Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH2:8]C)[CH:5](C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:29]([NH:33][CH2:34][CH2:35][C:36]#[N:37])=[N:30][O:31][N:32]=2)=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.[Cl-].[NH4+]>CN(C)C=O>[C:36]([CH2:35][CH2:34][NH:33][C:29]1[C:28]([C:20]2[N:19]([CH2:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([N:10]=[CH:1][N:4]([CH3:8])[CH3:5])=[CH:16][CH:15]=3)=[O:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[N:32][O:31][N:30]=1)#[N:37]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.05 ml N,N-diisopropylethylamine in 1 mL of N,N-dimethylformamide is slowly added to a solution of 116 mg (0.3 mmol) 3-(4-{1-[2-(4-amino-phenyl)-2-oxo-ethyl]-1H-benzoimidazol-2-yl}-furazan-3-ylamino)-propionitrile and 459 mg (0.3 mmol) phosphorus oxychloride in 3 mL of N,N-dimethylformamide at −10° C. After the addition, the mixture is allowed to warm to room temperature and stirred for three days. Then, saturated aqueous ammoniumchloride solution is added and the reaction mixture is extracted with dichloromethane. A precipitate is formed in the dichloromethane phase. This precipitate is collected by filtration, washed with water and dichloromethane, and dried under reduced pressure. The residue is solved in acetonitrile and the solution is added to a 2 N solution of sodium hydroxide in water at 0° C. The resulting pH value is above 11. The mixture is stirred at room temperature for 1 h. The formed precipitate is collected by filtration, washed with water and acetonitrile, and dried under reduced pressure to provide 89 mg of the desired product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 40 °C
Yield: 75.3 %

Procedure:
To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][S:10][CH2:11][CH:12]=1)(=O)=O.[F:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[S:10]1[CH2:11][CH:12]=[C:7]([C:21]2[C:16]([F:15])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9]1
Reactant: OB(O)c1cccnc1F
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ncccc1C1=CCSCC1
Temperature: 135 °C

Procedure:
A mixture of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (4.0 g, 16.11 mmol), 2-fluoropyridin-3-ylboronic acid (2.498 g, 17.72 mmol), sodium carbonate (5.12 g, 48.3 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(ii) (0.633 g, 0.806 mmol) in p-dioxane/H2O (10:1, 22 mL) was heated at 135° C. in 30 min. by microwave. The reaction mixture was cooled, diluted with H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (0-40% EtOAc/Hexanes) to give the expected product was a light brown oil. MS (M+1): 196.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(C=O)c1OC
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 529;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:20]1([CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[CH2:12][CH2:11]4)=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCC1CCCCC1
Reactant: O=C1CCc2cc(-c3ccc(O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CCc2cc(-c3ccc(OCC4CCCCC4)cc3)ccc21
Yield: 393.5 %

Procedure:
A solution of 5-(4-hydroxyphenyl)-1-indanone (0.52 g, 0.23 mmol, from Step A), bromomethylcyclohexane (0.53 g, 0.30 mmol) and potassium carbonate (0.58 g, 0.42 mmol) in acetonitrile (2.5 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with water. Silica gel chromatography eluting with 10% ethyl acetate/hexane yielded 0.29 g of product. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=8.3 Hz, 3H), 7.03 (d, J=8.2 Hz, 2H), 3.85 (s, 2H), 3.21 (s, 2H), 2.78 (s, 2H), 2.08 (s, 1H), 1.90–1.98 (m, 2H), 1.80–1.86 (m, 2H), 1.20–1.42 (m, 4H), 1.07–1.18 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[N:31][CH:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cncnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M97) (0.43 g, 0.84 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (230 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][OH:21])[N:3]=1
Reactant: NCCCO
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: OCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-hydroxypropyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-amino-1-propanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:8]#[N:9])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 80 °C

Procedure:
The solution of 100 parts of α-(4-biphenylyl)acetonitrile and 90 parts of 2-chloro-N,N-diisopropylethylamine in 850 parts by volume of toluene is heated to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes keeping the temperature at 80°-85° C. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, filtered and stripped of solvent to afford an oil which solidifies upon standing. The crude oil is crystallized from hexane to afford α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, melting at about 54°-56° C. This compound is represented by the following structural formula ##STR21##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:17]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][N:10]=2)[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:17]=1)=[C:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:9][N:10]=2)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2noc(-c3ccccc3)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2noc(-c3ccccc3)c2c1
Reaction time: 1 h
Yield: 105.5 %

Procedure:
A mixture of 15.4 g (0.069 mole) of 5-ethyl-3-phenyl-2,1-benzisoxazole, 12.4 g (0.0697 mole) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide in 300 ml of carbon tetrachloride was heated at reflux under floodlight illumination and an argon atmosphere for one hr and then filtered while still hot. The filtrate was concentrated under reduced pressure to give 22.0 g of a semi-solid residue (NMR indicated 80% product). A sample of this semi-solid was triturated with 3 ml of methylene chloride and filtered. The solid filter cake was recrystallized from ethyl ether to give yellow solid, m.p. 118°-119° C. (with decomposition).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][CH:4]([CH2:16][Br:17])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](O)=[O:14])=[N:11][CH:12]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:13](=[O:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:4]([Br:3])[CH2:16][Br:17])=[CH:12][N:11]=1
Reactant: CN
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 8 °C

Procedure:
According to the same method as Example 1 with cooling 30% aqueous methylamine solution (100 ml) was added to the chloroform solution (200 ml) of acid chloride prepared from 10 g of 5-(3,4-dibromobutyl)picolinic acid and 10 ml of thionyl chloride, and stirred at 8°C for an hour. Chloroform layer which was separated, was washed with 0.3% aqueous hydrochloride solution, 5% aqueous sodium bicarbonate solution, and then water. Chloroform was evaporated in reduced pressure to yield 8.7 g of crude product as oil. To purify the product, above crude product was chromatographed on silicagel using ethylacetate as developing solvent. The pure product was viscous oil and showed only one spot (Rf 0.60) on TLC (silicagel; ethylacetate, IR (liquid film) 1670 cm-1, UV λmaxMeOH 268 nm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(F)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(F)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-fluoro-pyrimidin-2-yl)-phenol (Preparation 20) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (85 mg, 49%)
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[F:28])[N:4]=3)[CH2:41]2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 69.1 mg (0.25 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 20A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 34 mg (28% of theory) of the product as a solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[CH:29]=[C:30]([O:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]=3[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=2)=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[CH2:37]([O:36][C:30]1[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])=[CH:14][CH:15]=3)[C:28]=2[CH:29]=1)[CH3:38]
Reactant: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.7 %

Procedure:
A solution of 2.3 g p-toluenesulfonic acid chloride in 5 ml absolute dichloromethane is added dropwise to a solution of 3.5 g (−)-cis-6-(4-Aminophenyl)-8,9-diethoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at room temperature for a further 3 h. After the evaporation of the solvents, the residue is extracted with dilute sodium hydroxide solution and dichloromethane. The organic phase is then washed with water, dried over sodium sulfate and concentrated. 5.4 g of the title compound are obtained as rough product, which is recrystallised twice in ethyl acetate/methanol. Yield: 4.3 g yellowish crystalls. M.p. 267-268° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=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>[F:30][C:31]1[C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=1
Reactant: Cc1cnc(F)c(B(O)O)c1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)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: C1COCCO1
Solvent: O
Product: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 500 mg, 1.121 mmol), 2-fluoro-5-picoline-3-boronic acid (136 μl, 1.121 mmol), potassium carbonate (775 mg, 5.61 mmol) and Pd(Ph3P)4 (130 mg, 0.112 mmol) was added Dioxane (5606 μl) and Water (1869 μl) and irradiated at 100° C. for 30 mins affording ˜75% conversion to desired product as the primary species. Additional boronic acid (80 mg) and Pd(PPh3)4 (65 mg) was added and the mixture irradiated an additional 30 mins at 110° C. affording complete conversion to desired product. The organics were decanted, rinsed with EtOAc and the combined organics were dried under reduced pressure. The crude material was dissolved in DCM (3 ml) and TFA (1 ml) was added and the mixture stirred at room temperature for 2 hrs affording complete PMB cleavage. The crude material was purified with a 25 g Interchim column (25 μm spherical) ramping EtOAc in heptane (0-100%, then isocratic at 100% EtOAc, where product elutes, 10% DCM throughout) affording 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid (377 mg, 0.941 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.89 (br. s., 1H), 8.74 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.3, 9.3 Hz, 1H), 7.97-7.91 (m, 1H), 7.91-7.85 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 2.40 (s, 3H). m/z (ESI) 401.2 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to 4-iodophenylacetic acid (11) (prepared by the process described in Chen, Q.-H. et al., Bioorg. Med. Chem., 14, 7898-7909 (2006)) (1.06 g, 4.05 mmol) was added thionyl chloride (5.00 mL, 68.6 mmol) and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-iodophenylacetyl chloride (12) as a brown oily crude product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 3-amino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (300 mg, 0.88 mmol; example 1, step 2) in a mixture of dichloromethane (10 ml) and pyridine (0.08 ml, 0.96 mmol) was added acetyl chloride (0.07 ml, 0.96 mmol). After stirring for 4 h, the mixture was partitioned between 10% aqueous citric acid (50 ml) and diethyl ether (100 ml). The organic extract was washed consecutively with water (50 ml), saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:1) to afford 183 mg (54%) of the titled compound as a yellow oil.
Reaction SMILES: CO.Cl.[N+:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[CH2:16][C:17]([OH:19])=O)([O-])=O.[H][H]>CCO.[Pd]>[NH2:13][C:11]1[CH:12]=[C:7]2[C:8]([CH2:16][C:17](=[O:19])[NH:4]2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methanol (15 mL) and 1.25 M HCl in EtOH (10 ml) was added to 2,4-dinitrophenylacetic acid (837 mg, 3.7 mmol) and Pd/C (10%; 205 mg) under Argon. The argon balloon was replaced with a hydrogen balloon and it was stirred at RT for 12 h and at 50° C. for 24 h. It was cooled to RT and filtered through celite. The solvent was removed and the residue was purified by silica gel chromatography (DCM/methanol gradient) to give the title compound as a red solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[Cl:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[NH:20][CH:21]=[N:22]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1cccc(OCCCCCBr)c1
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(OCCCCCn2cnc3c(Cl)ncnc32)c1
Yield: 19.4 %

Procedure:
A solution of 3-(bromopentyloxy)benzamide (500 mg, 1.7 mmols), 6-chloropurine (270 mg, 1.7 mmols) and potassium carbonate (240 mg, 1.7 mmols) in DMF (7.5 ml) was stirred for two days at room temperature. The solvent was then removed under vacuum (0.001 mmHg) and the white solid (mixture of N7 and N9 isomers) was chromatographed (silica, 10% MeOH/CH2CI2) to give a single product (N9 isomer) as a glass. This was triturated with ether (=5 ml) to give a white solid which was recrystallised from ethyl acetate to give the product (120 mg, 0.33 mmols, 20% yield)