Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:40][C:41]([O-:44])([CH3:43])[CH3:42].[K+]>C(OC(C)(C)C)(=O)C.C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1

Procedure:
To a stirring solution of methyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38A) (14 g, 24.1 mmol) in t-butyl acetate (200 mL) was added 2 mL of t-BuOK in THF (2M) under vacuum. 3×2 mL t-BuOK were added to the stirring solution under vacuum to drive the reaction to complete. The mixture was then acidified to neutrality and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 3.5 g of the desired product 38B: 1H NMR (300 MHz, CDCl3) δ ppm 8.29 (1H, m), 7.71 (1H, d), 7.62 (2H, m), 7.49 (2H, t), 7.34 (3H, m), 6.02 (2H, s), 5.20 (2H, s), 4.02 (2H, m), 3.71 (3H, m), 3.08 (2H, m), 1.59 (9H, t), 0.97 (2H, m), −0.09 (9H, m). MS (ESI(+)): m/z 623.0 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[F:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[N:37]=[CH:38][C:33]([F:32])=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2ncc(F)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.026 g (50%). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 2H), 7.99-7.95 (m, 2H), 7.80 (dd, J=2.0, 8.0 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.23-7.15 (m, 3H), 7.07 (bs, 1H), 6.18 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.27 (s, 3H), 1.81-1.78 (m, 2H), 1.55-1.53 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ−75.77 (TFA), −109.62, −119.26, −142.84 LCMS: (ES+) m/z=557.4 (M+H)+
Reaction SMILES: C1(CNC([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=O)C=CC=CC=1.C(O)C.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([O-:35])=O>[Pd].ClCCl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=[O:35]
Reactant: NC(=O)CC(NC(=O)NCc1ccccc1)C(N)=O
Reactant: O=C([O-])c1ccc2ccccc2n1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)CC(NC(=O)c1ccc2ccccc2n1)C(N)=O

Procedure:
A solution of [S-[1R*(R*),2S*]]-N1[3-[[[(1,1-dimethylethyl)amino]carbonyl]n-butyl)amino]-2-hydroxy-1-(phenylmethy)propyl]-2-[(phenylmethylcarbamoyl)amino]butanediamide (1.03 g, 1.77 mmol) in 40 mL of abs. ethanol was then deprotected by hydrogenolysis in the presence of 10% palladium on carbon catalyst to give, after filtration and concentration, the free amine (428 mg) which was coupled with N-hydroxysuccinimide ester of 2-quinoline carboxylate (270 mg, 1.0 mmol) in dichloromethane for 16 h to give 380 mg, 63% of [1S-[1R*(R*),2S*]]-N1[3-[[[1,1-dimethylethyl)amino]carbonyl](n-butyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide, mp 102.1°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a 2-(tert-butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol), HOBt (740 mg, 5.48 mmol) in DCM (25 mL) was added NMM (2.77 g, 27.42 mmol) at rt. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase prep HPLC to provide the desired product (705 mg, 71%) as white solid
Reaction SMILES: O[CH:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)[CH3:3].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)[CH3:3])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(C)N=[N+]=[N-])s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a mixture of ethyl 5-(1-hydroxyethyl)thiophene-2-carboxylate (1.01 g), diphenylphosphorylazide (1.67 g), and toluene (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (905 μL) under ice-cooling, followed by stirring for 30 minutes. The reaction mixture was warmed to room temperature, followed by stirring for 15 hours. The reaction liquid was washed with water and 1 M hydrochloric acid in this order, and dried over anhydrous sodium sulfate. Then, after concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-(1-azidoethyl)thiophene-2-carboxylate (1.03 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6](N)[C:7]=1[Cl:8].C(N=C=S)(C)C.[CH:17]1([N:23]=[C:24]=[N:25]C2CCCCC2)[CH2:22]CCC[CH2:18]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:10][C:24]([NH:23][CH:17]([CH3:22])[CH3:18])=[N:25][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)N=C=S
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
5,6-Dichloro-1,2-phenylenediamine (0.61 g, 3.4 mmol), and isopropyl isothiocyanate (0.39 g, 3.8 mmol) were combined in anhydrous pyridine (10 mL) and were heated to 80° C. for 15 min. Dicyclohexylcarbodiimide (1.06 g, 5.14 mmol) was then added and the resulting mixture was allowed to stir at 100° C. for 5 h. Toluene (30 mL) was added and the mixture was concentrated by rotary evaporation leaving a brown residue. The product was further purified by silica gel chromatography using 6.5:3:0.5 ethyl acetate/hexane/triethylamine to afford a gummy solid which was recrystallised from acetonitrile to give 0.46 g (60%) of a tan solid; m.p. 218-220° C. Anal. Calcd for C10H11Cl2N3 : C, 49.20; H, 4.54; N, 17.21. Found: C, 49.31; H, 4.59; N, 17.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-5-methylphenol (10.7 g, 75 mmol) in DMF (40 mL) was added potassium carbonate (26 g, 188 mmol) followed by neat methyl iodide (4.9 mL, 79 mmol). The reaction mixture was stirred at room temp for 6 hr, extracted with EtOAc, washed with water and brine, dried and concentrated in vacuo to give 4-chloro-3-methoxytoluene (10.8 g, 92%). 1H-NMR (DMSO-d6): δ 2.26 (s, 3H), 3.79 (s, 3H), 6.71-6.73 (dd, 1H), 6.94 (s, 1H), 7.22-7.24 (d, 1H).
Reaction SMILES: C(N1C[CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:31])=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25](CC5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)CC1)C1C=CC=CC=1.[CH2:32](NN)[CH3:33].NN.C12OC(CC1)CNC2>>[Cl:31][C:20]1[N:19]=[C:18]2[N:14]([CH2:11][CH3:12])[N:15]=[CH:16][C:17]2=[C:22]([N:23]2[CH:29]3[CH2:32][CH2:33][CH:24]2[CH2:25][O:30][CH2:28]3)[N:21]=1
Reactant: CCNN
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Agent: C1CC2CNCC1O2
Agent: NN
Product: CCn1ncc2c(N3C4CCC3COC4)nc(Cl)nc21

Procedure:
A procedure similar to that used for the synthesis of 3-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane is used, using ethyl hydrazine as the hydrazine component and substituting 3-oxa-8-azabicyclo[3.2.1]octane for 8-oxa-3-azabicyclo[3.2.1]octane. (65%, MS=294.3 (M+H))
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[S:39][CH:43]=[CH:42][CH:41]=1)(=[O:20])=[O:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccs3)c2c1
Yield: 36.5 %

Procedure:
2-Methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)-benzenesulfonamide can be obtained as described in Example 47 from 1.5 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 339 mg of 2-thiopheneboronic acid, 50 ml of dimethylformamide, 4.8 ml of a saturated aqueous sodium hydrogencarbonate solution and 64 mg of tetrakis(triphenylphosphine)palladium[0]. 350 mg of 2-methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of an ochre solid melting at 246° C. (analysis C18H15N3O4S3 % calculated C, 49.87; H, 3.49; N, 9.69; O, 14.76; S, 22.19. % found C, 49.82; H, 3.67; N, 9.08; S, 20.42).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].Cl.Cl.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(N(C)C)cc1

Procedure:
The title compound was prepared as a white solid (0.160 g, 23% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using p-dimethylamino-benzyl amine dihydrochloride and a procedure similar to steps 3-4 of Example 1, mp >215° C. (decomp.); 1H NMR (DMSO-d6) δ2.97 (s, 6H), 3.94 (s, 3H), 4.14-4.23 (m, 2H), 4.39-4.48 (m, 2H), 6.88-7.14 (bs, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.59 (d, J=9.3 Hz, 1H), 7.97 (dd, J=1.7, 8.9 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.59 (d, J=1.6 Hz, 1H), 9.05-9.24 (bs, 2H), 11.90-13.75 (bs, 1H); IR (neat) 3320, 2330-3130, 1705, 1670, 1625, 1580, 1515, 1485, 1460, 1430, 1280, 1260, 1220, 1200, 1175, and 1100 cm−1; mass spectrum [(+) ESI], m/z 365 (M +H)+ and [(−) ESI], m/z 363 (M−H)−; Anal. Calcd. for C22H24N2O3. 2HCl.1.25H2O: C, 57.46; H, 6.25; N, 6.09, Found: C, 57.25; H, 6.37; N, 5.93.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38](=[O:46])[O:39][C:40]4([CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:27]=3[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CCCCC>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)([OH:46])[O:39][C:40]4([CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[C:27]=3[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3(O)c1ccc(C(F)(F)F)cc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
2.31 g 1-Iodo-4-(trifluoromethyl)benzene are dissolved in 30 ml tetrahydrofurane, cooled to −65° C. and treated dropwise with 9.2 ml of a 1.6 M solution of tert.-butyllithium in n-pentan. The mixture is stirred for 30 minutes and then a solution of 1.9 g (S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one in 30 ml tetrahydrofurane is added dropwise. The mixture is stirred for 30 minutes at −65° C. and for 30 minutes at −50° C. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 80:20).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[C:15]1([CH:21]2[CH2:23][CH:22]2[C:24](O)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24]([CH:22]1[CH2:23][CH:21]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:25])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: N[C@@H](CO)c1ccc2ccccc2c1
Reactant: O=C(O)C1CC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)c1ccc2ccccc2c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.2 mmol), EDAC.HCl (0.4 mmol), DMAP (0.2 mmol), and triethylamine (0.6 mmol) in dichloromethane (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 50% hexanes in ethyl acetate to give the desired product (52 mg) as a solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[N:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36].[H-].[Na+]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:32][CH2:33][CH2:34][C:35]3=[O:36])=[CH:18][CH:19]=2)[N:4]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}aniline (166 mg, 0.56 mmol) in dichloromethane (4 ml) was treated with diisopropylethylamine (1.12 mmol, 146 mg) followed by 4-chlorobutyryl chloride (80 mg, 0.56 mmol). After stirring at room temperature for 15 minutes a solid suspension of sodium hydride (60% in mineral oil) (22 mg, 0.55 mmol) was added and stirring continued for 30 minutes. The dichloromethane was removed by blowing with air and dimethylformamide added (3 ml) and stirring continued for 30 minutes. The reaction mix was partitioned between dichloromethane and water (2×5 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give a yellow oil (190 mg) which was purified by mass directed auto prep to give the title compound as a yellow oil (39 mg, 19%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].Br[CH:45]1[CH2:49][CH2:48][O:47][C:46]1=[O:50]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:42][CH2:43]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH:45]5[CH2:49][CH2:48][O:47][C:46]5=[O:50])[CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: O=C1OCCC1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=CCN1CCN(C2CCOC2=O)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.42 ml of triethylamine is added to 608 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline in 3.0 ml of tetrahydrofuran. The mixture is cooled in the ice bath and a solution of 215 mg of 3-bromodihydrofuran-2-one in 1.0 ml of tetrahydrofuran is added dropwise and the mixture is stirred for one hour with cooling. The ice bath is then removed and the mixture is stirred for about 48 hours at ambient temperature. The reaction mixture is chromatographed directly, without further processing, over a silica gel column, with methylene chloride/methanol (95:5 to 90:10) as eluant. The foamy crude product is crystallized by trituration with a little diethylether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.O>[C:12]([C:3]1[C:2]([NH:1][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cnc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)ethanone (0.87 g, 4.26 mmol, 1 eq.) in DCM (20 ml) were added TEA (0.65 ml, 4.69 mmol, 1.1 eq.) and ethyl 3-chloro-3-oxopropanoate (0.71 ml, 5.54 mmol, 1.3 eq.) at 0° C. The reaction mixture was stirred at RT for 3 h. Then the mixture was diluted with water (50 ml) and extracted with DCM (3×80 ml). The combined organic layers were washed with water (80 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to provide ethyl 3-(2-acetyl-5-(trifluoromethyl)pyridin-3-ylamino)-3-oxopropanoate (1.35 g, 4.24 mmol, 99%) which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].C(OC(=O)C)C.[C:25]1([CH:35]=[N+]=[N-])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CO>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)CC2C1
Reactant: [N-]=[N+]=Cc1cccc2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)NCCSC1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Reaction time: 1 h

Procedure:
A solution of 100 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid in 5 mL of a mixture of ethylacetate and methanol was treated with a slight excess of α-naphthyldiazomethane. After the solution was stirred for 1 hr and then concentrated on a rotary evaporator, the crude product was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with 5% methanol in methylene chloride affording 130 mg (85.5%) of 3-(2'-acetamidoethylthio)7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, as a glass. IR (neat): 3200, 1780, 1690, 1660 cm-1 ; NMR (220 MHz; CDCl3): δ 1.86 (3H, s), 2.6-3.0 (5H, m), 3.0-3.5 (4H, m), 4.43 (1H, m), 5.61 (1H, d, J=18), 5.64 (1H, d, J=18 ), 6.30 (1H, m), and 7.3-8.2 (7H, m); MS (chemical ionization) confirmed molecular weight of 409.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([CH3:21])=[O:20]>C1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:18][C:19](=[O:20])[CH3:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]-pyridine-3-carbaldehyde (0.50 g) and acetonylidenetriphenylphosphorane ##STR11## (0.82 g) in benzene (6 ml) was refluxed for 4 hours and then the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound, were combined and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3-buten-2-one (trans isomer) (0.21 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:22][N:21]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Fc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-fluorophenylboronic acid (176 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 112 mg, 0.44 mmol, 70%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.18 (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (bs, 1H), 7.15 (ddd, J=11.7, 8.2, 1.3 Hz, 1H), 7.26 (dt, J=7.9, 1.3 Hz, 1H), 7.36-7.40 (m, 1H), 7.48 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.78 (ddd, J=8.2, 2.2, 0.9 Hz, 1H), 7.97 (dt, J=7.9, 1.9 Hz, 1H), 8.60 (dd, J=2.5, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 116.2 (d, J=23.0 Hz), 119.0, 124.5 (d, J=9.1 Hz), 124.6, 126.6, 126.7, 130.0 (d, J=9.1 Hz), 130.7 (d, J=9.1 Hz), 130.9 (d, J=2.7 Hz), 135.3, 137.3, 148.5, 153.6 (d, J=2.7 Hz), 160.4 (d, J=250.2 Hz); MS (ESI): m/z=254.18 [M+H]+.