Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:38]([N:37]([CH3:36])[C:33]([CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([N:8]([CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:26][C:25]=2[CH:27]=1)=[O:34])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCNC
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCN(C)C(=O)COc1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under nitrogen, a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (100 mg) in dichloromethane (3 ml) were added N-methylbutylamine (29 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg) in the presence of catalytic amounts of 4-dimethylaminopyridine at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give N-[3-[(butylmethylcarbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine (96 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][C:3]=1[C:18]([NH:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)=[O:19].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][C:3]=1[C:18]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1)=[O:19]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(OC)c3)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(COc2ccc(Cl)c(C(=O)NCc3ccc(C(=O)O)cc3)c2)c1

Procedure:
A solution of methyl 4-[({[2-chloro-5-({[3-(methyloxy)phenyl]methyl}oxy)phenyl]carbonyl}amino)methyl]benzoate (106 mg, 0.24 mmol) and lithium hydroxide (2 eq, 20 mg, 0.48 mmol) in dioxane (3 ml) and H2O (1.5 ml) was heated at 65° C. for 3 hours. On cooling solvent was evaporated in vacuo, residue acidified with 2M HCl and filtered to give the title compound as a white solid. MS (ES+) m/z 426 [M+H]+ (C23H2035ClNO5). 1H-NMR (400 MHz, d6-DMSO) δ 3.76 (3H, s), 4.50 (2H, d, J 6), 5.12 (2H, s), 6.91 1H, dd, J 1.6, J 7.6), 7.02 (1H, s), 7.09 (2H, m), 7.30 (1H, t, J 4), 7.40-7.47 (2H, m), 7.92 (2H, d, J 8), 9.04 (1H, t, J 6)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1Cl.[CH3:13][C:14]1([CH3:24])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:16]=2[O:15]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:23][C:22]1[C:16]2[O:15][C:14]([CH3:24])([CH3:13])[CH2:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)Cc2cccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)c2O1
Temperature: 25 °C

Procedure:
To a solution containing 32.83 g of 1,2,3-trichloro-5-nitrobenzene and 26.11 g of 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran in 300 ml of methyl ethyl ketone under an atmosphere of nitrogen and at room temperature was added 21.98 g of anhydrous potassium carbonate. The reaction mixture was heated to reflux. Reflux was maintained for 30 hrs. The reaction mixture was cooled to room temperature and the solvents removed. The tan solid residue was dissolved in hot hexane containing a little ethyl acetate. This was filtered and the filtrate allowed to cool to room temperature then placed in freezer to cool further to promote crystallization. The crystals were collected and placed in a vacuum dessicator for drying. A second crop of crystals was obtained from the mother liquors. This afforded 29.2 g of pale tan crystals. mp 105°-110° C. NMR (CDCl3): 1.47 (s, 6H), 3.03 (s, 2H), 6.3-7.0 (m, 3H), 8.22 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:33])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:33])[C:19]2[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@H](CCO)C1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1OCCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5.68 g (11 mmol) of the resulting alcohol derivative were dissolved in methylene chloride (60 ml) followed by the addition of 2.3 ml (16.5 mmol) of triethylamine under a nitrogen atmosphere, the addition of 1.02 ml (13.2 mmol) of methanesulfonyl chloride with ice-cooling, and stirring for 30 minutes at room temperature under a nitrogen atmosphere. Water was then added to the reaction solution followed by washing the methylene chloride layer with water and a saturated aqueous solution of sodium chloride and drying with anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/2) to obtain 6.09 g of the desired compound (93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[C:3]=1[OH:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=S.[CH3:24]O>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[O:13][C:3]2[C:4]([F:12])=[C:5]([CH2:8][C:9]([O:11][CH3:24])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: S=C=Nc1ccccc1Cl
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)c(F)c1O
Product: COC(=O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
In methanol (50 ml) was dissolved 4-amino-2-fluoro-3-hydroxyphenylacetic acid (2.52 g, 12.7 mmol). At room temperature, 2-chlorophenyl isothiocyanate (1.99 ml, 12.7 mmol) was added to the resulting solution. After the resulting mixture was stirred at room temperature for 2.5 hours, mercuric oxide (yellow) (3.29 g, 15.2 mmol) was added thereto. The mixture was stirred further for 14 hours at 70° C. The reaction mixture was allowed to cool down to room temperature. The insoluble matter was filtered off through Celite under reduced pressure, followed by washing with methanol. From the filtrate, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 100 g, chloroform/ethyl acetate (30/1)), whereby from eluate fractions, methyl 2-(2-chlorophenyl)amino-7-fluoro-6-benzoxazolylacetate (2.12 g, 50%) was obtained as a pale pink solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: OCc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2ccccc2CO)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodobenzylalcohol (234 mg, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-(4-methoxyphenyl)sulfanylbenzylalcohol (219 mg, 89% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=5/1). Rf=0.3 (hexane/ethyl acetate=5/1). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dd, 1 H, J=6.6 Hz, 1.5 Hz), 7.29 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 7.13-7.21 (m, 2 H), 7.08 (dd, 1 H, J=8.1 Hz, 2.1 Hz), 6.86 (dt, 2 H, J=9.0 Hz, 2.1 Hz), 4.78 (d, 2 H, J=6.3 Hz), 3.80 (s, 3 H), 2.12 (t, 1 H, J=6.3 Hz). 13C NMR (CDCl3, 75 MHz) δ 159.7, 140.0, 135.9, 134.3, 130.8, 128.6, 128.5, 127.1, 124.5, 115.3, 63.9, 55.7. IR (neat, cm−1) 3365 (broad), 3015, 2962, 2904, 2867. MS (EI) m/z (relative intensity) 246 (100), 138 (40), 108 (70). HRMS (EI), Cald. for C14H14O2S 246.0709. Found 246.0707.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:23][N:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:9]2[CH2:8][C:7]1=O)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:29]>CO>[CH2:1]([O:3][C:4]([C:6]1[CH2:23][N:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:9]2[CH2:8][C:7]=1[NH2:29])=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of 9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 4.00 g, 12.0 mmol) and ammonium acetate (13.9 g, 180 mmol) in methanol was stirred 5 h at room temperature. After evaporation of the solvent the residue was partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was dried (MgSO4), and triturated with heptane to afford the title compound (3.71 g, 93%). Off-white solid, MS (ISP) 333.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(C)C>C(Cl)Cl>[OH:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COc1ccc2cc(C)sc2c1OC(C)C
Solvent: ClCCl
Product: COc1ccc2cc(C)sc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 140.1 %

Procedure:
To a mixture of the product of Step D (0.033 g; 0.0941 mmol) in CH2Cl2 (1 ml) TiCl4 (0.02 ml; 0.182 mmol) was added at room temperature under N2. After stirring for 10 min at room temperature, the mixture was diluted to 15 ml with CH2Cl2 and quenched with H2O (5 ml) and the organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure to give 7-hydroxy-6-methoxy-2-methyl-benzo[b]thiophene (0.0256 g; 100%). This was diluted to 1.ml with CH2Cl2 and tosyl chloride (0.03 g; 0.158 mmol), followed by triethylamine 0.022 ml; 0.158 mmol) of were added to it. The resulting mixture was stirred for 1 h at room temperature, washed with H2O, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from hexane/ethyl acetate mixture (9.5:0.5) to give the title compound (0.035 g; 68%), as creamy crystals. 1H-NMR (CDCl3) 2.45 (s, 3H); 2.48 (s, 3H); 3.63 (s, 3H); 6.83 (s, 1H); 7.32 (d, 2H, J=8.27 Hz); 7.43 (d, 1H, J=8.62 Hz), 7.87 (d, 2H, J=8.62 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:18][C:17](=O)[C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][O:12][C:8]=2[CH2:7]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][O:12][C:8]=2[CH2:7]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccco2)Cc2occ(C(F)(F)F)c21
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccco2)Cc2occ(C(F)(F)F)c21
Temperature: 90 °C
Reaction time: 4 h
Yield: 40.6 %

Procedure:
To a mixture of 6-(2-furyl)-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g) and aminoguanidine hydrochloride (90 mg) were ethanol (16 ml) and 6N hydrochloric acid (0.070 ml), and the mixture was stirred at 90° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-furyl)-4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 54) (0.12 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[CH:32]=[N:33][N:34]([CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][CH2:38][C:39](=[O:42])[CH2:40][CH2:41]4)[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1CCC(n2cc(I)cn2)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A 20 ml sealable vial was charged with 3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80.0 mg, 0.156 mmol), 4-(4-Iodopyrazol-1-yl)cyclohexanone (52.5 mg, 0.172 mmol), Pd(PPh3)4 (12.0 mg, 0.0103 mmol), potassium carbonate (71.8 mg, 0.514 mmol), and 4:1 dioxane:water (5 mL). The cap was sealed and the vial was evacuated and backfilled with nitrogen (3×). After that, the vial was heated at 90° C. for 2 h. The reaction mixture was partitioned between EtOAc/H2O (15 ml/10 ml). The aqueous phase was extracted with EtOAc (10 ml). The combined organic extracts were washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil that was purified by prep. TLC eluting with 4% MeOH/DCM to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=7.2 Hz, 3H), 2.31-2.68 (m, 8 H), 4.64 (tt, J=11.8, 4.0 Hz, 1 H), 5.28 (q, J=7.2 Hz, 1 H), 7.01 (dd, J=8.0 & 8.8 Hz, 1 H), 7.30 (s, 1 H), 7.32 (brs, 1 H), 7.48 (s, 1 H), 7.60 (d, J=0.8 Hz, 1 H), 7.66 (d, J=0.8 Hz, 1 H), 8.41 (brs, 1 H), 9.77 (brs, 1 H). MS (ES+): m/z=471.16/473.11 (100/68) [MH+]. HPLC: tR=3.39 min (polar—5 min, ZQ3).
Reaction SMILES: C([C@@:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])(OC(C)(C)C)=O.[C:18]1(=[O:28])[O:23][C:21](=O)[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:18]([NH:17][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][N:10]1[C:18](=[O:28])[C:19]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]1=[O:23])=[O:28])[CH2:20][CH2:19][CH3:27]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)[C@](N)(CN)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
Boc-(R)-1,2 diamino-1-phenylethane (prepared by the method of O'Brien, P. et al. J. Med. Chem. 37 (1994) 12, 1810-1822) (0.3 g, 1.27 mmol.), phthalic anhydride (0.2 g., 1.4 mmol.) and TEA (0.1 ml) were dissolved in chloroform (20 ml.) and stirred under reflux for 2 days. The reaction mixture was then washed with 10% hydrochloric acid, 2M sodium hydroxide solution and brine, dried over magnesium sulphate, filtered and evaporated to give the product. The above product was further elaborated by Method 4 to the title compound.
Reaction SMILES: N1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[N+:12](=[CH2:14])=[N-].[CH3:15]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1>CCOCC>[CH3:15][O:5][C:4]1[C:2](=[O:3])[NH:12][C:14]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: C=[N+]=[N-]
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CCOCC
Product: COc1cc2ccccc2[nH]c1=O
Reaction time: 3 h
Yield: 52 %

Procedure:
To a mixture of 1.05 g (7.1 mmol) of isatin in 15 mL of ether in ice-bath was added dropwise a solution of diazomethane in ether (prepared from 4.4 g (20 mmol) of Diazald according to Aldrichimica Acta 16:3 (1983)). The resulting solution was stirred in ice-bath for 3 h then room temperature overnight. The mixture was filtered and dried to leave white solid 0.684 g (52%), mp 188°-189° C. (lit. 191° C.; Greibrokk and Undheim, Acta Chem. Scand. 25:2935 (1971)). 1H NMR (CDCl3) 3.977 (s, 3), 7.014 (s, 1), 7.21 (m, 1), 7.39 (m, 2), 7.509 (d, 1, J=7.8), 11.429 (s, 1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:19]>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:4][C:5]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:18]([CH3:17])[CH3:19])=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: Cc1cccc(Nc2nc(Cl)ncc2Br)n1
Reactant: CN(C)CCCOc1ccc(N)cc1
Product: Cc1cccc(Nc2nc(Nc3ccc(OCCCN(C)C)cc3)ncc2Br)n1

Procedure:
Using an analogous method to that described in Example 136, but starting from 5-bromo-2-chloro-4-[(6-methylpyrid-2-yl)amino]pyrimidine (Method 84) and 4-[3-(N,N-dimethylamino)propoxy]aniline (obtained as described in WO 9909030), the product was obtained. MS (MH+): 457, 459; HPLC (RT): 5.26.
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][O:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:26]([NH:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])=[O:36])=[O:27])([CH3:32])([CH3:31])[CH3:30].[NH2:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])=[O:36]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(N)C(C)C)N2C(=O)C(N)C2SC1
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)N2C(=O)C(N)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethyl formamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness to give 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by standard procedures to give the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[N:41][N:42]2[CH2:47][C:48]1[CH:49]=[C:50]([CH:55]=[CH:56][CH:57]=1)[C:51]([O:53][CH3:54])=[O:52]>CCOC(C)=O.CN1C(=O)CCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:37][C:38]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:39]=3[CH:40]=[N:41][N:42]4[CH2:47][C:48]3[CH:49]=[C:50]([CH:55]=[CH:56][CH:57]=3)[C:51]([O:53][CH3:54])=[O:52])=[O:17])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(=O)OC)c3)cnc2c1
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a vial was added 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.260 g, 1.05 mmol) and NMP (3.5 mL). Triethylamine (0.243 mL, 1.74 mmol) was added and the mixture was stirred until homogeneous. 2,4,6-Trichlorobenzoyl chloride (0.153 mL, 0.975 mmol) was added and the mixture was stirred at ambient temperature for 0.5 hours. Methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.196 g, 0.697 mmol) was added as a NMP solution (1.2 mL), and the reaction mixture was sealed in the vial and warmed to 80° C. with stirring overnight. The reaction mixture was cooled and diluted with EtOAc (20 mL), and then filtered to remove white solids. The solids were washed with EtOAc and the filtrate was concentrated under vacuum until only DMA was left. The concentrated solution diluted with water/saturated aqueous NaHCO3 (25 mL, 1:1) forming a precipitate. The precipitate was isolated by filtration and the solid was washed with water, Et2O, and hexanes, then dried under vacuum at 40° C. for 4 hours to provide 0.279 g (74%) of the title compound. MS (ES+APCI) m/z=500 (M+H).
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:5][CH2:6][CH3:7])[CH3:4].[CH2:8]([OH:11])[C:9]#[CH:10]>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:3]([N:5]([CH2:6][CH3:7])[CH2:1][C:10]#[C:9][CH2:8][OH:11])[CH3:4]
Reactant: CCNCC
Reactant: C=O
Reactant: C#CCO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCN(CC)CC#CCO
Temperature: 62.5 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A mixture of para formaldehyde (105.0 g), N,N-diethyl amine (300 g) and copper(II) acetate (7.5 g) in 1,4 dioxane (900 ml) was heated to 60-65° C. After 1.5 h, 2-propyne-1-ol (150 g, 2.7 moles) was added and the mixture was heated at 90-95° C. after 2 hrs; excess solvent, 1,4 dioxane, evaporated at reduced pressure to afford 315 g (84%) of the product as an oil.