Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16].Cl.C([O-])([O-])=O.[Na+].[Na+].O>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[C:19]([O:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])=[N:20][CH:21]=[N:22][CH:23]=1)=[O:16]
Reactant: CC1(C)OCC(CCOc2ncncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OCCC(O)CO
Reaction time: 4 h
Yield: 60.1 %

Procedure:
At room temperature (25° C.), to a solution of 5-amino-2-(2,6-difluorophenyl)-N-(4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)pyrimidin-5-yl)thiazole-4-carboxamide (38) (20 mg, 0.0419 mmol) in methanol (2 mL) was added concentrated HCl (0.5 mL) and the solution was stirred for 4 hours. 10% Na2CO3 solution was added to neutralize the solution to pH=7, the water (20 mL) was added and a precipitate was formed. An off white solid product 49 (11 mg, 0.0252 mmol) was obtained after filtration and air drying at 25° C.
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(OC(=O)c2ccc([SiH](C)C)cc2)cc1

Procedure:
A solution of 19.9 g (0.100 mol) of p-dimethylsilylbenzoyl chloride and 12.4 g (0.100 mol) of a p-methoxyphenol in 40 ml of dry toluene was boiled for 15 hours. The completeness of the reaction was checked by thin-layer chromatography. After the solvent had been stripped off in vacuo on a rotary evaporator, the crude product was recrystallized from n-hexane, to give p-methoxyphenyl 4-dimethylsilylbenzoate, melting point 67° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1
Reactant: N#Cc1cn[nH]c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnn(C2CCCCO2)c1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
The reaction was carried out in a 3 liter three-necked flask with internal thermometer under argon. 50 g (537 mmol) of 1H-pyrazole-4-carbonitrile were suspended in 1.66 liter of methylene chloride and, after 3 h, cooled to 3° C. using an ice bath. At this temperature, 10.2 g (53.7 mmol) of 4-toluenesulphonic acid monohydrate were added. At 3° to 6° C., 58.8 ml (54.2 g, 644 mmol) of 3,4 dihydro-2H-pyran were then added dropwise over a period of 30 min. The reaction was then stirred at RT overnight. The clear reaction solution was then washed with 2 M aqueous sodium carbonate solution and with water, dried over magnesium sulphate, filtered and concentrated. The residue was triturated with cyclohexane and the solid obtained was filtered off with suction and dried in a vacuum drying cabinet at 30° C. for 4 h. This gave 91.8 g (96% of theory) of the title compound as a light-yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[C:33]([C:44]([OH:46])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[S:49]1[CH:50]=[CH:51][N:52]=[C:48]1[NH:47][C:44]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:30])[CH3:29])[CH:32]=1)=[O:46]
Reactant: Nc1nccs1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(C(F)(F)F)cc21
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of triphenylphosphine (377 mg, 1.44 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N-bromosuccinimide (256 mg, 1.44 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid (300 mg, 1.11 mmol). The reaction was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (255 mg, 2.54 mmol) and stirred at 25° C. for 24 h. At this time, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, diethyl ether) afforded 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (43 mg, 11%) as a light pink solid: mp 246-247° C.; EI-HRMS m/e calcd for C16H14F3N3OS (M+) 353.0810, found 353.0801.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:22])[CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:21].Cl.[CH3:24][N:25]1[CH2:31][C:30]2[CH:32]=[C:33](/[CH:36]=[CH:37]/[C:38](O)=O)C=N[C:29]=2[NH:28][C:27](=O)[CH2:26]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH3:22][N:3]([CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([N:28]([CH3:29])[CH2:27][C:26]3[N:25]([CH3:24])[C:31]4[C:37]([CH:38]=3)=[CH:36][CH:33]=[CH:32][CH:30]=4)=[O:20])[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:21]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CN(C)CCN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(C)CCN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Yield: 22 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-[3-(2-dimethylamino-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (40 mg, 22%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.98 (br s, 1H), 8.38-8.33 (m, 1H), 8.00-7.91 (m, 1H), 7.57-7.42 (m, 3H), 7.22-7.01 (m, 3H), 6.42-6.16 (m, 1H), 5.04-4.85 (m, 2H), 4.53-4.47 (m, 2H), 3.72-3.68 (m, 3H), 3.51-3.31 (m, 4H), 3.11-2.99 (m, 4H), 2.72-2.39 (m, 5H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:38]([NH:37][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)[CH:31]=1)(=[O:43])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)cc4)nn23)c1
Yield: 95.8 %

Procedure:
4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.0827 mmol) was treated with trifluoroacetic acid (191 uL, 2.48 mmol) in methylene chloride (3.00 mL). The reaction was diluted with DCM (25 mL) and washed with saturated sodium bicarbonate (25 mL). The aqueous layer was extracted with DCM (25 mL) three times and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as an orange foam (40 mg, 96%). LCMS (m/e) 505 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.73 (s, 1H), 8.29 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.62-7.51 (m, 3H), 7.28 (d, 2H, J=8.3 Hz), 7.07 (d, 1H, J=4.8 Hz), 6.92 (bs, 1H), 6.84 (d, 1H, J=4.8 Hz), 4.77-4.57 (m, 1H), 3.01-3.20 (m, 2H), 2.87-2.73 (m, 2H), 2.72-2.59 (m, 1H), 1.94-1.82 (m, 2H), 1.79-1.63 (m, 2H), 1.17 (s, 9H).
Reaction SMILES: [CH:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)[N:13]=3)=[C:10]([CH3:26])[O:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:58][CH2:59][CH2:60]O>C1COCC1>[Br:58][CH2:59][CH2:60][O:25][C:21]1[CH:20]=[C:19]([NH:18][C:14]2[N:13]=[C:12]([C:11]3[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[N:8][O:9][C:10]=3[CH3:26])[CH:17]=[CH:16][N:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1onc(C2CCCCC2)c1-c1ccnc(Nc2cccc(O)c2)n1
Reactant: OCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(C2CCCCC2)c1-c1ccnc(Nc2cccc(OCCBr)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of phenol 11 (880 mg, 2.51 mmol) in THF (anhydrous, 5 ml) was added diethyl azodicarboxylate (0.52 ml, 3.27 mmol) and triphenylphosphine (857 mg, 3.27 mmol) followed by 2-bromoethanol (0.23 ml, 3.27 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (30% EtOAC:hexanes) to afford the desired bromo derivative 12 (745 mg) as a white solid in 65% yield. 1H NMR (CDCl3) δ 1.2-2.0 (m, 10H), 2.5 (s, 3H), 3.1 (m, 1H), 3.6 (t, 2H), 4.3 (t, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 7.1 (d, 1H), 7.1(s, 1H), 7.3 (dd, 1H), 7.4 (s, 1H), 8.4 (d, 1H)
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[N:60]1([CH:66]2[CH2:71][CH2:70][CH:69]([C:72]3[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=3)[CH2:68][CH2:67]2)[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:78][C:75]4[CH:76]=[CH:77][C:72]([CH:69]5[CH2:68][CH2:67][CH:66]([N:60]6[CH2:61][CH2:62][O:63][CH2:64][CH2:65]6)[CH2:71][CH2:70]5)=[CH:73][CH:74]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc(C2CCC(N3CCOCC3)CC2)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCC(N6CCOCC6)CC5)cc4)nn23)c1

Procedure:
The title compound was prepared in the following manner: N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (82.6 mg, 0.231 mmol), N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol), and N,N-Dimethylformamide (2 mL, 20 mmol) and stir at room temperature for half an hour. Added 4-(4-Morpholin-4-yl-cyclohexyl)-phenylamine (280 mg, 1.1 mmol) and stir at 80° C. overnight. The mixture was concentrated and purified using the gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give a yellow solid (30 mg, 20%). MP 160-163 C. LCMS (E/I+) 589 (M+H). NMR 1H (DMSO-d6)-9.44 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 8.33-8.40 (m, 1H), 7.86 (d, 1H, J=8.03), 7.59-7.76 (m, 3H), 7.18-7.24 (m, 2H), 6.98 (d, 1H, J=4.8 Hz), 3.60-3.64 (m, 2H), 3.55-3.59 (m, 1H), 2.55-2.64 (m, 1H), 2.49-2.51 (m, 4H), 2.36-2.42 (m, 2H), 2.14-2.19 (m, 1H), 1.89-1.98 (m, 2H), 1.78-1.88 (m, 2H), 1.44-1.54 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[C:6]([NH2:10])[NH:7]2)=[N:3][CH:2]=1.[C:11]([C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[C:18]([C:24](=O)[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)#[N:12].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:11]([C:13]1[CH:28]=[CH:27][C:16]([CH:17]2[N:7]3[C:6](=[N:5][C:4]4[N:3]=[CH:2][N:1]=[CH:9][C:8]=43)[NH:10][C:24]([CH3:25])=[C:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1)#[N:12]
Reactant: Nc1nc2ncncc2[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc3ncncc3n2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 7H-purine-8-amine (300 mg, 2.2 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (702 mg, 2.9 mmol, 1.3 eq.) were dissolved in DMF (5 ml), and solid sodium bicarbonate (932 mg, 11.1 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→90:10). After lyophilization of the appropriate fractions, the title compound was obtained as a solid (430 mg, 54% of theory). The isomeric compound (rac)-ethyl 9-(4-cyanophenyl)-7-methyl-6,9-dihydropyrimido[1,2-e]purine-8-carboxylate (see Example 23A) was obtained as a byproduct.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:21][O:22][CH3:23])[C:13](=[O:20])[C:14]([CH3:19])([CH3:18])[C:15]([O-])=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:23][O:22][CH2:21][CH:12]1[NH:11][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[C:13]1=[O:20]
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)C(C)(C)C(=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCC1NC(=O)C(C)(C)C1=O
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 4-{[(benzyloxy)carbonyl]amino}-5-methoxy-2,2-dimethyl-3-oxopentanoate (10.2 g) in methanol (100 mL) was added 10% palladium carbon (containing 50% water, 3.1 g), and the mixture was stirred overnight under a hydrogen atmosphere. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as colorless crystals (yield: 4.16 g, 84%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:17]2[C:18](=[O:21])[CH2:19][O:20][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16]2)=[CH:25][CH:24]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC1CCCC1
Product: COc1ccc(C2CN(Cc3ccc(Br)cc3)C(=O)CO2)cc1OC1CCCC1
Yield: 96.5 %

Procedure:
According to the same procedure as used in Example 12, using the 2-(3-cyclopentyloxy-4-methoxyphenyl)morpholin-5-one produced in Example 2 instead of 2-(3,4-dimethoxyphenyl)morpholin-5-one, and using 4-bromobenzyl bromide instead of methyl iodide, the above-described compound (yield 96.5%) was obtained as a brown oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:9](=[O:11])[C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)C#Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 14.61 g (0.10 mole) phenylpropiolic acid, 14.28 g (0.12 mole) thionyl chloride and 50 mL benzene was stirred and heated between 60°-70° C. for 3 hrs. The reaction was allowed to cool to room temperature and solvent was evaporated. The reaction vessel was charged with 50 mL of fresh benzene and the mixture cooled in an ice bath. Added next, dropwise in 50 mL benzene, was 21.43 g (0.20 mole) of 4-toluidine. After addition was complete, the ice bath was removed and the mixture stirred at room temperature for one hour. The mixture was poured into 200 mL cold water and the layers were separated. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were then washed sequentially with 100 mL portions of 5% aqueous hydrochloric acid, water, 5% aqueous sodium carbonate and water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was recrystallized twice from ethanol/water to provide 11.58 g (49.20 mmol, 49%) N-(4-methylphenyl) phenylpropiolamide as a white powder, mp=139°-141°. NMR (CDCl3 /TMS): 2.35 (S, 3H), 7.1-7.6 (m, 10H). IR (Nujol):2214, 1636. High resolution mass spectrum: Calculated; 236. 107539. Measured; 236. 107101. Anal. calcd. for C16H13NO: C 81.70, H 5.53, N 5.96; Found C 3581.55, H 5.40, N 6.05.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 50.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.78 mmol) and dichlorobis(triphenylphosphine)palladium (II) (65.3 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 35% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (270 mg, 93%) as a light yellow solid: LC/MS m/e calcd for C28H25F3N2O4S2 [M+H]+ 575.65, observed 574.7.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1C
Yield: 47.9 %

Procedure:
2,3-Dimethylphenylboronic acid (39 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (28 mg, 48%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1.N1C=CC=CC=1.[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].Cl>C1COCC1>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=3)[CH:4]=2)[NH:8][CH:7]=1)=[O:29]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOc1ccc(-c2cc3cc[nH]c3cc2Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOc1ccc(-c2cc3c(C(=O)C(Cl)(Cl)Cl)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
To a solution of 6-chloro-5-(4-ethoxyphenyl)-1H-indole (500.0 mg, 1.84 mmol) in anhydrous THF (5 mL) was added pyridine (436.0 mg, 5.52 mmol) and trichloroacetyl chloride (10 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature under N2 for 12 hours. The mixture was poured into 0.5 N HCl (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (9-25% EtOAc/petroleum ether:EtOAc) to give the title compound (70.0 mg, 9%) as a green solid. 1H NMR (400 MHz, CDCl3) δ 8.80 (br, 1 H), 8.40 (s, 1 H), 8.36 (d, J=3.2 Hz, 1 H), 7.59 (s, 1 H), 7.42 (d, 2H), 6.97 (d, 2 H), 4.12 (q, J=7.00 Hz, 2 H), 1.45 (t, J=7.00 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])C(F)(F)F.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:37]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=2[F:29])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:15]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1cc(Oc2ccc(C#N)cc2F)ccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4, 100 mg) in N,N-dimethylacetamide (1.8 ml) were added 3,4-difluorobenzonitrile (41 mg) and cesium carbonate (235 mg). The mixture was heated under microwave conditions for 30 min to 120° C. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give 4-{4-chloro-3-[1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxo-ethyl]-phenoxy}-3-fluoro-benzonitrile (92 mg). In analogy to Example 1, step 3, this compound was reacted with trifluoromethyl trimethylsilane and tetramethylammonium fluoride to give the title compound (89 mg) as a colorless solid. MS (m/e)=535.1 [M+H+].