Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[I:12]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Commercially available 4-chloro-2-nitro-phenylamine (17.4 g, 131.5 mmol) was dissolved in ethanol (300 mL), and thereto silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) were added. The mixture was stirred for 8 hours at room temperature. At the end of reaction, the mixture was filtered using celite and washed with 100 ml of ethylacetate and concentrated. To the concentrate, added water and extracted with ethylacetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 2-amino-5-chloro-3-nitro-phenyliodide (27.4 g, Yield 69%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (20.4 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.57 g (24.5 mmol) piperazine 1-carboxylic acid tert-butyl ester using 10.4 mL (61.3 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure yielding 7.5 g (94%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12

Procedure:
0.33 g (7.77 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.96 g (2.59 mmol) of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.59 g of 3-carboxy-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M+•), m/e 311.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>ClCCl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10])[C:20](=[O:21])[CH2:19][Br:18]
Reactant: CNc1cccc(C)c1C
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N(C)C(=O)CBr)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methyl-2,3-dimethylaniline S14 (4.6 g) and triethylamine (5.0 ml) were dissolved in dichloromethane (50 ml). 2-Bromoacetyl bromide (3.0 ml) in dichloromethane (30 ml) was added to the resulting solution under ice cooling and the solution was stirred for 2 hours at room temperature. The reaction mixture was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 8.4 g of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19](O)([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:2].O=S(Cl)Cl>N1C=CC=CC=1>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:10]
Reactant: CCCC(O)(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC=C(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol (0.6 g, 1.7 mmol) in anhydrous pyridine (10 mL) is added 1.5 mL of SOCl2 dropwise under nitrogen. The reaction mixture is stirred at room temperature for 3 h, quenched with a saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography eluting with 10% EtOAc-hexanes to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.24-7.29 (m, 1H), 7.13 (d, J=9 Hz, 2H), 5.39 (t, J=7.5. Hz, 1H), 3.91 (s,3H), 2.46 (s,3H),2.24-2.43 (m, 6H), 1.28-1.33 (m,4H), 1.10 (q, J=7.8, 4.8 Hz, 6H), 0.91 (t, j=7.2 Hz, 6H); LC-MS found 352 (MH+).
Reaction SMILES: S(N[C@H](C([O:16][C:17]1[C:26]2[O:25][CH2:24][C@H:23]([O:27][N+:28]([O-:30])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)=O)CC1C=CC=CC=1)(C)(=O)=O.CO.[OH-].[Na+].Cl>O1CCCC1>[O:27]([C@@H:23]1[CH2:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:16])[C:26]=2[O:25][CH2:24]1)[N+:28]([O-:30])=[O:29]
Reactant: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cccc2c1OC[C@H](O[N+](=O)[O-])C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])O[C@H]1COc2c(O)cccc2C1
Reaction time: 1 h
Yield: 38 %

Procedure:
21.6 g of the ester obtained in (A) was dissolved in 200 ml of tetrahydrofuran, and at room temperature, 100 ml of methanol and then 40 ml of a 10% aqueous solution of sodium hydroxide were added. The mixture was stirred for 1 hour. The reaction mixture was adjusted to a pH of about 4 with cold hydrochloric acid, and concentrated. To the residue were added 300 ml of chloroform and dilute hydrochloric acid. The aqueous layer was adjusted to pH 2, and the chloroform layer was separated. The chloroform layer was washed with an aqueous solution of sodium hydrogen carbonate and also with water, and the solvent was evaporated. Recrystallization of the residue from ethyl acetate-hexane gave 9.2 g (yield 38.0%) of the desired product as colorless prisms having a melting point of 129.0° to 130.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CC(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:20][C:19](=[O:21])[C:18]2[CH:22]=[C:14]([C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[O:1][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(=O)Nc1cc(C(=O)O)cc(C2=C(c3cc(C)ccc3O)CCC2)c1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)OCc2ccc(F)cc2)cc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure 5 but using 5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid instead of 6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide and acetone instead of 2-butanone.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12](N)=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([O-])([O-])=[O:23].[Na+].O>C(O)(=O)C>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12]([OH:23])=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2oc3cc(C#N)c(N)nc3c(=O)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc2oc3cc(C#N)c(O)nc3c(=O)c2c1
Temperature: 70 °C

Procedure:
To a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid was added gradually 1.0 g of sodium nitrate at 70° C. After one hour period, 3 ml of water was added to the mixture which was heated at 70° C. for a further one hour. The solvent was distilled off under reduced pressure and then, to the residue, water was added. The yellow precipitate was collected by filtration, rinsed with water and recrystallized from ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals, m.p. > 300° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)[CH3:26]
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and iodoethane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-ethyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as white needles (61%), m.p. (EtOAc/hexanes) 138-142° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.29 (s, 1H), 8.52 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.45 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H). Anal. Calcd for C16H16FIN2O3: C, 44.7; H, 3.8; N, 6.5. Found: C, 45.0; H, 3.6; N, 6.4.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[Cl:58])[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[Cl:58])[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Trimethylaluminium (2M in toluene) (0.638 mL, 1.28 mmol) was added to 6-aminonicotinonitrile (152 mg, 1.28 mmol) in toluene (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 15 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AR1) (425 mg, 0.64 mmol) in toluene (8 mL) was added sealed into a 20 mL microwave tube. The reaction was heated to 120° C. for 4 hours in the microwave reactor and cooled to RT. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (450 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46]O)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.P([N:97]=[N+:98]=[N-:99])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:97]([CH2:46][C@@H:45]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:34]([C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:13]=[CH:12][C:11]=1[C:14]1[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:35])=[N+:98]=[N-:99]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol) in THF (2 mL) was added triphenylphosphine (55.8 mg, 0.213 mmol) followed by DIAD (0.041 mL, 0.213 mmol) and diphenyl phosphorazidate (58 mg, 0.21 mmol). After stirring at room temperature overnight, a second addition of all three reagents was added (1.2 eq each) and stirring was continued for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (Isco 40 g column eluting with 0-50% EtOAc/hexanes) to give the title compound (86 mg, 73%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.25 (s, 0.5H), 8.15-8.10 (m, 1H), 7.97 (s, 0.5H), 7.51-7.34 (m, 5H), 7.25-6.90 (m, 5H), 5.04-4.97 (m, 1.5H), 4.41-3.97 (m, 3.5H), 3.50-3.01 (m, 3.5H), 2.88-2.46 (m, 3.5H), 1.66-1.62 (m, 3H), 1.61 (s, 4.5H), 1.60 (s, 4.5H), 1.18-0.94 (m, 4H), 0.64-0.56 (m, 3H); MS(ESI) m/z 663.5 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([CH3:20])[C:9]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[O:10].[F:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1>C(O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH:27]2[CH2:28][CH2:29][N:30]([CH:8]([CH3:20])[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=3)=[O:10])[CH2:31][CH2:32]2)=[CH:33][CH:34]=1
Reactant: Cc1cc(C(=O)C(C)Br)cc(C)c1O
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)C(C)N2CCC(Cc3ccc(F)cc3)CC2)cc(C)c1O
Reaction time: 8 h

Procedure:
2.12 g (0.02 mol) of sodium carbonate are added to a mixture of 5.14 g (0.02 mol) of 2-bromo-4'-hydroxy-3',5'-dimethylpropiophenone and 4 g (0.02 mol) of 4-(4-fluorobenzyl)-piperidine in 25 ml of ethanol and the mixture is heated under reflux for 3 hours. It is left to stand overnight and then purified by chromatography on a column of silica using acetone as the eluant. This give 6.6 g of a brown oil, which is used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:23][CH:22]=2)=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)Nc1ccc(S(=O)(=O)O)cc1

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.732 g (10 mmol) of 4-aminobenzenesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger, thus obtaining the title compound by freeze-drying of the aqueous solution.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:5][CH:6]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: Cc1nc(-c2ccccc2)ncc1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1nc(-c2ccccc2)ncc1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 4-methyl-2-phenyl-5-pyrimidinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][CH3:21])=[N:17][CH:18]=1>C(Cl)Cl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:18]1[C:13]([Cl:12])=[CH:14][CH:15]=[C:16]([CH2:19][O:20][CH3:21])[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
3-chloroperbenzoic acid (80%, 4.83 g, 13.96 mmol) was added portion-wise to a solution of 5-chloro-2-(methoxymethyl)pyridine (Preparation 57, 2 g, 12.69 mmol) in DCM (50 mL) at 0° C. The reaction was stirred for 18 hours at room temperature. The reaction mixture was quenched with 2M aqueous sodium hydroxide (25 mL) and brine (25 mL) and stirred vigorously. The organic layer was collected, washed with 2M aqueous sodium hydroxide (2×10 mL), water (10 mL), dried over sodium sulfate and concentrated in vacuo. A portion of the residue (100 mg, 0.576 mmol) was stirred in phosphoryl chloride (2 mL) at 80° C. for 2 hours. The reaction was concentrated in vacuo and vigorously stirred in DCM (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) for 5 hours. The organic layer was collected dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM to afford the title compound (38 mg, 34%).
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:3]([S:4]([CH3:7])(=[O:6])=[O:5])[C:8]1[CH:13]=[C:12]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-Ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (3.2 g, 12.2 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO at 50° C. for 5 hours. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. The product was purified by flash chromatography (ethyl acetate:petrol 1:1). Yield 2.6 g (48%) 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.33 Hz, 3 H), 1.39 (s, 9 H), 2.0 (br, 2 H), 2.99 (s, 3 H), 3.2 (br, 2 H), 3.54-3.75 (br, 8 H), 6.65 (br d, J=9.3 Hz, 1 H), 6.67 (d, J=2.93 Hz, 1 H), 8.1 (d, J=9.3 Hz, 1 H); MS (ESI+) for C19H30N4O6S m/z 442 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1I)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-isopropyl-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (85%). MS (ESI): m/z=347.15 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][N:28](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][NH:28][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cn1ncc2ccc(Nc3nc(Nc4ccc(C(N)=O)cc4)nc4[nH]ccc34)cc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
To a solution of 4-(4-(1-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (12 mg, 0.022 mmol) in dioxane (2 mL), aq. 1N KOH (2 mL, 2.00 mmol) was added. The mixture was stirred at 70° C. for 20 h. HOAc (1.0 mL) was added. The mixture was purified by HPLC to give the titled compound (2 mg). MS 399.2 (M+H) (Compound 23-1).