Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(N(CC)CC)C>CC(N(C)C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]#[C:22][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 4-(5-iodopyridin-2-yl)piperazine-1-carboxylate (4.087 g, 10.5 mmol) in DMA (75 mL) at RT was added 2-ethynylpyridine, (CAS number 1945-84-2, 1.17 mL, 11.5 mmol), triethylamine (4.4 mL, 31.5 mmol), CuI (800 mg, 4.2 mmol) and Pd(PPh3)4 (1.21 g, 1.05 mmol). After stirring for 30 minutes, the DMA was removed in vacuo, and the residue diluted with EtOAc (100 mL). The dark solution was then washed with water (100 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×50 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 50% EtOAc in hexanes) to give tert-butyl 4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine-1-carboxylate as a brown oil (3.8 g, 10.5 mmol, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@@H:14]([CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:25])[CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Yield: 108 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-[(4-cyano-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 10) (2.88 g, 7.59 mmol) and TFA (10 ml, 130 mmol) in dry DCM (10 ml) was stirred at room temperature for 1 hour, then concentrated in vacuo, azeotroping with toluene (25 ml) to give a brown oil. This was partitioned between DCM (50 ml) and saturated aqueous NaHCO3 (50 ml), then the aqueous layer was extracted with DCM (50 ml). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to give the title compound as a yellow oil (2.29 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22].O>CN(C=O)C>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 4-nitro-1H-pyrazole (Example 4-1d) (3.8 g, 34 mmol) in DMF (80 mL) cooled to 0° C., via an ice/water bath, was added t-BuOK (4.2 g, 38 mmol). After addition of the base the ice bath was removed and the mixture was stirred for 30 minutes followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (5 g, 34 mmol). The reaction was refluxed for 16 hours then cooled to ambient temperature. H2O was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was washed with additional H2O then dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (5.8 g, 78%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:15])=[CH:11][CH:10]=1)(=O)C.[CH3:30]O>>[CH3:30][O:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:16][C:14]([CH2:13][C:12]1[CH:28]=[CH:29][C:9]([OH:8])=[CH:10][CH:11]=1)=[S:15]
Reactant: CC(=O)Oc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 Ml of thionyl chloride was dropwise added to 100 ml of anhydrous methanol at a temperature below -10° C. To the mixture was added 6 g (0.016 mol) of N-(4-acetoxybenzylthiocarbonyl)-L-phenylalanine synthesized according to Example 3. After the mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure to obtain crude crystal. Further, the crude crystal was recrystallized from 30 ml ethyl acetate and 100 ml of n-hexane to obtain 5.1 g of white purified crystal.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](C3C=CC=CC=3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:27]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([O:11][C:8]3[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=3)=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[C:3]([OH:2])=[O:28]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1
Yield: 136.8 %

Procedure:
A mixture of 4-[[2-[4-(1,1'-biphenyl)oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.8 g) in methanol (20 mL) and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl etherhexane to give 0.55 g of colorless alpha-oxo-4-[[2-(4-phenoxyphenoxy)ethyl]oxy]benzeneacetic acid, mp 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[CH3:36])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[CH3:36])[CH2:23][CH2:22]1)=[O:8]
Reactant: COC(=O)c1ccc(Cl)c(OCC(=O)O)c1
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Product: COC(=O)c1ccc(Cl)c(OCC(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3C)CC2)c1

Procedure:
Prepared as for Example 15 Step 2 using [2-Chloro-5-(methoxycarbonyl)-phenoxy]acetic acid and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a colourless oil (0.084 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Cl:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Cl:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Reactant: CC(Cl)c1ncnc(Cl)c1I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g), then, 4-chloro-6-(1-chloroethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1.CCCCC>[CH:1]1([C:4]([O:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCCCCCCCO
Solvent: CCCCC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2.25 g. of cyclopropane carboxylic acid chloride in dry benzene, under nitrogen, is added 8 g. of 1-dodecanol. The mixture is stirred overnight and then diluted with pentane. The reaction mixture is worked up by washing with water and brine and then removing the solvent to yield dodecyl cyclopropanecarboxylate, b.p. 99°-100° (bath) at 0.03 mm. (I; p" is zero, R is n-dodecyl).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:10][C:3]=12
Reactant: COc1ccc(-c2cc3nccc(Cl)c3s2)cn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 170 °C
Yield: 43 %

Procedure:
A suspension of 418 (0.638 g, 2.31 mmol), 2-fluoro-4-nitrophenol (0.725 g, 4.61 mmol) and potassium carbonate (0.638 g, 4.61 mmol) in diphenyl ether (6 mL) was heated to 170° C. for 8 h in a pressure tube. The resulting dark solution was cooled to room temperature, diluted with CH2Cl2 and then filtered. The filtrate was concentrated and the residue was purified by flash chromatography (eluent 100% hexanes to 50/50 ethyl acetate/hexanes) to produce title compound 419 as a yellow solid (0.395 g, 43% yield). MS (m/z): 398.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[OH:20])=[N:7][CH:8]=[N:9]2)=[C:4]([F:21])[CH:3]=1.[CH2:22]([O:24][C:25](=[O:29])[C@@H:26](O)[CH3:27])[CH3:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:20][C@H:26]([CH3:27])[C:25]([O:24][CH2:22][CH3:23])=[O:29])=[N:7][CH:8]=[N:9]2)=[C:4]([F:21])[CH:3]=1
Reactant: Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12
Reactant: CCOC(=O)[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12

Procedure:
To a mixture of 28 g (79.5 mmol) 2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenol, 9.4 g (79.5 mmol) (S)-2-Hydroxy-propionic acid ethyl ester, 25.1 g (95.6 mmol) PPh3 and THF 22 g (95.4 mmol) di-tert-butyl azodicarboxylate are added and the mixture stirred over night. The solvent is evaporated and isopropanol is added, the precipitate is filtered off and dried furnishing ethyl (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH:3]=1.NC1C(OC)=C2C(C3C=C(C)C=NC=3N2)=C(C2C=C(N[C:54]([CH:56]3[CH2:58][CH2:57]3)=[O:55])C=CC=2)C=1>>[CH:56]1([C:54]([NH:1][C:2]2[C:10]([O:11][CH3:12])=[C:9]3[C:5]([C:6]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=4[NH:8]3)=[C:4]([C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])[CH:3]=2)=[O:55])[CH2:58][CH2:57]1
Reactant: COc1c(N)cc(-c2cccc(NC(=O)C3CC3)c2)c2c1[nH]c1ncc(C)cc12
Reactant: COc1c(N)cc(-c2cccc(C(=O)NC3CC3)c2)c2c1[nH]c1ncc(C)cc12
Product: COc1c(NC(=O)C2CC2)cc(-c2cccc(C(=O)NC3CC3)c2)c2c1[nH]c1ncc(C)cc12

Procedure:
The title compound was prepared from Compound 244 by using an analogous procedure to that outlined in the preparation of Compound 241. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.55 (m, 2H) 0.68 (m, 2H) 0.81 (br. m, 4H) 2.17 (m, 1H) 2.23 (s, 3H) 2.87 (m, 1H) 3.94 (s, 3H) 7.40 (s, 1H) 7.63 (t, J=7.71 Hz, 1H) 7.72-7.71 (m, 2H) 7.94 (d, J=7.58 Hz, 1H) 8.01 (s, 1H) 8.21 (d, J=1.77 Hz, 1H) 8.54 (d, J=4.04 Hz, 1H) 9.84 (s, 1H) 12.00 (s, 1H); [M+H] calc'd for C27H27N4O3, 455.2; found, 455.4.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([C:34]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][C:42]=2[NH2:43])=[O:35])=[CH:32][CH:31]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:21]=[CH:20][C:16]=2[C:17]([NH:43][C:42]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[NH:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=2)=[O:19])[CH2:10][CH2:9]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(C(=O)Nc2cnccc2N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 101-D, 2-(N-Boc-piperidine-4-yloxy)-4-(tert-butyl)benzoic acid (1.0 g, 2.65 mmol) is converted into the acid chloride and used to acylate N3-(4-methoxybenzoyl)-3,4-pyridinediamine (600 mg, 2.47 mmol). After purification by chromatography (SiO2: 30% to 50% EtOAc in chloroform) 589 mg (40%) of the title compound is obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(OCC)C.[OH-].[Na+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>O>[OH:4][N:3]([CH3:2])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)=[O:22]
Reactant: CSc1ccc(N=C=O)cc1
Reactant: CNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(NC(=O)N(C)O)cc1
Yield: 59.8 %

Procedure:
N-Methylhydroxylamine hydrochloride (1.1 g, 13 mmol) was dissolved in water (2 mL) then combined with diethyl ether (15 mL). The mixture was cooled in an ice bath then combined with a solution of sodium hydroxide (0.53 g, 13 mmol) in water (2 mL). The reaction mixture was allowed to stir for several minutes then 4-(methylthio)phenyl isocyanate (2.1 g, 13 mmol) was added dropwise via Pasteur pipette. A heavy white precipitate formed almost immediately. Diethyl ether (20 mL) was added and the reaction mixture was allowed to stir at ambient temperature overnight. The solid was isolated by filtration then recrystallized from 1,2-dichloroethane to afford 1.65 g of the desired product as a white crystalline solid, m.p. 146°-148° C. Analysis: Calculated for C9H12N2O2S: %C, 50.93; %H, 5.70; %N, 13.20; Found: %C, 50.82; %H, 5.63; %N, 13.11.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](=[N:19]O)[NH2:18]>>[Br:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[N:19]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][N:18]=1
Reactant: NC(=NO)c1sccc1Br
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Clc1ccc(-c2nc(-c3sccc3Br)no2)cc1

Procedure:
The title compound was prepared from 4-chloro-benzoyl chloride (60 μL, 0.47 mmol) and 3-bromo-thiophene-2-amidoxime (102 mg, 0.461 mmol) similar to Example 36c, and yielded 80 mg (51%) of white solid. 1H NMR (CDCl3): 8.15 (dd, J=9.09, 2.06 Hz, 2H), 7.54 (dd, J=8.51, 2.20 Hz, 2H), 7.50 (d, J=5.22 Hz, 1H), 7.18 (d, J=5.22 Hz, 1H).
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[Br:29][C:30]1[C:39]([C@H:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:41][OH:42])=[C:38]([CH3:48])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH3:49])=[N:35]2>>[Br:29][C:30]1[C:39]([C@H:40]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:41]([OH:5])=[O:42])=[C:38]([CH3:48])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH3:49])=[N:35]2
Reactant: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Product: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
Compound 5G was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol (5F) was used instead of compound 1K. LCMS-ESI+ (m/z): 366.1, 368.1 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:5])[CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>ClCCl>[C@H:2]([NH:5][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][Cl:13])[CH:16]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC[C@@H](C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)NC(=O)c1cccc(CCl)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of (R)-butan-2-amine (14.77 mmol, 1.478 mL, 1,081 g) and triethylamine (15.48 mmol, 2.157 mL, 1.566 g) in dichloromethane was added dropwise to a stirred solution of 3-(chloromethyl)benzoyl chloride (14.07 mmol, 2 mL, 2.66 g) in dichloromethane at room temperature. Upon complete addition the reaction was stirred for 2 hours, after which time the solvent was removed under vacuum and ethyl acetate (100 mL) added. The organic solution was then washed with water (200 mL), dried over sodium sulphate and concentrated under vacuum to give the title compound (2.47 g) as a cream solid. MS (ESI) m/z 226.3[M+H]+
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1>C(O)(=O)C.CO.[Pt](=O)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccnc(Cc2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)cc2)C1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
Methyl 2-(4-(trifluoromethyl)benzyl)isonicotinate (11.5 g, 38.95 mmol) was dissolved in acetic acid (200 mL) and methanol (100 mL). Platinum(IV) oxide (0.177 g, 0.78 mmol) was added and the mixture hydrogenated in a Büchi hydrogenator at room temperature and 7 bar for 6 h. The catalyst was filtered off. Fresh platinum(IV) oxide (0.18 g, 0.78 mmol) was added and hydrogenation continued at 9 bar for 7 h. The catalyst was filtered off, the solvent was evaporated and the residue partitioned between ethyl acetate and Na2CO3 (aq). The organic layer was dried over MgSO4, filtered through celite and the solvent evaporated. Methyl 2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (9.5 g, 81%) was isolated.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:37])[NH:30][C:31]3[C:36]\2=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>ClCCl>[ClH:44].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20]/[C:21](=[C:28]2\[C:29](=[O:37])[NH:30][C:31]3[C:36]\2=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and ethyl acetate/hydrogen chloride in dichloromethane.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=O)=[CH:10]2)(=[O:5])=[O:4].C[O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:1][C:2]([F:20])([F:19])[S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([OH:31])=[O:22])=[CH:25][CH:26]=1)=[O:18])=[CH:10]2)(=[O:4])=[O:5]
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2[nH]1
Reactant: COC(=O)c1ccc(N)cc1
Product: O=C(O)c1ccc(NC(=O)c2cc3cc(NS(=O)(=O)C(F)(F)F)ccc3[nH]2)cc1

Procedure:
Same procedure as Example 82 except 5-Trifluoromethansulfonylamino-1H-Indole-2-Carboxylic Acid and 4-aminobenzoic methyl ester was used. 1H-NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H, COOH), 11.99 (d, J=1.2 Hz, 1H, NHCO), 11.61 (s, 1H, SNH), 10.54 (s, 1H, NH-1), 7.95 (m, 4H, ArH), 7.61 (d, J=2.1 Hz, 1H H-4), 7.50 (m, 2H, H-7 & H-3), 7.14 (dd, J=2, 9 Hz, 1H, H-6), MS m/z 426 (M−H).
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:36])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 111.1 %

Procedure:
A solution of (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (263 mg, 720 μmol) in dioxane (24.0 ml) was treated at room temperature with Lawesson's reagent (233 mg, 576 μmol). The reaction mixture was stirred at 80° C. for 4 hours. For the workup, the reaction mixture was poured on a saturated solution of sodium hydrogencarbonate then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and evaporated at reduced pressure to give brown oil. This residue was purified by chromatography on silica gel using a gradient of heptane/dichloromethane=100:0 to 20:80. The (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepane-3-thione (244 mg, 89% yield) was obtained as a white foam. MS (ISP): m/z=382.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:21])[C:6]2[CH2:7][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][CH2:10][C:11]=2[CH:12]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:21][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]3[C:6]=2[CH2:7][CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10]3)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)cc(O)c3C2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.7 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1998, 39 (19), 2937-2940. To a solution of 3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-ol (853 mg) and 4-benzyloxyphenylboronic acid (1.4 g) in dichloromethane (30 ml) were sequentially added copper(II) acetate (545 mg), molecular sieves 4A and triethylamine (1.5 g), and the solution was stirred for 8 hours and 40 minutes at room temperature. The insoluble material was filtered through celite pad, the filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.2 g).