Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1.[CH:27]([NH:30][CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].CN1CCCC1=[O:40]>>[CH:8]([OH:19])=[O:40].[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[C:4]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][CH:27]([CH3:29])[CH3:28])[N:11]=2)[CH:6]=[CH:7][C:8]1=[O:19]
Reactant: CN1CCCC1=O
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(Cl)nc2n1-c1ccccc1Cl
Reactant: CC(C)NCCN
Product: CC(C)NCCNc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: O=CO
Yield: 26 %

Procedure:
7-chloro-1,5-bis(2-chlorophenyl)[1,8]naphthyridin-2(1H)-one (73 mg, 0.182 mmol) and N-isopropylethylenediamine (0.14 ml, 1.122 mmol) were dissolved in N-methylpyrrolidinone (2 ml) and heated in a Smith Creator microwave at 220° for 30 min. The solution was passed down an SCX-2 cartridge (10 g) and eluted with methanol, followed by 2M ammonia in methanol. The latter eluate was evaporated in vacuo and the residue purified by mass directed autoprep HPLC (per General procedure B) to afford the title compound as a clear gum (24 mg, 26%)
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[Si]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](=O)[CH:43](OCC)[O:44]CC)=[CH:37][CH:36]=1)(C(C)(C)C)(C)C.Cl.CCCCCC>O1CCOCC1>[OH:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]2[C:43](=[O:44])[N:19]3[CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[NH:16][C:17]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[C:18]3[N:21]=2)=[CH:39][CH:40]=1
Reactant: CCOC(OCC)C(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(-c3cccs3)[nH]c(-c3ccc(O)cc3)cn1-2
Temperature: 25 °C
Yield: 22.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (276 mg, 720 μmol) and 3-[4-(tert-butyldimethylsilyloxy)phenyl]-1,1-diethoxypropan-2-one (8) (381 mg, 1.08 mmol) dissolved in 1,4-dioxane (2 mL) was added 4 M hydrochloric acid (780 μL) at 0° C. and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography in an argon flow (acidic silica gel 20 g, n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=20/1). To the suspension obtained during the concentration under reduced pressure was added n-hexane. The precipitates were collected by filtration and dried in vacuo to give Compound 3f (TMD-278) (68.2 mg, 164 μmol, 22.8%) as a brown solid. Rf=0.67 (ethyl acetate/methanol=20/1); HPLC retention time 9.5 min; 1H NMR (400 MHz, CD3OD) δ 4.22 (s, 2H), 6.72-6.78 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 7.11-7.18 (AA′BB′, 2H), 7.32 (dd, 1H, J=3.8, 5.2 Hz), 7.87 (dd, 1H, J=1.1, 5.2 Hz), 7.91-7.97 (AA′BB′, 2H), 8.12 (dd, 1H, J=1.1, 3.8 Hz), 8.48 (s, 1H); IR (KBr, cm−1) 521, 581, 629, 721, 777, 841, 881, 966, 1109, 1172, 1261, 1341, 1429, 1508, 1533, 1609, 1653, 2822, 3107; HRMS (ESI+) m/z 416.1075 ([M+H]+, C23H18N3O3S+ requires 416.1063).
Reaction SMILES: [OH:1][CH:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18].C1COCC1.[OH-].[Li+].Cl>O.CO>[OH:1][CH:2]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 3-8 (45 mg, 0.11 mmol) in 5.5 mL 2:2:1 THF:MeOH:water, at 0° C., was added lithium hydroxide (170 μL of a 2M solution in water) and the resulting solution was allowed to warm up to room temperature and stirred overnight. To the solution was added a 1M aqueous solution of HCl (1 mL) and the solution was extracted with ethyl acetate. The organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 50–100% ethyl acetate/hexanes to yield 37 mg of 3-9 as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.30–7.18 (m, 5H), 5.81 (dd, 1H), 5.53 (dd, 1H), 4.39 (q, 1H), 4.33 (q, 1H), 3.45 (dd, 1H), 3.33 (m, 1H), 2.97 (m, 2H), 2.77 (dd, 1H), 2.67 (m, 1H), 2.30 (t, 2H), 1.65–1.21 (m, 8H); MS (+ESI): m/z 378.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[O:10])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnc(C)cn2)C3)cc1
Reaction time: 8 h

Procedure:
5-Methylpyrazine-2-carboxylic acid (0.0490 g, 0.000355 mol) in dry N,N-Dimethylformamide (1.80 mL, 0.0232 mol) was added 1-Hydroxybenzotriazole (0.0547 g, 0.000405 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0797 g, 0.000416 mol) then followed by N,N-Diisopropylethylamine (0.114 mL, 0.000654 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.1007 g, 0.0002633 mol). The reaction mixture was stirred overnight. The reaction mixture was vacuum filtered, washed with DMF and then washed with water. 1H NMR (400 MHz, DMSO) δ 8.81 (d, J=3.3, 1H), 8.64 (d, J=12.5, 2H), 8.26-8.10 (m, 2H), 7.47 (dd, J=18.5, 8.7, 2H), 6.15 (dd, J=13.1, 5.8, 1H), 4.74 (d, J=15.5, 2H), 3.87 (s, 1H), 3.71 (dd, J=14.7, 4.6, 5H), 3.48 (d, J=3.9, 4H), 3.18-3.03 (m, 2H), 2.75 (d, J=13.1, 2H), 2.59 (s, 3H), 1.06 (dd, J=12.5, 7.1, 3H). LC/MS-m/z+503.2 (M+H)+,
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH3:12].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH3:12]
Reactant: CCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzenesulfonamide was prepared, using the method of Example 90, from 5-amino-4-ethyl-3-trifluoromethylisoxazole and benzenesulfonyl chloride in 72% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give white needles, m.p. 105°-106° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)(Cl)=[O:14].[CH3:18]N(C)C=O>>[CH3:1][N:2]1[C:6]([CH3:18])=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: Cn1cccc1-c1cccnc1
Product: Cc1ccc(-c2cccnc2)n1C
Product: O=Cc1ccc[nH]1

Procedure:
The 1,5-dimethyl-2-(3-pyridyl) pyrrole is prepared from 1-methyl-2-(3-pyridyl) pyrrole by treatment with phosphorus oxychloride and dimethyl formamide to form a pyrrole-carboxaldehyde which is then subjected to a Wolff-Kishner reduction.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([C:35](=O)[CH2:36]Br)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:39])([F:40])[C:25]1[CH:26]=[C:27]([C:35]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:36]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 32 %

Procedure:
4-[4-(3,5-Bis-trifluoromethyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (110 mg, 32%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3′,5′-bis(trifluoromethyl)-2-bromoacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.79 (s, 1H), 8.72 (s, 2H), 8.55 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.12-8.17 (m, 2H), 7.79 (t, J=7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.41-7.50 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid (5 g, 31 mmol) in DMF (70 mL) under a nitrogen atmosphere at 0° C. was added cesium carbonate (11 g, 31 mmol) and benzyl bromide (4.05 mL, 34.1 mmol). The reaction mixture was stirred at RT for 48 h and poured into water. EtOAc was added and the layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was taken up in Et2O and the resulting precipitate was filtered-off to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.55; MS (LC-MS): 252.1 [M+H]+, 274.0 [M+Na]+, 525.1 [2M+Na]+, 250.1 [M−H]−; tR (HPLC conditions a) 3.77 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O[C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.BrCCCCBr>CN(C)C=O>[NH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:17]=2)[CH:12]=[CH:13][C:14]1=[O:18]
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCCCCBr
Product: O=c1ccc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
To a stirred suspension of anhydrous potassium carbonate (K2CO3) (10.50 g, 0.075 mol) in 100 mL of anhydrous N,N-dimethylformamide (DMF) was added 7-hydroxyquinolinone 1 (10.00 g, 0.06 mol) followed by 1,4-dibromobutane 2 (25.91 g, 0.12 mol). The resulting mixture was heated at 60° C. for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC) technique. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel and the precipitate was washed with ethyl acetate (25 mL×2). The combined filtrate was concentrated on a rotavapor. The residue was diluted with 250 mL of ethyl acetate, washed with water (100 mL×2), dried over anhydrous magnesium sulfate and evaporated the solvent. The residue was triturated with hexane and then filtered the precipitate to give the pure title compound 3. White solid, 12.88 g (72%). 1H NMR (400 MHz, CDCl3): δ 1.92-1.97 (m, 2H); 2.05-2.10 (m, 2H); 2.64 (t, J=9.2 Hz, 2H); 2.92 (t, J=9.2 Hz, 2H); 3.50 (t, J=7.6 Hz, 2H); 3.98 (t, J=7.6 Hz, 2H); 6.37 (d, J=3.2 Hz, 1H); 6.50-6.54 (m, 1H); 7.04 (d, J=11.2 Hz, 1H), 8.61 (broad s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24](B(O)O)=[CH:23][CH:22]=[C:21]3[CH2:20]1.C(N(CC)CC)C.COCCOC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[C:25]5[C:30]6[C:21]([CH2:20][CH2:19][C:29]=6[CH:28]=[CH:27][CH:26]=5)=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2c3c(cccc13)CC2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c6c(cccc46)CC5)cc3CC[C@@H]12
Yield: 68.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 5-acenaphtheneboronic acid (154 mg, 0.78 mmol), 0.20 mL of triethylamine and 2 mL of DME, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 170 mg (69%) of the title compound as a white solid. mp>200° (decomp.) FDMS: m/e=381 α[D]589 =+61.47(c=0.84, chloroform).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4](=[O:14])[N:5]([CH2:10][CH2:11][CH2:12][OH:13])[N:6]=[CH:7][C:8]=1Cl.[OH-].[K+]>C(O)C>[Cl:2][C:3]1[C:4](=[O:14])[N:5]([CH2:10][CH2:11][CH2:12][OH:13])[N:6]=[CH:7][C:8]=1[OH:1]
Reactant: O
Reactant: O=c1c(Cl)c(Cl)cnn1CCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=c1c(Cl)c(O)cnn1CCCO

Procedure:
To a mixed solvent of 150 ml of water and 150 ml of ethanol was added 22.3 g of 4,5-dichloro-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.1 mol) and 19.6 g of potassium hydroxide (0.35 mol) and then heated under reflux for about 10 hours. After reaction, ethanol was removed under reduced pressure and added with water to filter off the insoluble matters. The filtrate was converted into acidity by diluted hydrochloric acid and the crystals produced were filtered off. The crystals thus obtained were washed with water and dried to give 14.5 g of 4-chloro-5-hydroxy-2-(3'-hydroxypropyl)-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][N:24]=3)[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: c1cnc2[nH]ccc2n1
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (26, 162 mg, 0.47 mmol) in 1 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 67 mg, 0.56 mmol) and potassium hydroxide (79 mg, 1.4 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (27, 150 mg, 69%). MS (ESI) [M+H+]+=465.4.
Reaction SMILES: C[OH:2].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[N:8][CH:9]=1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH2:11])=[O:2])=[N:8][CH:9]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: CO
Solvent: O
Product: NC(=O)c1ccc(N)cn1
Temperature: 50 °C

Procedure:
MeOH (30 mL) was added into the mixture of 5-aminopyridine-2-carbonitrile (1191 mg, 10.00 mmol), NaBO3.H2O (2995 mg, 30.00 mmol), and H2O (30 mL), and the mixture was then heated at 50° C. for 16 h. The mixture was then concentrated in vacuo, then treated with water (30 mL), and extracted with EtOAc (4×50 mL). The combined extracts were dried over MgSO4, filtered, and concentrated in vacuo to obtain a yellow solid. The solid was triturated with 40 mL of 40% EtOAc/hexane to yield the title compound as yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=5.86 (s, 2H), 6.89 (dd, 1H, J=2.4 & 8.4 Hz), 7.07 (brs, 1H), 7.59 (brs, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=2.4 Hz). MS (ES+): m/z 138.18 (100) [MH+]. HPLC: tR=0.75 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(F)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(F)cc2)c1

Procedure:
334 mg of compound 30 was obtained in a similar manner to those described in the Examples 1 and 2 using 654 mg of ethyl 4-(2-aminophenoxy)butyrate and 454 mg of 3-[1-(4-fluorobenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:29]([NH:36][C@H:37]([C:47](O)=[O:48])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[N:46])[CH:40]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1COCC1>[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:47](=[O:48])[C@H:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[N:46])[CH:40]=2)[NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Reactant: CS(=O)(=O)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.92 g (24.5 mmol) of 1-methylsulfonylpiperazine hydrochloride and 2.7 ml (24.5 mmol) of NMM was dissolved in 50 ml of DMF. After addition of 4 g (29.6 mmol) of HOBt and a solution of 5.93 g (20.4 mmol) of Boc-3-cyano-(L)-phenylalanine in 200 ml of THF, the mixture was cooled to O° C. 5.1 g (24.7 mmol) of DCC were added and the mixture was stirred for 48 hours at room temperature. Afterwards, the precipitated dicyclohexyl urea was filtered off, the THF moiety of the solution evaporated under reduced pressure, filtered and the filtrate poured into a mixture of 100 ml of 5% sodium bicarbonate solution and 200 ml of ice water. The formed precipitate was filtered off, washed with water, dissolved in methanol and the solvent was evaporated under reduced pressure. To remove the still present water, a co-distillation with toluene/isopropanol was performed several times. The only slightly impure product was processed in this form. Yield: 7.9 g (89%)
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.[NH2:44][C:45]1[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:44][C:45]3[CH:49]=[C:48]([CH3:50])[N:47]([CH3:51])[N:46]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)nn1C
Reaction time: 24 h

Procedure:
DIPEA (517 mg, 3.00 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (364 mg, 0.75 mmol), 3-amino-1,5-dimethylpyrazole (109 mg, 0.90 mmol) and HATU (599 mg, 1.58 mmol) in DMF (3.0 mL) and the mixture stirred for 24 hours. Water (25 mL) was added and the mixture extracted with ethyl acetate (2×25 mL) dried (MgSO4) and reduced to a brown oil. The crude product was purified by chromatography on silica, eluting with ethyl acetate, to give the required product as a clear oil. (232 mg).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)/[CH:10]=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:25]([Mg]Cl)=[CH2:26]>C1COCC1>[Si:1]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH:10]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH:25]=[CH2:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)/N=C/C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 2.4 g (6.20 mmol) of N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethylidene]-2-methylpropane-2-sulfinamide in 20 mL anhydrous THF cooled to 0° C. under nitrogen atmosphere (from Step D) was added a 1.6 M solution of vinyl magnesium chloride in THF (3.90 mL, 6.2 mmol) via syringe and the resulting mixture stirred for 1 h. The mixture was allowed to warm to room temperate and stirred for an additional hour. The reaction was quenched with saturated solution of ammonium chloride and extract with ethyl acetate. Combine organics, dry over magnesium sulfate, filter and concentrate under vacuum. The residue was purified by Horizon MPLC, with a 40M+ silica gel column, eluting with a gradient eluent system of 0-35% ethyl acetate in hexane to afford all four diastereomers as single isomers.