Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>ClCCl>[C:32]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (6.5 g) and triethylamine (3 ml) in dichloromethane (150 ml) cooled to 0° C. was added dropwise a solution of acetylchloride (1.7 g) in dichloromethane (50 ml). The mixture was stirred for one hour at room temperature. Water (500 ml) was added, the organic phase separated, washed with brine (2×50 ml) and finally worked-up as above. The thus isolated crude title product was purified by column chromatography on silica gel (eluted with a mixture of ethyl acetate/heptane/triethylamine 75:25:4). Recrystallization from diethyl ether yielded 7.7 g of pure title compound 4a. Mp: 159-162° C. 1H NMR (CDCl3): δ 1.70-1.90 (m, 5H); 2.00-2.15 (m, 1H); 2.15 (s, 3H); 2.20-2.30 (m, 1H); 2.35-2.50 (m, 2H); 2.60 (dd, 1H); 2.70-2.90 (m, 2H); 2.95-3.15 (m, 2H); 3.45 (qui, 1H); 6.95 (t, 2H); 7.05-7.25 (m, 5H); 7.55 (s, 1H)
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12])([O-:4])=[O:3]>C(OCC)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:13]([NH2:1])(=[O:15])=[O:14])[CH3:12])([O-:4])=[O:3]
Reactant: N
Reactant: CC(c1ccccc1[N+](=O)[O-])S(=O)(=O)Cl
Solvent: CCOCC
Product: CC(c1ccccc1[N+](=O)[O-])S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquid anhydrous ammonia (10 ml) was added to a stirred suspension of the product from Example 13 in 350 ml dry diethyl ether at 0°-5° C. over a period of 20 minutes. The reaction mixture was stirred at 0°-5° C. for 30 minutes and was allowed to warm to room temperature over a two hour period. The solids were filtered and washed with diethy ether. Concentration of the filtrate in vacuo gave a yellow solid which was washed with water, 1-chlorobutane, and then dried under vacuum to yield 17 g of 1-(2-nitrophenyl)ethanesulfonamide as a pale yellow solid, m.p. 107°-109° C.
Reaction SMILES: O(Cl)Cl.[P+5].[NH2:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61](O)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:41][C:42]([NH:44][C@H:45]([C:61]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:7]=1[O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:11]1)=[O:62])[CH:46]([C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=1)[C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)=[O:43])([CH3:39])([CH3:40])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: ClOCl
Agent: [P+5]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phosphorus (V) oxychloride (118 μl, 1.262 mmol) was added to a solution of tert-butyl (2S,5S)-2-[(2-amino-6-fluorophenoxy)methyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (540 mg, 1.147 mmol) and N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (433 mg, 1.147 mmol) in pyridine (5.74 mL) at −15° C. The reaction was stirred for 30 minutes then warmed to 0° C. and stirred for another 1.5 hours. LC/MS at this time only shows pyridine and desired product. The reaction was quenched with a saturated aqueous solution of KH2PO4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to afford the title compound (977 mg, 1.106 mmol, 96% yield) as an off-white foam, MS (ESI): m/z=730.51 (M+H-boc). 94% pure by LC/MS. The material was taken on crude to the next step.
Reaction SMILES: C(OC([N:8]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](Br)[CH:31]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]([CH3:26])=[CH2:25])[C:9]1=[O:34])=O)(C)(C)C.N1C2C(=CC=CC=2)[CH2:37][C:36]1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH:11]([C:24]([CH3:26])=[CH2:25])[C:10]32[C:27]2[C:32](=[CH:31][C:30]([C:36]#[CH:37])=[CH:29][CH:28]=2)[NH:8][C:9]3=[O:34])[CH:21]=[CH:20][CH:19]=1
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Br)ccc12
Reactant: O=C1Cc2ccccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c(c1)NC(=O)C21C(C(=C)C)NC(=O)CC1c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester-1,3-dihydro-indole-2-one (54 mg, 0.1 mmol) prepared in example 173a, Pd(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (110 mg, 0.5 mmol), dimethyl trimethylsilylethynylborate (1 mL, 0.5 M, 0.5 mmol) in toluene (3 mL) was heated under microwave irradiation at 130° C. for 1 hour. The solvent was removed in vacuo. To the residue was added methanol (3 mL) and aqueous NaOH (2 N, 3 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was diluted with ethyl acetate (20 mL), washed with brine, saturated NH4Cl, brine, then organic layer was separated, and concentrated. The residue was purified by preparative HPLC to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-6-ethynyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:4][C:3]=1[N+:21]([O-])=O>CO.[Ni]>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[O:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1
Reactant: Nc1ccc(OCCN2CCc3ccccc3C2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OCCN2CCc3ccccc3C2)cc1N
Reaction time: 4 h
Yield: 96.2 %

Procedure:
A mixture of N-[(4-amino-3-nitrophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (250 mg, 0.8 mmol) and Raney Ni (about 200 mg) in MeOH (15 mL) was shaken under H2 (25 parr) for 4 h, then filtered. The filtrate was evapoated, and the residue was purified by chromatography over silica gel (CHCl3-EtOH-NH4OH, 60:40:0.5) to give 218 mg (96%) of N-[(3,4-diaminophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline as a brown viscous oil. 1H NMR (CDCl3): 2.87-2.96 (m, 10H), 3.764 (s, 2H), 4.122 (t, 2H, J=5), 6.545 (dd, 1H, J=8; 2), 6.362 (d, 1H, J=2), 6.633 (d, 1H, J=8), 7.01-7.20 (m, 5H).
Reaction SMILES: [Br:1][CH:2]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1.N#N.[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:1][C:2]1([Br:12])[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: BrC1Cc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Clc1ccccc1
Product: BrC1(Br)Cc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
Bromobenzocyclobutene (91.5 g, 0.5 mol) and chlorobenzene(anhydrous, 2500 mL) were charged into a four-neck 5 L flask equipped with mechanical stir, condenser, N2 (in and outlet) and thermometer. The reaction mixture was heated to 120° C., and N-bromosuccinimide (111.3 g, 0.625 mol) was gradually charged over 30 min., followed by slowly feeding a mixture of a free radical azo compound source (VAZO™ 68) (14.0 g, 0.05 mol) and chlorobenzene (500 mL) over 30 min. Then the reaction mixture was heated to 133° C. (mild reflux) and kept at that temperature for 6 hr. The mixture was then cooled to room temperature overnight, and chlorobenzene was removed by vacuum evaporation. The crude product was extracted with hexane. After removal of hexane, 1-bromo-bromobenzocyclobutene (1-Br-BrBCB) (80-85° C/0.35 torr, 90 g, ca. 93% purity) was obtained by vacuum distillation.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Reactant: CN(C)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A suspension of 2-(dimethylamino)ethanol (128 mg, 1.435 mmol) in DMF (5 mL) was added to a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.956 mmol) in DMF (5 mL). K2CO3 (264 mg, 1.913 mmol) was added and the mixture was stirred at 80° C. for 8 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between ethyl acetate and saturated NaHCO3 solution. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=5:1, Rf=0.6) to yield a light yellow solid of N,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine (75 mg, 0.270 mmol, 28.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.22-8.02 (m, 2H), 7.72 (s, 1H), 4.43 (t, J=5.1 Hz, 2H), 3.26 (t, J=4.9 Hz, 2H), 2.78-2.60 (m, 6H). ES-LCMS m/z 279 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:21].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:21])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(C)cc3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(C)cc3n2)c1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 19.5 g (68.3 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-methyl-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 200 ml anhydrous THF. Triethylamine (34 ml, 240 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (8.55 g, 81.8 mmol) was added dropwise and the mixture was stirred for 2 hr at 0° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with diethyl ether and the filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude product was recrystallized in ethanol to give 7.2 g (30%) of a light yellow solid. 1H NMR (CDCl3) delta: 11.28 (s, 1H, Ar—OH), 7.89 (s, 1H, Ar—H benzotriazole 4-position), 7.79 (d, 1H, Ar—H benzotriazole 6-position), 7.66 (s, 1H, Ar—H phenol 6-position), 7.26 (d, 1H, Ar—H benzotriazole 7-position), 7.03 (s, 1H, Ar—H phenol 4-position), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.54 (s, 3H, Ar—CH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [Cl-:1].[P+]=O.N1C2C(=CC=CC=2)C=CC=1.[Br:14][C:15]1[C:16](=O)[NH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21]>O>[Br:14][C:15]1[C:16]([Cl:1])=[N:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])c[nH]c(=O)c1Br
Reactant: [Cl-]
Agent: O=[P+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1c([N+](=O)[O-])cnc(Cl)c1Br
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a 25 ml single-necked round-bottomed flask, to 1.72 ml phosphorous oxide chloride kept at a temperature of 5° C., 0.857 ml quinoline and 3.40 g of 3-bromo-4-methyl-5-nitro-1H-pyridin-2-one are added consecutively. The resulting beige suspension is stirred under heating to 120° C. whereupon a brown solution is obtained. Stirring is continued for 2 hours. Afterwards, the solution is cooled down to an ambient temperature and poured into water. The resulting precipitate is collected by filtration, the filter cake washed with water (4×) and dried to give 3.15 g of the title compound in the form of a brown solid (MP: 60-62° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH2:34]([NH2:36])[CH3:35].N1C=CC=CC=1>O=S(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:36][CH2:34][CH3:35])=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CCN
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Temperature: 95 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
2-((2-Chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (0.15 g, 0.31 mmol) was dissolved in SOCl2 (10 mL). The solution was heated at 90-100° C. for 3 hours. Removal of the rest SOCl2 gave the crude product. A solution of the crude acid chloride in THF (12 mL) was treated with a solution of ethanamine (0.14 g, 3.1 mmol) and Pyridine (0.3 mL) in THF (8 mL) at 0° C. The reaction mixture was allowed to reach room temperature and stirred overnight. Concentrated to remove THF to afford the crude product, it was purified by preparative TLC to obtain 347 (48.5 mg, 31%). ESI-MS: 512. 1H NMR (CDCl3, 400 MHz): δ7.59 (s, 1H, ArH), 7.44-7.32 (m, 5H, ArH), 6.95 (s, 1H, ═CH), 6.12 (s, 1H, NH), 4.23 (t, J=5.0 Hz, 2H, CH2), 3.51-3.44 (m, 2H, CH2), 3.39 (s, 3H, CH3), 3.13 (s, 3H, CH3), 3.05 (t, J=5.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3), 1.24 (t, J=7.2 Hz, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:28][C:29]1(C)[C:33](C)(C)OB(CC=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14]([CH2:33][CH:29]=[CH2:28])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C=CCc1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Yield: 72.2 %

Procedure:
Using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (1.5 g, 3.6 mmol) produced in Example 13(ii), 4,4,5,5-tetramethyl-2-prop-2-en-1-yl-1,3,2-dioxaborolane (897 mg, 5.3 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(H) dichloride dichloromethane complex (180 mg, 0.22 mmol), cesium carbonate (3.5 g, 11 mmol), 1,2-dimethoxyethane (50 mL) and water (3 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (815 mg, 73%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:34]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Temperature: 100 °C

Procedure:
To a stirred mixture of 5-bromo-3-[1-(2,6-dichlorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine (10.00 mg, 0.027 mmol), 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (11.00 mg, 0.035 mmol), potassium carbonate (15.00 mg, 0.11 mmol) in DME (2.0 mL) and H2O (0.40 mL) was added (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (0.84 mg, 0.0011 mmol) under nitrogen atmosphere. The resulting mixture was refluxed at 100° C. for 90 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 8% MeOH in DCM) to give desired product. 1H NMR (400 MHz, CD3OD): δ=1.92 (d, J=7.1 Hz, 3H), 1.98-2.21 (m, 4H), 2.76-2.91 (m, 2H), 3.19-3.32 (m, 2H), 4.30-4.44 (m, 1H), 5.27-5.40 (m, 1H), 7.20-7.51 (m, 5H), 7.59 (s, 1H), 7.89 (s, 1H), 8.34 (d, J=2.0 Hz, 1H). MS (ES+): m/z 440.06, 442.06 [MH+]. HPLC: tR=2.46 min (ZQ3, polar—5 min)
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:24]=[C:23]2[C:25]3[CH:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]([C:13]1[CH:24]=[C:23]2[C:25]3[CH:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(N(C)c2cc3c4c(c2)CCCC4CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(C(=O)O)cc1)c1cc2c3c(c1)CCCC3CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A suspension of methyl 4-[N-methyl-(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.033 g) in ethanol (10 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol-chloroform to obtain the title compound (0.027 g, yield: 87%) as colorless needles (melting point: 288-289° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[CH:12]([C:14]1[O:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)(O)[O-].[Na+].O>CN1C(=O)CCC1.[Pd](Cl)Cl>[CH:12]([C:14]1[O:18][C:17]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)=[O:13]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(=O)Nc1nc(C)c(Br)s1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C=O)o2)s1
Yield: 37.6 %

Procedure:
To a solution of 3.0 g of N-(5-bromo-4-methylthiazol-2-yl)acetamide in 50 mL of NMP was added 3.0 g of 5-formylfuran-2-ylboronic acid. To the stirred solution was then added 300 mg of 1,1 bis-(diphenylphosphino)-ferrocene) palladium dichloride followed by 10 mL of saturated sodium bicarbonate. The resulting biphasic mixture was irradiated at 150° C. in a microwave for 20 min. The resulting mixture was poured into 200 mL of water and filtered. The filtrate was extracted with ether and the ether layers were combined, dried over sodium sulfate and concentrated. The resulting oil was precipitated with methylene chloride and filtered, yielding 1.2 g of N-(5-(5-formylfuran-2-yl)-4-methylthiazol-2-yl)acetamide as an orange solid which was used without further purification. LC/MS: 251.07 (M+H)/2.18 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[C:4]([F:14])[CH:3]=1.CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[NH:30]1[CH2:34][CH2:33][C@@:32]2([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36](=[O:43])[O:35]2)[CH2:31]1.F[P-](F)(F)(F)(F)F.[N:51]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:55]2C=[CH:57][CH:58]=[CH:59][C:54]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:14][C:4]1[CH:3]=[C:2]([C:55]2[CH:54]=[CH:59][CH:58]=[CH:57][N:51]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:30]2[CH2:34][CH2:33][C@@:32]3([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36](=[O:43])[O:35]3)[CH2:31]2)=[O:13])[CH2:9][CH2:10]1
Reactant: O=C(O)C1(c2ccc(Cl)cc2F)CC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccccn5)cc4F)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-chloro-2-fluorophenyl)cyclopropanecarboxylic acid (0.15 g, 0.7 mmol), [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) salt (0.29 g, 0.7 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.34 g, 0.77 mmol), and N,N-diisopropylethylamine (0.43 ml, 2.4 mmol) in N,N-dimethylformamide (2.0 ml) was stirred at room temperature overnight. The mixture then was diluted with ethyl acetate. The resulting solution was washed with saturated NaHCO3 solution, water, 1N HCl solution, water and brine successively; then dried over Na2SO4; and then filtered. The filtrate was concentrated to afford the desired product (275 mg).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[CH3:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[CH3:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: Cc1cccc(N)c1
Reactant: C/C(N)=C\C#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=CC#N)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-methylaniline (7.18 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.