Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[Cl:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:16][C:15]=2[Cl:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2Cl)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3ccccc3)ccc2Cl)c1
Temperature: 80 °C

Procedure:
[3-(5-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester (198 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]#[C:4][C:5](OCC)=[O:6].[CH3:11][NH:12][NH2:13]>C(Cl)Cl.C(OCC)(=O)C>[F:1][CH:2]([F:10])[C:3]1[N:12]([CH3:11])[N:13]=[C:5]([OH:6])[CH:4]=1
Reactant: CCOC(=O)C#CC(F)F
Reactant: CNN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(O)cc1C(F)F
Temperature: -78 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
10.2 g (0.068 mol) of ethyl 4,4-difluoro-2-butynoate in 20 ml of methylene chloride was added dropwise to a stirred solution of 4 ml (0.075 mol) of methylhydrazine in 80 ml of methylene chloride cooled to -78° C. The resultant reaction mixture was stirred overnight and subsequently concentrated in vacuo to afford 8.63 g of a clear, yellow oil. The oil was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate. The organic layer was dried, concentrated and recrystallized from carbon tetrachloride to give 2.2 g (21.7% yield) of a white crystalline solid, m.p. 115°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16]O)[O:8]1)[CH2:6][CH2:5]2.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][F:36])[O:8]1)[CH2:6][CH2:5]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CF)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3′,4′,5′-triol (10 mg, 0.024 mmol) in CH2Cl2 (1 mL), was added DAST (9 μL, 0.072 mmol) at −78° C. The mixture was stirred for 30 min at −78° C., then allowed to warm to room temperature and stirred for another 3 h. The reaction was quenched by aqueous saturated NaHCO3. The organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give 4 mg (40%) of title compound as a colorless solid. 1H NMR (CD3OD, 300 MHz): δ 7.24 (s, 1H), 7.19 (s, 1H), 7.08 (m, 4H), 4.63 (d, J=3.3 Hz, 1H), 4.47 (d, J=3 Hz, 1H), 4.04 (m, 2H), 3.59-3.38 (m, 4H), 2.93 (t, J=7.2 Hz, 2H), 2.58 (q, J=7.8 Hz, 2H), 2.54 (dt, J=13.5, 7.8 Hz, 1H), 2.08 (dt, J=13.5, 7.8 Hz, 1H), 1.19 (t, J=7.8 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.[I-].[Na+]>[N:19]([CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1cnc2c(CN=[N+]=[N-])cccc21
Yield: 83.6 %

Procedure:
A mixture of 4-(bromomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.08 g, 3.5 mmol), sodium azide (240 mg, 3.7 mmol), and sodium iodide (5 mg) in acetone (10 mL) was heated at reflux for 66 h. The solvent was evaporated and dichloromethane was added. The solution was washed with dilute aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to give 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (800 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:41]3[CH2:42][CH2:43][CH:38]([C:29]4[CH:30]=[CH:31][C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:28]=4)[CH2:39][CH2:40]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc12
Yield: 48.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (120 mg, 0.33 mmol) obtained in Example 90, step 2 and 4-(2-naphthyl)piperidine hydrochloride (WO1997/037979, 100 mg, 0.40 mmol), the title compound (89 mg, 49%) was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.CC(C)([O-])C.[K+].[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][CH:24]=1.[C:36](=[O:38])=[O:37]>CCOCC>[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][C:24]=1[C:36]([OH:38])=[O:37]
Reactant: O=C=O
Reactant: Cc1csc2cc(Cc3cccnc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2cc(Cc3cccnc3)ccc12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
n-Butyl lithium (0.65 ml. of 1.55 M solution in hexane) was added dropwise to a stirred mixture of diisopropylamine (0.10 g.) and potassium t-butoxide (0.11 g.) in dry ether (10 ml.) at -78° C. under an atmosphere of dry nitrogen. The mixture was stirred at -78° C. for 45 minutes and then a solution of 3-methyl-6-(3-pyridylmethyl)benzo[b]thiophene (0.20 g.) in dry ether (5 ml.) was added. The solution was stirred at -78° C. for 45 minutes and then an excess of crushed solid carbon dioxide was added. When all the carbon dioxide had evaporated, water (5 ml.) was added and the mixture was shaken. The aqueous layer was then separated and washed with ether. It was then acidified with acetic acid and the solid was filtered off and dissolved in 2 N sodium hydroxide. The solution was decolorized by warming with charcoal and then filtered. Acidification of the filtrate with acetic acid gave a solid which was filtered off, washed with water and dried to give 3-methyl-6-(3-pyridylmethyl)-benzo[b]thiophene-2-carboxylic acid (0.10 g.), m.p. 250°-252° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([NH:20][C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C)[CH:32]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[C:12]([NH:20][C:21]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(Oc2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2cccc(O)c2)ccc1C(=O)O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
0.22 g of aluminum chloride was added to 1.0 ml of toluene solution containing 0.10 g of 2-(benzamido)-4-(3-methoxyphenoxy)benzoic acid at room temperature and stirred at 80° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/b hydrochloric acid were added. The organic layer was separated, and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate; acetic acid=15:10:1]to obtain 54 mg of 2-(benzamido)-4-(3-hydroxyphenoxy)benzoic acid as white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCO)c1ccc2ncccc2c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(CC=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-quinolin-6-ylbutan-1-ol (0.060 g, 0.30 mmol) in methylene chloride (3.0 mL) was added 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (0.005 g, 0.03 mmol) and iodobenzene diacetate (0.10 g, 0.33 mmol). The reaction was stirred overnight at RT. The mixture was purified by chromatography on silica gel with EtOAc in hexanes (0-40%) to afford the desired product (0.050 g, 84%). LCMS: (M+H)=200.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH2:17]Cl)=[O:16]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:14][C:15](=[O:16])[CH3:17])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CSc1nnnn1C
Reaction time: 2 h
Yield: 48 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (0.01 mol), potassium carbonate (0.015 mol) and α-chloroacetone (0.015 mol) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] and the product is recrystallized from methanol-ether to obtain 1-methyl-5-acetylmethylthio-1,2,3,4-tetrazole (yield 48%) as colorless needles, m.p. 31° C.
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].[Cl:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][C:10]2=[N:11][C:12](=[O:14])[N:13]=[C:9]2[CH:8]=1.[H][H]>N.O[V](=O)=O.[Pt].O>[NH2:17][C:16]1[C:7]([Cl:6])=[CH:8][C:9]2=[N:13][C:12](=[O:14])[N:11]=[C:10]2[CH:15]=1
Reactant: [H][H]
Reactant: O=C1N=c2cc(Cl)c([N+](=O)[O-])cc2=N1
Agent: O=[V](=O)O
Agent: [Pt]
Agent: N
Solvent: O
Product: Nc1cc2c(cc1Cl)=NC(=O)N=2
Temperature: 65 °C
Yield: 95.3 %

Procedure:
0.01 g of ammonium vanadate and 8 g of aluminium oxide granules containing 0.5% by weight of metallic platinum and having a particle size of 3.2 mm (from Acros Organics) are added to a suspension consisting of 200 ml of water and 21.4 g of 5-chloro-6-nitrobenzimidazolone. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 65° C. At a hydrogen absorption of 85% of theory, another 50 ml of water are added to improve the stirrability and the mixture is then stirred at the same temperature under a hydrogen atmosphere for a total of 98 hours. During this time, 97% of the theoretical amount of hydrogen, based on 5-chloro-6-nitrobenzimidazolone, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 100 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 17.5 g (95%) of 5-amino-6-chlorobenzimidazolone. Only traces of 5-aminobenzimidazolone can be found in the NMR.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22](=[O:23])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: O=C=NC1CCCCC1
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(CSc1cccc(OC(=O)NC2CCCCC2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Cyclohexyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio) phenyl] N-cyclohexylcarbamate as the residue.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].Br[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1)=[O:11])([CH3:4])[CH3:3]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)[nH]1
Yield: 94.8 %

Procedure:
Following a procedure similar to that described in Preparation 31, but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] and 1.15 g of 3-bromophthalide, 1.63 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-fluorobenzaldehyde and acetophenone, 3-(4-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cnoc1-c1ccc(F)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.9 %

Procedure:
To a solution of ethyl 5-(3,4-difluorophenyl)isoxazole-4-carboxylate (6.68 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 75 ml) at 0° C. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3,4-difluorophenyl)-4-isoxazolylmethanol (6.68 g, yield 92%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 72–73° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[NH2:18][S:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]1[CH3:1])(=[O:17])=[O:16]
Reactant: NS(N)(=O)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(N)(=O)=O
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3R)-3-methylpiperazine-1-carboxylate ((the product from step i), 1.1 g) in dioxane (60 ml) was added sulfamide (1.06 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow oil. Yield: 1.44 g
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1-c1cc(N)cc(Nc2ccc(C)cc2)n1
Temperature: 190 °C
Yield: 79 %

Procedure:
A mixture of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine, prepared in Example 1, (120 mg, 0.45 mmol) and p-tolylamine (1.0 g, 9.3 mmol) was heated at 190° C. for 45 minutes. After cooling to room temperature, the mixture was treated with hydrochloric acid (1 M, 50 ml). The mixture was extracted with ethyl acetate (50 ml). The organic extract was dried over magnesium sulfate and purified by flash chromatography on silica gel column eluting with ethyl acetate-hexane (1:4 followed by 1:1) to give the title compound (120 mg, 79% yield). 1H NMR (acetone-d6) δ 2.27 (s, 3H, CH3), 3.89 (s, 3H, CH3), 5.30 (d, 2H, J=6.4 Hz, NH2), 6.11 (d, 1H, J=1.7 Hz, Ar), 6.89 (d, 1H, J=1.7 Hz, Ar), 7.07 (d, 2H, J=8.3 Hz, Ar), 7.10 (d, 1H, J=8.8 Hz, Ar), 7.32 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.51–7.54 (m, 2H, Ar), 7.68 (s, 1H, NH), 7.99 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-4-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H)+: m/z=613.2.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:36]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]2=[O:51])=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1>>[OH:27][C:28]1[C:36]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]2=[O:51])=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCC3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (46%): MS (ES+) m/z 368.3 (M+1), 380.4 (M+23).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1([Cl:16])[CH2:13][CH:12]1[CH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:15][CH2:14][CH:12]2[CH2:13][C:11]2([Cl:16])[Cl:10])[N:7]=1
Reactant: NCC1CC1(Cl)Cl
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1

Procedure:
A mixture consisting of 38.8 gm (0.24 mol) of 2-amino-4,6-dichloro-pyrimidine, 300 ml of ethanol, 33.1 gm (0.24 mol) of (2,2-dichloro-cyclopropylmethyl)amine and 36 ml (0.26 mol) of triethylamine was refluxed for six hours while stirring. Thereafter, the solvent was distilled off, the oily residue was stirred with about 300 ml of acetone, and the precipitated triethylamine hydrochloride was suction-filtered off. The acetone was distilled out of the filtrate in vacuo, and the residue was admixed with 500 ml of diisopropyl ether and 100 ml of water. The organic phase was separated and again washed with water, dried with magnesium sulfate, de-colorized and evaporated. The residue was triturated with gasoline (b.p. 40°-60° C.) to yield the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[N:21]([CH3:44])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]([CH:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH2:32][CH2:31]2)=[O:19])[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[N:21]([CH3:44])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:29][N:30]2[CH2:31][CH2:32][N:33]([C:36]([CH:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH2:34][CH2:35]2)=[O:19])[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CCCN5C)CC4)c3n2C)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CCCN5C)CC4)c3n2C)cc(C(C)(C)C)cc1C(=O)O

Procedure:
1.29 g methyl 5-tert-butyl-2-methoxy-3-({1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carbonyl}-amino)-benzoate are dissolved in 25 ml of tetrahydrofuran, combined with 4 ml of 4 N sodium hydroxide solution and heated for 2 hours to 40° C. Then the mixture is heated for 12 hours to 60° C., then a further 2 ml of 4 N sodium hydroxide solution are added and the mixture is heated for a further 12 hours to 60° C. It is then evaporated down in vacuo, the residue is taken up in water and the pH is adjusted to 5 by the addition of 4 N hydrochloric acid. It is extracted 5 times with dichloromethane/isopropanol 4:1 and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the product thus obtained is further reacted directly.