Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[CH2:13]1)C1C=CC=CC=1.C(Cl)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:19]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Clc1cccc(OC2CCN(Cc3ccccc3)C2)c1Cl
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCc1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc(Cl)c2Cl)C1
Reaction time: 8 h

Procedure:
To a solution of 200 ml of 2M phosgene in benzene, stirred under nitrogen gas, was added 96 g (0.3 mole) of 1-benzyl-3-(2,3-dichlorophenoxy)pyrrolidine in 300 ml of benzene. The reaction mixture was allowed to stir overnight and then concentrated to an oil. The oil was triturated with 30/60 petroleum ether to give an oil. Solid product, 89 g, was obtained containing a trace of benzyl chloride. The yield was nearly quantitative.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Oc3cccc(S(C)(=O)=O)c3)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Oc3cccc(S(C)(=O)=O)c3)cc2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 1.8 g (4.3 mmol) of 2-propionyl-3-hydroxy-5-(4-(3-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 5 mL of methylene chloride and 10 mL of absolute ethanol at room temperature was treated with 0.50 g (5.2 mmol) of ethoxyamine hydrochloride and 0.50 g (6.1 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted thrice with 15 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent left the above named product as a pale oil in a yield of 1.8 g (91 percent of theoretical). 1H NMR (CDCl3): δ1.09-1.48 (m, 6H, both --CH2CH3 's), 2.57-3.60 (m includes s at 3.02 for CH3SO2 --, 10H), 4.13 (q, J=7 Hz, 2H, OCH2), 6.92-7.75 (m, 8H, aromatics), 14.9 (broad s, H, enol 1H) (Compound 3).
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:40])[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=2)C=CC=CC=1.Cl>C(O)(=O)C.O>[OH:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:40])[C:37]([OH:39])=[O:38])=[CH:34][CH:35]=1
Reactant: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid (0.3 g) in acetic acid (20 mL) containing concentrated hydrochloric acid (5 mL) was stirred at 80° C. for 2.5 hours. The cooled solution was diluted with water (100 mL) and extracted with three portions of ethyl acetate, then the combined extracts were dried (Na2SO4), and evaporated in vacuo. The residual oil was triturated in turn with cyclohexane and carbon tetrachloride to remove non polar impurities, then was crystallized from dichloromethane and recrystallized from dichloromethane-carbon tetrachloride to give 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 127°-130° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.O.[NH2:27][NH2:28]>CO>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]([NH:27][NH2:28])=[O:2])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH3:24]
Reactant: CCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}acetate (3.816 g, 10.5 mmol), was dissolved in MeOH (30 mL). Hydrazine hydrate was added (3.3 mL). The reaction mixture was stirred overnight at room temperature. A white precipitate was formed. It was isolated by filtration and rinsed with cold MeOH. From mother liquors some more compound could be recovered, affording the desired product, e.g. 4-ethoxy-N-(2-hydrazino-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (2.745 g, 72%) as a colorless solid in 99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[CH:7][CH:6]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>C1COCC1>[C:19]1([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]4[NH:25][C:26](=[O:27])[O:1][N:2]=4)=[CH:10][CH:9]=3)[N:15]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N=C(Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)NO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c(Cc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of 4.06 g of the amidoxime from Example 14 Part A, 150 mL of THF and 1.98 g of carbonyldiimidazole was heated at reflux for 7 hours, cooled to 25° C., and stirred another 16 hours. The solvent was removed in vacuo. The residue was dissolved in 600 mL of EtOAc, washed with H2O and dried over anhydrous Na2SO4. The residue, obtained after filtration and evaporation of the solvent, was recrystallized from EtOH to give 3.11 g of 3-[(4-(2-(2-phenyl-4-oxazolyl)ethoxy)phenyl)-methyl]1,2,4-oxadiazolin-5-one, (71% mp 154.5°-157.5° C.).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15]C=1C.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:27]=1[C:26]([OH:29])=[O:28]
Reactant: Cc1ccc(I)cc1F
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(I)cc1F
Temperature: 90 °C

Procedure:
A round bottom (RB) flask containing a solution of 8.0 g (27.0 mmol) of sodium dichromate in 44 mL of glacial acetic acid was placed in an external water bath (21° C.) and left exposed to air. To the resultant orange slurry was added 3.2 g (13.6 mmol) of 2-fluoro-4-iodotoluene followed by the dropwise addition of 22 mL of c. sulfuric acid via syringe (caution: if added too quickly there is a tendency for the mixture to erupt). After the addition of approximately 8 mL of sulfuric acid, a green solid precipitated and the water bath temperature had risen (25° C.). The green reaction mixture was heated in an oil bath (90° C.) for one hour, allowed to cool to ambient temperature, diluted with 1N NaOH solution (aq.) and ethyl acetate (500 mL) and then quenched with sat. NaHCO3 (aq.) solution. The organic phase was separated and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to an orange oil. Residual acetic acid was removed by further extraction between ethyl acetate and sat. NaHCO3 (aq.) solution and washing of the organic phase with water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange solid.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.C(=O)([O-])[O-].[NH4+:17].[NH4+]>>[C:1]1(=[O:7])[NH:17][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: [NH4+]
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: O=C([O-])[O-]
Product: O=C1Cc2ccccc2C(=O)N1
Temperature: 280 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Homophthalic anhydride (1.62 g, 10 mmol) and ammonium carbonate (1.61 g, 10 mmol) are ground in a mortar and then slowly heated to fusion at about 280° C. After 2 h, the reaction mixture is allowed to cool. The product is practically pure and needs no further treatment. Thus homophthalimide is obtained in 95% yield (153 mg).
Reaction SMILES: CC(C)=CCC[N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1.Cl.Cl.NC1CCN([CH2:37][CH:38]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)CC1>>[CH:38]1([CH2:37][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)([OH:20])[C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH2:8][CH2:7]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2nccs2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1nccs1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-hydroxyl-2-(2-thiazolyl)acetic acid obtained in Example 51 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH2:53][CH3:54])[C@H:3]([NH:14][C:15]([C@:17]1([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH2:29][C:28]2[C:27]3[C:22](=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)=[O:16])[C:4](=S)[NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Na]>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][CH:2]([CH2:53][CH3:54])[C@H:3]([NH:14][C:15]([C@:17]1([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH2:29][C:28]2[C:27]3[C:22](=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)=[O:16])[CH2:4][NH:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](C(=S)NCC2CCOCC2)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](CNCC2CCOCC2)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Reaction time: 0.17 h

Procedure:
0.050 g (0.06 mmol) of (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl}-amide were dissolved in 7 mL of THF/Methanol (1:1). 0.123 g (0.52 mmol) of nickel(II)chloride hexahydrate were added at room temperature. The mixture was stirred for 10 min at this temperature. At 0° C. 0.059 g (1.55 mmol) sodium borhydrate were added. Stirring was continued for 18 h at room temperature. The mixture was filtered over silica gel and the silica gel layer was washed with MeOH. The filtrate and washes were combined, concentrated and the residue purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1>>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 27 %

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 3-amino-6-bromo-picolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (27%). LCMS (m/z): 621.2 (MH+); LC Rt=4.41 min.
Reaction SMILES: Cl[C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.[H-].[Na+].N#N.[CH3:24]N(C=O)C>>[Cl:18][C:17]1[C:2]2[O:13][N:12]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=3)[C:3]=2[CH:14]=[CH:15][C:16]=1[O:19][CH3:24]
Reactant: CN(C)C=O
Reactant: ON=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(-c3cccc(F)c3)noc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 3 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime in 20 ml of DMF, 0.25 g of NaH is added in an atmosphere of N2. The mixture is stirred for 18 hours. The mixture is heated to 100° C. for one hour. The reaction mixture is poured into ice water to yield 7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 149°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1cccc(F)c1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(F)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 11.25 g of 5-aminopyridine-2-carboxylic acid methyl ester, 10.0 g of m-fluorobenzaldehyde and 50 ml of benzene is refluxed for 22 hours on a water trap. It is evaporated and the residue recrystallized from acetonitrile, to yield the 5-(m-fluorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester, melting at 111°-114°.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].CI.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:23][C:2]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1COCCN1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)COCCN1C(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-Benzyl 3-methyl morpholine-3,4-dicarboxylate (13.98 g, 50.1 mmol) and methyl iodide (5.70 ml, 91 mmol) was dissolved in THF (100 ml). The solution was cooled to −70° C. A solution of NaHMDS in THF (1 M, 91 ml, 91 mmol) was added via syringe over 2 minutes. The reaction solution was stirred for 5 hours at −40 to −70° C. and then was quenched with MeOH (5 ml) and HOAc (3.5 g). The reaction mixture was concentrated. The residue was then partitioned between EtOAc (400 ml) and water (150 ml). The organic phase was separated. The aqueous phase (pH about 7) was extracted with EtOAc (100 ml). The combined organic phases were washed with water (100 ml). The organic solution was then concentrated to give an oil. The residue was purified by silica gel column (220 g silica gel, Hexane/EtOAc 5:1) to afford 11.6 g of 4-benzyl 3-methyl 3-methylmorpholine-3,4-dicarboxylate as an oil (79% yield). 1H NMR (400 MHz, CDCl3) δ=1.58 (s, 3H), 3.23-3.78 (m, 9H), 4.99 (m, 2H), 7.17-7.27 (m, 5H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][O:24][CH3:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(methoxymethyl)-1,4-oxazepane-4-carboxylate (58 mg) in ethyl acetate (2 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3.0 mL), and the mixture was stirred at room temperature for 2 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol to give the title compound (26.7 mg).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CO.[Pd]>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CC1CCN(CCC=C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CO
Product: O=C(O)CC1CCN(CCCC(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 0.460 g. (1.37 mmole) of 1-(4,4-diphenyl-3-butenyl)-3-pyrrolidineacetic acid in 30 ml. of absolute ethanol was reduced, using 0.15 g. of 10% palladium-on-carbon, for 1.5 hours at ambient temperature. The mixture was filtered and concentrated. A portion of the oily residue and one equivalent of maleic acid were mixed in methanol and concentrated to yield a solid which was recrystallized from isopropanol/ether to give 1-(4,4-diphenylbutyl)-3-pyrrolidineacetic acid maleate, m.p. 85°-87° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH2:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=3)[N:12]=[CH:11][C:10]=2[F:21])[CH2:4][C@H:3]1[CH2:22][NH:23][CH2:35][C:32]1[CH:33]=[CH:34][C:28]2[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=2[N:31]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@H](F)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](F)C3)c2n1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
To a stirred solution of (±)-[(trans-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.25 g, 0.77 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.24 g, 1.15 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.23 g, 60%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.25 (d, J=9.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.25 (d, J=9.1 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.43 (s, 2H), 4.19 (s, 3H), 3.90 (m, 2H), 3.77 (m, 4H), 3.65 (m, 4H), 3.57 (m, 2H), 3.32 (app s, 2H). LC-MS (ES) m/e 501 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH2:13]([O:15]C(=O)COC1C([N+]([O-])=O)=NC(Br)=CC=1)C>C(O)(=O)C.CCOC(C)=O.[Fe]>[O:12]=[C:8]1[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([CH:13]=[O:15])=[N:11][C:10]=2[NH:9]1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 90 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of (6-bromo-2-nitro-pyridin-3-yloxy)-acetic acid ethyl ester (3.14 g, 10.3 mmol) in glacial acetic acid (12.4 mL) was added iron powder (1.67 g, 29.9 mmol). The suspension was heated to 90° C. and stirred for 6 h, after which it was cooled to RT and diluted with EtOAc (50 mL). The mixture was filtered through a pad of SiO2 and the filtrate was concentrated. Recrystallization from CH3OH provided 1.32 g (57%) of the title compound as a solid. MS (ESI): exact mass calculated for C7H5BrN2O2, 227.95; m/z found, 228.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.98 (d, J=5.3, 1H), 7.16-7.09 (m, 1H), 6.98 (dd, J=8.0, 4.9, 1H), 4.68 (d, J=1.4, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)N>C(O)(=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 150 °C
Yield: 70.1 %

Procedure:
A suspension of N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (500 mg, 2.24 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (564 mg, 2.24 mmol) in acetic acid (2.5 ml) was heated under microwave at 150° C. for 2 minutes. The crude mixture was diluted with diethyl ether and the precipitated solid was filtered, rinsed with ether and dried under vacuum to give the title compound as a white solid (675 mg, 70%); NMR spectrum: 3.79 (t, 2H), 4.31 (t, 2H), 5.26 (s, 2H), 7.18 (t, 1H), 7.25 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.49 (m, 1H), 7.57 (d, 1H), 7.87 (s, 1H), 8.27 (s, 1H), 8.47 (s, 1H); Mass Spectrum: 430 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([OH:27])=[O:26])[CH2:14]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH:30]([B-](F)(F)F)=[CH2:31].[K+].CCOC(C)=O.O>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:21]([O:20][C:18]([N:16]1[CH2:17][C@H:13]([O:12][C:9]2[C:10]3[C:5](=[CH:4][C:3]([O:28][CH3:29])=[C:2]([CH:30]=[CH2:31])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:14][C@H:15]1[C:25]([OH:27])=[O:26])=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: COc1cc2ccnc(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c2cc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)nccc2cc1OC
Temperature: 100 °C
Reaction time: 18 h

Procedure:
TEA (0.24 mL, 1.70 mmol) was added to a solution of (4R)-4-[(7-bromo-6-methoxyisoquinolin-1-yl)oxy]-1-(tert-butoxycarbonyl)-L-proline (560 mg, 1.13 mmol) in EtOH (30 mL). Potassium vinyltrifluoroborate (227 mg, 1.70 mmol) and PdCl2(dppf)-CH2Cl2 adduct (46 mg, 0.06 mmol) were then added, and the reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was worked up with EtOAc and water, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified on silica (40% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H)+=443.4.