Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[NH:11][N:10]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[NH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3c(Cl)cccc3Cl)n[nH]2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)n[nH]2)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
The 3-(2,6-dichlorophenyl)-5-(3-nitrophenyl) pyrazole prepared in Step 2 (57 mg) was dissolved in 50% aqueous ethanol and treated with iron powder (57 mg, 6 molar equivalents), and ammonium chloride (18.2 mg, 2 molar equivalents). The mixture was heated at 70–80° C. for 4 h. The reaction mixture was cooled to room temperature then filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(2,6-dichlorophenyl)-5-(3-aminophenyl)pyrazole as a white solid (27 mg). NMR (300 MHz, CDCl3): 7.40 (d, 2H), 7.25 (t, 1H), 7.20 (m, 1H), 7.11 (m, 2H), 6.68 ppm (m, 2H). LC-MS tr=5.66 min (Method Z) MH+=303–307
Reaction SMILES: C(=O)([O-])OC1C=CC([N+]([O-])=O)=CC=1[CH2:12][CH:13]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[C:19]2[C:14]1=[C:15]1[CH:41]=[CH:40][CH:39]=[CH:38][C:16]1=[C:17]1[CH:37]=[CH:36][CH:35]=[CH:34][C:18]1=2.[C:44]([OH:47])(=[O:46])C.[C:48]([O:52][C:53](=[O:56])[CH2:54][NH2:55])([CH3:51])([CH3:50])[CH3:49].O.OS([O-])(=O)=O.[K+]>ClCCl>[C:48]([O:52][C:53](=[O:56])[CH2:54][NH:55][C:44]([O:47][CH2:12][CH:13]1[C:14]2[C:19](=[C:18]3[CH:34]=[CH:35][CH:36]=[CH:37][C:17]3=[C:16]3[CH:38]=[CH:39][CH:40]=[CH:41][C:15]3=2)[C:20]2[C:25]1=[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]1=[C:22]1[CH:30]=[CH:31][CH:32]=[CH:33][C:21]1=2)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: O=C([O-])Oc1ccc([N+](=O)[O-])cc1CC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)CN
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
To a solution of 17-tetrabenzo(a,c,g,i)fluorenylmethyl-p-nitrophenyl carbonate (39.2 mg, 0.07 mmol) and glycine tert-butyl ester acetate salt (14.7 mg, 0.077 mmol; 1.1 equiv.) in dichloromethane (1.5 ml) was added N,N′-dimethyl aniline (18 μl, 0.14 mmol; 2 equiv). The reaction mixture was stirred at room temperature, under nitrogen, for 72 h. After addition of water (10 ml) and acidification with KHSO4 (2M; pH=1), the reaction mixture was extracted with dichloromethane (3×15 ml), washed with water (3×20 ml) and dried over MgSO4. The solvent was removed in vacuo to give an orange oil which was triturated in ether. A yellow solid was obtained which was filtered, washed with petrol (b.p. 40-60° C.) and dried to give compound (42) (30.6 mg, 79%); m.p. 170-171° C.; (Found: C, 79.7; H, 5.51; N, 2.33; C37H31NO4 requires: C, 80.3; H, 5.60; N, 2.53%); t.l.c. Rf (H) 0.79, Rf (I) 0.95; νmax (CH2Cl2) 3440 (secondary amide NH), 3060 (CH stretching, aromatic), 2940 (CH stretching, alkyl), 175 (CO, urethane, ester and slide I), 1600, 1500 (aromatic rings), 1520 (amide II), 1340 (OH bonding) cm−1, 1220, 1160, 1110 (CO stretching), 865, 850 (out of plane CH bonding); λmax 384 (16323), 367 (17656), 302 (42641), 290 (34313), 262 (62296) nm; δH (CDCl3, 80 MHz) 8.85-8.60 (6H, m, aromatic), 8.39-8.28 (2H, m, aromatic), 7.81-7.56 (8H, m, aromatic), 5.27 (1H, t, 3J=6 Hz, CH), 4.98 (1H, s broad, NH), 4.61 (2H, d, 3J=6 Hz, CH2), 3.74 (2H, d, 3J=6 Hz, CH2 glycine), 1.44 (9H, s, CH3×3); δc (CDCl3, 50 MHz) 168.7 (CO, ester), 156.1 (CO, urethane), 141.9, 136.7, 131.5, 130.3, 128.7, 127.9 (quaternary aromatic C's), 127.4, 126.8, 126.0, 125.8, 125.3, 124.9, 123.5, 123.1 (aromatic CH's), 82.0 (quaternary C, CMe3), 69.0 (CH2), 47.5 (CH), 43.2 (CH2, glycine), 27.9 (CH3×3); m/z (FAB) 553, 379. HRMS 553.22527, C37H31NO4 requires 553.22529 ( ) <1 ppm.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:16]=[C:17]([CH2:21][NH2:22])[CH:18]=[CH:19][CH:20]=4)=[CH:14][C:9]=3[N:8]([CH3:23])[S:7]2(=[O:25])=[O:24])[CH2:4][CH2:3]1.F[C:27]1[N:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CO>[CH:2]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=4)[CH2:21][NH:22][C:27]4[N:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])=[CH:14][C:9]=3[N:8]([CH3:23])[S:7]2(=[O:24])=[O:25])[CH2:4][CH2:3]1
Reactant: N#Cc1cccnc1F
Reactant: CN1c2cc(-c3cccc(CN)c3)ccc2N(CC2CC2)S1(=O)=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2cc(-c3cccc(CNc4ncccc4C#N)c3)ccc2N(CC2CC2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a microwave vial was added 1-{3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride (23-2) (0.037 g, 0.097 mmol), 2-fluoronicotinonitrile (0.18 g, 0.15 mmol), NMP (0.7 mL), and finally DIPEA (0.039 mL, 0.22 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 2-({3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]benzyl}amino)nicotinonitrile (24-1) as a tan solid. HRMS (M+H)+: observed=446.1642, calculated=446.1645.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[NH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:23])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1nc2ccc(OC)cc2nc1Cl
Temperature: 100 °C

Procedure:
6-Methoxy-3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid ethyl ester (5.2 g, 20.9 mmol) was suspended in 75 mL of POCl3 and resulting mixture heated to 100° C. for 1 h. The reaction mixture was poured onto 500 mL of ice-water and the pH of the solution adjusted to 3 with conc. NH4OH. Mixture was extracted twice with 300 mL of EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to give the 3-chloro-6-methoxy-quinoxaline-2-carboxylic acid ethyl ester (4.6 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:18]2)[CH:8]=[C:7]([F:28])[C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.CCN(C(C)C)C(C)C.C1(N)CC1>C(Cl)Cl>[CH:37]1([NH:39][C:4](=[O:6])[C:3]2[C:2]([F:1])=[CH:10][C:9]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:18]3)=[CH:8][C:7]=2[F:28])[CH2:38][CH2:36]1
Reactant: O=C(O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CC1)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Reaction time: 8 h

Procedure:
2,6-Difluoro-4-(2-{(1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl}ethoxy)benzoic acid (40 mg, 0.098 mmol) in 0.5 mL of DCM was stirred with EDC (37.6 mg, 0.196 mmol), HOBt (30 mg, 0.196 mmol) and DIPEA (64 mg, 0.49 mmol) at RT for 15 min. Cyclopropylamine (11.2 mg, 0.196 mmol) was added. The reaction mixture was stirred overnight. Solvent was removed under vacuum. The residue was purified by mass directed RPHPLC. The product fraction was basified with 2 M sodium bicarbonate aq. solution. The product was extracted with EtOAc. The organic layer was dried with sodium sulfate and concentrated to yield Example 3. LCMS calc: 446.45; obs: 447.01 (M+1); Human GPR119 EC50: 5.28 nM.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[C:23]#[CH:24])[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:2].[CH:28]([N-]C(C)C)([CH3:30])[CH3:29].[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(I)CC>O1CCCC1>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH2:29][CH2:28][CH3:30])[C:13]=3[C:23]#[CH:24])[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:27]
Reactant: CC(C)[N-]C(C)C
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCI
Product: C#Cc1c2c3c(cccc3n1CCC)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under argon, 109 mg of 1,1-diethyl-3-(2-ethynyl-6-methyl-8α-ergolinyl)urea in 5 ml of absolute tetrahydrofuran is added dropwise at -30° C. to a solution of lithium diisopropylamide, prepared from 0.15 ml of diisopropylamine and 1.8 ml of 0.6-molar n-butyllithium solution (hexane) in 3 ml of absolute tetrahydrofuran at 0° C. within 15 minutes. After 30 minutes of agitation at -30° C., 0.07 ml of propyl iodide is added thereto. The mixture is stirred for one hour at -20° C. and overnight at room temperature. After evaporation, the mixture, after adding sodium bicarbonate solution and a small amount of ethanol, is extracted by shaking with ethyl acetate. The organic phase is concentrated and chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1, thus obtaining 30 mg of 1,1-diethyl-3-(2-ethynyl-1-propyl-6-methyl-8α-ergolinyl)urea as an oil.
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([N+:18]([O-])=O)[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:12]=1[F:13]>C(O)(=O)C.C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[C:12]=1[F:13])[NH2:18]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(C(F)(F)F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114 %

Procedure:
In a mixture of 7.0 g of reduced iron, 4 mL of acetic acid and 50 mL of water, a solution of 6.0 g of 5-chloro-6-fluoro-3-nitrobenzotrifluoride in 80 mL of acetic acid-ethyl acetate (1:1) was added dropwise at 80° C. with stirring over 30 minutes. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off through Celite, the organic phase was collected and washed with 100 mL of water and then 100 mL of saturated sodium hydrogen carbonate aqueous solution. The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.0 g of the crude aimed product as red-brown oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Br[C:19]1C=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32].C([N:36](CC)CC)C>CN(C)C=O>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[C:20]([N+:31]([O-:33])=[O:32])=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:36]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Br
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ncc(-c4ccccc4)cc3[N+](=O)[O-])cc12
Temperature: 110 °C
Yield: 24 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-bromo-3-nitrobiphenyl were used. Triethylamine was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 12 hours. Column chromatography afforded the title compound (24%) as a red amorphous solid: 1H NMR (CDCl3) δ9.63 (br s, NH), 8.97 (br s, NH), 8.42 (d, J=2.2 Hz, 1H), 7.56-7.25 (m, 9H), 7.08 (d, J=9.0 Hz, 2H), 3.50-3.32 (m, 2H), 2.95-2.79 (m, 2H), 2.59-2.52 (m, 1H), 2.53 (s, 3H), 2.05-1.71 (m, 4H); 13C NMR (CDCl3) δ144.4, 138.8, 134.9, 134.5, 132.4, 131.1, 130.2, 129.7, 129.0, 127.3, 126.2, 124.7, 124.1, 120.8, 116.7, 115.9, 112.7, 112.0, 67.9, 57.4, 40.6, 31.2, 28.6, 21.9; FAB HRMS calculated for [C26H26N4O2.H]427.2136, found 427.2099.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:44][C:45]([NH:47][CH2:48][CH:49]1[CH2:53][O:52][C:51]([CH3:55])([CH3:54])[O:50]1)=[O:46].CN(C)C=O>O>[CH3:54][C:51]1([CH3:55])[O:50][CH:49]([CH2:48][NH:47][C:45]([CH2:44][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)=[O:46])[CH2:53][O:52]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC1(C)OCC(CNC(=O)CCl)O1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 24 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 300 mg, 487 μmol) and 2-chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide (101 mg, 487 μmol) were combined with dry dimethyl formamide (5 mL) to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with methanol in ethyl acetate) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-carbamoyl]-methyl ester as an off-white solid (92 mg, 24% yield). LCMS (ES+) m/z calcd. for C39H42Cl2F2N4O7 [(M+H)+]: 787. found: 787.
Reaction SMILES: C(O[CH:5]1[CH2:9][N:8]([C:10]([CH3:18])([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:19])[CH:6]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:18][C:10]([N:8]1[CH2:9][CH:5]=[C:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7]1=[O:19])([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC1CN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(c1ccccc1)N1CC=C(c2ccccc2)C1=O
Yield: 72.1 %

Procedure:
0.7 g (2 mmol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-pyrrolidinone prepared by the method of Reference Example 15, was dissolved in 30 ml of toluene, and 0.36 g (2.4 mmol) of DBU was added thereto. The mixture was refluxed under heating for five minutes. The reaction solution was cooled, and toluene was added. The toluene solution was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude product thereby obtained was purified by silica gel column chromatography to obtain 0.4 g (yield: 73%) of the desired compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O.[CH:22]1([NH:25][C:26]2[S:27][CH2:28][C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:22]1([NH:25][C:26]2[S:27]/[C:28](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)/[C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1
Reactant: O=C1CSC(NC2CC2)=N1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC1CCOCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc2c1OC1CCOCC1

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile (example 76b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(tetrahydropyran-4-yloxy)quinoline-3-carbonitrile. LC-MS m/e 421 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C=O)C.CCOCC>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COCCc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCOc1cc(CCOC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-hydroxy-5-(2-methoxyethyl)benzoate (1 eq.) from the previous step in DMF (0.2 M) was added Cs2CO3 (2 eq.) and 1-bromo-2-methoxy-ethane (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether and washed extensively with water and brine. The organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1.C(OCC)(=O)C.ClCCl>C(C(C)=O)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,4-dichlorophthalazine (5.00 g, 25.1 mmol) and (R)-2-methylpiperazine (6.29 g, 62.8 mmol) were dissolved in methyl ethyl ketone (80 mL) and stirred at rt for 2 days. The reaction was added to ethyl acetate (350 mL) and washed once with aqueous K2CO3 (10%), once with water, and once with saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of dichloromethane/0-5% methanol gave a pale yellow solid. MS (M+H)+=263.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[NH:9][CH:8]=[CH:7][C:6]2=O)#[N:2].CN(C=O)C.S(Cl)([Cl:26])=O>>[ClH:26].[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cc2[nH]ccc(=O)c2cc1C#N
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Cl)c2cc1C#N
Product: Cl
Yield: 82 %

Procedure:
6-Cyano-7-(2-methoxyethoxy)-1,4-dihydroquinolin-4-one (1.9 g, 7.8 mmol) and DMF (0.2 ml) in thionyl chloride (50 ml) were heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene and dried under vacuum to give 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (2.4 g, 82%) as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:21][CH:20]=2)=[C:11]([C:16](O)=[O:17])[S:12][C:13]=1[CH2:14][CH3:15])#[N:8].C[N:31](C=O)C.N>ClCCl.O1CCOCC1>[C:7]([C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:21][CH:20]=2)=[C:11]([C:16]([NH2:31])=[O:17])[S:12][C:13]=1[CH2:14][CH3:15])#[N:8]
Reactant: CCc1sc(C(=O)O)c(-c2ccc(-c3nccs3)cc2)c1C#N
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1sc(C(N)=O)c(-c2ccc(-c3nccs3)cc2)c1C#N
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Add oxalyl chloride (0.050 mL, 0.57 mmol) to a suspension of 4-cyano-5-ethyl-3-(4-thiazol-2-yl-phenyl)-thiophene-2-carboxylic acid (0.15 g, 0.44 mmol) and DMF (0.1 mL) in dichloromethane at 0° C. Stir 1 h at 23° C. and add 1M solution of ammonia in dioxane (5 mL). Concentrate in vacuo, suspend the solid in ethyl acetate and filter to give 0.052 g of the title compound as a white solid. Mass spectrum ESI positive (m/z): 340 (M+1), 362 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#N)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[OH-:26].[Na+].Cl.C[OH:30]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:24]([OH:30])=[O:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [OH-]
Reactant: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 64 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (103 mg, 0.30 mmol) was stirred at 100° C. in MeOH (10 mL) and 6N NaOH (10 mL) for 2.5 hours. The reaction was acidified with 1N HCl and partitioned between CH2Cl2 and water, and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield a white solid (69.0 mg, 64%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 4.82 (s, 2H), 4.32 (s, 2H), 2.84 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([OH:6])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1[C:33](=O)C2C(=CC=CC=2)C1=O.FC1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]1[CH2:24][NH:25][C:33]1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1)=[O:6]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Fc1ncc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1F
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 2-fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-fluoro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 478 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-7.00 (m, 7H), 4.94-2.70 (m, 5H), 2.35-0.65 (m, 11H).