Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C.CCCCCCC>C(#N)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:37]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: O
Solvent: CC#N
Solvent: CCCCCCC
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm) was suspended in acetonitrile (40 ml) and then added a solution of calcium acetate (4 gm) in water (2 ml) at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9.8 gm of raltegravir calcium.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10](=[O:17])[C:11](=O)[CH:12](Br)[CH2:13][CH3:14])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:11]1[N:1]=[C:2]2[N:6]([C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:4][S:3]2)=[O:17])[CH3:8]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C(=O)C(Br)CC
Solvent: CCO
Product: CCOC(=O)c1nc2sccn2c1CC

Procedure:
A mixture of 2-aminothiazole (2 g, 20 mmol) and 3-bromo-2-oxo-pentanoic acid ethyl ester (4.4 g, 20 mmol) in ethanol (40 mL) is refluxed for 20 h. The solvent is removed in vacuo until dryness. The residue is purified by column chromatography (5% methanol in methylene chloride) to give 5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester as an oil. Step 2. Preparation of 5-ethyl-6-hydroxymethyl-imidazo[2,1-b]thiazole
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[CH2:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:15][O:25]1)=[O:16])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCCCC1CC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCCC2CC2)CO1

Procedure:
1.18 g of the title compound, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 2.5 g of 8-cyclopropyl-2-methyleneoctanoic acid ethyl ester and 3.85 g of m-chloroperbenzoic acid in 30 ml of methylene chloride.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E208) (100 mg, 0.29 mmol) was dissolved in ethanol (10 ml). Palladium (20 mg, 10% on charcoal paste) was added and the reaction mixture was stirred at room temperature under hydrogen (1 atmosphere) for 12 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (E236); MS (ES+) m/e 310 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].C1CCN2C(=NCCC2)CC1.C(Cl)Cl>CN(C=O)C.CCN(C(C)C)C(C)C>[O:15]=[C:14]1[CH2:13][CH2:12][CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(N2CCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
g of 3-Aminobenzonitril were dissolved in 20 ml DMF and 4.4 ml of DIPEA. The reaction mixture was cooled to 0° C. and 2 ml of 4-chloro-butyryl chloride added. The reaction mixture was stirred at rt for 1 h. 5 ml of DBU were added and the reaction mixture stirred at rt overnight. DCM was added and the organic phase washed with 1N HCL and water. The organic layer was separated, dried over Na2SO4 and evaporated. MS(ISO): 187.2 (MH+)
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:30][O:29][C:24]1([O:27][CH3:28])[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Yield: 99.1 %

Procedure:
A mixture of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.5 g, 1.6 mmol), trimethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (2.0 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled, was partitioned between aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.57 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](Cl)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH:27][CH3:26])=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Reactant: CN
Product: CNc1nccc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc12

Procedure:
154 mg (0.42 mmol) of 4-(1-Chloro-isoquinolin-6-yloxy)-piperidine-1-carbocyclic acid tert-butyl ester (162) were heated in 15 ml of an aqueous methylamine-solution (41%)) at 110° C. in a sealed tube. After 7 h the reaction mixture was evaporated and the residue was taken up in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and the solvent was removed i. vac. The residue was purified by silica gel chromatography (ethyl acetate/methanol 5:1). Yield: 45 mg. Rt=1.14 min (Method #4). Detected mass: 358.3 (M+H+).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][O:17][CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[CH:22]=[CH:23][C:24]=2[F:25])[N:15]=1)(=O)C1C=CC=CC=1.CO[NH3+].[Cl-].N1C=CC=CC=1>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][O:17][CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)[CH:22]=[CH:23][C:24]=2[F:25])[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COC[C@H]2CS1)c1ccccc1
Agent: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COC[C@H]2CS1
Reaction time: 0.08 h
Yield: 108.6 %

Procedure:
A solution of N-(3-((4aS,7aS)-2-benzamido-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide (23.7 g 40.8 mmol), o-methylhydroxylamine hydrochloride (34.4 g, 412 mmol) and pyridine (33.3 mL) in ethanol (735 mL) is heated to 50° C. for 4 h. The mixture is concentrated. The residue is washed twice with methyl tert-butyl ether (2×250 mL) and poured into a saturated aqueous solution of sodium bicarbonate (453 mL). The suspension is shaken for 5 min and extracted with dichloromethane (1×1 L and 2×0.5 L). The organic layer is washed with water (0.5 L) dried over magnesium sulfate and the solvent is removed under reduced pressure to afford a solid. Additional solid is obtained from the aqueous phase by filtration. The solids are combined and triturated with water (300 mL) in an ultrasound bath for 30 min. The suspension is filtered off, washed with water, and dried under vacuum to give title compound (17.3 g, 100%). ES/MS m/e: 391 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4](C2C=CC(=C(C)C)C=2)[CH2:3]1.[CH:19]1([CH:24]2CC(C)(C)CC(C)(C)C2)[CH:23]=[CH:22][CH:21]=[CH:20]1.CC(C)=O.N1CCCC1>C(OCC)C.O.C(O)(=O)C.CO>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:18])([CH3:1])[CH2:3][CH:4]([C:20]2[C:19](=[CH2:24])[CH:23]=[CH:22][CH:21]=2)[CH2:5]1
Reactant: CC1(C)CC(C2C=CC=C2)CC(C)(C)C1
Reactant: CC(C)=C1C=CC(C2CC(C)(C)CC(C)(C)C2)=C1
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: C=C1C=CC=C1C1CC(C)(C)CC(C)(C)C1
Reaction time: 52 h

Procedure:
Hexane washed sodium spheres (2.40 g, 104 mmol) were slowly added to 100 mL absolute ethanol. The sodium had fully reacted before cyclopentadiene (6.0 mL, 72.6 mmol) and 3,3,5,5-tetramethylcyclohexanone (10.0 mL, 57.1 mmol) were added. After 30 hours, the reaction was poured into 200 mL water and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were extracted with water (3×50 mL), dried over MgSO4, filtered, and rotavapped to produce the product in quantitative yield as a yellow oil. MS (GC-MS) m/z 202.3 (M+). 1H NMR (CDCl3): δ 0.97 (s, 12H, CH3), 1.04 (s, 2H, CH2), 2.39 (s, 4H, CH2), 6.52, 6.52 (m, 4H, fulvene-H). 1-(cyclopentadienyl)-3,3,5,5-tetramethylcyclohexane. A 500 mL flask was charged with LiAlH4 (2.50 g, 65.9 mmol) and 200 mL tetrahydrofuran. An addition funnel containing 3,3,5,5-tetramethylcyclohexylfulvene (11.89 g, 58.8 mmol) dissolved in 50 mL tetrahydrofuran was attached. The vessel was cooled to 0° C. before dropwise addition over 25 minutes. After 17 hours of stirring at room temperature, the vessel was cooled to 0° C. and 20 mL of water were added dropwise. Then, aqueous NH4Cl (100 mL) and water (200 mL) were added before the organic layer was isolated. 15 mL of concentrated aqueous HCl were added to the aqueous layer and it was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to provide 11.87 grams of product (98.8%) as a light orange oil. MS (GC-MS) m/z 204.3 (M+). 3-(3,3,5,5-tetramethylcyclohexyl)-6,6-dimethylfulvene. A 500 mL flask was charged with 1-(cyclopentadienyl)-3,3,5,5-tetramethylcyclohexane (11.87 g, 58.1 mmol), 100 mL methanol, acetone (30 mL, 430 mmol), and pyrrolidine (1.0 mL, 12 mmol). After stirring for 52 hours, 5 mL of acetic acid were added, along with 200 mL water and 100 mL diethyl ether. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were extracted with H2O (3×30 mL) and 10% aqueous NaOH (3×30 mL). The organic layer was dried over MgSO4, filtered, rotavapped, dried in vacuo, and pushed through a short column of alumina to provide the product in quantitative yield as a yellow oil. MS (GC-MS) m/z 244.4 (M+).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C.[O-][Mn](=O)(=O)=O.[K+]>C(#N)C.CCCCCC.C(OCC)(=O)C>[CH3:12][O:11][C:9](=[O:10])[C:8](=[N+:33]=[N-:34])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Yield: 87 %

Procedure:
To a stirred solution of dimethyl 3-oxopentanedioate (50.0 g, 287.1 mmol) and triethylamine (47.8 mL, 344.5 mmol) in acetonitrile (1.2 L) at 0° C. was added 4-acetamidobenzene sulfonyl azide (69.0 g, 287.1 mmol) portion wise. After addition was completed, the reaction mixture was stirred at room temperature for 1 h (silica TLC; ethyl acetate:hexane=1:4, Rf=0.3; showed KMnO4 activity). The reaction mixture was filtered, and the filtrate was concentrated to get a viscous mass, which was diluted with n-hexane (3 L). The unwanted solid byproduct was removed by filtration then filtrate was concentrated under reduced pressure to give 2-diazo-3-oxo-pentanedioic acid dimethyl ester (50.0 g, 87% crude yield) as a light yellow liquid, which was directly used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][CH2:10][CH2:11][F:12])[CH:7]=[C:6]([C:13]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:17]=[C:16]([NH2:18])[N:15]([CH3:19])[C:14]2=[O:20])[CH:5]=1)(=[O:3])[CH3:2].Cl[CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH2:35])=[O:34].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[N:8]([CH2:9][CH2:10][CH2:11][F:12])[CH:7]=[C:6]([C:13]2([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([NH2:35])=[O:34])[C:14](=[O:20])[N:15]([CH3:19])[C:16]([NH2:18])=[N:17]2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C2(c3cccc(O)c3)N=C(N)N(C)C2=O)cn1CCCF
Reactant: NC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C2(c3cccc(OCc4cccc(C(N)=O)c4)c3)N=C(N)N(C)C2=O)cn1CCCF
Temperature: 45 °C

Procedure:
A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([O:16]CC)=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1B(O)O>O.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>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([OH:16])=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1
Reactant: CCOC(=O)c1cc2cnnc(Cl)c2n(C)c1=O
Reactant: OB(O)c1ccc(F)cc1F
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: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 100 °C

Procedure:
To a suspension of ethyl 8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate (6) (1.40 g, 5.23 mmol) in 3:1 1,4-dioxane: 2 M aq Na2CO3 (16 mL) was added 2,4-difluorophenylboronic acid (1.03 g, 6.54 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.484 g, 0.418 mmol). The reaction mixture was heated in a microwave at 100° C. for 75 min, then more Na2CO3 solid (100 mg) was added and the reaction mixture was heated in the microwave at 100° C. for an additional 2 h. The mixture was diluted with water and washed with CH2Cl2. The aqueous layer was then acidified with 5 N HCl to pH ˜2 and extracted with CHCl3/iPrOH (4:1). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid as a brown solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.O.C[N:21]([CH:23]=[O:24])C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1)(=[O:24])[NH2:21]
Reactant: CC(C)(C)OC(=O)Cn1nc(I)c2ccncc21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccncc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (3.76 g, 10.5 mmol), Zn(CN)2 (1.35 g, 11.5 mmol), Pd(dppf)C2 (855 mg, 1.05 mmol), Pd2(dba)3 (959 mg, 1.05 mmol), water (4 mL) and DMF (30 mL) was stirred at 100° C. for 16 h under argon. The reaction mixture was diluted with EtOAc and then was successively washed with water, sat. aq. NaHCO3 (2×) and brine, dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:1 then 100% EtOAc). MS (LC/MS): 259.0 [M+H]+; tR (HPLC conditions k): 3.10 min. Further elution of the column with CH2Cl2/MeOH 8:2 and subsequent purification by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) afforded tert-butyl 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate as a side-product. MS (LC/MS): 277.0 [M+H]+; tR (HPLC conditions d): 2.39 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16](=[O:30])[CH2:17][CH:18]1[C:22]2[CH:23]=[C:24]([F:29])[C:25]([OH:28])=[C:26]([F:27])[C:21]=2[O:20][CH2:19]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[C:24]([F:29])=[CH:23][C:22]4[CH:18]([CH2:17][C:16]([OH:30])=[O:15])[CH2:19][O:20][C:21]=4[C:26]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC1COc2c1cc(F)c(O)c2F
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)CC1COc2c1cc(F)c(OCc1cccnc1SC1CCC1)c2F
Yield: 79.8 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (18 mg, 0.08 mmol) obtained in Step C of Preparation Example 23 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (26 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([F:42])([F:41])[CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][NH:30][CH2:29][C:28]([F:42])([F:41])[F:27])[CH:33]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: OB(O)c1cccc(CNCC(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N1CCc2ccc(Cl)c(-c3cccc(CNCC(F)(F)F)c3)c2CC1)C(F)(F)F
Temperature: 80 °C

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.1 equiv.), 3-[(2,2,2-trifluoroethyl-amino)-methyl]-phenyl-boronic acid (465 mg, 2.0 mmol) and sodium carbonate (2 equiv.) in THF/water (2:1, 15 mL) and heat the mixture at 80° C. for 6 h. Cool the reaction mixture to ambient temperature, dilute with EtOAc and wash with water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo to obtain 7-chloro-3-(2,2,2-trifluoroacetyl)-6-{3-[(2,2,2-trifluoroethyl-amino)-methyl]-phenyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine, suitable for use without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])(CC)C.[CH3:43][Si:44](Cl)([CH3:46])[CH3:45]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Si:44]([CH3:46])([CH3:45])[CH3:43])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2ccc([Si](C)(C)C)c(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)-7-(triisopropylsilyloxy) naphthalene, as described above in Step A, (12.47 g, 30.0 mmol) and N,N,N′,N′-tetramethylethylenediamine (10.0 mL, 66.0 mmol) in THF (300 mL) at −78° C. was added sec-butyllithium (1.3 M in cyclohexane, 24.2 mL, 31.5 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 min, then trimethylsilyl chloride (4.2 mL, 33.0 mmol) was added dropwise and stirring was continued for 30 min. sec-Butyllithium (1.3 M in cyclohexane, 24.2 mL, 31.5 mmol) was added and the mixture was stirred dropwise was stirred at −78° C. for 5 hours, then quenched with saturated aqueous NH4Cl (400 mL) and extracted with CH2Cl2 (2×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—30% to 50% CH2Cl2 to yield the above-titled product.