Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:40][CH3:41])[CH2:33][CH3:34])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 85 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N,N-diethyl-1,3-propanediamine (available from Aldrich Chemical Company, Inc.; 81 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-diethylamino-propylcarbamoyl)-biphenyl-2-carboxylic acid (104 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.63 (br s, 1H), 9.48 (br s, 1H), 1H NMR (400 MHz, DMF), d ppm 9.14 (t, J=5.6 Hz, 1H), 8.92 (s, 1H), 8.83 (d, J=1.8 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.68 (dd, J=8.0, 2.0 Hz, 1H), 8.52 (dd, J=8.3, 2.0 Hz, 1H), 8.34 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 3.77-3.84 (m, 2H), 3.51-3.63 (m, 6H), 2.28-2.38 (m, 2H), 1.62 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]=[C:16]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[C:15]=2[NH:14][C:13](=[NH:29])[CH2:12]1.[CH2:30](OC(OCC)CBr)[CH3:31]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[C:16]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH3:28])[N:17]=[C:18]([CH3:21])[N:19]=2)[N:14]2[CH:30]=[CH:31][N:29]=[C:13]2[CH2:12]1
Reactant: CCCCN(CC)c1nc(C)nc2c1NC(=N)CN2c1ccc(C(C)C)cc1Br
Reactant: CCOC(CBr)OCC
Solvent: CCO
Product: CCCCN(CC)c1nc(C)nc2c1-n1ccnc1CN2c1ccc(C(C)C)cc1Br

Procedure:
A solution of the compound of Example 248 and a slight excess of bromoacetaldehyde diethyl acetal in ethanol is heated to reflux until the starting material is consumed. The reaction mixture is evaporated, and the residual material is purified by chromatography or recrystallization to afford the title product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=CC=C[C:6]=2[O:5][CH2:4]1.C(C1OC1)Cl>>[CH2:6]([O:5][CH2:4][CH:3]1[O:1][CH2:2]1)[CH:7]1[O:8][CH2:9]1
Reactant: OCC1COc2ccccc2O1
Solvent: ClCC1CO1
Product: C(OCC1CO1)C1CO1

Procedure:
The novel process involves reaction of a 2-hydroxymethyl-1,4-benzodioxan with epichlorohydrin to produce an intermediate glycidyl ether, which is then reacted with a primary amine to produce the final 3-amino-1-[(1,4-benzodioxan)-2-yl-methoxy]-2-propanol or an acid addition salt thereof.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:26]C)=[O:10].B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl.C(#N)C.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[OH:26])=[O:10]
Reactant: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2O)c(Cl)c1Cl
Temperature: 40 °C

Procedure:
Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 35; 100 mg) was suspended in anhydrous DCM. BBr3/DCM (15 ml) was added and the mixture was heated at 40° C. for 18 h. The reaction mixture was cooled to −50° C. and water was added. The mixture was extracted with EtOAc and the organic phase was washed with water, dried over Na2SO4. The organic phase was concentrated in vacuo to yield a pale brown solid which was dissolved in acetonitrile/water mixture and was lyophilized (46 mg). MS (ES) MH+: 419 for C15H16Cl2N4O4S; NMR: 1.87 (m, 2H), 2.20 (s, 3H), 3-4 (brm, 6H), 6.9 (d, 1H), 7.51 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:32]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 403.00 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([C:24](OCC)=[O:25])=[C:9]1[CH:29]([CH3:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([CH2:24][OH:25])=[C:9]1[CH:29]([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OC3CCCCO3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1c(CO)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To −78° C. solution of 1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxylic acid, ethyl ester (Compound 11, 2.11 g, 5 mmol) in THF (30 mL) was added a 1 M solution of LiAlH4 in THF (9 mL, 9 mmol) dropwise over 5 minutes. The mixture was gradually warmed to 0° C. over 4 h. The reaction was cooled to −78° C. and quenched by adding EtOAc (5 mL) and saturated aqueous Na2SO4 (9 mL). The solution was warmed to room temperature and stirred for 20 minutes. The resulting precipitate was filtered off, and the organic layer was dried (Na2SO4). The solvent was removed under vacuum to obtain (1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)methanol (Compound 12) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCOCC4)nc3cc21

Procedure:
Morpholine-4-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and morpholine 4-carbonyl chloride. The title compound was obtained as light yellow powder (51 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-])=O)[C:4]=1[OH:26].[OH-].[Na+].C(S(O)=O)(N)=N>O.C(O)CC>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]3=[N:23]2)[C:4]=1[OH:26]
Reactant: COc1cc(CO)c(O)c(N=Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: N=C(N)S(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: COc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer was added 7.70 g (20.7 mmol) 2-(hydroxymethyl)-4-methoxy-6-((2-nitro-4-(trifluoromethyl)phenyl)diazenyl)-phenol from Example 2 part 1, 25 ml deionized water, 1.85 g sodium hydroxide, and 80 ml 1-propanol. The mixture was heated to 80° C. and 6.55 g (60.6 mmol) formamidine sulfinic acid (Aldrich) was added slowly and concurrently with a solution of 3.0 g NaOH in 50 ml deionized water. The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled at −20° C. for 2 hours and filtered. The solid was dissolved in 2.5 L deionized water containing 4 grams NaOH. The pH was adjusted to 2.0 using 1 N HCl. The resultant solid was filtered, washed with ample amounts of deionized water, filtered and dried to give 2.2 g (31%) of a yellow solid. 1H NMR (CDCl3) delta: 11.03 (s, 1H, Ar—OH), 8.30 (s, 1H, Ar—H benzotriazole 4-position), 8.07 (d, 1H, Ar—H benzotriazole 6-position), 7.88 (s, 1H, Ar—H phenol), 7.69 (d, 1H, Ar—H benzotriazole), 7.08 (s, 1H, Ar—H phenol), 4.84 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[K+].C1(C)C=CC(S(O[C:15]2[CH2:16][C@@H:17]3[CH2:31][C:30](=[O:32])[N:18]3[C:19]=2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1.O1CCOCCOCCOCCOCCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>C(#N)C.ClCCl>[CH2:23]([O:22][C:20]([C:19]1[N:18]2[C:30](=[O:32])[CH2:31][C@H:17]2[CH2:16][C:15]=1[N:1]=[N+:2]=[N-:3])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)C[C@H]3C2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Potassium azide (11.6 mg, 143. micromol) was added to a stirred ambient temperature solution of benzyl 2-(p-toluenesulfonyloxy)-carbapen-2-em-3-carboxylate (20.0 mg, 48.4 micro mol) prepared according to the analogous procedure described in U.S. Pat. No. 4,424,230, hereby incorporated by reference for this particular purpose, and 1,4,7, 10,13,16-hexaoxacyclooctadecane (12.8 mg, 48.4 micro mol) in anhydrous acetonitrile (1.0 ml) and dichloromethane (0.2 ml). After 1 hour the mixture was applied to two 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates and developed with 3:2 (v/v) toluene-ethyl acetate. The band centered at Rf 0.6 was eluted with ethyl acetate and the elulate was evaporated under vacuum to provide 9.2 mg (67%) benzyl-2-azido-carbapen-2-em-3-carboxylate as a pale yellow glass. The glass was crystallized from 5:1 (v/v) diethyl etherdichloromethane to provide pale yellow rosettes of needles, m.p. 84°-85° C. (dec); I.R. (neat film): 2110, 1785, 1710, 1605, 1285, 1210, 1190 cm-1 ; NMR (CDCl3): δ(del) 2.99 dd (J1 =3 Hz, J2 =16 Hz, 1H), 3.07 d (J=9 Hz, 2H), 3.52 dd (J1 =5 Hz, J2 =16 Hz, 1H), 4.25 m (1H), 5.30 d (J=8 Hz, 1H), 5.33 d (J=8 Hz, 1H), 7.37 m (5H); UV (CH2Cl2) λmax (ε): 310 (10,000)nm; MS (m/e): 256 (M+ -N2), 243, 228, 214, 178, 162, 160, 127, 120, 107.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:21])=[C:7]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[C:6]([OH:21])=[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(CCC(=O)O)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Operating under a nitrogen current, 29.8 g of methyl 3-(3',5'-di-tert-butylhydroxyphenyl)propionate, 80 mL of ethanol, and 6 g of sodium hydroxide were introduced into a 0.5-L four-neck flask equipped with a stirrer, addition funnel, and thermometer and were stirred for 1 hour while heating under reflux. After the completion of the stirring period, the ethanol was removed by distillation and the reaction mass was then neutralized by the gradual addition of concentrated hydrochloric acid. 150 mL of a 1:1 liquid mixture of toluene and ethyl acetate was added followed by washing twice with water. The solvent was then distilled from the washed organic layer to give 27.2 g of 3-(3',5'-di-tert-butylhydroxyphenyl)propionic acid in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]1[CH2:22]O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]1[CH2:22][N:29]1[C:25](=[O:35])[C:26]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]2[C:28]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cn(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)c(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)c(CN2C(=O)c3ccccc3C2=O)n1

Procedure:
In the manner given in Example 17, 2',5-dichloro-[2-(hydroxymethyl)-4-methylimidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azocarboxylate to give 2',5-dichloro-2-[4-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[CH3:11][S:12]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:14])=[O:13]
Reactant: OCCc1ccc(I)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCc1ccc(I)cc1

Procedure:
Prepared analogously to Example 1.2.b. from 2-(4-iodophenyl)ethanol and methanesulfonic acid chloride. Yield: 5.7 g (77.4% of theory); C9H11IO3S (M=326.15); calc.: molecular ion peak (M)+: 326; found: molecular ion peak (M)+: 326.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33]([O:35][CH2:36][CH2:37]O)[CH3:34].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl>O1CCCC1>[CH2:33]([O:35][CH2:36][CH2:37][N:5]1[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]1)[CH3:34]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: CCOCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCn1nc(CC)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A 1 L flask was charged with 3-ethyl-4-nitropyrazole-5-carboxamide (prepared as described in EP 1176142 at page 18) (15.0 g, 81 mmol), triphenylphosphine (25.6 g, 97.8 mmol), and tetrahydrofuran (120 mL). The resulting mixture was cooled by placing the flask in a 0° C. bath and 2-ethoxyethanol (9.5 ml, 98 mmol) was added to the flask. A solution of di-tert-butyl azodicarboxylate (22.5 g, 97.8 mmol) in tetrahydrofuran (90 mL) was then added to the flask over a period of 2.5 hours. The mixture was stirred with cooling for an additional hour and then warmed to room temperature and stirred for one additional hour. The mixture was again cooled to 0° C., treated with 6M hydrochloric acid (40 ml), and heated to 40° C. for one hour. The mixture was partially concentrated and extracted between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over magnesium sulfate, filtered and then concentrated. The resulting viscous oil was treated with 2-propanol and this mixture was then concentrated. The resulting material was treated with 2-propanol and heated. Upon cooling, the resulting crystals were filtered, rinsed with cold 2-propanol, and dried to afford 16.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][C@H:15](C)[NH:14][C:13]2=[O:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:19][C:20]1N=C(N2CCNC2=O)S[C:24]=1[C:25](OCC)=O.BrCCC=C>>[CH2:25]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:18])[CH2:24][CH:20]=[CH2:19]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: CCOC(=O)c1sc(N2C[C@H](C)NC2=O)nc1C
Agent: C=CCCBr
Product: C=CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O

Procedure:
Following the procedure as described in Preparation 5, making variations as required to replace (S)-ethyl 4-methyl-2-(4-methyl-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate and with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate to react with 4-bromobut-1-ene, the title compound was obtained as an off-white solid (2.05 g, 85%): mp 97-98° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 5.86-5.72 (m, 1H), 5.16-5.02 (m, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.02-3.79 (m, 2H), 3.60-3.55 (m, 2H), 3.34-3.29 (m, 2H), 2.51 (s, 3H), 2.33-2.26 (m, 2H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 309.8 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10]C)=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].Br>>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1cc(CC(=O)O)c(OC)cc1C
Agent: Br
Product: Cc1cc(O)c(CC(=O)O)cc1O

Procedure:
0.285 mol (60 g) of 2-(2',5'-dimethoxy-4'-methylphenyl)-acetic acid is heated under reflux for 5 hours in 480 ml of 48% strength hydrobromic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([CH3:16])[N:13]=[N:14][CH:15]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[N:12]([CH3:16])[N:13]=[N:14][CH:15]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1nncc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cn1nncc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 28 mg (0.12 mmol) of (2-Amino-5-chloro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl)methanone and 56 mg (0.24 mmol) of 4-tert-butylphenylsulfonyl chloride were combined in 0.5 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR CD3OD δ (ppm): 1.20 (s, 9H), 4.15 (s, 3H), 7.37 (d, 2H), 7.52 (d, 2H), 7.59-7.62 (m, 2H), 8.27 (d, 1H), 8.53 (s, 1H); MS: (M+H)/z=433.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CO)cn2)n1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A solution of ethyl 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinate (1.50 g, 3.70 mmol) in THF (15 mL) was added to a 1.0 M solution of lithium aluminum hydride (18.5 mL, 18.5 mmol) in ether at 0° C. and stirred for 30 minutes. The reaction was quenched with sodium sulfate decahydrate, stirred 30 minutes, and filtered. The solids were washed with THF, filtered, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, and concentrated. The residue was triturated with hexanes and filtered to afford (6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)methanol (1.10 g, 81.8% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.68 (bs, 1H), 8.25 (s, 1H), 8.05 (d, 1H), 7.92 (d, 2H), 7.53-7.64 (m, 3H), 7.36 (d, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 5.20 (t, 1H), 4.71 (d, 2H), 2.13 (s, 3H); Mass spectrum (esi) m/z=364 (100) (M+H).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:27]([CH2:26][C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[C:21]([CH3:28])[CH:22]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)cnc1OCC(F)F
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: Cc1cc(CN2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)F
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (63 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (206 mg, 0.86 mmol, Amine-4) in a similar manner to Intermediate-2.
Reaction SMILES: C(O[C:4](=[O:30])/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=2)=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13])C.C1CCN2C(=NCCC2)CC1.O>C(N(CC)C(C)C)(C)C.C1COCC1>[CH3:13][C:12]1[C:7]2[CH:6]=[CH:5][C:4](=[O:30])[N:16]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:28][CH:29]=3)[C:8]=2[N:9]=[C:10]([S:14][CH3:15])[N:11]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(C)c2ccc(=O)n(-c3ccc(C(=O)OC(C)(C)C)cc3)c2n1
Yield: 70.8 %

Procedure:
A mixture of compound H (19 g; 0.04423 mol) and DBU (14 mL; 0.0936) in 110 mL of N,N-diisopropylethylamine and 30 mL of THF was refluxed for 30 h. The reaction mixture was poured into 600 mL of iced water and extracted with ethyl acetate (3×500 mL). The organic phase was washed with water and brine, dried over anhydrous sodium sulphate and concentrated. The crude was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=2/1 to 1/2) to yield compound 1 (12 g; 71%) as a yellow solid.