Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]3)[CH2:19][CH2:18]4)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:33][C:25]([CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=4)[O:14][N:13]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)([CH2:26][OH:27])[CH2:30][OH:29]
Reactant: COc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC(N)(CO)CO)no2)cc1Cl
Yield: 67 %

Procedure:
When the product of Step G was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 67% yield, as a creamy solid. 1H-NMR (CDCl3) 1.54 (broad s, 4H+H2O); 3.07 (m, 2H); 3.19 (s, 2H); 3.47 (s, 2H); 3.55-3.62 (m, 6H); 3.98 (s, 3H); 6.67 (m, 1H); 7.03 (m, 1H); 7.82-7.9 (m, 2H); 8.01-8.06 (m, 1H); 8.22 (s, 1H); 1H-NMR (DMSO-d6) 1.52 (m, 2H); 2.9-3.03 (m, 4H); 3.57 (tr, 2H, J=8.6 Hz); 3.95 (s, 3H); 4.6 (s, 2H); 6.66 (d, 1H, J=8.4 Hz); 7.36 (d, 1H, J=8.4 Hz); 7.62-7.7 (m, 2H); 8.05-8.11 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:13]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1nccs1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1nccs1

Procedure:
Using General Procedure B: Reaction of [4-(1-thiazol-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester and 3-methyl-2-pyridine carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridin-2-ylmethyl)-(1-thiazol-2-yl-ethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCl3) δ 1.25-1.41 (m, 2H), 1.43 (s, 9H), 1.45-1.53 (m, 2H), 1.55 (d, 3H, J=Hz), 2.47-2.52 (m, 5H), 2.98-3.04 (m, 2H), 3.83 (d, 1H, J=Hz), 4.00 (d, 1H, J=Hz), 4.11 (q, 1H, J=Hz), 4.53 (bs, 1H), 7.10 (dd, 1H, J=7.6, 4.8 Hz), 7.23 (d, 1H, J=3.3 Hz), 7.44 (d, 1H, J=6.8 Hz), 7.66 (d, 1H, J=3.3 Hz), 8.36 (dd, 1H, J=4.8, 1.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]1[C@H:20]([O:21][C:22](=O)[CH3:23])[NH:19][C:18]1=[O:25])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]1[C@@H:20]([O:21][CH2:22][CH2:23][Br:26])[NH:19][C:18]1=[O:25])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: OCCBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OCCBr
Yield: 12 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-alanyl)amino-4-acetoxy-azetidin-2-one (1.36 g, 3.894 mmole), 2-bromoethanol (440 mg, 3.5 mmole), and zinc acetate dihydrate (642 mg, 2.9 mmole) in a mixture of benzene (40 ml) and toluene (40 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (200 ml), acetone (25 ml) and water (150 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (2:1) as eluent and (3S,4R)-3-(N-benzyloxycarbonyl-L-alanyl)amino-4-bromoethoxy-azetidin-2-one was obtained (169 mg, 12% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=O)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)Cc2ccc(N)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCc2ccc(N)cc2)CC1

Procedure:
4-(4-Methylpiperazin-1-yl)carbonylmethylaniline (596 mg, 2.55 mmol) was treated in anhydrous THF (20 mL) under nitrogen with lithium aluminum hydride (291 mg, 2.67 mmol) overnight. The reaction was quenched with water (3×0.29 mL), 15% sodium hydroxide (3×0.29 mL) and again water (3×0.29 mL). The resulting precipitate was removed by filtration. Evaporation of the filtrate afforded the title compound as an orange oil, 380 mg.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2C=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:28]1([C:8]([OH:34])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].[N:21]1([C:31](N2C=C[N+](C)=C2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1>>[CH3:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][C:31]([N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:32])=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(-c2ccccc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(-c2ccccc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12
Yield: 72.9 %

Procedure:
The title compound (150 mg, 73% yield, white solid) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[C:23]1([CH2:33][NH:34][C:35]2[N:43]=[C:42]([C:44]#[N:45])[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:46]([O:54][C@H:55]1[C@@H:59]([O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:58](OC(=O)C)[O:57][C@@H:56]1[C:73]([NH:75][CH2:76][CH3:77])=[O:74])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O[C@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.C(OCC)(=O)C>[C:61]([O:60][C@@H:59]1[C@H:55]([O:54][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:56]([C:73]([NH:75][CH2:76][CH3:77])=[O:74])[O:57][C@H:58]1[N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([C:44]#[N:45])=[N:43][C:35]=2[NH:34][CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2nc[nH]c2n1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Diazabicycloundecane (0.18 ml, 1.2 mmol) was added to a solution of (6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (200 mg, 0.67 mmol) (Preparation 10) and (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3furanyl benzoate and (2S,3S,4S,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (309 mg, 0.70 mmol) (Preparation 18) in acetonitrile (5 ml). Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was added and the reaction mixture heated under reflux for 30 minutes. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (20 ml) and washed twice with water (20 ml). The ethyl acetate layer was then washed with 10% w/w aqueous citric acid and saturated aqueous sodium chloride solution (20 ml). The organic phase was dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane increasing in polarity to dichloromethane:methanol (98:2 by volume). The solvent was removed under reduced pressure to give the title compound (235 mg) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NCCO
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCCO)s1
Yield: 41 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (65 mg, 41%) which was obtained as a white solid. MS: m/e=377.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.CC(N([CH2:30][CH2:31][O:32]C1C=CC(N)=CC=1)C(N)=O)C.C(Cl)(=O)C>C(N(CC)CC)C>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[N:7]([CH:18]([CH3:19])[CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:31](=[O:32])[CH3:30])=[CH:15][CH:16]=1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(N)=O
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)NCCN(C)C
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(OCCN(C(=O)NCCN(C)C)C(C)C)cc1

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with acetyl chloride in triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:21]([O:34][CH3:35])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CNCCNC.Cl.CCOCC>C(Cl)Cl.[Cu]I.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[C:21]([O:34][CH3:35])[CH:20]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Reactant: COc1cc(Br)ccc1NC(=O)CN1CCCC1
Agent: [Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
Combine 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (1.8 g, 6.88 mmol), N-(4-bromo-2-methoxy-phenyl)-2-pyrrolidin-1-yl-acetamide (2.58 g, 8.25 mmol), Cs2CO3 (4.48 g, 13.8 mmol), 1,4-dioxane (69 mL), and CuI (0.520 g, 2.75 mmol). Purge the mixture with nitrogen for 10 min. Add sym-dimethylethylene diamine (0.49 g, 5.50 mmol) and heat the mixture at 100° C. overnight. Cool the mixture to RT, dilute with CH2Cl2, and wash twice with a solution of 5% NH4OH/H2O (2×). Dry the organic layer over Na2SO4, filter, and concentrate. Filter the crude with H2O and Et2O. Purify the crude material by chromatography using a gradient of 20-50% acetone in hexane. Prepare the HCl salt by dissolving the solid with CH2Cl2. Add 1 eq of 1 M HCl/ether, allow the solution to stir for 15 min, and concentrate to give 1.95 g (53%) of the title compound. LC-ES/MS m/z (35Cl) 494.0 [M+H]+.
Reaction SMILES: N[C@H](C(C)(C)C)C.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:17]1[C:18](=[O:29])[C:19](=[O:28])[C:20]=1[NH:21][C@H:22]([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:17]1[C:18](=[O:29])[C:19](=[O:28])[C:20]=1[NH:21][CH:22]([CH3:27])[C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: Cc1cccc(O)c1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Agent: C[C@H](N)C(C)(C)C
Product: Cc1cccc(O)c1Nc1c(NC(C)C(C)(C)C)c(=O)c1=O

Procedure:
(S)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,1-trimethylpropylamino)-(cyclobut-3-ene-1,2-dione is produced by the same method by substituting (S)-2-amino-3,3-dimethylbutane for the (R)-2-amino-3,3-dimethylbutane employed in the preceding paragraph.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:16]=2)=[O:11])=[C:4]([F:19])[C:3]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[C:23]([Cl:29])[CH:22]=1
Reactant: C1COCCN1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(C=O)c[nH]3)c2F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc(CN4CCOCC4)c[nH]3)c2F)c1
Yield: 10.8 %

Procedure:
A solution of N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-formyl-1H-imidazole-2-carboxamide (0.11 mmol), morpholine (0.020 mL, 0.22 mmol), NaBH(OAc)3 (0.047 g, 0.22 mmol) in CH2Cl2 (1.5 mL) was stirred at RT overnight. Sat'd NaHCO3 was added and the solution was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) and silica gel chromatography to afford the title compound (0.006 g, 11%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, J=1.47 Hz, 1H), 7.36-7.42 (m, 2H), 7.28 (t, J=2.06 Hz, 1H), 7.22-7.25 (m, 1H), 7.20 (br. s., 1H), 4.63 (s, 2H), 3.65-3.75 (m, 4H), 3.54 (br. s., 2H), 2.44-2.60 (m, 4H). ES-LCMS: m/z 504.1, 506.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CCC2
Yield: 81.5 %

Procedure:
A suspension of 7-nitro-1-tetralone (2.00 g, 10.5 mmol) in MeOH (20 mL) was treated with 10% Pd-C (100 mg) and hydrogenated at 1 atm for 5 h. Filtration through Celite gave a brown solid (1.38 g). It was suspended in CHCl3 and flash chromatographed over silica gel (69 g) eluting with EtOAc/hexane (1:2) to afford a tan solid (0.62 g, 37% yield): mp 137-138° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH3:3].[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[CH:18][C:19]=1Br.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:22])[CH3:23])[N:17]=[CH:18][C:19]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCOc1ccc(CN)cc1
Reactant: CC(C)n1ncc(Br)c(Br)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(CNc2cnn(C(C)C)c(=O)c2Br)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 0.38 g of 4-ethoxybenzylamine hydrochloride, 0.4 g of 4,5-dibromo-2-iso-propyl-3(2H)pyridazinone, 0.34 g of potassium carbonate, 6 ml of 1,4-dioxane and 18 ml of water, was heated at 90° C. under stirring for 10 hours. The sovent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off. The product was crystallized from ether to obtain 220 mg of the above identified compound having a melting point of from 151° to 152.5° C. as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Cl:14][C:15]1[C:16]([O:25][CH3:26])=[C:17]([C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][CH:15]1[CH2:22][CH:18]([C:17]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:15]([Cl:14])[C:16]=2[O:25][CH3:26])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:16]1=[O:25]
Reactant: COc1ccc(Cl)c(OC)c1C=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: COc1ccc(Cl)c(OC)c1C1CC(Cl)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10D (GP10D) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3-chloro-2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 463.84 g/mol.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[Na+].O.S(C1C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=CC=1)([O-])(=O)=O.[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c[nH]c(=O)c(-c2ccc(F)cc2)c1
Temperature: 125 °C
Yield: 65.5 %

Procedure:
To a solution of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (0.50 g, 2.16 mmol) in DMF (8.1 mL) and water 2.7 mL) were added (4-fluorophenyl)boronic acid (0.38 g, 2.69 mmol), palladium(II) acetate (36.3 mg, 0.16 mmol), tris(3-sulfonatophenyl)phosphine hydrate sodium salt (0.31 g, 0.49 mmol) and diisopropylamine (1.54 mL, 10.8 mmol). The mixture was heated in the microwave reactor at 125° C. for 15 min. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate and the organic layer was washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→70% dichloromethane/ethyl acetate) gave the title compound (0.35 g). MS 248.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(O)c(C)c1
Product: Cc1ccc(OCC(=O)c2ccccc2)c(C)c1

Procedure:
Using the method described in Example 1, 2,4-dimethylphenol is reacted with alpha-bromoacetophenone to provide alpha-(2,4-dimethylphenoxy)acetophenone.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=12.[CH2:18]([OH:21])[CH2:19][OH:20]>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([O:16][CH3:17])=[CH:10][C:9]2[CH:3]([CH2:2][O:20][CH2:19][CH2:18][OH:21])[S:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: OCCO
Reactant: COc1cc2c(cc1OC)=C(CBr)SC=CC=2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(COCCO)SCCC2

Procedure:
A mixture of 1-bromomethyl-7,8-dimethoxy-2-benzothiepin, dilsopropylethylamine, and ethylene glycol is heated at 30° to 100° C. for 5-50 hours. The reaction mixture is then cooled, diluted with methylene chloride and extracted with water followed by brine. The organic layer is filtered through Na2SO4, taken to dryness, and chromatographed on silica gel to give 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S-:10])=[N:2]1.[K+].Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O>[F:19][C:15](=[C:16]([F:18])[F:17])[CH2:14][CH2:13][S:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: FC(F)=C(F)CCBr
Reactant: [S-]c1nsc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1nsc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.05 g (0.01 mol) Potassium 1,2-benzoisothiazole-3-thiolate was suspended in 25 ml dimethylformamide. At a temperature of 20° C., a solution of 2.3 g (0.01 mol) 4-bromo-1,1,2-trifluorobut-1-ene in 10 ml dimethylformamide was added dropwise. The mixture was then stirred for 2 hours at room temperature. The mixture was added to 300 ml ice/water and extracted several times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (eluent: hexane/diethyl ether 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: Brc1ccccc1I
Product: Clc1ccc(Sc2ccccc2Br)c(Cl)c1

Procedure:
Prepared from 2,4-dichloro-benzenethiol and 2-bromo-1-iodo-benzene.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]=[CH2:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Si](O/C(=C\C1C=CC(F)=CC=1)/C=C)(C)C)(C)(C)C.[C:39]([O:48][CH2:49][CH3:50])(=[O:47])/[CH:40]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43]>>[Si:5]([O:8][C:9]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:40]([C:39]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:11][CH:10]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:7])[CH3:6]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Agent: C=C/C(=C/c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane (Example 1, step C) and 17 mL (18 g, 104.6 mmol) diethyl (2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmosphere was heated at 160° C. for 5 hr then cooled to RT. The solvent was evaporated under vacuum to give an oil which was used without further purification.