Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[C:9]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:13])[NH:12]/1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[CH2:10][CH:9]1[O:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)OC1=CC(=O)N/C1=C\c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC(=O)OC1CC(=O)NC1Cc1ccccc1

Procedure:
46.66 g of (Z)-5-benzylidene-4-butyryloxy-3-pyrrolin-2-one (produced according to Example 8) was suspended in 467 ml of toluene and hydrogenated for 28 hours with 4.67 g of palladium/activated carbon (5 percent of Pd) in an autoclave at room temperature and 2 MPa (20 bar). Then the catalyst was filtered off and the filtrate was concentrated by evaporation in a vacuum. The residue was recrystallized from diisopropyl ether. The yield of the title compound was 32.88 percent (69 percent of theory). The title compound had a melting point of 85.6° to 87° C. Other data concerning the title compound was:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:30]=[CH:29][C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][CH2:22][C:16]=4[CH:15]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>C(O)C>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:30]=[CH:29][C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][CH2:22][C:16]=4[CH:15]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 40 °C
Yield: 75 %

Procedure:
A mixture of ethyl (7-{5-[2-(trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)acetate (Preparation 49) (22 mg, 0.04 mmol), aqueous sodium hydroxide (2M, 220 μL, 0.44 mmol) and ethanol (2.2 ml) was heated at 40° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken up in water, which was then acidified to pH 6 with acetic acid. The aqueous phase was extracted with EtOAc (2×20 ml) before the combined organic fractions were concentrated and the residue was triturated with EtOAc and the title compound was filtered off and dried in a vacuum oven to give a white solid (13 mg, 0.03 mmol). δH (d6DMSO, 400 MHz): 8.52 (1H, d), 8.50 (1H, dd), 7.92-7.86 (2H, m), 7.73 (1H, d), 7.54-7.49 (3H, m), 7.44-7.35 (3H, m), 3.18 (2H, s), 3.05-2.96 (4H, m), 2.85-2.79 (4H, m); MS (ES−): C27H22F3N3O3 requires 493; found 492 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20]/[CH:21]=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[OH:10])=[CH:4][C:3]=1[Cl:36].Cl>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[OH:10])=[CH:4][C:3]=1[Cl:36]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOC/C=C\c2ccccn2)Cc2ccccc2)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCc2ccccn2)cc1Cl
Yield: 59.1 %

Procedure:
A solution of (Z)-4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[[3-(2-pyridinyl)-2-propenyl]oxy]hexyl]amino]methyl]benzenemethanol (0.65 g) in ethanol (15 ml) containing hydrochloric acid (2.7 mmol) was hydrogenated over 10% palladium on charcoal (0.15 g), filtered and evaporated. The residue was partitioned between aqueous sodium bicarbonate (1M; 30 ml) and ethyl acetate (150 ml) and the dried organic phase was evaporated to give a brown gum. The gum was purified by FCC eluting with System A (93:7:1→85:15:1), to give the title compound as a white solid (0.32 g) m.p. 38°-41°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][CH:28]([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([CH:28]([F:36])[F:27])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(difluoromethyl)aniline (Intermediate-29, 0.058 g, 0.40 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 3.95 (s, 3H), 7.04 (m, 1H), 7.35 (d, 1H), 7.41 (m, 1H), 7.50 (m, 3H), 7.69 (d, J=8.7 Hz, 1H), 7.77-7.82 (m, 3H), 8.07 (s, 1H), 10.25 (s, 1H), 12.52 (br s, 1H); MS (m/z): 485.06 (M+H+).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[C:16]([O:20][C:21](=[O:32])[CH:22]([NH2:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-]>CN(C)C(=O)C>[C:16]([O:20][C:21](=[O:32])[CH:22]([NH:31][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(O)cc1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(O)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (31.2 mg, 0.116 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester (30.22 mg, 0.127 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.2 mg product was obtained. Yield: 71%; 1H NMR (500 MHz, DMSO-d6): δ 1.33577 (s, 9H), 2.94185–3.02295 (m, 2H), 3.6550(b, 1H), 4.0878 (s, 2H), 6.70174–6.72384 (dd, J1=8.545 Hz, J2=2.59 Hz, 2H), 7.02394–7.04103 (d, J=8.545 Hz, 2H); 9.38501 (s, 1H); ESI-MS: 412 (M++1)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=O>>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:26][N:25]=1
Reactant: NNC(=O)c1cc(F)ccc1F
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cc(F)ccc3F)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 2,5-difluorobenzohydrazide: MS (ES) m/z 405 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([O-])(O)=O.[Na+]>C(OC(C)=O)(C)(C)C>[C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[O:10][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 124.1 %

Procedure:
To a solution of (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (13 g, 0.036 mol) in t-BuOAc (300 mL) at 0° C. was added HClO4 (20.7 g, 0.144 mol) slowly. The solution was stirred at 0° C. for 5 min, then warmed to room temperature and stirred at this temperature for 1.5 h. The solution was alkalized by saturated aqueous NaHCO3 until the pH of solution >8. The mixture was extracted with EtOAc (3×1 L). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (Petroleum Ether:EtOAc (50:1)) to afford (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9.3 g, 62%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.26 (s, 1H), 7.98 (s, 1H), 5.60-5.57 (m, 1H), 4.32-4.27 (m, 1H), 4.18-4.14 (m, 1H), 2.73 (s, 3H), 1.17 (s, 9H), 1.14 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21](OC)=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH2:26][OH:27].C(O)(=O)C>CO>[CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21]([NH:26][OH:27])=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Reactant: NO
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NO)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h
Yield: 36 %

Procedure:
To a vial containing methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH) and the resulting mixture was shaken at rt for 13 h. The solution was quenched with acetic acid (0.200 mL, 3.52 mmol) before being concentrated. To the resulting residue was added DMSO (1.2 mL) and it was purified via prep-HPLC to yield N6-benzyl-N2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicarboxamide (0.0113 g, 36.0%). LC-MS: (FA) ES+ 327; 1H NMR (Methanol-d4, 400 MHz) δ 7.86 (d, J=7.8 Hz, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.25-7.19 (m, 5 H), 4.68 (s, 2 H), 4.39 (s, 2 H), 3.79 (t, J=6.0 Hz, 2 H), 3.03 (t, J=6.0 Hz, 2 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].I[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:16][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(C(C)=O)cc1C(=O)OC
Yield: 87.8 %

Procedure:
A stirred mixture of methyl 5-acetyl-2-hydroxybenzoate (10 g, 0.052 mol), iodoethane (16.4 g, 0.104 mol), anhydrous potassium carbonate (14.4 g, 0.104 mol) and 2-butanone (200 ml) was heated under reflux for 3 days. The solvent was then removed by evaporation under vacuum, the residue dissolved in water (200 ml) and this solution extracted with ethyl acetate (4×200 ml). The organic fractions-were combined, washed with brine (2×200 ml), dried (Na2SO4) and evaporated under vacuum, then the residue chromatographed on silica gel (130 g) using a methanol in dichloromethane elution gradient (0-1%). Crystallization of the product from ethyl acetate-hexane gave the title compound as colorless crystals (10.15 g, 88%), m.p. 50°-55° C. Found: C,64.88; H,6.38. C2H14O4 requires C,64.85; H,6.35%.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCN3CCCCC3)CC2)c2ccccc21
Yield: 16 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(piperidin-1-yl)propyl)-piperidin-1-yl]ethanamine in a yield of 16% of theory. Colourless crystals, m.p. 192°-193° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][C:11]=1[CH3:12].O.NN>C(O)C.[Pd]>[F:1][C:2]([F:20])([C:16]([F:17])([F:19])[F:18])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[NH2:13]
Reactant: Cc1ccc([N+](=O)[O-])cc1COCC(F)(F)C(F)(F)F
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1COCC(F)(F)C(F)(F)F
Yield: 92.7 %

Procedure:
In 40 ml of ethanol, 7.30 g (0.0244 mol) of the nitro compound obtained in Example 1 was dissolved. The solution was added with 0.1 g of 10% Pd-C and 3.66 g (0.073 mol) of hydrazine hydrate and refluxed on a hot water bath for one hour. After allowed to cool by itself, the solution was passed through a Celite layer to filter out the catalyst and then washed with ethanol. The filtrate was concentrated, dissolved in dichloromethane, washed with water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous potassium carbonate. The solvents were distilled off and the residue was fractionally distilled, collecting the fraction having a boiling point of 82°-83° C. at 0.18 mmHg. There was obtained 6.09 g of 3-(2,2,3,3,3-pentafluoropropoxy)methyl-4-methylaniline in a 93% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22](O)=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41](=[O:53])[NH:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1)=[NH:44])([CH3:39])([CH3:38])[CH3:37].C([O-])(O)=O.[Na+].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[C:36]([O:40][C:41]([NH:42][C:43](=[NH:44])[C:45]1[CH:46]=[CH:47][C:48]([CH2:51][NH:52][C:22]([C@H:19]2[N:16]3[C:17](=[O:18])[C:12]([N:11]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)[C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][N:14]=[C:15]3[CH2:21][CH2:20]2)=[O:23])=[CH:49][CH:50]=1)=[O:53])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(O)[C@@H]1CCc2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N(Cc4cccc(C(F)(F)F)c4)C(=O)OCc4ccccc4)c(=O)n32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
To a solution of intermediate 25a (0.281 mmol) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester (84 mg, 0.337 mmol) in 3 mL 5:1 CH2Cl2/DMF at 0° C., were added NaHCO3 (59 mg, 0.703 mmol), HOAT (42.1 mg, 0.309 mmol), and EDCI (75.5 mg, 0.393 mmol). The mixture was allowed to warm to rt and stir 20 h, then was diluted with EtOAc. The organic phase was washed with H2O, 1N HCl, H2O, and sat. NaHCO3, and brine, dried (Na2SO4) and brine. The crude residue was triturated with Et2O to afford 160 mg (79%) of intermediate 25b as a white solid. MS (ESI) 719.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11](#[N:14])[CH:12]=[CH2:13].C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH2:13][CH2:12][C:11]#[N:14])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: C=CC#N
Agent: C[O-]
Agent: N#CCc1ccc(F)cc1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CCCC(C#N)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Twenty-five g of 4-fluorobenzylcyanide is mixed with approximately 3.5 ml of freshly distilled acrylonitrile in a suitable reaction vessel. To this stirred mixture is added dropwise a solution of 80 mg of sodium methoxide in 1 ml of methanol. When about half of the sodium methoxide is added, there is an exothermic reaction. After all the sodium methoxide is added, the mixture is kept on a steam-bath for 2 hours and is then dissolved in toluene and washed with water. The toluene is removed by evaporation and the residue is separated into its components by fractional distillation to give 18 g of 4-fluorobenzylcyanide, and 2 g of 2-(4-fluorophenyl)glutaronitrile, bp 118°-122° C. at 0.03 mm.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>CC(O)C.Cl>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH2:20])(=[O:18])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 2-amino-benzenesulfonamide (340 mg, 1.97 mmol) in 2-propanol (3 mL), concentrated hydrochloric acid (0.06 mL) is added and the mixture is stirred at 90° C. for 4.5 hours. The mixture is poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate three times. The organic layer is washed with water, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by column chromatography (hexane:ethyl acetate=2:1) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Brc1ccccc1-n1cccn1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccccc1-n1cccn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-bromophenyl)-1H-pyrazole (230 mg), 2-tert-butoxy-2-oxoethylzinc chloride (0.5M in Et2O, 2.2 mL), Pd(dba)2 (28.8 mg) and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (37.4 mg) in THF (3 mL) was degassed with argon and was stirred at 70° C. overnight. The reaction mixture was diluted with EA and washed with water and brine, dried (Na2SO4), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 8 for 4CV, 8 to 66 over 10CV, 66 for 2CV, 66 to 100 over 1CV, 100 for 6CV. Second CC: SNAP 10 g cartridge, solvent A: DCM; solvent B: MeOH; gradient in % B: 0 for 15CV, 0 to 1 over 1CV, 1 for 5CV, 1 to 5 over 1CV, 5 for 2CV, 5 to 10 over 1CV, 10 for 2CV, 10 to 20 over 1CV, 20 for 2CV) to afford 33 mg of (2-pyrazol-1-yl-phenyl)-acetic acid tert-butyl ester. LC-MS (B): tR=0.87 min; [M+H]+: 259.34.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[C:23]([CH:32]([OH:33])[CH2:34][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]3[CH:19]=[CH:18][C:13]4[C:14](=[O:17])[O:15][CH2:16][C:12]=4[C:11]=3[CH3:20])[CH2:5][CH2:6]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)c(F)cc1C#N

Procedure:
5-fluoro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 5-fluoro-2-(methyloxy)-4-oxiran-2-ylbenzonitrile. LC/MS (M+1)+=470.56.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1)#[N:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ccc(C#N)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C#N)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-cyano-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH:25]=C)[C@H:12]([CH2:13][CH:14]=C)[C:11](=[O:16])[N:10]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC=CC=1.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH:25]=[CH:14][CH2:13][C@@H:12]1[C:11](=[O:16])[N:10]([C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(C=C)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: c1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)C=CC[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
(3S,4S)-4-Allyl-5-oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester (130.0 mg, 0.37 mmol) was dissolved in benzene (8 mL). The second generation Grubbs' catalyst (31.0 mg, 0.04 mmol) was added, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (15% ethyl acetate/hexane) to give 93.2 mg of the title compound as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([CH:13]=[C:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[O:10][N:9]=1.[CH3:20]N1CCC(=O)C1.CC1C=C(C[Si](C)(C)C)ON=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([CH:13]=[C:14]2[CH2:18][CH2:17][CH2:20][N:16]([CH3:19])[CH2:15]2)[O:10][N:9]=1
Reactant: CN1CCC(=O)C1
Reactant: Cc1cc(C=C2CCN(C)C2)on1
Agent: Cc1cc(C[Si](C)(C)C)on1
Agent: O=C(O)C(=O)O
Product: Cc1cc(C=C2CCCN(C)C2)on1

Procedure:
3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.