Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](N(OC)C)=[O:15])=[N:13][N:7]3[C:6]=2[CH:30]=1.[CH3:31][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](=[O:15])[CH3:31])=[N:13][N:7]3[C:6]=2[CH:30]=1
Reactant: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Reactant: C[Mg]Br
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: -78 °C

Procedure:
8-Chloro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-3; a racemic mixture, 37 mg, 86 μmol) was dissolved in anhydrous THF (1 mL) and cooled to −78° C. Methylmagnesium bromide (0.25 mL, 258 μmol) was added and the reaction stirred to 25° C. An additional portion of MeMgBr (0.16 mL, 165 mmol) was added and the reaction stirred 1 h. Upon completion the reaction was quenched by the addition of NH4CL (1 mL) and extracted with EtOAc (3×5mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography (ISCO Redisep 0-100% EtOAc/hexanes gradient) provided 1-[8-chloro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (4-4; a racemic mixture) and (4-10; a racemic mixture) as a side product. 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=2.4 Hz 1H), 7.32-7.20 (m, 3H), 7.07 (m, 2H), 6.85 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.15 (dd, J=11.3, 3.8 Hz, 1H), 3.73 (dd, J=11.0, 3.8 Hz, 1H), 3.73 (br s, 1H), 2.93 (t, J=11.0 Hz, 1H), 2.56 (dt, J=12.2, 4.0 Hz, 1H), 2.56 (s, 3H), 2.42 (dt, J=12.9, 4.6 Hz, 1H), 1.72 (m, 1H), 1.40 (m, 3H); MS (M+H+, C21H21ClN2O3) 385.4 found 385.9 required.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42]>C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[NH:40][C:41]([NH:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][CH:21]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1)=[O:42]
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 126 (125 mg, 0.288 mmol) in DCM (6 mL) was added the 2,4-difluorophenyl isocyanate (134 mg, 0.865 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was then concentrated and the resultant solid was triturated with acetone and collected by filtration to give title compound 127 (100 mg, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 8.61 (s, 1H), 8.51 (d, J=5.48 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 1H), 7.94 (m, 2H), 7.76 (m, 1H), 7.64 (m, 2H), 7.45 (t, J=8.99 Hz, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 6.63 (d, J=5.48 Hz, 1H), 3.48-3.37 (m, 4H), 1.85 (m, 4H). MS (m/z)=589.546 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])O.[Na+].C(O)C.[C:21]([NH:29][C:30]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.C1(C)C=CC=CC=1.O>[C:21]([NH:29][C:30]1[CH:42]=[C:41]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 18 %

Procedure:
0.11 g of 4-nitrophenylboronic acid, 0.11 g of sodium hydrogen carbonate, 1.2 mL of ethanol, 0.6 mL of water and 31 mg of tetrakis(triphenylphosphine)palladium(0) were added to 4.0 mL of toluene solution containing 0.20 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. A saturated sodium hydrogen carbonate aqueous solution was added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 40 mg of tert-butyl 2-(benzamido)-4-(4-nitrophenyl)benzoate as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][C:40]=1[C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=1>>[CH3:57][O:56][C:50]1[CH:49]=[C:48]([C:40]2[NH:41][C:42]3[C:47]([C:39]=2[CH2:38][CH2:37][NH:36][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:53]=[CH:52][C:51]=1[O:54][CH3:55]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a stirred solution of 4-nitrophenylacetic acid (100 mg in 2.5 mL N,N-dimethylformamide) was added 1-hydroxybenzotriazole (90 mg) and the mixture cooled to 0° C. After 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg) was added. The mixture was warmed to room temperature and 3-(2-aminoethyl)-2-(3,4-dimethoxyphenyl)indole (316 mg) was added. After 17 hours the reaction was quenched by the addition of water and extracted with ethyl acetate. The organic portion was washed with water, 0.5M sodium bisulfate and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (116 mg).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH:16]3[CH2:18][CH2:17]3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:19][CH2:20][C:21]1[C:22](=[O:34])[NH:23][C:24]([CH3:33])=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:16]1([C:10]2[CH:11]=[C:12]([C:13]([NH:19][CH2:20][C:21]3[C:22](=[O:34])[NH:23][C:24]([CH3:33])=[CH:25][C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])[C:7]3[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=3[N:9]=2)[CH2:18][CH2:17]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1
Product: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 11 from 1-(1-methylethyl)-6-(cyclopropyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.612 mmol) and 3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (153 mg, 0.612 mmol). The product was collected as a white solid, 0.067 g (24%). LCMS E-S (M+H)=442.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.11 (m, 3 H), 1.47 (d, J=6.57 Hz, 5 H), 2.22 (s, 3 H), 2.24-2.29 (m, 1 H), 3.17 (d, J=5.31 Hz, 2 H), 4.07-4.15 (m, 1 H), 4.19 (d, J=4.29 Hz, 2 H), 5.06-5.18 (m, 1 H), 6.01 (s, 1 H), 7.36 (s, 1 H), 7.38-7.49 (m, 5 H), 8.18 (s, 1 H), 8.70 (s, 1 H), 11.88 (s, 1 H).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.[I-].[Na+].C(N(CC)CC)C>CN(C=O)C.O>[CH3:15][C@@H:16]1[N:21]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:17]1
Reactant: FC(F)(F)c1ccc2c(c1)C(Cl)CC2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of 1-chloro-6-(trifluoromethyl)indane (1.52 g, 6.89 mmol), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (2.1 g, 10 mmol), sodium iodide (3 g, 20 mmol) and triethylamine (3 g, 30 mmol) in DMF (20 mL) was stirred at 60° C. overnight. After cooling to room temperature, water was added. The resulting solution was extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. Column chromatography on silica (10%-30% EtOAc in hexane) afforded two isomers. Isomer 1: 0.52 g (brown oil). MS calculated for C20H27F3N2O2: (M+H)+ 385; found 385.2. Isomer 2: 0.41 g (brown oil). MS: (M+H)+ 385.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:11]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:11]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cn1c(SCc2ccccn2)nc(-c2ccc(Cl)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2c(-c3ccc(Cl)cc3)nc(SCc3ccccn3)n2CC(=O)O)cc1

Procedure:
Starting substances: 788 mg (1.6 mmol) of Z28 from Example 127; 5 ml (10 mmol) of 2 N NaOH
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19]([OH:21])=O.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[NH2:55][CH2:56][C:57]1[C:58]([OH:65])=[N:59][C:60]([CH3:64])=[CH:61][C:62]=1[CH3:63].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[OH:65][C:58]1[C:57]([CH2:56][NH:55][C:19]([C:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:10]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2]=2[CH3:1])=[O:21])=[C:62]([CH3:63])[CH:61]=[C:60]([CH3:64])[N:59]=1
Reactant: Cc1c(C(=O)O)c2ncccc2n1C(C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3cccnc23)c(O)n1
Reaction time: 12 h
Yield: 32.9 %

Procedure:
The mixture of 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (20 mg, 0.11 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (50 mg, 0.13 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (19 mg, 0.12 mmol) and triethylamine (23 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was stirred for 12 hours. After the reaction was completed, the reaction was diluted with ethyl acetate (100 mL), and washed with water (20 mL×3) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=30:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15 mg, 33%). LRMS (M+H+) m/z: calcd 415.20. found 415. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO) δ 11.46 (s, 1H), 9.49 (t, J1=4.2 Hz. J2=8.1 Hz, 1H), 8.28 (d, J=3.6 Hz, 1H), 7.50 (d, J=6.3 Hz, 1H), 7.36-7.27 (m, 3H), 7.16 (d, J=5.7 Hz, 1H), 7.03-7.00 (m, 1H), 6.03 (m, 1H), 5.85 (s, 1H), 4.37 (s, 2H), 2.89 (s, 3H), 2.50 (s, 3H), 2.10 (s, 3H), 1.89 (d, J=5.4 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.C(=O)=O.[C:28](=[O:31])([O-])[NH2:29].S(Cl)([Cl:34])=O>C1(C)C=CC=CC=1>[C:28]([Cl:34])(=[O:31])[NH2:29].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: NC(=O)[O-]
Agent: O=C=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: NC(=O)Cl
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
In a 100 mL round bottom flask was added 0.02 mol piperidine, 0.02 mol pyridine, 0.02 mol CyTMG, 1 mmol biphenyl as G.C. internal standard and 20 mL toluene. This solution was cooled to -10° C. using an ice salt bath and carbon dioxide was added subsurface to the cooled solution for 30 min. After this period of time the preformed carbamate solution was added all at once by cannula to a cooled (-10° C.) toluene (20 mL) solution of thionyl chloride (0.02 mol). The reaction mixture was stirred at -10° C. for 15 min. under atmospheric CO2 pressure.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[NH:8][N:7]=[C:6]([C:9](OC)=[O:10])[CH:5]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+]>C(O)(C)(C)C>[CH3:14][O:13][CH:3]([O:2][CH3:1])[C:4]1[NH:8][N:7]=[C:6]([C:9]([O:18][C:16]([CH3:19])([CH3:17])[CH3:15])=[O:10])[CH:5]=1
Reactant: COC(=O)c1cc(C(OC)OC)[nH]n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(OC)c1cc(C(=O)OC(C)(C)C)n[nH]1
Temperature: 50 °C
Reaction time: 45 h
Yield: 76.8 %

Procedure:
To a solution of methyl 5-[bis(methyloxy)methyl]-1H-pyrazole-3-carboxylate (20 g) in tert-butanol (250 ml) at 40° C. was added potassium tert-butoxide (28.1 g) and the mixture stirred at 50° C. for 45 h. The solution was evaporated under reduced pressure, diluted with water (150 ml) and extracted with ethyl acetate (4×100 ml). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (18.6 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:10]([CH3:14])[C:11](=O)[CH3:12])#[N:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][NH:27][CH2:28][C:29]#[N:30].Cl>C(Cl)(Cl)Cl.O>[NH2:9][C:8]1[C:10]([CH3:14])=[C:11]([CH3:12])[N:27]([CH3:26])[C:28]=1[C:29]#[N:30]
Reactant: CC(=O)C(C)C#N
Reactant: CNCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N)c(C#N)n(C)c1C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
10.3 ml (0.74 mole) of triethylamine, 7.2 g (0.74 mole) of 3-cyanobutan-2-one and 0.5 g of p-toluenesulfonic acid are successively added to a suspension of 7.8 g (0.74 mole) of N-methylaminoacetonitrile hydrochloride in 70 ml of chloroform, and the mixture is boiled for 5 hours, using a water separator. After it has been boiled, the mixture is washed twice with 10 ml of water each time and dried over sodium sulfate; the solvent is then stripped off in vacuo. In order to remove all of the chloroform, the residue is twice taken up in 100 ml (each time) of dry ethanol, and the mixture concentrated each time in vacuo. The resulting oil is warmed (bath temperature of 50° C.) in 100 ml of 1 N sodium ethylate/ethanol for 2 hours; some of the ethanol is removed. The mixture is then taken up in 100 ml of water and extracted several times with methylene chloride. After being dried over sodium sulfate and concentrated on a rotary evaporator, the extracts yield a solid residue, which is recrystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:19])=[CH:5][CH:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=CC1c1ccc(F)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(F)cc2)cc(C)nc1C

Procedure:
8.6 g (33 mmol) of crude product from Example 27 and 3.3 g of chromium(VI) oxide are heated under reflux for 1 hour in 90 ml of glacial acetic acid. The solvent is then removed on the rotary evaporator, ethyl acetate/petroleum ether 1:1 is added to the residue and undissolved material is filtered off with suction. The mother liquor is concentrated in vacuo and chromatographed over 500 g of silica gel using ethyl acetate/petroleum ether 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([NH2:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:12][N:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nsc(-c2ccc(Cl)cc2)n1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nsc(-c3ccc(Cl)cc3)n2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1,2,4-thiadiazol-3-amine (423 mg, 2.0 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. EtOH was used in the second extraction to assist solubilizing the sulfonamide. After drying over Na2SO4, solvent was removed in vacuo. The crude crystalline product weighed 0.45 g. The crude product was taken up in 13 mL of hot HOAc, diluted with 7 mL of H2O and seeded to give white needles (384 mg) after collection by filtration, washing with H2O, and drying in vacuo. The product had mp 220-221° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N)[CH3:2].N([O-])=O.[Na+].[BrH:14]>S(O)=O.[Cu]Br>[Br:14][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cccc(N)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=[SH]O
Product: CCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a solution of 3-ethylaniline (10.0 g, 82.5 mmol) in 50% sulfanic acid (43.6 g) was added dropwise an aqueous solution (16.5 mL) of sodium nitrite (6.83 g, 99.0 mmol) over 30 minutes at 0° C. The resulting reaction mixture was stirred for 45 minutes at 0° C. This diazonium salt solution was added dropwise to a solution of copper (I) bromide (12.4 g, 86.6 mmol) in a 48% hydrobromic acid (82.5 mL) while heating gently under reflux. After the addition, the reaction mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and extracted with ether. The extracts were sequentially washed with a 1N-aqueous sodium hydroxide solution and brine, and filtrated, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:1) to obtain a title compound (6.13 g, yield 40%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1)C2
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (568 mg, 2.1 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (256 mg, 2.1 mmol), DIEA (1.1 ml, 6.3 mmol) then WSCD (520 mg, 2.7 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (450 mg, 1.9 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (503 mg, 54%).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])CCC.[Cl:17][C:18]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>O1CCCC1>[CH2:11]([O:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:18]=1[Cl:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: N#Cc1ccc(CN)c(Cl)c1
Solvent: C1CCOC1
Product: CCCCOc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O
Yield: 76.1 %

Procedure:
A solution of 3,4-dibutoxy-3-cyclobutene-1,2-dione (2.263 g, 10 mmol) and 2-chloro-4-cyanobenzylamine (1.666 g, 10 mmol, Example 2, Step 3) in tetrahydrofuran (25 mL) was stirred at room temperature for 22 hours. The residue remaining after removal of solvent was dissolved in chloroform and was chromatographed (flash, ethyl acetate/hexane) on silica. The solid isolated from the appropriate fractions was recrystallized from ethyl acetate to provide 2.427 g of a white solid: mp 147.5°-149° C. MS (m/z) 318 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[C:6]([CH:20]=O)=[CH:5]2)[CH2:3][CH2:2]1.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CCO>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[C:6]([CH3:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(OC)c2c(C=O)cn(C3CC3)c2c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(OC)c2c(C)cn(C3CC3)c2c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a stirred solution of 3.30 g of ethyl 1-cyclopropyl-3-formyl-4-methoxy-1H-indole-6-carboxylate in 33 ml of EtOH was added 2.57 g of TsNHNH2 and the mixture was refluxed for 30 min. After evaporation of EtOH, the mixture was diluted with 28 ml of DMF and 28 ml of sulfolane, then 2.89 g of NaBH3CN and 0.57 g of TsOH H2O was added thereto successively. The mixture was refluxed for 30 min and cooled to room temperature. After diluted with Et2O, the mixture was washed successively with water, saturated NaHCO3aq, and saturated brine, dried over Na2SO4, concentrated. The residue was purified on SiO2 column chromatography (EtOAc/n-hexane system) to give 2.78 g of Ethyl 1-cyclopropyl-3-methyl-4-methoxy-1H-indole-6-carboxylate as a colorless powder.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:17]CC)=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:24][CH:23]=[CH:22][CH2:21]1>>[CH2:1]([C:8]1[C:22]2[CH2:21][O:20][CH2:24][C:23]=2[C:10]([OH:17])=[C:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1oc(Cc2ccccc2)nc1CC(C)C
Reactant: C1=CCOC1
Product: CC(C)Cc1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
2-Benzyl-4-isobutyl-5-ethoxyoxazole is reacted with 2,5-dihydrofuran, using the method described in Example 22. 38 g of crude 4-benzyl-6-isobutyl-1,3-dihydro-furo[3,4-c]pyridine-7-ol are obtained. Recrystallization from ethyl acetate gives a pure product, melting point 174°-175° C.