Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].C([Li])CCC>O1CCCC1>[CH:1]1([CH2:6][C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([N:37]2[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]2=[O:41])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 38, 5.00 g, 17.4 mmol) in tetrahydrofuran (150 mL) cooled to −78° C. was treated with triethylamine (2.77 mL, 19.9 mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol). The resulting white slurry was stirred at −78° C. for 15 min and then at 0° C. for 45 min. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in tetrahydrofuran (80 mL) cooled to −78° C. was treated with a 2.0M solution of n-butyllithium in hexanes (8.7 mL, 17.4 mmol). The solution was stirred at −78° C. for 10 min and then allowed to warm to 25° C. where it was stirred for an additional 10 min. At this time, the first reaction mixture was recooled to −78° C. The second reaction mixture was added to the first reaction mixture over a period of 5 min via cannula. The combined reaction was then stirred at −78° C. for 15 min and then allowed to warm to 25° C. where it was stirred for an additional 1.5 h. At this time, the reaction was quenched by the addition of a saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded (1) 3-[3-cyclopentyl-2(S)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (2.15 g, 33%) as a clear oil: [α]23589=+87.5° (c=0.160, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3 (M+) 397.1211, found 397.1215 and (2) 3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 28%) as a white solid: mp 71.9-74.6° C.; [α]23589=−27.6° (c=0.188, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3 (M+) 397.1211, found 397.1212.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[N+:25]([C:24]1[CH:23]=[CH:22][N+:21]([O-:28])=[CH:20][C:19]=1[O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)([O-:27])=[O:26]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol in 50 ml of DMF was added Na2CO3 (10 g) portionwise and this mixture was stirred for 15 minutes at room temperature. A solution of 3-fluoro-4-nitropyridine-N-oxide in 50 ml DMF was added dropwise and the reaction was allowed to proceed for four hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat NaCl, anhy MgSO4).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[N:3]=1.[NH4+].[Cl-]>C1COCC1.CCO.O.[Fe]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:10]3[C:2]([I:1])=[N:3]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cc1
Temperature: 50 °C
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (28) (4.29 g, 8.7 mmol) in THF/EtOH/H2O (40 mL/20 mL/10 mL) was added Fe powder (2.43 g, 43.45 mmol) and NH4Cl (4.65 g, 86.9 mmol). The resulting mixture was purged with N2 before heated to 50° C. for 2 h. The mixture was cooled and filtered through a Celite pad. The solvents were evaporated and the residue was separated in DCM and water. The aqueous layer was extracted with DCM (×4). The combined organic layers were dried over Na2SO4. Solvent was removed under vacuum and purified by flash chromatography (0-60% EA in PE with 0.5% TEA) to provide tert-butyl 1-(4-aminophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (29) (3.4 g, 86%) as a yellow solid. LC-MS (ESI): m/z (M+1) 453.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[NH:6]2.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[N:6]2[CH3:21]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CCOC(=O)c1nc2ccc(OC)cc2n(C)c1=O

Procedure:
3,4-Dihydro-6-methoxy-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1.9 g), methyl iodide (2 ml) and anhydrous potassium carbonate (6 g) in 2-butanone (100 ml) were stirred and heated under reflux for 1.5 hours. The solid was filtered off and the filtrate was evaporated. The residue was crystallised from aqueous methanol, m.p. 166° (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=4)(=[O:36])=[O:35])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: CCC1(CC)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B7) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6](=[S:16])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59](O)=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6]([NH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[S:16])=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=S)NCCc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of #23 (337 mg, 0.983 mmol, 1 eq.) in dichloromethane (8 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #8 (564 mg, 0.885 mmol, 0.9 eq.), diisopropylethylamine (383 mg, 2.95 mmol, 3 eq.) and HATU (472 mg, 1.18 mmol, 1.2 eq.). After 2 hours, the mixture was diluted with dichloromethane, washed sequentially with 0.1 M aqueous hydrochloric acid and with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (Method G) to give #35 (600 mg, 66%); LC-MS: m/z 926.6 [M+H+], retention time=1.16 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [9.94 (br t, J=5 Hz) and 10.16-10.23 (br m), total 1H], 7.90 (d, J=7.2 Hz, 2H), [7.71 (br d, J=7 Hz) and 8.06 (br d, J=8 Hz), total 1H], 7.60-7.65 (m, 2H), 7.41 (br dd, J=7, 7 Hz, 2H), 7.15-7.36 (m, 7H), 3.29 (s, 3H), 1.16-1.22 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1>CN(C)C=O.C(OCC)(=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-1H-purin-6-amine trifluoroacetic acid salt (2.89 g) in dry N,N-dimethylformamide (32 ml) under nitrogen and at room temperature, was added potassium carbonate (4.41 g) in one go. The reaction was heated to 60° C. and stirred for 90 minutes. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (1.869 g) in dry DMF (3 ml) was then added gradually via pipette. The reaction was heated to 70° C. and left to stir overnight. Still 22% starting material present by LCMS, therefore increased temperature to 90° C. and stirred for a further 3 hours at this temperature. The reaction was cooled and diluted with ethyl acetate (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was concentrated in vacuo to yield an orange oil. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-60%) to afford the title compound as an orange viscous oil (1.45 g).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[F:44][C:45]1[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])=[CH:52][CH:51]=[CH:50][C:46]=1[C:47]([OH:49])=O.[CH:60]12[CH2:66][CH:63]([CH2:64][CH2:65]1)[CH2:62][CH:61]2[NH:67][C:68](=[O:83])[C@H:69]([CH3:82])[CH2:70][C@H:71]([OH:81])[C@@H:72]([NH2:80])[CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>>[CH2:73]([C@H:72]([NH:80][C:47](=[O:49])[C:46]1[CH:50]=[CH:51][CH:52]=[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])[C:45]=1[F:44])[C@@H:71]([OH:81])[CH2:70][C@H:69]([C:68](=[O:83])[NH:67][CH:61]1[CH2:62][CH:63]2[CH2:66][CH:60]1[CH2:65][CH2:64]2)[CH3:82])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cccc(N2CCCC2=O)c1F
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(N2CCCC2=O)c1F)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 2-fluoro-3-(2-oxopyrrolidin-1-yl)benzoic acid (D27) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([C:7](=[O:27])[C:8](=[CH:23]OCC)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5]1.C([O-])(=O)C.[Na+]>C(O)C>[CH:4]1([C:7]2[O:27][N:2]=[CH:23][C:8]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[CH3:6][CH2:5][CH2:4][CH2:7][CH2:8][CH3:9]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCC
Product: O=C(c1ccc(S(F)(F)(F)(F)F)cc1)c1cnoc1C1CC1

Procedure:
Hydroxylamine hydrochloride (0.42 g) was added to a stirred solution of 3-cyclopropyl-2-ethoxymethylene-1-(4-pentafluorosulphanyl- phenyl)-propan-1,3-dione (0.97 g) in ethanol. Anhydrous sodium acetate (0.49 g) was then added and stirring maintained for 1 hour. The solvent was evaporated and the residue distributed between dichloromethane and water. The organic phase was dried (magnesium sulphate) and evaporated, and the residual oil purified by chromatography eluting with ethyl acetate/hexane to give after trituration with hexane 5-cyclopropyl-4-(4-pentafluorosulphanyl- benzoyl)isoxazole (Compound 1) as a white solid, m.p.57-58° C. Further elution gave, after trituration with hexane, 4-cyclopropylcarbonyl- 5-(4-pentafluorosulphanylphenyl)isoxazole (Compound 2) as a white solid, m.p.53-55° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[C:45]([CH3:49])[N:46]=[N:47][CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:44]=[C:45]([CH3:49])[N:46]=[N:47][CH:48]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cnn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnnc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-(4-chloro-3,5-dimethyl-phenyl)-3-methyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.09 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH2:26]Br)[N:22]=[N:21][N:20]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[CH3:32][NH:33][CH3:34]>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:23]([CH2:24][CH2:25][CH2:26][N:33]([CH3:34])[CH3:32])[N:22]=[N:21][N:20]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CCCc1c(COc2ccc(Cc3nnnn3CCCBr)cc2)ccc(C(C)=O)c1O
Solvent: CC#N
Product: CCCc1c(COc2ccc(Cc3nnnn3CCCN(C)C)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-1-(3-bromopropyl)-1H-tetrazole (2.0 g, 0.004 mol) was added to acetonitrile (40 ml). Dimethylamine (large excess) was cooled in the unopened reagent bottle then added to the acetonitrile solution. The mixture was cooled and stirred at 0° C. for 5 hours then concentrated in vacuo. Water was added to the concentrate and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted isocratically with a mixture of 9.5:0.5% methylene chloride:methanol plus 0.5% diethylamine added) to yield 1.4 g, 77.8% yield of the title product as a yellow oil; n.m.r. (300 MHz, CDCl3) δ: 1.0 (t, 3H); 1.6 (m, 2H); 1.9 (m, 2H); 2.1 (s, 6H; m, 2H); 2.6 (s, 3H); 2.65 (t, 2H); 4.2 (t, 2H); 4.3 (s, 2H); 5.1 (s, 2H); 6.9 (d, 2H); 7.0 (d, 1H); 7.15 (d, 2H); 7.6 (d, 1H); 12.7 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5][CH:4]=[C:3]([NH2:9])[CH:2]=1.Cl[C:11]1C=C[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[CH2:20](O)[CH3:21]>>[C:7]([C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH:21]=[CH:20][C:13]([NH2:14])=[C:12]([N+:17]([O-:19])=[O:18])[CH2:11]2)=[CH:2][CH:1]=1)#[N:8]
Reactant: CCO
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the method of J. C. S. Perkin Trans. I, 1979, 135, P-cyanoaniline (6.894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, 58.4 mmol) in ethanol (200 ml) and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered. The solid was treated with 150 ml of boiling ethanol, cooled in ice, and filtered to give N-(4-cyanophenyl)-4-amino-3-nitropyridine, 12.15 g, as a bright yellow powder, m.p. 210°-211° C.
Reaction SMILES: [C:1]([OH:4])(=O)C.C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH:1]([N:9]([CH2:10][C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1)[CH3:8])=[O:4]
Reactant: CC(=O)O
Reactant: CNCc1csc2cncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=CO
Product: CN(C=O)Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
A mixed solution of 0.25 ml of anhydrous acetic acid and 0.50 ml of formic acid which had been beforehand reacted with each other at 50° C. for 5 minutes was added to 6 ml of a dichloromethane solution containing 294 mg of 3-(N-methylamino)methylimidazo[5,1-b]thiazole under ice-cooling, followed by stirring at the same temperature for 30 minutes. Then, water was added to the reaction solution, and the solution was then alkalified with anhydrous potassium carbonate under stirring, followed by extraction three times with dichloromethane. The organic layer was dried over anhydrous potassium carbonate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 174 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28].C1CCN2C(=NCCC2)CC1.C1C[O:50][CH2:49]C1>C(OC(=O)C)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:49]([NH:33][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[O:50])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: C1CCOC1
Reactant: CCN(CC)CCCN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 150 °C

Procedure:
A suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (100 mg, 0.22 mmol), Mo(CO)6 (58 mg), Hermann's palladacycle (trans-Di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II), 31 mg), and N,N-diethyl-1,3-propanediamine (58 mg) in THF (2.0 mL) in a 10 mL microwave vial was treated with DBU (0.02 mL, 0.5 equiv) and immediately sealed. The whole was heated in a microwave at 150° C. for 25 min, cooled to room temperature and diluted with ethylacetate. The crude suspension was filtered through celite and the eluent concentrated to give a residue that was purified by flash column chromatography (1-10% methanol in dichloromethane) to give 103 as a colorless solid. MS: (ESI+)=526.2. 1H NMR (DMSO-d6) δ 8.53 (m, 1H), 7.66 (m, 2H), 7.55-7.44 (m, 4H), 6.55 (m, 1H), 4.20 (m, 2H), ca. 3.2 (m, 2H, obstructed by water), 3.24 (s, 3H, obstructed by water), 2.97 (m, 2H), 2.67-2.56 (m, 6H), 1.69 (m, 2H), 0.99 (m, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)[C:15]([NH:17][NH2:18])=[O:16]
Reactant: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-{[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]carbonyl}hydrazinecarboxylate (8.00 g) in ethyl acetate (50 mL) was added hydrogen chloride (4-Methyl acetate solution, 100 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration. The solid was recrystallized from methanol/ethyl acetate to give the title compound (5.94 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH-:14].[Ba+2].[OH-].[CH2:17]=O>>[OH:14][CH2:17][NH:11][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=O
Reactant: CCCOc1ccc(C(N)=O)cc1
Agent: [Ba+2]
Product: CCCOc1ccc(C(=O)NCO)cc1
Reaction time: 48 h

Procedure:
4-Propoxybenzamide, 2.02 g of barium hydroxide and 90 ml of 35% aqueous formaldehyde were heated to 80° C. When the solution had become almost transparent, it was filtrated hot. This solution was stored at 0° C. for two days, and 100 ml of water was added. The precipitated crystals were collected and dried, to give 17.0 g of the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1(Cl)[CH2:11][C:10]1([CH3:13])[CH3:12].Cl>>[Cl:8][C:9]1[CH2:11][CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:12][C:10]=1[CH3:13])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CC1(C)CC1(Cl)Cl
Agent: Cl
Product: CC1=C(Cl)CC2C(=O)OC(=O)C2C1
Yield: 13.6 %

Procedure:
To a glass tube was added maleic anhydride (73.3 mg., 0.75 mmole) and 1,1-dichloro-2,2-dimethylcyclopropane (119.3 mg., 0.86 mmole). The tube was sealed and heated at 165°-170°C. for 6-8 hours. The tube was allowed to cool and was opened (caution HCl pressure). The initially liquid product mixture crystallized with vigorous evolution of hydrogen chloride. Extraction of the crude solid (m.p. 60°-70°C.) with boiling n-hexane gave 1-chloro-2-methylcyclohexene-4,5-dicarboxylic anhydride (20.5 mg., 10 percent yield, white plates m.p. 76°-78°C.). The melting point of 1-chloro-2-methylcyclohexene-4,5-dicarboxylic anhydride as reported in the literature, J. Applied Chem. (London) 3, 145 (1953), is 79°-80°C.