Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1Cl
Yield: 57.8 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-chloro-4-(methyloxy)phenyl]boronic acid (831 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), powdered molecular sieves (400 mg) and pyridine (0.36 mL, 4.46 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 5 days the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.06 g) was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc (0 to 20%) in hexane to afford 470 mg of title compound (D33) containing an impurity.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1>CCOC(C)=O>[NH2:1][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)COc1ccc(CBr)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCc1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Dissolve sodium azide (270 mg, 4.0 mmol) in DM (30 mL). Cool the solution to 0° C., then add 2-bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at 0° C. Slowly heat the mixture from 0° C. to 80° C. over 30 min. Cool the reaction, dilute with EtOAc (100 mL) and wash with 10% aqueous NaCl (3×25 mL). Collect the organic layer and concentrate in vacuo to a volume of 50 mL. Transfer the solution to a pressure vessel. Add 10% Pd/C (Degussa type E101, 50% water by wt, 500 mg) and pressurize the vessel under hydrogen (10 psi) for 1 h with stirring. Filter the mixture through Celite® and wash filter cake with warm methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (180 mg, 54%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C=O)C.[N-:16]=[N+:17]=[N-:18].[Na+]>C(Cl)Cl>[N:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCBr
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCC(=O)O
Temperature: 60 °C

Procedure:
7-azidoheptanoic acid (64) was synthesized from 7-bromoheptanoic acid 63 as shown above. To 914 mg of 7-bromoheptanoic acid (63) (commercially available from Matrix Scientific, Columbia, S.C.) (4.4 mmol) was added 15 mL anhydrous DMF. To the stirring solution was added 914 mg NaN3 (14 mmol, 3.2 eq) at room temperature. The clear solution was warmed to 60° C. for a period of 6 h. The solution was then cooled to room temperature and diluted with 50 mL CH2Cl2. The organic layer was washed with cold 1N HCl (7×50 mL) and brine (2×50 mL), then dried over anhydrous Na2SO4. Filtration and removal of solvent afforded 709 mg crude 7-azidoheptanoic acid 64 in 94% yield which was of suitable purity for continued progression enroute to materials 65 and 66. An NMR analysis was performed where: 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 3.14 (t, J=6.8 Hz, 2H), 2.22 (t, J=7.2 Hz, 2H), 1.56-1.45 (m, 4H), 1.30-1.24 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 178.3, 51.1, 33.7, 28.5, 28.4, 26.2, 24.4. HRMS (ESI) calculated. for C7H13N3O2 (M−H): 170.0930, measured: 170.0930.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=CC1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
A solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.23 g, 2.83 mmol, Adesis) in THF (10 mL) was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 2.3 mL, 3.7 mmol) was added drop-wise while keeping the temperature below about −70° C. The mixture was stirred for about 40 min, and a solution of (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde (0.83 g, 2.8 mmol, Step B) in THF (3 mL) was added drop-wise, and the resulting mixture was stirred at about −75° C. for about 2 h. The reaction mixture was quenched by a drop-wise addition of saturated aqueous NH4Cl (20 mL), and the organic solvent was removed under reduced pressure. The aqueous mixture was extracted with EtOAc (25 mL) and the organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in heptane to yield (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol (1.14 g, 67%): LC/MS (Table 2, Method a) Rt=3.31 min; MS m/z: 602 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14](CC(N)=O)[CH:15]=[CH:16][C:3]1=2.C(OC(=O)C(OCC)=O)C.CC(C)([O-])C.[K+]>CN(C)C=O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: NC(=O)Cc1ccc2c(c1)Sc1ccccc1CC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(=O)C(=O)OCC
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2Sc2ccccc21
Temperature: 25 °C

Procedure:
Stir at room temperature a mixture of 5.118 gm. of the amide of Step 5, 2.939 gm. of diethyloxalate, 4.723 gm. of potassium t-butoxide and 40 ml. of dimethylformamide for 6 hours. Pour the reaction mixture into 300 ml. of ice-water and extract with 300 ml. of ethyl acetate. Acidify with 6N hydrochloric acid and separate the ethyl acetate layer. Wash with saturated sodium chloride solution and dry. Evaporate to dryness and dissolve the residue in warm dioxane. Treat with a slight excess of ammonia and separate the solid by filtration. Wash with dioxane and dry. Suspend the product in water, acidify with 6N hydrochloric acid and extract with ethyl acetate. Wash the extract with saturated sodium chloride solution, dry over magnesium sulfate and evaporate to obtain the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].Br[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Br
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 15 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and AlCl3 (24 g, 0.18 mol) in CH2Cl2 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) dropwise at 0° C. After being stirred at 15° C. overnight, the reaction mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 3-tert-butyl-5-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J=2.0, 8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.42 (d, J=1.6 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[OH:18]>C(Cl)Cl>[C:5]([O:18][C:12]1[C:13]([CH3:17])=[CH:14][C:15]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:16][C:11]=1[CH3:10])(=[O:8])[CH2:6][CH3:7]
Reactant: Cc1cccc(C)c1O
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Oc1c(C)cc(C(=O)CC)cc1C
Reaction time: 2 h
Yield: 170.5 %

Procedure:
To a mixture of aluminum chloride (32.0 g, 24 mmol) in methylene chloride (100 mL) was added propionyl chloride (3.56 mL, 40.95 mmol) all at once followed by 2,6-dimethylphenol (5.0 g, 40.93 mmol in 25 mL of methylene chloride) over 5 min. After stirring 1 h at ambient temperature a second equivalent of propionyl chloride was added (3.56 mL). The reaction was stirred 2 h more and then carefully quenched with water. The mixture was extracted with ether (3x) and the combined organic phase was washed with aqueous bicarbonate and brine; then it was dried over magnesium sulfate and concentrated to give 8.18 g (85%) of 2,6-dimethyl-4-propionylphenyl propionate as a waxy tan solid which had: NMR δ7.68 (s, 2 H), 2.95 (q, J=7.3 Hz, 2 H), 2.65 (q, J=7.5 Hz, 2 H), 2.19 (s, 6 H), 1.32 (t, J=7.6 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H). This product also contained some minor impurities in the NMR spectrum but was found suitable for use without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12](Br)[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[C:32]([Si:36]([CH3:42])([CH3:41])[O:37][CH2:38][C:39]#[CH:40])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([C:40]#[C:39][CH2:38][O:37][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:41])[CH3:42])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC#Cc1nc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cs1
Temperature: 100 °C
Yield: 16 %

Procedure:
Under argon, 500 mg (0.916 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)pyridine-3,5-dicarbonitrile and 0.186 ml (0.916 mmol) of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane were initially charged in 10 ml of acetonitrile, and 105 mg (0.092 mmol) of tetrakis(triphenylphosphine)palladium(0), 35 mg (0.183 mmol) of copper(I) iodide and 0.255 ml (1.832 mmol) of triethylamine were added in succession. The mixture was then heated under reflux at 100° C. for 4 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC. This gave 239 mg of the target compound in a purity of 38% (yield: 16%). The batch obtained in this manner contained the desilylated compound in a proportion of 62%. The mixture was used without further purification for the subsequent hydrogenation.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:17]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CC(C)=NNC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(C)Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 64 grams (0.5 moles) of acetone t-butylhydrazone and 51 grams (0.504 moles) of triethylamine in 400 ml of pentane in a 1 liter 4 neck flask equipped with a mechanical stirrer, thermometer and gas inlet tube, was added 35.5 grams (0.5 moles) of chlorine gas, holding the temperature at -5° to 0° C. After the chlorine addition was complete, the reaction mixture was stirred an additional 15 minutes and the insoluble triethylamine hydrochloride filtered off. The filter cake was washed with an additional 150 ml pentane and the filtrate used in the subsequent reaction.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@H:4]([OH:9])[CH2:5][N:6]=[N+:7]=[N-:8].[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C.C(N(CC)CC)C>C(#N)C>[N:6]([CH2:5][C@@H:4]([OH:9])[C@@H:3]([NH:2][C:20]1[C:21](=[O:25])[C:22](=[O:23])[C:19]=1[O:18][CH3:17])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:7]=[N-:8]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)CC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The HCl salt of (2R,3S)-3-amino-1-azido-4-cyclohexylbutan-2-ol (˜74 mg, 0.30 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (70 mg, 0.49 mmol) were dissolved in acetonitrile (3 mL). Triethylamine (84 μL, 0.60 mmol) was added. The reaction was stirred at rt for 4 h. The solvent was evaporated and the crude material was redissolved in CH2Cl2. The solution was washed with 2% aq HCl, followed by brine, and dried over Na2SO4. The solution was filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with hexanes/EtOAc. 3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (63 mg) was isolated as a solid; MS m/z 323.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 33 %

Procedure:
Nα-tert-butoxycarbonyl-Nδ-(9-fluorenylmethoxycarbonyl)-L-ornithine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 33% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: C(OC([CH:6]1[C:12](=[O:13])[CH:11](C(OCC)=O)[CH2:10][C:9]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:8]=2[CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:8]2[CH2:7][CH2:6][C:12](=[O:13])[CH2:11][CH2:10][C:9]=2[CH:19]=1
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2CC(C(=O)OCC)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)CC2
Yield: 58 %

Procedure:
2-Methoxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6,8-dicarboxylic acid diethyl ester (18.2 g, 0.0544 mol) was dissolved in ethanol and the solution was treated with Potassium hydroxide (24.4 g, 0.435 mol) in Water (140 g, 7.6 mol). The reaction was then refluxed until HPLC showed consumption of starting material (˜5 hours). The reaction was then acidified with 1N HCl and the product was extracted with dichloromethane. Organic extracts were dried over sodium sulfate, filtered and reduced. The crude mixture was filtered through a plug of silica rinsing with dichloromethane before purification. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 6.0 grams (58%) of 2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Clc1ccc(Br)cc1
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1Cl

Procedure:
Using methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate and 4-bromochlorobenzene, 2-chloro-4-(4′-chlorophenyl)benzoic acid was obtained in the same method as in Production Example 292b).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=2)[NH2:34])[CH2:27][CH2:26]1)[CH3:24]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:34][C:33]3[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:31]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)[CH:32]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Product: CCN1CCN(c2cc(NC(=O)c3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid and 3-(4-ethylpiperazine-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1cc2cccc(C(=O)OC)c2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1[nH]c2c(C(=O)OC)cccc2c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(n-butyl)indole-7-carboxylate (P) (0.3 g) in 6 ml of dimethylformamide at room temperature was added N-chlorosuccinimide (0.17 g). The solution was stirred at room temperature for 16 hours, then water was added, and the mixture extracted with ether. The extract was separated and solvent evaporated under reduced pressure, to give methyl 2-(n-butyl)-3-chloroindole-7-carboxylate, a compound of Formula (Q) where X is chloro, as an oil.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O.O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
In 100 ml of dimethyl sulfoxide, 4.05 g (30.0 mmol) of adenine was dissolved, and 3.5 g (31.0 mmol) of potassium tert-butoxide and 5.0 g (35.0 mmol) of 4-fluoronitrobenzene were added thereto, and the mixture solution was stirred at 80° C. for three hours. The solution was diluted with 200 mL of water and the precipitate formed was collected by filtration, washed with 100 mL of water and 30 mL of methanol in the order named and vacuum dried to obtain 7.2 g (84%) of a target product as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[NH2:10][CH2:11][C@@H:12]1[C@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@H:15]2[C@H:14]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH2:31])[O:13]1.[BH3-]C#N.[Na+]>CO>[NH2:31][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[C:28]=1[N:29]=[CH:30][N:22]2[C@H:14]1[C@@H:15]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][C@@H:16]2[C@@H:12]([CH2:11][NH:10][C@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]2)[O:13]1
Reactant: COC(=O)C1CC(=O)C1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (4.60 g, 35.94 mmol), 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (11.0 g, 35.94 mmol) and Ti(iPrO)4 (4.0 g, 14.08 mmol) in MeOH (80 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (4.5 g, 71.87 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL) and filtered, extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to obtain the title compound (6.2 g, Yield 41%). 1H NMR (500 MHz, CDCl3): δH 8.38-8.34 (m, 1H), 7.90 (s, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.75 (br s, 2H), 5.48-5.46 (m, 1H), 5.03-5.01 (m, 1H), 4.35-4.33 (m, 1H), 3.69-3.66 (m, 3H), 3.50-3.17 (m, 1H), 3.05-2.73 (m, 3H), 2.48-2.44 (m, 2H), 1.95-1.91 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 419.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C(N(CC)CC)C>CCO>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: CCCOC(=O)Cl
Reactant: COc1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCOC(=O)Nc1ccc2c(C#N)cn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CH2Cl2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.