Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][C@H:9]1[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:11](/[CH:22]=[CH:23]/[C@@H:24]([O:37][Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C@H:10]1[CH2:45][CH:46]=C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[Si:15]([O:14][C@@H:12]1[CH2:13][C@@H:9]2[O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:46][CH2:45][C@@H:10]2[C@H:11]1/[CH:22]=[CH:23]/[C@@H:24]([O:37][Si:38]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:43][CH3:44])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: C=CCCCC(=O)O[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H]1CC=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@H]2C/C=C\CCCC(=O)O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)COc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@H]2CC=CCCCC(=O)O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)COc1cccc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A 50 ml two-necked round-bottom flask was flame dried and allowed to be cooled under nitrogen. (1S,2R,3R,4R)-2-allyl-4-(tert-butyldimethylsilyloxy)-3-((R,E)-3-(triethylsilyloxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl hex-5-enoate (0.2 g, 0.29 mmol) in 4 ml of dichloromethane, and 0.02 g of Grubb's catalyst were added to the reaction flask. The reaction mixture was heated at 40° C. for 18 hours. The reaction was quenched with 0.4 ml ethylamine with stirring for 1 hour. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate and 4 ml saturated aqueous sodium bicarbonate solution. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography and then concentrated under educed pressure to provide 30 mg of the title compound (16% yield).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:29]5([OH:28])[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1(O)CCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CCCC1

Procedure:
The title compound, white solid (17 mg, 53.5%), MS (ISP) m/z=444.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclopentanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]1C(=O)O[C:23](C)([CH3:27])[O:22][C:21]1=[O:29].C(OCC)(=O)C>C(O)C.N1C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][C:21]([O:22][CH2:23][CH3:27])=[O:29]
Reactant: COCOc1cc(OC)c(OCOC)c(CC2C(=O)OC(C)(C)OC2=O)c1OC
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCc1c(OC)c(OCOC)cc(OC)c1OCOC

Procedure:
4.07 Grams of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methane was dissolved in 20 ml of ethanol and 40 ml of pyridine, then a catalytic amount of copper powder was added thereto and refluxed for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, to the residue thus obtained was added 20 ml of ethyl acetate. The organic layer was washed with a diluted hydrochloric acid, water, a saturated sodium chloride aqueous solution in this order, dried over anhydrous sodium sulfate, concentrated under a reduced pressure to yield 3.42 g of ethyl 3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propionate as an ethyl ester. Colorless oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COC(=O)C1CC(=O)N(c2cccc(CO)c2)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)N(c2cccc(C=O)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(3-(hydroxymethyl)phenyl)-5-oxopyrrolidine-3-carboxylate in CH2Cl2 was added pyridinium chlorochromate (PCC). The reaction was stirred at room temperature overnight. The mixture was then filtered through a pad of celite. The filtrate was concentrated in vacuo and the desired product was obtained after silica gel chromatograph. MS (ES+): 248.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[CH3:25][O:24][C:22](=[O:23])[NH:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCOCC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of Intermediate 5 (0.3 g) in dichloromethane (30 ml) was added triethylamine (0.3 ml) and methyl chloroformate (0.15 ml). After 3 h, the dichloromethane was removed in vacuo, and the resulting slurry dissolved in ethyl acetate (20 ml), washed with aqueous citric acid (10%, 15 ml), saturated aqueous sodium bicarbonate (15 ml) and brine (15 ml). The organic solvent was dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield the title compound as a yellow oil (0.26 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:3][CH2:2][CH2:1][NH:4][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCNS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 15 h
Yield: 96.7 %

Procedure:
A mixture of ethylenediamine (18.0 g, 0.30 mol) and sodium carbonate (64.0 g, 0.60 mol) in 750 mL of deionized water was heated to 75 C. To the mixture was added p-toluenesulfonyl chloride (125.0 g, 0.66 mol) in 5 g portions over 45 minutes. Then the reaction was stirred at 75 C. for 15 hours. After the mixture was cooled to 25 C., the white precipitate was filtered, washed with water and dried in a vacuum desiccator at 1 mm to yield 1,4-bis(p-toluenesulfonyl)-1,4-diazabutane (100.1 g, 0.29 mol, 98%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7])[CH3:3].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>CN1CCN(C)C1=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: Cc1ccccc1F
Reactant: CN(C)CCC(O)c1ccccc1
Solvent: CN1CCN(C)C1=O
Product: Cc1ccccc1OC(CCN(C)C)c1ccccc1

Procedure:
reacting an alkoxide of N,N-dimethyl-3-phenyl-3-hydroxypropylamine) with 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone to give N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine;
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:7].C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH:3]=[CH:4][N:5]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)[C:6]2=[O:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(NC(=O)N(CC(OC)OC)c2ccc(Oc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reaction time: 16 h

Procedure:
A solution of 1-(2,2-dimethoxyethyl)-3-(4-methoxyphenyl)-1-(4-phenoxy-phenyl)urea (6.8 g) in trifluoroacetic acid (20 ml) was left to stand for 16 hours and then neutralized with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 358.40 (C22H18N2O3); MS (ESI): 359 ([M+H]+), was obtained in this way.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:54]=[CH:55][C:56]=1[Cl:57])[CH2:8][O:9][CH:10]1[O:15][CH:14]([CH2:16][O:17][C:18](=[O:32])[CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]([O:33][CH:34]2[O:43][CH:42]3[CH:37]([O:38][CH:39]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:40][CH2:41]3)[CH:36]([OH:50])[CH:35]2[OH:51])[CH:12]([OH:52])[CH:11]1[OH:53])(=[O:3])[CH3:2].[K+].[Br-]>O>[C:14]([O:52][CH:12]1[CH:11]([O:53][C:18](=[O:17])[CH3:19])[CH:10]([O:9][CH2:8][C:7]2[CH:54]=[CH:55][C:56]([Cl:57])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[O:15][CH:14]([CH2:16][O:17][C:18](=[O:32])[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:13]1[O:33][CH:34]1[O:43][CH:42]2[CH:37]([O:38][CH:39]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[O:40][CH2:41]2)[CH:36]([O:50][C:8](=[O:9])[CH3:7])[CH:35]1[O:51][C:1](=[O:3])[CH3:2])(=[O:15])[CH3:13]
Reactant: CC(=O)Nc1cc(COC2OC(COC(=O)C(c3ccccc3)c3ccccc3)C(OC3OC4COC(c5ccccc5)OC4C(O)C3O)C(O)C2O)ccc1Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1cc(COC2OC(COC(=O)C(c3ccccc3)c3ccccc3)C(OC3OC4COC(c5ccccc5)OC4C(OC(C)=O)C3OC(C)=O)C(OC(C)=O)C2OC(C)=O)ccc1Cl

Procedure:
The title compound was prepared as a white foam (0.289 g, 76%) from diphenyl-acetic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro-pyran-2-ylmethyl ester using a procedure similar to Example 25, mp >99° C. (decomp.); 1H NMR (DMSO-d6) δ1.92 (s, 3H), 1.94 (s, 3H), 1.96 (s, 3H), 1.99 (s, 3H), 2.08 (s, 3H), 3.66 (t, J=9.9 Hz, 1H), 3.72-3.78 (m, 1H), 3.78 (t, J=9.0 Hz, 1H), 3.87 (t, J=9.7 Hz, 1H), 3.98-4.05 (m, 2H), 4.18-4.24 (m, 1H), 4.44 (ABq, J=12.7 Hz, Δδ=0.16, 2H), 4.61-4.67 (m, 2H), 4.80 (d, J=7.9 Hz, 1H), 4.88 (dd, J=4.2, 10.3 Hz, 1H), 5.16 (d, J=4.0 Hz, 1H), 5.22 (t, J=9.9 Hz, 1H), 5.29 (t, J=9.2 Hz, 1H), 5.31 (s, 1H), 5.60 (s, 1H), 6.99 (dd, J=1.5, 8.1 Hz, 1H), 7.20-7.25 (m, 2H), 7.27-7.35 (m, 8H), 7.35 (s, 5H), 7.43 (d, J=8.1 Hz, 1H), 7.59 (s, 1H), 9.51 (s, 1H); IR (KBr) 3410, 3070, 3025, 2930, 2860, 1755, 1690, 1600, 1525, 1450, 1410, 1375, 1240, 1140, 1055, and 1030 cm−1; mass spectrum [(+) FAB], m/z 974 (M+H)+, 996 (M+Na)+; Anal. Calcd. for C50H52ClNO17.1.25 H2O: C, 60.24; H, 5.51; N, 1.40, Found: C, 59.97; H, 5.10; N, 1.37.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.C(OC([N:17]1[CH2:22][CH2:21][CH:20]([C@@H:23]2[CH2:25][C@@H:24]2[CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]1)=O)(C)(C)C>>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:25][CH:24]3[CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]2)=[N:3][CH:4]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Product: Cc1nc(N2CCC(C3CC3CCO)CC2)ncc1F
Temperature: 90 °C

Procedure:
The titled compound was prepared from 2-chloro-5-fluoro-4-methylpyrimidine and rac cis-tert-Butyl-4-[-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to example 6 step 2, with the exception of reaction temperature. The reaction was heated at 90° C. for 2 h.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][C@H:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH:1]=1
Reactant: COC(=O)[C@H](C)O
Reactant: Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of the m-cresol (1.0 g, 9.2 mmol) in anhydrous THF (15 mL) at 0° C. under argon protection was added triphenylphosphine (2.55 g, 9.7 mmol), followed by addition of the (S)-methyl 2-hydroxypropanoate (926 μL, 9.7 mmol). Then diisopropylazodicarboxylate (DIAD) (2.85 mL, 13.8 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted by ethyl acetate, washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The obtained oil was purified by flash chromatography (Hexane/Ethyl acetate 0˜50%) to afford a colorless oil (820 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][S:36][CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: C1CSCCN1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCSCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thiomorpholin-4-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and thiomorpholine following General Procedure B.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[C:6]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(c2ccsc2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-3-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.03 (s, 1H), 7.84 (dd, J=6.9, 2.2 Hz, 1H), 7.62 (m, 2H), 7.56 (dd, J=5.2, 3.0 Hz, 1H), 7.48 (m, 2H), 7.27 (m, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.16 (dd, J=5.2, 1.4 Hz, 1H), 4.04 (d, J=15.4 Hz, 1H), 3.94 (d, J=15.4 Hz, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 0.75 (t, J=7.1 Hz, 3H); MS (ES) m/z 402 (M+H)+;
Reaction SMILES: [F-:1].[K+].C([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[C:25](=[O:28])[CH:26]=[CH2:27])C.F[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][N:35]=[CH:34]2.C(O)=O>CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:29])=[C:10]([CH:16]2[C:24]3[C:19](=[CH:20][C:21]([F:1])=[CH:22][CH:23]=3)[CH2:18][N:17]2[C:25](=[O:28])[CH2:26][CH2:27][N:36]2[C:37]3[C:33](=[CH:32][CH:31]=[CH:39][CH:38]=3)[CH:34]=[N:35]2)[CH:11]=1
Reactant: [F-]
Reactant: Fc1ccc2[nH]ncc2c1
Reactant: C=CC(=O)N1Cc2ccccc2[C@H]1c1cc(Cl)ccc1OCC(=O)OCC
Agent: [K+]
Solvent: CC#N
Solvent: O=CO
Product: O=C(O)COc1ccc(Cl)cc1C1c2ccc(F)cc2CN1C(=O)CCn1ncc2ccccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Potassium fluoride 40 wt. % on alumina (218 mg, 3.75 mmol, 25 eq.) was added to a mixture of [2-((S)-2-acryloyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic acid ethyl ester (58 mg, 0.15 mmol, 1.0 eq.) and 5-fluoro-1H-indazole (25 mg, 0.18 mmol, 1.2 eq.) in MeCN (1 mL). The resulting suspension was stirred at 80° C. for 18 hours. Formic acid was added (0.2 mL). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired product as a white foam.
Reaction SMILES: [C:1]1([CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34](O)=[O:35])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34]([NH:20][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:35])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: NC(c1ccccc1)c1ccccc1N1CCCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Product: COC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1OC

Procedure:
Prepared from α-phenyl-2-piperidino-benzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[NH2:10][CH2:11][C:12](O)=O.[ClH:15]>>[ClH:15].[ClH:15].[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:12]1[CH2:11][NH2:10]
Reactant: NCC(=O)O
Reactant: CNc1ccccc1N
Agent: Cl
Product: Cn1c(CN)nc2ccccc21
Temperature: -15 °C

Procedure:
Combine N-methyl-o-phenylenediamine (12.2 g, 100 mmol) and glycine (11.3 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux 90 hours, allow to cool, and concentrate in vacuo to 60 g. Add EtOH (50 mL) and chill at −15° C. Filter the solid and wash with cold 90% EtOH. Dissolve the blue solid in water (30 mL), add EtOH (100 mL) and treat with decolorizing charcoal. Wash the solid with 2:1 EtOH-water and concentrate filtrates in vacuo to 33 g. Add water (15 mL) and warm while adding EtOH (150 mL). Allow to cool, filter, and wash with 90% EtOH to obtain the product as blue flakes. Process the filtrate to obtain a second crop.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[CH:20][CH2:21][OH:22])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>CS(C)=O.[O-2].[Mn+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=[O:22])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: OCC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
16.32 g of activated manganese oxide were added to a solution of 1.63 g (5.54 mmol) of 2-(4-fluorophenyl)-4-(3-hydroxy-1-propen-1-yl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 66(i) above] in 80 ml of dimethylsulfoxide. The resulting mixture was stirred at room temperature for 24 hours. At the end of this time, ethyl acetate was added to the reaction mixture and then this was filtered. Water was added to the resulting filtrate and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was washed with dichloromethane to afford 1.36 g (yield 84%) of the title compound as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][C:27]=2F)[C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:14]2)=[O:12])=[C:5]([CH3:7])[N:6]=1.CC1C(C)=C(C2C(F)=CC(C)=C(C=2)C([N:43]2[CH2:46][CH:45](C3C=CC(C#N)=CC=3)[CH2:44]2)=O)NN=1>>[N:43]1([C:27]2[CH:26]=[CH:25][C:10]([C:11]([N:13]3[CH2:16][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)[CH2:14]3)=[O:12])=[CH:9][C:8]=2[C:4]2[NH:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1cc(F)c(-c2[nH]nc(C)c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2F)[nH]1
Product: Cc1nc(C)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2N2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 377, except 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)azetidin-3-yl)benzonitrile (compound 376.2) was used instead of 4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-4-fluoro-2-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 377.2). m/z (ES+) 412 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25])[CH2:19][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCN2Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 20 (300 mg, 1.69 mmol), 3,4,5-trimethoxybenzaldehyde (365 mg, 1.86 mmol) and dibutyltin dichloride (51 mg, 0.17 mmol) in THF (8 mL) was added phenylsilane (229 μl, 1.86 mmol). The mixture was stirred overnight at room temperature under nitrogen. Additional aldehyde and phenylsilane were added and the stirring continued until starting material was consumed. THF was evaporated in vacuum and the residue was purified by flash chromatography (eluent 20% EtOAc in hexane). The compound was further purified by re-crystallization in a mixture EtOAc/hexane and finally by a second flash chromatography (eluent 20% EtOAc in hexane) to give the title compound 21 (428 mg, 71%) as a white solid. 1H-NMR (DMSO) δ: 2.96 (t, J=8.4 Hz, 2H); 3.45 (t, J=8.7 Hz, 2H); 3.61 (s, 3H); 3.71 (s, 6H); 3.72 (s, 3H); 4.30 (s, 2H); 6.59 (s, 2H); 6.61 (d, J=8.4 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H); 7.63 (dd, J=1.8, 8.4 Hz, 1H).