Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si](C(C)(C)C)(C)C)=[N:7][C:6]([O:20][Si](C(C)(C)C)(C)C)=[CH:5]2.[CH:28]1([Mg]Br)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOCC.Cl>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.O.C1COCC1>[CH:28]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:20])[CH2:5]3)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2cc(Br)ccc2c(O[Si](C)(C)C(C)(C)C)n1
Reactant: Br[Mg]C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Cc2cc(C3CCCC3)ccc2C(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6-bromo-1,3-bis-(tert-butyl-dimethyl-silanyloxy)-isoquinoline (1.76 g, 3.75 mmole) is added tetrakis(triphenylphosphine)palladium (110 mg, 0.095 mmole) and 2M cyclopentyl magnesium bromide in ether (3.0 mL, 6.0 mmole). This mixture is heated using a microwave reactor at 75° C. for 600 sec. The mixture is cooled to room temperature, transferred to a flask with THF and water, then 2M hydrochloric acid (20 mL) is added and stirred for 4 hours at room temperature. The organic solvents were removed in vacuo, the mixture extracted with ethyl acetate, the organic layer dried over sodium sulfate filtered, evaporated and chromatographed with hexanes-ethyl acetate on silica gel to give a white solid, 268 mg (31%) MS (ESI): m/z 230.2 (M+H).
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[CH:10]=O.C[Si]([C:21]#[N:22])(C)C.[NH3:23]>C(O)C.[I-].[Zn+2].[I-]>[NH2:23][CH:10]([C:9]1[CH:8]=[C:7]([F:6])[C:14]([F:15])=[C:13]([F:16])[CH:12]=1)[C:21]#[N:22]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[Si](C)(C)C#N
Reactant: N
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC(N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a THF solution (20 mL) of 3,4,5-trifluorobenzaldehyde (1.3 g), trimethylsilylcyanide (1.35 mL) and zinc iodide (259 mg) were added, and the reaction solution was agitated at room temperature for 40 minutes. 2N ammonia solution in ethanol (15 mL) was added to the reaction solution, and the reaction solution was agitated at 50° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate, the solvent was removed under reduced pressure, and 780 mg of the title compound was obtained by purifying the residue with silica gel chromatography (Carrier: Chromatorex, elution solvent: heptane-ethyl acetate system). The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]2[CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(N)nc1
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc2nc(CCl)cn2c1
Reaction time: 2.75 h
Yield: 17.9 %

Procedure:
A mixture of 2-amino-5-picoline (Aldrich; 5.028 g), 1,3-dichloroacetone (Aldrich; 5.893 g), and 1,2-dimethoxyethane (Aldrich; 43 mL) is stirred for 1 h at 55° C., at which time ethanol (47 mL) is added and the mixture is stirred for 2.75 h at reflux. The mixture is then concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (1/99) and the appropriate fractions are combined and concentrated to give, after crystallization from ethyl acetate, 0.411 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine. Methanol is added to the filtrate, which is then concentrated to a reduced volume. The addition of hexane gives an additional 1.50 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine in two crops; mp 88-89.25° C.; ms m/z 180; IR (mineral oil) 796, 705, 699, 1343, 1510 cm-1 ; 1H NMR (CDCl3) δ 2.32, 4.76, 7.03, 7.47, 7.53, 7.86.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:28])[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:28])[C:20]2[C:25]([CH:26]=[CH:1][CH3:2])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=Cc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirring suspension of (ethyl)triphenylphosphonium bromide (1.75 g, 4.72 mmol) in dry THF (150 ml) at 20°-25° under nitrogen is added n-butyl lithium (1.6M in hexane, 2.95 ml, 4.72 mmol). The resulting mixture is stirred for 10 min followed by addition of 1-benzyl-4-[N-methyl-N-(3-formyl-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 13, 1.40 g, 4.72 mmol) in THF (10 ml) under nitrogen. The mixture is stirred at 20°-25° for 1 hr and quenched with saturated aqueous ammonium chloride (50 ml). Water is added (100 ml) and the aqueous is extracted with ethyl acetate (3×75 ml). The organic phases are combined, dried over sodium sulfate and the solvent evaporated to dryness. The residue is purified via flash column chromatography (silica gel; hexane/ethyl acetate (6/1→1/1)) to give the title compound, NMR (CDCl3) 1.64, 1.81-1.93, 2.80, 2.91, 3.46, 5.77, 6.13, 6.26, 6.40, 6.78, 7.20-7.56 and 8.11δ; MS (EI, m/e) 321 (M+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[C:17]#[C:18][Si](C)(C)C)[C:10]([O:12][CH3:13])=[O:11])([O-:6])=[O:5].[C:23]([OH:26])(=O)C>CO>[CH3:1][O:2][CH:18]([O:26][CH3:23])[CH2:17][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CC(OC)OC)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 82.5 %

Procedure:
To a methanol solution of 2.92 g (54.1 mmol) of sodium methoxide was added 3.00 g (10.8 mmol) of methyl 3-nitro-4-trimethylsilylethynylbenzoate prepared above. The mixture was refluxed for 30 minutes. After cooling to 0° C., 5.52 g (54.1 mmol) of acetic acid was added to the reaction mixture and the solvent was then distilled off under reduced pressure. Ice water was poured onto the resulting residue followed by extraction three times with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 2.40 g (82.4%) of methyl 4-(2,2-dimethoxyethyl)-3-nitrobenzoate.
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][Cl:16])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C.O=C(Cl)[O:20][C:21](Cl)(Cl)Cl.[CH:26]1[C:39]2[C:30](=[N:31][C:32]3[C:37]([C:38]=2[NH:40][C:41]2[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([NH2:48])[CH:42]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1.CN(C=O)C.N1C=CC=CC=1>[CH:36]1[C:37]2[C:32](=[N:31][C:30]3[C:39]([C:38]=2[NH:40][C:41]2[CH:42]=[C:43]([NH:48][C:21]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:6]([CH2:14][CH2:15][Cl:16])[CH2:5][CH2:4][Cl:3])=[CH:8][CH:9]=4)=[O:20])[CH:44]=[C:45]([CH3:47])[CH:46]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)cc(Nc2c3ccccc3nc3ccccc23)c1
Temperature: 92.5 °C
Reaction time: 24 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.918 g, 3.0 mmol) and charcoal (20 mg) in dry dioxane (30 mL) was added diphosgene (0.494 g, 2.5 mmol) and then heated at 90-95° C. for 5 h. The mixture was filtered through a pad of Celite and the filtrate containing crude N-mustard isocyanate 39 was added dropwise into the solution of N-acridin-9-yl-5-methylbenzene-1,3-diamine 33 (0.517 g, 1.7 mmol) in dry DMF (25 mL) containing pyridine (2 mL) at −10° C. The reaction mixture was allowed to cool down to room temperature and continuously stirred for 24 h and then evaporated in vacuo to dryness. The residue was dissolved in a mixture of CHCl3/MeOH containing silica gel (10 g) and evaporated under reduced pressure to dryness. The residue was put on the top of a silica gel column (4×30 cm) and chromatographed by using CHCl3/MeOH (100:3 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness to give 1-[3-(acridin-9-ylamino)-5-methylphenyl]-3-{4-[bis(2-chloroethyl)amino]phenyl}urea (18, BO-1079), 0.375 g (39%); mp 280-285° C.; 1H NMR (DMSO-d6) δ 2.26 (3H, s, Me), 3.68 (8H, s, 4×CH2), 6.68 (2H, d, J=9.0 Hz, ArH) 6.75-6.89 (1H, m, ArH), 7.19-7.32 (3H, m, ArH), 7.40-7.62 (3H, m, ArH), 7.93-8.14 (4H, m, ArH), 8.29 (2H, d, J=9.0 Hz, ArH), 8.94 (1H, brs, exchangeable, NH), 9.37 (1H, brs, exchangeable, NH), 11.51 (1H, brs, exchangeable, NH). Anal. Calcld. for (C31H29C12N5.0.3 H2O): C, 60.88; H, 6.11; N, 11.45. Found: C, 61.08; H, 6.18; N, 11.32.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5](C#N)=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.O.O.N>P(=O)(O)(O)O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)ccc1-c1ccc2nccn2c1
Yield: 44.4 %

Procedure:
In 10 ml of 85% phosphoric acid was refluxed 1 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile for 18 hours. After cooling, water was added and then conc. ammonia water was further added to the reaction mixture to render alkaline. The mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from ethanol-ether to obtain 0.4 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-pyridine.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C([C:10]1[CH:14]=[CH:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[C:11]=1C)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[CH:10]=[CH:11][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[C:13]=1[CH3:14])=[O:3]
Reactant: Cc1c(C(=O)O)ccn1-c1ccnc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)Cl)ccn1-c1ccnc2ccccc12
Product: Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
11.8 mL (134.8 mmol) of oxalyl chloride are added at 20° C. under an argon atmosphere to 2.09 g (7.24 mmol) of 3-carboxy-2-methyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 150 mL of dichloromethane. After stirring at 20° C. for 16 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 2.2 g of 3-chlorocarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole hydrochloride in the form of an orange-coloured solid which is used directly in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69](O)=[O:70])=[C:64]([F:72])[CH:63]=1>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])=[C:64]([F:72])[CH:63]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2ccc(Cl)cc2F)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 57 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(4-chloro-2-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0126 g (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.06 (d, J=2.44 Hz, 1H), 7.56 (s, 1H), 7.45 (t, J=8.24 Hz, 1H), 7.40 (dd, J=8.54, 2.44 Hz, 1H), 7.31 (dd, J=9.77, 2.14 Hz, 1H), 7.25 (dd, J=8.24, 2.14 Hz, 1H), 7.17 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.58 (m, 2H), 4.05 (s, 3H), 3.77 (s, 2H). MS (APCI+) m/z 531.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[H][H]>[Pt]=O.C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Reactant: C=O
Agent: O=[Pt]
Solvent: CCO
Product: CN(C)C1CCN(Cc2ccccc2)CC1

Procedure:
To a suspension of 0.5 g. of platinum oxide in 25 ml. of ethanol (prereduced as described above) was added a solution of the 1-benzyl-4-methylaminopiperidine and 29.7 ml. of 37 percent aqueous formaldehyde in 60 ml. of ethanol. This suspension was reduced at 50 psi of hydrogen until one equivalent of hydrogen was consumed. The mixture was then filtered and the filtrate concentrated in vacuo. A solution of the residue in benzene was extracted with dilute hydrochloric acid. The aqueous phase was made alkaline with 40 percent aqueous sodium hydroxide and extracted with methylene chloride. The organic layer was dried over anhydrous potassium carbonate and concentrated in vacuo to afford 1-benzyl-4-dimethylaminopiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.C(N(CC)CC)C.C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([N:41]=[N+:42]=[N-:43])=[O:19])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(Br)cc1/C=C/C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(Br)cc1/C=C/C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of (2E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylic acid (4.5 g) in DMF (40 mL) was added a solution of triethylamine (2.0 mL) and diphenylphosphoryl azide (3.75 g) in DMF (5 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.56 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH2:11]([S:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: N#Cc1ccc(SCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: N#Cc1ccc(SCc2ccccc2)c(NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 64.7 %

Procedure:
Following General Procedure B, the title compound (419 mg, 65%) was prepared from 3-amino-4-(benzylthio)benzonitrile (370 mg, 1.54 mmol) and benzofuran-2-sulfonyl chloride (333 mg, 1.54 mmol) in pyridine (3 ml).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:13][C:14](=[O:17])[CH2:15][NH2:16])([CH3:12])([CH3:11])[CH3:10].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CCOCC>[C:9]([O:13][C:14](=[O:17])[CH2:15][NH:16][S:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)(=[O:30])=[O:29])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Yield: 87.3 %

Procedure:
14.4 ml of triethylamine are added dropwise to 6.91 g of glycine t-butyl ester hydrochloride and 12.1 g of 2-naphthylsulfonyl chloride in 70 ml of methylene chloride. The reaction mixture is subsequently diluted with 200 ml of ether. The organic phase is washed with 1N hydrochloric acid and with water. After drying and evaporation the residue is suspended in ether and suction filtered. After drying the crystals there are obtained 11.57 g of N-(2-naphthylsulfonyl)-glycine t-butyl ester, Rf=0.49 (ether/hexane 2:1).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].Cl[CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: ClCC=Cc1ccccc1
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)cc(OCC=Cc2ccccc2)c(C)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 4-hydroxy-2,3,6-trimethylphenyl acetate (10.0 g, 51.5 mmol) in N,N-dimethylformamide (100 mL) was added 1-chloro-3-phenyl-2-propene (7.86 g, 51.5 mmol) and potassium carbonate (7.10 g, 51.5 mmol) and the mixture was stirred under an argon atmosphere at 60° C. for 2 hours. This reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (13.0 g, yield 81%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1/C=C/CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A solution of tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 0.0597 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(E)-3-(piperidin-4-yl)prop-1-enyl]benzofuran-3(2H)-one (0.0173 g, 70%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH2:20].C(O)(=O)C>CO>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[N:20][NH:19][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a stirred solution of 1-(diphenylmethyl)azetidin-3-one (Preparation 693, 11.4 g, 48 mmol) and tert-butyl hydrazinecarboxylate (6.3 g, 48 mmol) in methanol (110 ml) at 0° C. was added acetic acid (5.56 ml, 96 mmol) dropwise and stirred at room temperature for 18 hours. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (500 ml). The organic layer was washed with 1M aqueous sodium hydroxide solution (2×150 ml), water (3×150 ml), saturated aqueous sodium chloride solution (150 ml), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was triturated with diethyl ether to get 15.8 g (94%) of the title compound as a white solid.