Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:25][NH:26][CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]1[N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]([CH:27]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CNC1Cc2ccccc2C1N1CCCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)C1Cc2ccccc2C1N1CCCC1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A mixture of 2.66 g of 3,4-dichlorophenyl-acetic acid, 2.10 g of carbonyl-diimidazole and 25 ml of tetrahydrofuran was stirred for 1 hour at 20 to 25° C. and then 2.16 g of the product of Step C was added in 10 ml of tetrahydrofuran with stirring for 3 hours 30 minutes at 20 to 25° C. after which the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in ether, washed with a saturated solution of sodium bicarbonate and then with water saturated with sodium chloride. After drying and concentrating to dryness under reduced pressure, 5.048 g of [Trans (±)] 3,4-dichloro-N-[2,3-dihydro-1-(pyrrolidinyl)-1H-inden-2-yl]-n-methyl-benzene-acetamide as a fluid resin.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[CH:31]([CH3:33])[CH3:32]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH:31]([CH3:33])[CH3:32])[CH:24]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cc[nH]c(=O)c3)cc1-2
Product: CC(C)Oc1cc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)ccn1

Procedure:
Following the procedure for Example 478, 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one 505 and 2-iodopropane were reacted to give 540. 1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.24 (d, J=5.4 Hz, 1H), 8.13 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.25 (d, J=5.3 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 5.85 (dt, J=13.3, 6.7 Hz, 1H), 5.38-5.22 (m, 1H), 4.44 (s, 2H), 3.48 (s, 2H), 1.59 (d, J=6.5 Hz, 6H), 1.32 (d, J=6.0 Hz, 6H). MS (ESI(+)): m/z 448.1 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(N(C(C)C)CC)(C)C>CN(C=O)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>[CH3:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]#[C:2][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: C#Cc1cc(C(=O)OC)ccc1C
Reactant: Ic1cnc2ccccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(C#Cc2cnc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-ethynyl-4-methylbenzoate (0.341 g, 2 mmol), 3-iodoquinoline (0.5 g, 2 mmol), Pd(PPh3)4 (0.11 g, 0.01 mmol), CuI (0.179 g, 0.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in DMF (15 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoate.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=2)[CH:23]=[CH:22]1.Cl>ClCCl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc2cc[nH]c2c1
Yield: 99 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5 g, 26.1 mmol) was added to a stirred solution of benzyl alcohol (2.47 ml, 23.9 mmol), 1H-indole-6-carboxylic acid (3.5 g, 21.7 mmol) and N,N-dimethylaminopyridine (3.4 g, 28.3 mmol) in dichloromethane (40 ml) at room temperature under a nitrogen atmosphere. After 12 h the reaction mixture was poured into 1M hydrochloric acid (200 ml) and extracted with dichloromethane (2×200 ml). The combined organics were dried (MgSO4) and concentrated to give a brown oil. Flash column chromatography (elution with dichloromethane) gave the subtitle compound (5.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[O:28][N:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1.[CH3:35][NH2:36].C1COCC1>>[Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:36][CH3:35])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[O:28][N:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3Cl)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 47.6 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (0.113 g, 0.225 mmol) and 2.0M MeNH2/THF (1.12 ml, 2.25 mmol) were combined to afford 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (52 mg, 48% yield) as a faintly yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 8.94 (brs, 1H), 8.62 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.88 (brq, J=4.8 Hz, 1H), 7.77 (s, 1H), 7.58 (d, J=10.8 Hz, 1H), 6.46 (s, 1H), 3.59 (s, 3H), 3.00 (septet, J=6.8 Hz, 1H), 2.91 (d, J=4.8 Hz, 3H), 1.20 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 486.2 (M+H+), 488.3 (M+2+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)[CH3:2].[CH3:16][C:17]1([CH3:26])[CH2:22][CH2:21][C:20](B(O)O)=[CH:19][CH2:18]1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:20]2[CH2:21][CH2:22][C:17]([CH3:26])([CH3:16])[CH2:18][CH:19]=2)[N:7]=1)[CH3:2]
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Product: CCOC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)n1

Procedure:
This compound was prepared from (5-nitro-pyridin-2-yl)-acetic acid ethyl ester (as prepared in the previous step) according to the procedure for nitro reduction and bromination in Example 33, step (b), followed by Suzuki coupling to 4,4-dimethyl-1-cyclohexen-1-ylboronic acid according to the procedure in Example 1, step (e). Mass spectrum (APCI, m/z): Calcd. for C17H24N2O2, 289.2 (M+H). found 289.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH2:51])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH:51][C:7]([C:5]3[N:4]=[CH:3][C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=3)=[O:9])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cnc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)cn1
Reaction time: 5 h

Procedure:
Pyrazine-2,5-dicarboxylic acid (0.58 g; 3.42 mmol), anhydrous HOBt (0.69 g; 5.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) were added to 5 ml of DCM. 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (1.0 g; 3.42 mmol) and DIPEA (0.89 ml; 5.13 mmol) were dissolved in 5 ml of DCM and added dropwise to the previous mixture. The reaction mixture was stirred overnight after which pyrazine-2,5-dicarboxylic acid (0.58 g; 1.59 mmol) and DIPEA (0.60 ml; 3.42 mmol) were added and the mixture was again stirred for 5 h. Anhydrous HOBt (0.69 g; 5.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.98 g: 5.13 mmol) and DIPEA (0.89 ml; 5.13 mmol) were again added to drive the reaction to completion. After overnight stirring the mixture was diluted with 20 ml of DCM and washed with 3×10 ml water. The organic phase was dried over Na2SO4, filtered and used as such without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH:9]3[CH2:11][CH2:10]3)(=[O:15])=[O:14])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cn1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
A mixture of 2-amino-5-bromopyridine (3.58 g, 20.7 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (5.00 g, 20.7 mmol), sodium carbonate (3.29 g, 31.05 mmol), and PdCl2(PPh3)2 (0.436 g, 0.62 mmol) in 3:1 acetonitrile:water was microwave heated at 80° C. for 20 min, and then at 100° C. for 15 min. The reaction was then heated in an oil bath at 80° C. for 16 h. The reaction was cooled to room temperature and filtered. The solid was washed with methanol (10 mL), and the combined filtrates were concentrated. The crude material was purified by flash chromatography over silica gel (0-5% MeOH/DCM) to give 4-(6-aminopyridin-3-yl)-N-cyclopropylbenzenesulfonamide (2.08 g, 35% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.27 (d, J=2.01 Hz, 1H), 7.88-7.95 (m, 2H), 7.85 (d, J=2.51 Hz, 1H), 7.81-7.84 (m, 1H), 7.71-7.79 (m, 2H), 6.45-6.88 (m, 1H), 1.89-2.41 (m, 1H), 0.13-0.82 (m, 4H); MS (EI) m/z: 290 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq. NH4OAc, 2 min gradient) tR=1.34 min, 88% integrated area.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C[N:25](C=O)C>>[Br:8][C:5]1[N:4]=[C:3]2[N:9]([CH2:10][C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:25]=[N:1][C:2]2=[N:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Br)cnc2N)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Cn2nnc3ncc(Br)nc32)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(R)-tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, 5.70 mmol) was dissolved in DMF (15 ml), and then isoamylnitrile (0.92 ml, 6.84 mmol) was slowly dropped at 0° C. After that, the mixture was stirred at 70° C. for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:8), to give (S)-tert-butyl 3-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (1.39 g, 62%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.Cl.N([O-])=O.[Na+].[I-:21].[K+]>O.C1(C)C=CC=CC=1>[I:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1S(N)(=O)=O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
1000 g (4.34 mol) of methyl 4-amino-2-aminosulfonylbenzoate and 3400 ml of H2O are admixed rapidly with 3700 ml of concentrated hydrochloric acid (37% strength). 10 ml of toluene are added to this mixture. The mixture is cooled to 15° C. and a solution of 315 g of NaNO2 (4.56 mol) in 1740 ml of H2O is added within a period of 1 h (h=hour) at 15-20° C. Stirring is continued for 1 h and the excess of nitrite is destroyed using amidosulfonic acid. In a second vessel, 1082 g of potassium iodide (6.51 mol) and 7000 ml of H2O are initially charged. At 15 to 20° C., the diazonium salt solution is added over a period of 1 to 2 h. The resulting suspension is diluted with 10 liters of H2O and the precipitate is filtered off with suction. The filter cake is then washed free of iodine using a mixture of 435 g of Na2S2O5 in 8.5 liters of H2O, and then washed neutral with 25 liters of H2O. The compound of the formula (IV) is obtained in a quantity of 1771 g (moist). After drying at 50° C. in vacuo (=under reduced pressure), 1403 g (94.8% of theory) of methyl 4-iodo-2- aminosulfonylbenzoate (sulfonamide of the formula IV) of a melting point of 175-177° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:25]([CH3:26])[NH:28][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=N)N
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)[nH]c1CC2
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester-(1.66 mmol) in 15 mL 1,4-dioxane is added acetamidine hydrochloride (3.32 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. To the residue is added 14 mL CHCl3 and 2 mL MeOH and the mixture is stirred for 10 min. The solid is filtered off. The mother liquid is concentrated and is chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 2-methyl-3,4,5,6-tetrahydro-imidazo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (30%). 1H NMR (DMSO-d6) 1.30 (t, 3H), 2.28 (s, 3H), 2.70 (t, 2H), 2.79 (t, 2H), 4.22 (q, 2H), 7.20 (s, 1H), 10.58 (s, 1H), 11.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O1CCCC1>O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)C1CC(Cl)=NN1c1cccnc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nn1-c1cccnc1

Procedure:
In step b of Scheme 2, methyl 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (6c) is oxidized with diammonium cerium (IV) nitrate (CAN) in water and polar solvents such as tetrahydrofuran at temperatures from about 0° C. to about 30° C. to yield methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (6d). It was surprisingly discovered that the oxidation in step b can also proceed with potassium permanganate (KMnO4) as the oxidant in polar solvents such as acetone at temperatures from about 0° C. to about 30° C. However, many standard oxidation procedures such as, for example potassium persulfate (K2S2O8), iodine pentoxide (I2O5), copper oxide (CuO), and hydrogen peroxide were found to be inoperative.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:38]=[CH:37][C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:38]=[CH:37][C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCNCC3)cc2)CC1
Yield: 90.4 %

Procedure:
tert-Butyl 4-[2-[4-(1-(benzyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]ethyl]piperazine-1-carboxylate (66% pure by weight) (34.62 g, 43.80 mmol) and 5% palladium on carbon (50% wet) (4.47 g, 1.05 mmol) in MeOH (250 mL) were stirred under an atmosphere of hydrogen at 5 bar and 60° C. for 4 hours. The catalyst was removed by filtration and the solvents evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with 60% EtOAc in isohexane then 15% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-1-carboxylate (15.42 g, 90%) as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=1)(=O)C.[OH-].[K+]>CO>[S:14]1[CH:15]=[CH:16][C:12]([C:8]2[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=2)=[CH:13]1
Reactant: CC(=O)OCc1cccc(-c2ccsc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 105.1 %

Procedure:
To 3.3 g (0.014 mol) of 3-(3-thienyl)phenylmethyl acetate was added with stirring a solution of 1.4 g (0.021 mol) of potassium hydroxide in 100 mL of methanol. The reaction mixture was stirred at ambient temperature for 19 hours. The volume of the reaction mixture was reduced to to 30 mL by concentration under reduced pressure. The concentrate was placed in a separatory funnel, and 100 mL of a saturated aqueous solution of sodium chloride was added. The mixture was extracted with five portions of 60 mL each of methylene chloride. The extracts were combined and washed with 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with toluene:pentane (3:2). The appropriate fractions were combined to give 2.8 g of 3-(3-thienyl)phenylmethanol.
Reaction SMILES: [C:1]([C:4](=[CH:7]N(C)C)[C:5]#[N:6])(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[CH2:20][CH2:19]1>C(O)C>[CH3:2][C:1]1[C:4]([C:5]#[N:6])=[CH:7][N:30]=[C:28]([NH:27][CH2:26][CH2:25][CH2:24][CH:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:29]=1
Reactant: CC(=O)C(C#N)=CN(C)C
Reactant: CN1CCC(CCCNC(=N)N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Reaction time: 24 h

Procedure:
To a 5-L round-bottom flask equipped with overhead mechanical stirrer, nitrogen inlet, and thermocouple probe were added 2-acetyl-3-dimethylamino-acrylonitrile (103.65 g, 0.75 mol), anhydrous potassium carbonate (powdered, not granular) (165.85 g, 1.2 mol), and N-[3-(1-methyl-piperidin-4-yl)-propyl]-guanidine (119.02 g, 0.60 mol) in ethanol (2.125 L). The resultant mixture was heated to reflux with stirring and held for 24 h. The resultant mixture was then concentration and the resultant residue partitioned between ethyl acetate (1.5 L) and 1 N NaOH (1.5 L). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2×1.5 L). The combined organic layers were concentrated to yield the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:33]1[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:42]3[C:43]4[NH:44][C:45]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:38]=4[CH:39]=[CH:40][CH:41]=3)=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:32])=[O:31])=[CH:25][CH:26]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccccc1NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 35.6 %

Procedure:
To a solution of 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.25 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.10 g, 36%). HRMS calcd for C36H29FN2O4: 572.6357. Found: 572.6354. MA calcd for C36H29FN2O4: C, 75.51%; H, 5.11%; N, 4.89%. Found: C, 75.83%; H, 5.10%; N, 4.90%.