2.88 (q, J=7.58 Hz, 2H), 7.22-7.30 (m, 1H), 7.35-7.42 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:44])[C@@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:35]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:44])=[O:33])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Product: O=C(O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and (R)-(+)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 90-92° C.; MS m/e 679 (M−H+;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][C:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:15])[CH2:7]2)(=O)[CH3:2].C(C1C=C2C(=CC=1)CC(NC(=O)C1C=CC=CC=1)(C)C2)C>>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:1][CH3:2])[CH2:7][C:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:15])[CH2:9]2)[CH3:14]
Reactant: CCc1cc2c(cc1C(C)=O)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2
Product: CCc1cc2c(cc1CC)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
N-(5,6Diethyl-2-methyl-indan-2-yl)benzamide is prepared from N-(5-acetyl-6-ethyl-2-methyl-indan-2-yl)-benzamide (1.1 g) following the procedure used to prepare N-(5-ethyl-2-methyl-indan-2-yl)-benzamide. ES+ MS m/e 308 (MH+)
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL, 1.1 g, 4.4 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. at rt, the clear solution was cooled in an ice bath and 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. Stirring was continued for a total of 2 h, with slow warming to rt. The mixture was then partitioned between ether (120 mL) and 2.5 N aq. NaOH (60 mL). The organic layer was washed with saturated aq. brine (60 mL), dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 15-20% ethyl acetate in hexane, to give 0.95 g of the title compound as a colorless syrup.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26]O)=[C:11]([CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2].CCN(S(F)(F)[F:36])CC.C(=O)(O)[O-].[Na+]>ClCCl>[F:36][CH2:26][C:10]1[C:9]([O:8][CH2:7][C:6]2[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CF)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a solution of 4-(5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (14) (600 mg, 1.6 mmol) in dry dichloromethane (20 mL) was slowly added DAST (251 mg, 1.6 mmol, in 50 mL dry dichloromethane) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using ethyl acetate:hexane:methyl alcohol (7:7:1) as an eluant to give 4-[4-fluoromethyl-6-methyl-5-(4-cyano-benzyloxy)-pyridin-3-ylmethoxy]-benzonitrile (18) (314 mg, 52% yield) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1C[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:44])C=CC=2)N=1.Cl.COC(=O)[C@@H]1CCCN1>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C@H:4]3[C:3]([O:2][CH3:1])=[O:44])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])(=[O:25])[NH2:27]
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B22 was obtained as a white crystalline solid by following the procedure reported for B4 using A1 and (S)-proline methyl ester hydrochloride; yield: 169 mg (48%). MS (ES) C16H20N6O4S requires: 392. found: 393 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:18][N:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N(C)c1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (2.0 g) was dissolved in DMF (15 ml) prior to the addition of K2CO3 (2.07 g) and MeI (0.71 ml). After 2 h, the solution was concentrated and 1N HCl solution (aq) was added. The solution was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Filtration through a plug of silica of the resulting residue gave N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide. This material (2 g) was dissolved in EtOH prior to the addition of a solution of NaOH (2 g) in H2O (2 ml). The mixture was heated to reflux for 2 h, cooled to rt, and neutralized with 1N HCl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (2.07 g). This solution was placed on a Parr apparatus under H2 (50 psi) for 2 h. The Pd/C was filtered off and the solution was concentrated. The resulting residue was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 45 min. After cooling to rt, flash chromatography of the crude reaction gave (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.05 g). A portion (200 mg) of this material was dissolved in THF (17 ml) prior to the addition of a solution of LiOH (31 mg) in H2O (6 ml). MeOH (6 ml) was added. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (189 mg). MS found: (M+H)+=259.2
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:20]([F:19])([F:39])[F:40])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CS(=O)(=O)c1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Yield: 44.4 %

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (6.9 mmol) and 2-(trifluoromethyl)-4′-(methylsulfonyl)benzhydrol (169) (13.8 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was partially purified by flash column chromatography [SiO2; ethyl acetate-iso-hexane (30:70→80:20)] to afford an off-white foam (1.69 g) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)ccc1Cl
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-5-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 5-(bromomethyl)-2-chlorobenzoate (4.06 g, 95% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].[NH:23]1[CH2:27][CH2:26][C@@H:25]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)[CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15]([N:23]4[CH2:27][CH2:26][CH:25]([N:28]5[CH2:29][CH2:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33]5)[CH2:24]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Reactant: O=S1(=O)CCN([C@@H]2CCNC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CCC(N4CCS(=O)(=O)CC4)C3)oc(=O)c12

Procedure:
To 5-ethyl-2-(2-fluoropyridin-3-yl)-7-methoxy-4H-benz[d][1,3]oxazin-4-one (50.0 mg, 0.17 mmol) in anhydrous 1,4-dioxane (850 μL) was added compound Z (52.9 mg, 0.22 mmol) and diisopropylethyl amine (120 μL, 0.85 mmol) at room temperature under N2 overnight. The solution was concentrated, and the resulting residue was purified on a Biotage 40M amine column using a gradient of 20-75% ethyl acetate/hexanes to obtain the title compound. The fractions containing the title compound were combined and concentrated by speedvac to afford the title compound as a yellow oil (19.2 mg, 23% yield). 1H NMR (CDCl3, 400 MHz) δ: 8.33 (dd, 1H, J=1.0 Hz), 8.1 (d, 1H, J=7.0 Hz), 6.92 (dd, 2H, J=2.5 Hz), 6.83 (m, 1H), 3.93 (s, 3H), 3.83 (m, 1H), 3.62 (m, 2H), 3.39 (m, 1H), 3.26 (m, 1H), 3.22 (m, 4H), 3.17 (m, 6H), 2.16 (m, 1H), 1.94 (m, 1H), 1.29 (t, 3H, J=7.5 Hz); ESMS m/z 485.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 84 %

Procedure:
Amer. Chem. Soc., 72 (1950), 798, discloses that 2,6-dichloro-4-nitroaniline, ethanol and sodium nitrite can be reacted at the boil, in the absence of water and in the presence of concentrated sulfuric acid, to give 3,5-dichloronitrobenzene in a yield of 84%. A corresponding reaction to give the 3,5-dibromo derivative gives a yield of 91%. The process is unsatisfactory in respect of yield and purity of the end product and simple, reliable and economical operation, especially on an industrial scale.