Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:39]>CO.[H][H]>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:39]
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C

Procedure:
Pd-on-charcoal catalyst is added to a solution of 31 g (58.8 mmoles) of Z-Val-Tyr(But)-OBut in 300 ml of methanol and hydrogen is passed through the solution at pH 4.5 (autotitrator) while stirring and adding approx. 2 N methanolic hydrochloric acid, until no further methanolic hydrochloric acid is taken up. The catalyst is then filtered off and the filtrate is concentrated. The residue is triturated with ether, filtered off and dried. Yield 23.6 g (94%), melting point 159°-161°, [α]D20 =+19.4° (c=1, methanol).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:16]([N:17]2[CH2:22][CH2:21][N:20](CC3C(OC)=CC(OC)=CC=3OC)[CH2:19][C:18]2=[O:36])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:37]([O-:39])=[O:38].C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[C:16]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:36])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1cc(OC)c(CN2CCN(c3cc(C#N)cc([N+](=O)[O-])c3Cl)C(=O)C2)c(OC)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N2CCNCC2=O)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.6 %

Procedure:
To a solution of triphenylphosphine (263 mg, 1.002 mmol) in THF (2 mL) was added DIAD (0.195 mL, 1.002 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybenzyl)amino)acetamide (160 mg, 0.334 mmol) in TIIF (1.000 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 3 h. LC-MS indicated the desired peak. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg) as a yellow solid. TFA (1 mL) was added to the above obtained solution of 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg, 0.065 mmol) and ANISOLE (0.028 mL, 0.260 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed completion. Solvent was evaporated and purification via flash chromatography (0-10% MeOH in DCM, 24 g) gave 4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCOc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Product: CCOc1nc(NC(C)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile dissolved in 1 mL of pyridine was added 60 μL (0.84 mmol) of acetyl chloride. The mixture was stirred at ambient temperature for 2 hours then diluted with 7 mL of water. The precipitate was filtered and washed with 5 mL of water. The supernatant was extracted with ethyl acetate (3×5 mL), then the combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a solid. This was combined with the precipitated product, dissolved in methanol/ethyl acetate, and concentrated. Most of the remaining pyridine was removed by coevaporation with toluene under reduced pressure. The product was purified via silica gel chromatography, eluting with 50% ethyl acetate/hexanes to provide 31 mg (50%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.73 (s, 1H), 7.17 (s, 1H), 6.88 (s, 2H), 4.32 (q, 2H, J=7.1 Hz), 2.07 (s, 3H), 1.29 (t, 3H, J=7.1 Hz); MS (ESI) m/e=221 (M+H)+, m/e=219 (M−H)−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1>C(OCC)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C(C#N)CC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(C(CN)CC(C)C)c1
Yield: 93.8 %

Procedure:
By working in a way similar to that described in example 17 but using LiAlH4 (0.7 g, 0.018 moles) in anhydrous ethyl ether (35 ml) and 2-(3-methoxy-phenyl)-4-methyl-pentan-nitrile (3.8 g, 0.018 moles), obtained as described in example 20, in anhydrous ethyl ether (35 ml), 3.5 g of the title compound were obtained (yield: 90.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[C:26]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:13]=12
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Reactant: OB(O)c1ccccc1F
Product: O=C(Cn1nc(-c2ccccc2F)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1

Procedure:
Compound 6 was synthesised according to Example 1, but using 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid and 2-(4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-1-(pyrrolidin-1-yl)ethanone instead of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone in Step 8.
Reaction SMILES: [NH2:1][C:2](=[O:35])[CH:3]([OH:34])[CH:4]([NH:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C2C=CC=CC=2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[C:39](=O)[CH3:40])C>>[NH2:1][C:2](=[O:35])[C:3](=[O:34])[CH:4]([NH:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:8][CH2:7][CH:6]([C:39]3[CH:40]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)=[N:21]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CNc2ccccc2)n1
Reactant: CCOC(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)C2)n1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((phenylamino)methyl)-1H-pyrazol-1-yl)nicotinamide (120 mg, 0.255 mmol) as described in example 1.4, subsequent crystallization of the crude product from 2-propanole and then from ethylacetate afforded the title compound as white amorphous solid; 80 mg, ESI-MS [M+H]+: 523.3. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.93 (m, 1H), 8.50 (m, 1H), 8.32 (m, 1H), 8.06 (m, 1H), 7.82 (m, 1H), 7.71 (m, 1H), 7.42-7.25 (m, 10H), 6.42 (m, 1H), 5.38 (m, 1H), 3.49 (m, 2H), 3.25 (m, 1H), 3.17 (dd, 1H), 2.88 (m, 2H), 2.63 (m, 2H), 2.39 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:36][CH:35]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (33.6 mg, 0.33 mmol) (Aldrich), followed by the addition of 1-fluoro-4-isocyanato-benzene (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide as a white solid (Yield 40 mg, 59%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1.OC1C2N=NNC=2C=CC=1.C(O)C(N)(CO)CO>CN(C)C=O.C(#N)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)=[O:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccc3c(c2)OCO3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 1a) (8 mg, 35 μmol) and benzo[d][1,3]dioxole-5-carboxylic acid (7 mg, 42 μmol) were each dissolved in 200 uL dimethylformamide. Si-Carbodiimide resin (70 mg, 70 μmol) was loaded into a 1.2 mL 96 well Greiner plate, followed by the addition of amine and acid. Hydroxybenzotriazole (6 mg, 42 μmol) was dissolved in 100 uL dimethylformamide and was added into the reaction well. The reaction was shaken overnight at room temperature. To remove excess carboxylic acid and hydroxybenzotriazole, PS-Trisamine resin (35 mg, 70 μmol) was added into the reaction mixture and was allowed to shake overnight at room temperature. 200 uL of Acetonitrile was added into the reaction well and shaken for 1 minute. The top clear solution was transferred into a new plate. The extraction process was repeated two more times. The solution was evaporated under vacuum and gave the desired product. Yield 6%. MS M+H calculated 341.1, found 341.2.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C:53]3([CH2:56][C:57]([O:59]C)=[O:58])[CH2:55][CH2:54]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:35]([O:34][C:32]([N:9]1[CH2:10][CH2:11][C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:15][CH:14]=2)[C@@H:7]([C:5]([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[O:51][CH2:52][C:53]2([CH2:56][C:57]([OH:59])=[O:58])[CH2:54][CH2:55]2)[CH:1]2[CH2:2][CH2:3]2)=[O:6])[CH2:8]1)=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)OC)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)O)CC2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-{[1-(2-methoxy-2-oxoethyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from Example 11/Step Step 1 in ethanol (0.1 M) was added 1 M aqueous NaOH (3 eq.). The reaction was heated at 100° C. in a microwave (Biotage) for 5 min. The reaction was cooled to rt and concentrated in vacuo. The residue was suspended in 1 N aqueous HCl and EtOAc. The aqueous layer was extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a foam.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5])C.[OH-].[K+].Cl>O1CCOCC1>[C:4]([CH2:6][O:7][C:8]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cc(OC)cc(OC)c1C(=O)C=Cc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Then, 15.1 g of 2'-ethoxycarbonylmethoxy-4,4',6'-trimethoxychalcone was dissolved in 80 ml of dioxane, and 80 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 1 hour to effect a reaction. After the reaction, the reaction mixture was made acidic by hydrochloric acid, extracted with ethyl acetate and filtered, and the solvent was removed from the filtrate by distillation. The residue was recrystallized from a mixed solvent of diethyl ether and ethyl acetate to obtain 11.4 g (yield=81.0%) of 2'-carboxymethoxy-4,4',6'-trimethoxychalcone in the form of a yellow prism.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([O:14][CH3:15])=[CH:5]1)(=O)C.C[O-].[Na+]>CO>[F:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[C:6]2[O:14][CH3:15]
Reactant: COc1cn(C(C)=O)c2ccc(F)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c[nH]c2ccc(F)cc12
Yield: 76.3 %

Procedure:
A solution of 1.25 g of 1-acetyl-5-fluoro-3-methoxyindole and 0.35 g of sodium methylate in 23 ml of methanol was stirred at room temperature for one hour. After removal of the solvent the residue was extracted with water and ethyl acetate and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed and the residue was distilled in a bulb-tube at a bath temperature of 200° and a pressure of 50 mbar. 0.76 g (76%) of 5-fluoro-3-methoxyindole was obtained.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.I[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(O[Na])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: Cc1ccc(I)cc1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
9.70 g (57.3 mmols) of N,N-diphenylamine (31a), 12.5 g (57.3 mmols) of 4-iodotoluene (32b), 6.61 g (68.8 mmols) of t-BuONa, 260 mg (1.15 mmols) of Pd(CH3COO)2 and 1.20 g (4.58 mmols) of triphenylphosphine were dissolved in xylene and refluxed in an atmosphere of nitrogen for 4 hours.
Reaction SMILES: [F:1][C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([CH3:11])[CH2:3][C:4]([CH3:13])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CC(C)(F)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
To a solution of Intermediate 288A (0.13 g, 0.812 mmol) in THF (2 mL) was added LDA (1.623 mL, 1.623 mmol, 1 M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.203 mL, 3.25 mmol) was then added at −78° C. and the mixture was allowed to slowly warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 307A as a yellow liquid (85 mg, 60%). The crude product was reacted under saponification conditions without further purification 1H NMR (400 MHz, DMSO-d6) δ ppm 4.08 (q, J=7.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.36 (s, 3H) 1.22-1.11 (m, 3H).
Reaction SMILES: [CH3:1][Li].[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](N(OC)C)=[O:7]>O1CCCC1.O>[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](=[O:7])[CH3:1]
Reactant: [Li]C
Reactant: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
At −78° C. a solution of methyl lithium (1.6M in diethyl ether, 25 ml, 40 mmol) was added dropwise to a solution of 2-amino-3,6-dichloro-N-methoxy-N-methyl-benzamide (2.5 g, 10 mmol) in tetrahydrofurane (100 ml). After complete addition, the reaction was warmed to r.t. The dark solution was stirred for 3 hours at room temperature. Under ice cooling 2N aqueous hydrochloride solution (25 ml) was added dropwise and stirred at r.t. for 30 minutes. The reaction was diluted with water, extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to yield the title compound as an orange oil (0.59 g, 29%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[P:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35]>C(#N)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[P:32](=[O:36])([O:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[O:33][CH2:34][CH3:35]
Reactant: O=c1c2ccccc2oc2c(O)cccc12
Reactant: CCOP(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=O)(Oc1cccc2c(=O)c3ccccc3oc12)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxyxanthen-9-one (0.01 mole), acetonitrile (25 ml) and potassium carbonate (0.01 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. O-Ethyl (2,4,6-trichlorophenyl)phosphonochloridate (0.01 mole) in acetonitrile (6 ml) is added dropwise, with stirring, at room temperature. The reaction mixture is stirred for a period of about 48 hours at a temperature of from about 35° C. to 50° C. It is then cooled to room temperature and filtered. Solvent is stripped from the filtrate using a rotary evaporator (70° C., 15 mm Hg). The devolatilized residue is redissolved in 1/1 v/v chloroform/cyclohexane (25 ml). This solution is then slurried with silica gel (2 grams) at room temperature for a period of about 2 hours, then filtered. Solvent is stripped from the filtrate using a rotary evaporator to yield the desired product O-ethyl O-(xanthen-9-one-4-yl) (2,4,6-trichlorophenyl)phosphonate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 529.0 [(M+H)+]; mp 155° C.