Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of (3-aminopropyl)carbamic acid phenylmethyl ester (7.08 g, 34 mmol) and N,N-diisopropylethylamine (4.5 mL, 26 mmol) in anhydrous dimethylformamide (100 mL) under nitrogen was cooled to 10° C. and treated with t-butyl bromoacetate (2.80 mL, 17 mmol) over 5 minutes. After one hour the bath was removed and the reaction mixture was stirred overnight, poured into water (500 mL), and made basic (pH 12) with 2.5N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (2×250 mL), which was dried over sodium sulfate and concentrated in vacuo with heat to remove dimethylformamide. The residue was purified by flash chromatography (9 cm diameter, gradient elution with 2.5-3.5% methanol in dichloromethane) to yield [3-[[(1,1-dimethylethyloxycarbonyl)-methyl]amino]propyl]carbamic acid phenylmethyl ester as a pale yellow oil (4.50 g 82%); 1H NMR (CDCl3 200 MHz): δ 7.35 (m, 5H), 5.43 (br s, NH), 5.09 (s, 2H), 3.35-3.24 (m, 4H), 2.68 (t, J=6.5 Hz, 2H), 1.68 (p, J=6.5 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[C:23]([CH:24]=O)=[CH:22][N:21]=[CH:20]2)=[CH:16][CH:15]=1)#[N:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(C(Cl)Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:24][C:23]3[N:19]([CH2:18][C:17]4[CH:26]=[CH:27][C:14]([C:12]#[N:13])=[CH:15][CH:16]=4)[CH:20]=[N:21][CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: Brc1ccc2c(c1)CNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCc3ccc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (0.742 g, 3.5 mmol) in CHCl2CHCl2 (15 mL) was added 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (0.812 g, 3.85 mmol), 4 Å sieves and NaBH(OAc)3 (1.11 g, 5.25 mmol). The mixture was stirred at room temperature for 16 h. and a further portion of NaBH(OAc)3 (0.55 g, 2.6 mmol) was added. After an additional 24 h the mixture was diluted with EtOAc, filtered through celite, washed with brine, dried (Na2SO4) and concentrated. The residue was stirred in 2N Hcl (50 mL) for 2 h. then extracted with ether. The aqueous layer was basified with 6N KOH and extracted 3× CH2Cl2 which was then washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. Crystallization from ether afforded the title compound as a white solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([SiH](C(C)C)C(C)C)(C)C.[NH:18]([C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:57])[CH2:19][C:20]([NH:22][C@H:23]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:24][C:25]1[N:29]=[CH:28][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:26]=1)=[O:21]>O>[NH:18]([C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:57])[CH2:19][C:20]([NH:22][C@H:23]([C:49]([OH:51])=[O:50])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21].[F:4][C:3]([C:1]([OH:7])=[O:2])([F:6])[F:5]
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OC(C)(C)C
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of TFA (206 ml), triisopropylsilane (10.8 ml), and H2O (10.8 ml) was added to N-palmitoyl-Gly-His(Trt)-OtBu (23.0 g, 30.8 mmol) while cooling with ice and the whole was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was washed with diisopropyl ether and then diethyl ether, and then collected by filtration with a membrane-filter. The residue was reprecipitated with TFA (35 ml) and diethyl ether (800 ml), and the precipitate was dried under reduced pressure to give 16.2 g (93%) of a target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A mixture of 4-chlorophenol (5.61 g, 43.65 mmol), 2-bromoethanol (6.0 g, 48.0 mmol), sodium hydroxide (2.62 g, 65.47 mmol), and water (18 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath at 80° C. The solution was heated for 19 hours. Progress of the reaction was monitored by analytical HPLC with UV detection. The reaction mixture was partitioned using ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted once more with ethyl acetate (40 mL). The combined organic layer was washed with 1N NaOH (6×40 mL) and saturated aqueous NaCl (40 mL), dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography using 30-100% ethyl acetate in hexanes to afford the title compound as a clear oil (5.67 g, 75% yield).
Reaction SMILES: Cl.[CH:2](=[NH:6])[O:3][CH2:4][CH3:5].Cl.[F:8][C:9]([F:13])([F:12])[CH2:10]N.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:8][C:9]([F:13])([F:12])[CH2:10][N:6]=[CH:2][O:3][CH2:4][CH3:5]
Reactant: NCC(F)(F)F
Reactant: CCOC=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC=NCC(F)(F)F
Reaction time: 0.05 h

Procedure:
Ethyl formimidate hydrochloride (0.555 g, 5 mmole), 2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2Cl2 and treated with 2 ml H2O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2Cl2The combined organic phase is dried and the CH2Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. δ1.33 t (CH3CH2); 3.8 q (j=10 c.p.s., CF3CH2) 4.23 q (j=7.5, CH3CH2O); 7.6 S (H-C=N).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: Cc1ccsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1C1OCCO1

Procedure:
3-Methyl-2-thiophenecarboxaldehyde (12 g), 1,2-ethanediol (20 ml) and a trace of toluene-p-sulphonic acid were heated at reflux in toluene (250 ml) under Dean and Stark conditions for 4 h. The reaction mixture was cooled and washed with 5% aqueous sodium carbonate solution and water. The toluene solution was evaporated to give an oil which was distilled to give the title compound as a pale yellow oil (14.5 g) b.p. 95°/0.1 mm.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:17](Cl)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1nc(N)sc1-c1ccccc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (3 g) was dissolved in pyridine (30 ml), and then acetyl chloride (2.73 ml) was added dropwise to the solution at 0° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 1.5 hours. Water was added to the solution at 0° C. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-phenyl-1,3-thiazole-4-carboxylate (2.37 g) as a pale brown solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:11]=[CH:12][C:13]=1[CH2:14][C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: FC(F)(F)c1cc(Cl)c(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCc1cnc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Trimethylsilylcyanid (TMSCN) (69.3 g, 0.7 mol) was added to a solution of 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 0.348 mol) and Tetra-n-butylammoniumfluoride (129.5 g, 0.7 mol) in acetonitrile (1.5 L) slowly. Then the mixture was stirred at 20-30° C. for 2 hours. Thin layer chromatography (petroleum ether: EtOAc=3:1) showed all of starting material was consumed. The mixture was concentrated and the residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc=20:1˜3:1 to yield [4-chloro-6-(trifluoromethyl)pyridin-3-yl]acetonitrile (Int-14) (50 g, 60% from NMR, 39% of yield) as yellow syrup.
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]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].O[Li].O>C1COCC1.O>[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]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Methyl 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)-carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (25.00 g, 50.1 mmol) was dissolved in THF (50 mL) and water (50 mL). The solution was treated with LiOH.H2O (5.26 g, 125.3 mmol). The reaction mixture was stirred at room temperature for 2 h. Concentrated to remove the solvent THF and the mixture was acidified by 2N HCl. The resulting precipitate was filtrated, washed by water, dried to give 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl) carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (20.00 g, 82%). ESI-MS: 485.1. 1H NMR (CDCl3, 400 MHz): δ7.66-7.60 (m, 3H, ArH), 7.46-7.42 (m, 3H, ArH), 6.99 (s, 1H, ═CH), 4.23 (t, J=5.0 Hz, 2H, CH2), 3.39 (s, 3H, CH3), 3.14 (s, 3H, CH3), 3.07 (t, J=5.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CO
Agent: [K]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 56.2 %

Procedure:
To a solution of (6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methanol (0.70 g, 2.15 mmol) in toluene (15 ml) was added thionyl chloride (0.31 ml, 4.3 mmol), and the mixture was heated under reflux for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (10 ml). Thereto was added potassium phthalimide (0.6 g, 3.2 mmol) and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml)-water (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the extract and the organic layer were combined. The mixture was washed twice with water (50 ml) and then saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 2-[(6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1-H-isoindole-1,3(2H)-dione (0.55 g, yield 57%) as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1
Solvent: O
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl-1-butynyl]benzenamine (Example 14) and acetyl chloride, containing 0.1 mol of water; mp 172°-173.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30][N:31]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14]([NH:31][OH:30])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 0.204 g (0.49 mmol) of 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, 0.079 g (0.58 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.112 g (0.84 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and stirred at room temperature for 1 h. Then added 0.3 mL of 50% aqueous hydroxylamine and stirred for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH/CH2Cl2 to provide 0.077 g (36%) of the desired product as a white solid. Electrospray Mass Spec: 435.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:22]=[CH:21]3)=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].C(OC(=O)C)C.[ClH:45]>C1COCC1>[ClH:45].[NH:29]1[CH2:28][CH2:27][CH:26]([CH2:25][N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[CH:17][C:16]=3[C:14]([NH:13][C@H:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[CH3:12])=[O:15])[CH:21]=[CH:22]2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCN(C(=O)OC(C)(C)C)CC4)c23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(CC4CCNCC4)c23)cc1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 4-{[7-({(1S)-1-[4-(methoxycarbonyl)phenyl]ethyl}carbamoyl)-1H-indol-1-yl]methyl}piperidine-1-carboxylate (1.67 g), and THF (20 mL) was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 hour. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate and diethyl ether, collected by filtration, and dried under reduced pressure to obtain methyl 4-[(1S)-1-({[1-(piperidin-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate hydrochloride (1.46 g).
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][C:10](Br)=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:18][C:17]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:11]
Reactant: O=C(Br)CBr
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CBr)cc(OC)c1OC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Add triethylamine (1.53 mL, 11.0 mmol) and bromoacetyl bromide (0.87 mL, 10.0 mmol) dropwise to a 0° C. solution of 3,4,5-trimethoxy-aniline (1.74 g, 9.5 mmol) in tetrahydrofuran (30 mL). Allow the reaction to warm to room temperature overnight. Filter the mixture, wash with tetrahydrofuran, and concentrate. Dissolve the resulting brown solid in chloroform, wash with 1N HCl, saturated aqueous sodium bicarbonate solution, brine; dry over magnesium sulfate; and concentrated. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 2.50 g of the title compound as an orange solid, 87% yield. 1H NMR: consistent with structure. MS (ion spray) 304 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[OH-].[CH2:15]([N+](C)(C)C)[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.ClC(C)(C)C#C>ClCCl.O>[CH3:15][C:16]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([CH3:21])[C:17]#[CH:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
4-t-Butylphenol (10 g) and sodium hydroxide (3.99 g) were added to a stirred mixture of water (60 ml) and dichloromethane (60 ml) followed by benzyltrimethylammonium hydroxide (40% solution in methanol, 150 ml) and 3-chloro-3-methyl-butyne (13.65 g). After stirring at ambient temperature for 11 days, the layers were separated and the aqueous layer extracted with chloroform. The combined organic extracts were concentrated in vacuo and the residue dissolved in diethyl ether. The solution was washed with water, 10% sodium hydroxide solution, then brine, and dried over magnesium sulphate. Removal of drying agent and solvent gave 3-methyl-3-(4-t-butylphenoxy)-but-1-yne as a yellow oil (13.35 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]4[CH2:37][CH2:36]4)=[O:34])[N:31]=3)[CH:28]=2)=[C:20]([F:40])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:18]([NH:17][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:19][C:20]=4[F:40])=[CH:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
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
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 14.4 %

Procedure:
Using 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (220 mg, 0.99 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (220 mg, 0.66 mmol), HATU (380 mg, 0.99 mmol), diisopropylethylamine (260 mg, 2.0 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (50 mg, 15%) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH:8]1[CH:9]=[C:10]2[C:2]([N:3]([CH2:12][C:13]([Cl:18])=[O:15])[C:4](=[O:11])[C:5]2=[CH:6][CH:7]=1)=[O:1]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (7.00 g) and thionyl chloride (12 mL) was stirred at reflux under nitrogen for one hour. The thionyl chloride was distilled from the reaction, and the resulting crude product was further purified by distillation via a kugelrohr apparatus (BUCHI, Flawil, Switzerland). [Bp: 160°-180° C. (oven temperature) at 10 mm Hg.]The yield of the title compound was 6.88 grams (90.2%). The structure of the title compound, and of all of the compounds synthesized in each of the subsequent examples, was confirmed by 1H NMR.
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-:18].[Cl-].[Cl-].[CH:21]1([Zr+3:26])[CH:25]=[CH:24][CH:23]=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)C>[Cl-:18].[Cl-:18].[C:1]1([Zr+2:26][CH:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C1=CC([Zr+2]c2cccc3c2C=C2C3=Nc3ccccc32)C=C1
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum to give the catalyst (16.5 g, 78%).