Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:9][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1cnc(NS(=O)(=O)c2ccc(F)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred solution of 3,5-dimethylpyridin-2-amine (129 mg, 1.056 mmol) in pyridine (5 mL) at room temperature, was added 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand for 16 hours. Additional 4-fluorobenzene-1-sulfonyl chloride (205 mg, 1.056 mmol) was then added and the reaction stirred for an additional 4 hours. The reaction mixture was concentrated in vacuo and purified by passing through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. Concentration of the product-containing fractions provided the title compound (84.1 mg) as a yellow oil. LCMS (2 min, formic) Rt 0.89 min, m/z (ES+) 281 (M+H).
Reaction SMILES: [F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.N1C=CC=CC=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.O>C(Cl)Cl>[CH:36]1([C:39]([N:4]2[CH2:3][C:2]([F:1])([C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH2:16][C:15]([C:21]5[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=5)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=4)=[CH:8][CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CC1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of the 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 9, 94 mg) in 2 mL CH2Cl2 was added pyridine (0.05 mL) followed by cyclopropane carbonyl chloride (31 mg). The reaction was allowed to stir at room temperature for 1 hour. Water (10 mL) was added. The reaction was diluted with an additional 10 mL of CH2Cl2, stirred for 30 minutes at room temperature then passed through a phase separation tube. The CH2Cl2 layer was collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 20% EtOAc/hexane to 80% EtOAc/hexane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vac overnight resulted in formation of the product as a white foam (87 mg). 1H NMR (CDCl3) δ ppm 7.76 (d, 2H), 7.67 (s, 2H), 7.58 (d, 2H), 4.8-4.7 (m, 1H), 4.6-4.2 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5-1.4 (m, 1H), 1.08 (m, 2H), 0.86 (m, 2H). LC/MS retention time=3.710 minutes, MS calculated for (C23H17Cl3F4N2O2), 534.03; found 535.0 M+H.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[C:6]([OH:13])[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1.[H][H].[CH2:19]([O:21][C:22]1[C:23](=O)[C:24](=[O:29])[C:25]=1[O:26]CC)[CH3:20]>CO.O.[Pt]=O>[Cl:1][C:2]1[C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[C:6]([OH:13])[C:5]([NH:14][C:23]2[C:24](=[O:29])[C:25](=[O:26])[C:22]=2[O:21][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: O=[Pt]
Solvent: CO
Solvent: O
Product: CCOc1c(Nc2ccc(Cl)c(C(=O)N(C)C)c2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
A solution of 5.96 g (24.4 mmol, 1 eq) of 6-chloro-2-hydroxy-N,N-dimethyl-3-nitrobenzamide in 100 ml of methanol in the presence of 0.58 g of platinum oxide hydrate was stirred at hydrogen atmospheric pressure for 3 hours. The reaction medium was filtered through celite and the filtrate was concentrated. The solution obtained was added dropwise to 8.0 g (48.8 mmol, 2 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in solution in 50 ml of methanol. The reaction medium was stirred at ambient temperature for 18 hours. The solvent was evaporated off and the residue was chromatographed on silica gel (300 g prepacked column, eluent heptane/acetone, from 50 to 100% of acetone). 4.42 g of 6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of a beige solid. Yield=54%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(F)c4)nc23)CC1
Yield: 76.9 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.776 mMol) 3-fluorobenzoyl chloride, 0.100 gm (77.5%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [OH-].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][P:10]([OH:19])([O:12][CH:13]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])=[O:11].C(N(CC)CC)C.C1C(=O)N(O[C:35]([CH2:37][CH2:38][S:39][S:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])C(=O)C1>CS(C)=O>[OH-:9].[N:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:40][S:39][CH2:38][CH2:37][C:35]([C:13]([O:12][P:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH2:2])([OH:19])=[O:11])([N+:15]([CH3:17])([CH3:18])[CH3:16])[CH3:14])=[O:36]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: CC(OP(=O)(O)OCCCCCCN)[N+](C)(C)C
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(OP(=O)(O)OCCCCCCN)(C(=O)CCSSc1ccccn1)[N+](C)(C)C
Temperature: 25 °C

Procedure:
2-[(6-Aminohexoxyhydroxyphosphinyl)oxy-N,N,N-trimethylethanaminium hydroxide, inner salt (90 mg, 0.28 mmol) was dissolved in dry dimethyl sulphoxide (2 ml). Triethylamine (197 μl, 1.41 mmol) was added, followed by N-succinimidyl 3-(2-pyridyldithio)propionate (88 mg, 0.28 mmol). The mixture was stirred at ambient temperature for eighteen hours. The solvent was evaporated under vacuum at a temperature of 60° C. and re-evaporated from methanol. The residue was chromatographed on silica gel eluting with methanol. The relevant fractions were combined and evaporated to dryness to give 2[N(3-(2 pyridyldithio)propionyl)(6-aminohexoxyhydroxy
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:2][OH:3])=[O:27])=[CH:14][CH:13]=1
Reactant: NO
Reactant: COc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold stirring suspension of 1 gm hydroxylamine hydrochloride and 1.3 gm sodium carbonate in 25 ml CH2Cl2 was added dropwise 1.58 gms 9(4-methoxyphenyl)nonanoyl chloride over a period of 15 min. The mixture was then stirred in the cold for a further 45 min, then 1.5 ml H2O was added, the mixture was allowed to warm up to room temperature, and stirring was continued for 72 hrs. The precipitated solid was filtered, washed with water, and crystallized twice from CH2Cl2 to give A. The filtrate from the reaction mixture was evaporated in vacuo to give a granular solid which was also crystallized twice from CH2Cl2 to give B. A and B were shown to be the same by spectral comparison. Total yield (A+B)=1.58 gm (51%) m.p. 96°-98° C. Elemental analysis: calculated C 67.90, H 8.90, N 4.95. Found C 67.96, H 9.08, N 4.95 (calculated for 0.2 moles H2O).
Reaction SMILES: Br[CH2:2][C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[NH2:12][C:13]([NH2:15])=[S:14].C>O.C(O)C>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(=O)CBr
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
195 g of ethyl bromoacetylglyoxylate are added dropwise to a solution of 66 g of thiourea in 450 ml of water and 450 ml of ethanol at 5° and after the addition has ended, the mixture is stirred at room temperature for 30 minutes and at 50° for 30 minutes and, after adding active charcoal, the resulting reaction mixture is then filtered. The filtrate is brought to pH 7 by adding sodium bicarbonate solution, whereupon ethyl 2-amino-thiazol-4-ylglyoxylate crystallizes out in crystals of melting point 147°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[CH2:22]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH3:18])[C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4
Reactant: C=Cc1ccccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C2CCCN(C1)C2

Procedure:
The coupling of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (226.0 mg, 0.999 mmol; Example 201) and 2-methylstyrene (209.0 mg, 176.9 mmol, Alfa Aesar) was performed as described in Example 202, except that the material was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.09-1.17 (m, 1H), 1.29-1.47 (m, 2H), 1.65-1.74 (m, 1H), 1.97 (s, 3H), 2.18-2.24 (m, 1H), 2.42 (s, 3H), 2.60-2.65 (m, 1H), 2.94-3.08 (m, 5H), 3.81 (d, J=16.3 Hz, 1H), 4.05-4.15 (m, 1H), 4.23 (d, J=16.3 Hz, 1H), 4.36-4.45 (m, 1H), 6.78 (d, J=7.1 Hz, 1H), 6.95-7.06 (m, 4H), 7.16-7.18 (m, 1H), 7.27 (d, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH2:36]Cl.CC#N.O>C(O)=O>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH2:36][N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:13]=2[N:12]=[C:11]1[C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: ClCc1n[nH]c2ccc(Cl)cc12
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2n[nH]c3ccc(Cl)cc23)CC1

Procedure:
1-(5-Chloro-1H-indazol-3-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 200 mg (0.58 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 116.8 mg (0.58 mmol) 5-chloro-3-chloromethyl-1H-indazole. Hydrolysis of the resulting ester and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[C:8]([CH3:16])[CH:9]=1)(=[O:15])[CH3:14]
Reactant: CS(N)(=O)=O
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A test tube for microwave was charged with tris(dibenzylidenacetone)dipalladium (0) chloroform adduct (205 mg, 0.20 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine] (345 mg, 0.60 mmol), 4-acetyl-2-methylphenyl trifluoromethanesulfonate (1.41 g, 5.0 mmol), methanesulfonamide (570 mg, 6.0 mmol), cesium carbonate (1.63 g, 7.0 mmol) and 1,4-dioxane (5 ml). The mixture was subjected to microwave irradiation at 120° C. with stirring for 10 minutes. Then, it was filterd off and the filtrate was concentrated under reduced pressure to furnish the crude residue which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane:ethyl acetate (2/1) to give 390 mg (34% yield) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)\[CH3:10])=[CH:4][CH:3]=1.[P:25]([O:32][CH2:33][CH3:34])([O:29]CC)[O:26][CH2:27][CH3:28].C(Br)C>[Ni](Br)Br>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:32][CH2:33][CH3:34])=[CH:7][CH:6]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: CCOP(OCC)OCC
Reactant: C/C(=C\c1ccc(Br)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Br[Ni]Br
Solvent: CCBr
Product: CCOP(=O)(OCC)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
20 g (52 millimoles) of (E)-1-(4-bromophenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propene and 0.86 g (7.5 mol %) of anhydrous nickel(II) bromide were heated to about 160° C. under nitrogen in a distillation apparatus equipped with a dropping funnel. 104 g (60 millimoles) of triethyl phosphite were then added dropwise in such a way that the rate of dropwise addition corresponded to the rate at which the ethyl bromide distilled off. Stirring was continued for 0.5 hour, after which the mixture was cooled, a little toluene was added and the mixture was evaporated down. The residue was filtered with ethyl acetate over silica gel. 14.2 g (62%) of the title compound of melting point 72.5°-73.5° C. (from heptane) were obtained in this manner. Preparation of 1-(bromophenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propene
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12
Reactant: Cc1cc2ncc(C#N)c(Cl)c2s1
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(C)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (507 mg, 2.64 mmol) and 60% sodium hydride (105.6 mg, 2.64 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-methylthieno[3,2-b]pyridine-6-carbonitrile (275.3 mg, 1.32 mmol) is added. The reaction mixture is heated at reflux for 6 hours, cooled to room temperature and partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane followed by preparative thin layer chromatography developing with 20% ethyl acetate in dichloromethane, to provide 108 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 213–214° C.; 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 3.85 (s, 3H), 7.20 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H); MS 362.1, 364.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.N1CCOCC1.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: COCC(C)O
Solvent: O
Solvent: C1COCCN1
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 112.5 °C
Reaction time: 1.75 h
Yield: 88.8 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and morpholine (1.3 g, 14.9 mmol, 1.16 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of morpholine (9.6 g, 110.2 mmol, 8.54 equiv) and 1-methoxy-2-propanol (0.8 g) and the solution added in portions to the Thebaine mixture over 1 h 10 min while maintaining the batch temperature in the range 110 to 115° C. The reaction mixture is held at 110 to 114° C. for 1.75 h then cooled to less than 20° C. and water (24 g) added. The resulting slurry (pH 9.7) is stirred and further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.59 g, 89.1% yield; 98.7 area % purity by HPLC).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3=[N:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:17]=[C:12]3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH3:23].N12CCCN=C1CCCCC2>C(O)CCC>[CH3:22][C:23]1[O:19][C:18]([C:15]2[N:14]=[C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][O:11][C:12]3=[CH:17][CH:16]=2)=[N:20][N:21]=1
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)nc23)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCO
Product: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 68.2 %

Procedure:
A solution of 3-[4-(methylthio)phenyl]furo[3,2-b]pyridine-5-carbohydrazide (0.20 g, 0.68 mmol) and triethyl orthoacetate (0.27 mL, 1.49 mmol) in n-butanol (5 mL) was heated under reflux for 1.5 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.68 mmol) was added to the reaction mixture, and the mixture was further heated under reflux overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.15 g, yield 67%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[CH:9][CH:10]=O.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>CO>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]\[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:23].[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]/[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:23]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccccc1F)c1ccccc1F
Solvent: CO
Product: CCOC(=O)/C=C/C=C(c1ccccc1F)c1ccccc1F
Product: CCOC(=O)/C=C\C=C(c1ccccc1F)c1ccccc1F

Procedure:
As described in Example 99, 3,3-bis(2-fluorophenyl)-2-propenal (1.85 g) was reacted with (carbethoxymethylene)triphenylphosphorane (2.8 g) in methanol. The mixture of esters obtained from the usual work up was separated by HPLC (dichloromethane-hexane; 1:2) to yield 0.4 g of (Z)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid ethyl ester as an oil and 1.7 g of (E)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid ethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][NH:21][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was added methylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of ACOH. The solution was allowed to stir at RT for 1 h followed by the addition of sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resulting mixture was stirred at RT for 16 h and quenched with MeOH. After stirring for 30 min the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel by eluting with EtOAc/MeOH to give 0.62 g (60%) of tert-butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.47 (bs, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)+.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH2:5]([Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[ClH:12].[CH2:5]([S:3][C:1](=[NH:4])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: CC(N)=S
Solvent: ClC(Cl)Cl
Product: CC(=N)SCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of thioacetamide (15.0 g, 0.20 mol) and benzyl chloride (25.3 g, 0.20 mol) in chloroform (75 ml) was heated under reflux for 90 minutes (the thioacetamide required ~40 minutes to go into solution). The reaction mixture was then allowed to cool to room temperature and was then stood at 0° C. overnight, when colourless crystals formed as a layer on the surface. The product was filtered off, washed with cold 10% ether-chloroform and sucked dry to give the title compound (25.55 g) as colourless prisms. Mpt.=161°-163° C.
Reaction SMILES: CC(S(/[N:7]=[CH:8]/[C:9]1[O:13][CH:12]=[N:11][CH:10]=1)=O)(C)C.[Cl:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[Cl:21].[NH4+].[Cl-].Cl.O1CCOCC1>CCOCC.C1(C)C=CC=CC=1>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([CH:8]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)[NH2:7])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(C)(C)S(=O)/N=C/c1cnco1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A dried-flask was charged with 20 (1.211 g, 6.047 mmol) and toluene (5 mL) was added. The reaction was cooled to −78° C. and (3,4-dichlorophenyl)magnesium bromide (18.14 mL, 9.071 mmol, 0.5 M in THF) was added. The reaction was warmed to −10° C. for 15 min. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered, and concentrated. The resulting residue was dissolved in DCM (10 mL) then 4 N HCl in dioxane (15.12 mL, 60.47 mmol) was added and the solution was stirred for 30 min. The reaction mixture was added dropwise to a stirred solution of ether. The resulting solid was filtered and washed with ether to afford (3,4-dichlorophenyl)(oxazol-5-yl)methanamine hydrochloride (22, 1.24 g, 4.436 mmol, 73.35% yield).