Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:40])[CH:38]=[CH2:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:37]([NH:40][C:28]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:8][C:2]=1[Cl:1])=[O:34])[CH:38]=[CH2:39]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (45 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, allylamine hydrochloride (21 mg) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 45 mg (yield 72%) of the title compound.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[CH2:31]([C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[O:36][CH2:37][C@@H:38]1[CH2:40][O:39]1)[CH:32]=[CH2:33]>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:40][C@H:38]([OH:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][CH:43]=[CH:44][C:34]=3[CH2:31][CH:32]=[CH2:33])=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C=CCc1ccccc1OC[C@@H]1CO1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: C=CCc1ccccc1OC[C@@H](O)CNCCc1ccc(NC2CCN(C(=O)NCCCCCCCC)CC2)cc1
Yield: 14 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.40 g, 0.95 mmol) was reacted with (2S)-2-[(2-allylphenoxy)methyl]oxirane (0.125 g, 0.713 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.060 g, 0.1 mmol).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]([CH3:31])[CH:19]=4)=[CH:17][C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]([CH3:31])[CH:19]=4)=[CH:17][C:10]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 11.4 %

Procedure:
Phenyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a and, starting with 0.120 g of phenyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,33-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a, and 0.95 cm3 of 5N potassium hydroxide. 0.010 g of phenyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](I)[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1c2cnccc2c(I)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2cnccc12
Temperature: 95 °C
Yield: 52.7 %

Procedure:
A mixture of 2-benzyl-4-iodo-2,7-naphthyridin-1(2H)-one (0.540 g, 1.49 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.315 g, 2.24 mmol) and Na2SO4 (0.474 g, 4.47 mmol) in toluene (25 mL), ethanol (25 mL) and water (4 mL) was degassed. Pd(PPh3)4 (0.172 g, 0.15 mmol) was then added and the reaction mixture was heated at 95° C. for 6 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed with water then brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 99:1 ethyl acetate/methanol) to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one (0.260 g, 54%) as an off-white solid: mp 174-177° C.; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 7.31-7.41 (m, 5H), 7.16 (s, 1H), 7.02 (d, J=5.4 Hz, 1H), 5.26 (s, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:14]=2)[CH:5]=1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N:11]([C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH:14]=2)[CH3:31])[CH:5]=1
Reactant: CCCN(CCC)Cc1cccc(C(=O)Nc2cc(C(=O)OC)ccc2N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1cccc(C(=O)N(C)c2cc(C(=O)OC)ccc2N)c1
Reaction time: 1 h
Yield: 21.1 %

Procedure:
The compound (380 mg) obtained in Example 18-3 was dissolved in DMF (7.6 ml) and 60% sodium hydride (60.0 mg) was added thereto, and the whole was stirred for 1 hour. After that, methyl iodide (213 mg) was gradually added thereto and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (83.0 mg) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Cl)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].O.C(O)(=O)C>CN1CCCC1=O>[NH2:25][CH2:24][CH2:23][NH:26][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]2=[O:19]
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccc(Cl)cc2c1=O
Reactant: NCCN
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: NCCNc1ccc2c(c1)c(=O)c(C(=O)O)cn2Cc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To a solution of 1-Benzyl-6-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (300 mg) in 1-methyl-2-pyrrolidinone (6 mL) was added ethylenediamine (170 mg) under argon atmosphere. The mixture was heated at 120° C. for 18 h and then at 145° C. for 4 h. The reaction mixture was cooled and poured into water (12 mL). The pH value was adjusted with acetic acid to 7.0–7.5. The reaction mixture was extracted with DCM (5×30 mnL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica SPE-column (eluent: from DCM 100% to DCM/MeOH/NH4OH 85/13/2) giving the title compound (80 mg).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][C:17](=[O:29])[C@@H:18]([N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[CH3:19])[N:8]=1)[CH3:5]>C1COCC1.C(O)(=O)C.CO.[Pd]>[C:25]([O:24][C:22](=[O:23])[N:20]([CH3:21])[C@H:18]([C:17](=[O:29])[NH:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:3](=[O:2])[C@H:4]([CH3:5])[NH:6][C:7]=2[N:8]=1)[CH3:19])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@H](C)Nc1nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H]1Nc2nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)ccc2NC1=O
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a solution of (S)-2-{6-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-nitro-pyridin-2-ylamino}-propionic acid methyl ester (90 mg, 0.21 mmol) in THF (3 mL) and acetic acid (3 mL) and MeOH (3 mL) was added Pd/C (10%, 90 mg) and the reaction mixture was hydrogenated for 3 h. The catalyst was filtered and the filtrate evaporated. The residue was partitioned between saturated NaHCO3 and EtOAc. The organic phase was dried (MgSO4), filtered and evaporated. The crude material was purified by preparative HPLC to afford methyl-[(S)-1-((S)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (33 mg). MS: [M+H]+=364.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:13]2>C(Cl)Cl.CN(C=O)C>[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:23](=[O:24])[CH2:22][NH:21][C:19]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)=[O:20])[CH2:4]1
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1C[C@@H](O)[C@@H](O)C1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
(3R,4S)-3,4-Dihydroxypyrrolidine hydrochloride (the cis, or meso isomer, 1.79 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (0.85 mmol) were coupled according to procedure A (1:1 CH2Cl2/DMF reaction solvent) with the following workup: the reaction mixture was concentrated, the residue suspended in 10 ml EtOAc and 10 ml 2 N NaOH, the solids filtered and washed successively with aqueous 1 N NaOH, EtOAc, aqueous 1 N HCl, H2O, and ether. This washing sequence was repeated and the resulting solids were suspended in EtOAc, stirred for 1 hour, filtered and dried: Yield 252 mg, 88%; HPLC (60/40) 2.33 minutes (93%); TSPMS 338/340 (MH+, 100%);
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C@@H:3]([NH2:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.ClCCl>O1CCOCC1>[Cl:57][C:50]1[N:51]=[C:52]([NH:12][C@H:3]([CH:2]([CH3:13])[CH3:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](N)COc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](COc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 40 h
Yield: 45.1 %

Procedure:
(R)-3-methyl-1-phenoxy-2-butylamine (0.6 g, 2.8 mmol) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.4 g, 2.2 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.0 mmol). The reaction mixture was stirred at room temperature for 40 h before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the product (after column chromatography) as a foam which solidified on coevaporation with dichloromethane. 2-Chloro- N-[(R)-3-methyl-1-phenoxy2-butyl]adenosine (0.46 g, 44%) was obtained as a white solid, mp 95°-100° C., 1H NMR (DMSO-d6)δ 0.95, 0.98 (6H, 2d, 2×--CH3), 2.10 (1H, m, --C H(CH3)2), 3.53-3.60 (1H, m, H-5'a), 3.63-3.71 (1H, m, H-5'b), 3.95 (1H, q, H-4), 4.07-4.23 (3H, m, H-3' and --CH2 --), 4.96 (1H, m, --C--H), 4.56 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.23, 5.49 (2H, 2d, 2' and 3'-OH), 5.84 (1H, d, H-1'), 6.87-6.97 (3H, m, Ar--H), 7.24-7.31 (2H, dd, Ar--H), 8.36 (1H, d, --N--H), 8.40 (1H, s, H-8).
Reaction SMILES: [C:1]1([C:7]2[C:11](=O)O[CH:9]([C:13]([F:16])([F:15])[F:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(=C)[C:19]#[N:20].[C:22](#N)C>>[C:1]1([C:7]2[NH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:22][C:11]=2[C:19]#[N:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(Cl)C#N
Reactant: CC#N
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccccc1
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccccc1
Temperature: 25 °C
Yield: 73 %

Procedure:
4-Phenyl-2-(trifluoromethyl)-5(2H)-oxazolone (13.5 g, 0.059 mol), 2-chloroacrylonitrile (26 mL, 0.295 mol) and acetonitrile (250 mL) are heated at reflux temperature for 52 hours. The reaction mixture is then cooled to room temperature and concentrated in vacuo to give a solid. Recrystallization of the solid from toluene gives the title product as a yellow solid 10.1 g, 73%). Identified by NMR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:12][C:11](=[O:13])[C:10]2[N:5]([S:6](=[O:18])(=[O:17])[C:7]3[S:16][CH:15]=[CH:14][C:8]=3[CH:9]=2)[CH2:4]1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH2:19]([O:21][CH:22]([O:1][CH2:2][CH:3]1[O:12][C:11](=[O:13])[C:10]2[N:5]([S:6](=[O:17])(=[O:18])[C:7]3[S:16][CH:15]=[CH:14][C:8]=3[CH:9]=2)[CH2:4]1)[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: O=C1OC(CO)CN2C1=Cc1ccsc1S2(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(C)OCC1CN2C(=Cc3ccsc3S2(=O)=O)C(=O)O1
Yield: 54.3 %

Procedure:
A suspension of the product from Step C (10 g, 34.84 mmol) in anhydrous THF (200 mL) at 0° C. was combined with ethyl vinyl ether (5.02 g, 69.68 mmol) and p-toluenesulfonic acid (1.32 g, 6.9 mmol); this mixture was stirred until it became homogeneous. The reaction mixture was filtered through silica and the solvent evaporated to give a residue which was purified by column chromatography (silica, ethyl acetate/hexane, 3:7) to give 6.8 g (54%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([O:25][CH3:26])=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.Br[CH2:32][CH2:33]Br.[Br-].[NH:36]1[CH2:41]C[O:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([O:25][CH2:26][CH2:41][N:36]3[CH2:33][CH2:32][O:39][CH2:38][CH2:37]3)=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COc1c(C)c(C)c(C(C)=O)c(OC)c1OCCCc1ccc(F)cc1
Reactant: BrCCBr
Agent: ClB(Cl)Cl
Agent: [Br-]
Product: COc1c(C)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCCc1ccc(F)cc1
Yield: 33 %

Procedure:
Example 3b (50 mg, 0.139 mmol) was reacted with BCl3 (1.1 eq.) according to General Procedure C. The material thus obtained was then reacted with 1,2-dibromoethane (3.0 eq.) according to General Procedure F and the product bromide reacted with morpholine according to General Procedure G to afford the product as a clear oil (21 mg, 33% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 7.19-7.14 (m, 2H), 6.98-6.93 (m, 2H), 4.09-4.00 (m, 4H), 3.77 (s, 3H), 3.71-3.68 (m, 4H), 2.79 (t, J=7.4 Hz, 2H), 2.62 (t, J=5.7 Hz, 2H), 2.50 (s, 3H), 2.49-2.46 (m, 4H), 2.11 (s, 3H), 2.05 (s, 3H), 2.05-1.97 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1(C=CC(O)=CC=1)O.C[O-].[Na+]>CN(C)C=O.O>[C:10]([O:9][CH2:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: OCC1CC2C=CC1C2
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC1CC2C=CC1C2

Procedure:
5-norbornen-2-ylmethyl methacrylate monomer was prepared in a flask fitted with a vertical condenser with water at 75° C circulating through the jacket, attached at the top to a downwards cold water-cooled condenser. There were refluxed for 2 hours 372 grams (3.0 moles) of 5-norbornen -2-methanol, 450 grams (4.5 moles) of methyl methacrylate, 526 grams of N,N-dimethylformamide, 28.8 grams of hydroquinone, and 8.1 grams (0.15 mole) of sodium methoxide. A total of 252 ml of distillate was collected (theoretical methanol equals 121 ml.). The flask contents were cooled, diluted with ether, and washed with water, excess dilute hydrochloric acid, water, 5% aqueous sodium hydroxide until the washes were colorless, and again with water. The ether solution was dried with anhydrous sodium sulfate, 11.5 grams of p-(p-tolylsulfonyl-amido) diphenylamine were added, and the ether was removed in a rotary evaporator at 60° C and about 15 mm pressure. To the residual oil 0.58 gram of hydroquinone was added and the product was distilled through a Vigreux column to give 431 grams of product having a boiling point of 770 C/1.4 mm, nD20 = 1.4848. The monomer was then passed through a column of activated sodium aluminum silicate.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18].[C-:23]#[N:24].[Na+]>>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[CH:11]([C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[C:23]#[N:24])[CH2:17][CH3:18]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Reactant: CCCNCCC
Agent: [Na+]
Product: CCCN(CCC)C(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
α-(Di-n-propylamino)-3-phenoxybenzeneacetonitrile (2) was prepared from 3-phenoxybenzaldehyde, di-n-propylamine and sodium cyanide following essentially the same procedure as that described in Example 1. The product was isolated as a golden oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[OH2:12].CN([CH:16]=[O:17])C>FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:16]([OH:17])=[O:12])[CH3:2]
Reactant: CN(C)C=O
Reactant: O
Reactant: CCc1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1cccc2c(C(=O)O)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.0 g of 7-ethylindole in 25 mL of DMF, 3.5 mL of trifluoroacetic anhydride was added under ice cooling and the resulting mixture was stirred at room temperature for 3 hours. To the solution, 100 mL of water was added, and the precipitated solid was collected by filtration. The solid thus obtained was suspended in 100 mL of 5 M aqueous sodium hydroxide solution and the resulting suspension was stirred at 100° C. for 5 hours. After the solution was allowed to cool, it was washed twice with 30 mL of 1,2-dichloroethane. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to pH2 and the precipitated solid was collected by filtration and washed with ether to obtain 3.14 g of 7-ethylindole-3-carboxylic acid as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:12]2)=[O:10])=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.Cl[C:37]([O:39][CH3:40])=[O:38]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:15][C:14]([C:37]([O:39][CH3:40])=[O:38])([CH3:16])[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To 3.4 g of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide and 1.1 g of diisopropylamine dissolved in 20 ml of tetrahydrofuran and cooled in an acetone bath maintained at -20° C., was added 8.0 ml of a 2.7 molar solution of butyllithium in hexane. The resulting solution was stirred for 20 minutes and then cooled to -70° C. To this solution was added 0.9 ml of methyl chloroformate. The reaction was allowed to stir of 10 minutes and then allowed to warm to room temperature over 10 minutes. The reaction was quenched with 1.0 ml of acetic acid and the reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 2.9 g of N,3-bis-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR and IR data were consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH2:15]([SH:17])[CH3:16].C(N(CC)CC)C>O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([S:17][CH2:15][CH3:16])[C:10]=2[CH:11]=1
Reactant: CCS
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCSC1=CCC(C)(C)c2ccc(Br)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 1.03 g (4.1 mmol) of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) in 30.0 mL of tetrahydrofuran, was added dropwise 0.49 g (0.85 mL, 7.8 mmol) of titaniumtetrachloride and the resulting solution stirred for 10 min. A solution of 35 mg (0.50 mL, 6.7 mmol) of ethanethiol and 0.54 g (0.75 mL, 5.4 mmol) of triethylamine in 10.0 mL of tetrahydrofuran was added and the reaction stirred at room temperature for 13 h. The mixture was diluted with water and extracted with ether (2×). The organic phase was washed with brine, dried over Na2SO4 and then concentrated in vacuo. Purification by flash chromatography (silica, 100% hexane) gave the title compound as an oil.