Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([CH3:18])[CH2:24]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC1CNCCN1
Product: CC1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CCN1
Yield: 91.8 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2-methylpiperazine (100 mg, 1.0 mmol) were reacted according to GP4 to give 30 mg of the title compound (160FE38). MS (ESI) 327 (MH+). Purity for MH+(UV/MS) 100/89.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20](I)[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C.[Cu]I>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20]([O:2][CH3:1])[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[O-]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(I)cc2n1Cc1ccccc1
Agent: [Cu]I
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(cc1F)c(C(=O)NCc1ccc(F)c(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 110 °C

Procedure:
To a mixture of sodium methoxide (freshly prepared from 25 mg sodium and 1 ml MeOH) and CuI (30 mg, 0.16 mmol) was added a solution of 1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-6-iodo-2-isopropyl-1H-indole-3-carboxamide (Compound 179, 30 mg, 0.053 mmol) in DMF (0.5 ml). The reaction was heated to 110 ° C. for 16 h, and was filtered and concentrated. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][NH:27][CH2:25][CH3:26])[CH:6]=1
Reactant: CCN
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[CH:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:60](OCC)(=[O:62])[CH3:61]>>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:61])=[O:62])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)C12)C3(C)C
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 24 h
Yield: 100 %

Procedure:
After 19 hrs of reaction, 0.36% of 7-TES-taxol remained in this mixture. After 24 hrs, 7-TES-taxol and 10-desacetyl-taxol were not present (impurity index II<0.04%) in the reaction mixture. The solution was then diluted with ethyl acetate (1 L) and washed with 1N HCl (800 ml×2). The combined aqueous layer was extracted with ethyl acetate (400 ml×1). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (800 ml×5), brine (300 ml×1), dried over sodium sulfate, filtered and concentrated to give 17.46 g (˜100%) of crude taxol as a white solid. The HPLC HI for the crude taxol obtained above was 98.7%. The yield is uncorrected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>C(O)(C)C>[Br-:13].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N+:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: [Br-]
Product: c1ccc(N2CC[N+]3(CCCC3)CC2)nc1

Procedure:
A mixture of 40.8 g (0.25 mol) of 1-(2-pyridyl) piperazine (IV), 75.5 ml (134.9 g, 0.625 mol) of 1,4-dibromobutane (V) and 27.5 g (0.26 mol) of sodium carbonate was refluxed in 500 g of isopropyl alcohol for 16 hours, the hot mixture was filtered off from the salt precipitate, cooled, and the crystalline product was isolated. The additional amount of the product can be obtained by dilution of the mother liquor with a double volume of ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]2[CH3:31])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1c2ccccc2CCC1CN
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN1c2ccccc2CCC1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydro-1-methyl-quinoline hydrochloride and DBU in DME. ES-MS m/e (%): 361 (M+H+, 100).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
(+,−) Trans-2-phenyl-cyclopentylamine (5.95 g, 37.0 mmol, preparation 3) was dissolved in dry methylene chloride and cooled to 0° C. under a nitrogen atmosphere. 6.1 mL (40.7 mmol) of DBU was added followed by dropwise addition of 2-propanesulfonyl chloride (4.6 mL, 40.7 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was judged incomplete by TLC and an additional 20% of DBU and 2-propanesulfonyl chloride were added. Stirring at room temperature was continued for 3 days. The reaction was diluted with methylene chloride and washed (1×100 mL) with 1N HCl. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to 9.3 g. The product was purified on silica by Chromatotron® eluting with 99:1 methylene chloride:ethyl acetate to yield 5.7 g (31%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12]Br.[OH-].[Na+]>C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1ncc(C(F)(F)F)cc1Br
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[Mn]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:5][CH:4]=1
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/CO
Agent: [Mn]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Manganese IV dioxide (13.3 g, 153 mmol) was suspended in toluene (300 ml) and refluxed overnight with the azeotropic removal of H2O. The unsaturated alcohol (5.17 g, 15.3 mmol, Step D) was added and reflux was continued for four hours. The reaction was cooled and filtered through a bed of silica. Filtrate was evaporated to give 4.73 g (92%) of product as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:32])[CH:8]([O:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C.Cl>O.O1CCCC1>[CH2:30]([O:29][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)[C:7]([OH:32])=[O:6])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 86 %

Procedure:
Lithium hydroxide hydrate (57 mg; 1.37 mmole) dissolved in water (2 ml) was added to a solution of 2-ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 87) (384 mg; 0.91 mmole) in tetrahydrofuran 6 ml. After stirring at room temperature for 2 hours more lithium hydroxide hydrate (30 mg) dissolved in water (1 ml) was added. The reaction mixture was stirred at room temperature for 4 more hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 4. Tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the product was extracted with ethyl acetate (10 ml). The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate:acetic acid (10:10:1) as eluant gave 0.307 g (yield 86%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid as a pale yellow oil that crystallizes when vacuum dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:13][C:12](=[O:14])[CH:11]([CH2:15][OH:16])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCC(CO)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)C(CO)CCc1ccc(OC)cc1
Temperature: 70 °C

Procedure:
A mixture of [4-(4-methoxyphenyl)]-2-hydroxymethyl butanoic acid (6.0 g, 0.027 mol), iodomethane (5.68 g, 0.04 mol) and potassium carbonate (7.45 g, 0.054 mol) in dimethylformamide (40 ml) was heated at 70° C. for 1 h. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (400 ml), washed with water (3×200 ml), sodium hydrogen carbonate solution (2×200 ml) and again with water (2×200 ml). Drying (MgSO4) and removal of solvent at reduced pressure gave the product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)=[O:5])[CH3:2].[CH3:20][Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](C)(C)[CH2:32][CH2:33][O:34][CH2:35]Cl.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[NH:8][C:9](=[O:12])[N:10]([CH2:35][O:34][CH2:33][CH2:32][CH3:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)NC1=O
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (205 mg, 0.78 mmol) in THF (3 mL) was added lithium hexamethyldisilazide (LiHMDS, 0.78 mL of 1M THF solution, 0.78 mmol) at 0° C. under argon atmosphere. The reaction mixture was stirred for 10 minutes, and then 2-trimethylsilylethyoxymethyl chloride (SEMCl, 0.137 mL, 0.78 mmol) was added dropwise at 0° C. The mixture was allowed to reach rt and was stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried under Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 4-(4-fluoro-phenyl)-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (155 mg, 51%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:8]=1.[C:19](Cl)(Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]2[O:15][C:19](=[O:20])[NH:11][C:10]2=[O:14])[CH:8]=1
Reactant: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C)cc(Cl)cc1C1OC(=O)NC1=O
Temperature: 0 °C

Procedure:
By the procedure of Example 9, except that methylene chloride was used in place of chloroform for product extraction following the quench, ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride (2.5 g., 8.5 mmoles) in 250 ml. of tetrahydrofuran was reacted with phosgene in the presence of triethylamine (2.7 g., 27 mmoles). The product was isolated by pouring the reaction mixture slowly over 1 liter of crushed ice. The aqueous phase was separated and extracted with three portions of methylene chloride. The combined organic phase/extracts was evaporated to solids. The crude product was taken up in 1N sodium hydroxide, extracted with ether, and acidifed with 3N hydrochloric acid to precipitate the desired product (1.81 g., 83%, m.p. 184°-186° C.). Recrystallization from toluene gave purified 5-(5-chloro-2-methoxy-3-methylphenyl)oxazolidine-2,4-dione (1.57 g., 72% overall; m.p. 187°-189° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:35][C:36]1[C:44]2[C:43]([N:45]3[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]3)=[N:42][CH:41]=[N:40][C:39]=2[NH:38][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:51][CH:48]2[CH2:47][CH2:46][N:45]([C:43]3[N:42]=[CH:41][NH:40][C:39]4=[N:38][CH:37]=[C:36]([CH3:35])[C:44]=34)[CH2:50][CH2:49]2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)cn1
Reaction time: 0.17 h

Procedure:
To a mixture of 6-methyl-3-pyridinecarboxylic acid (46.1 mg, 0.336 mmol), EDC (68.7 mg, 0.359 mmol), HOBt (54.9 mg, 0.359 mmol) and DIPEA (0.098 mL, 0.560 mmol) in DCM (1 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (60 mg) and the mixture stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL) and the aqueous phase was extracted with further DCM (4 mL). The combined organic fractions were concentrated in vacuo and purified by MDAP. The solvent was then removed in vacuo from the product containing fractions, to afford E22 (14 mg), 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.90 (1H, s), 8.47 (1H, d), 8.22 (1H, s), 8.10 (1H, d), 7.35 (1H, d), 7.07 (1H, s), 4.08 (1H, m), 4.02 (2H, d), 3.95 (2H, t), 2.47 (3H, s), 2.37 (3H, s), 1.95 (2H, d), 1.73 (2H, ddd), MS(ES+) 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]#[N:24])=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:23]#[N:24])=[CH:14]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2c[nH]c3ccccc23)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4-dimethoxybenzaldehyde in 75 ml absolute ethanol are added 2.07 g (13.3 mmole) 3-indolylacetonitrile and 1.83 g (13.3 mmole) anhydrous potassium carbonate. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction was stirred and heated. After refluxing for 24 hours, the reaction is allowed to cool to room temperature. The reaction mixture is filtered to remove the salts, and the solvent is removed by rotary evaporation. The residue is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 3:1. The yellow solid is recrystallized from acetone-hexane to give 2-(3-indolyl)-3-(3,4-dimethoxyphenyl)-2-propenenitrile, m.p. 139°-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.B([O-])([O-])O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[C:12]1([N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=4)=[CH:22][C:6]=3[CH:7]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccccc2)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A mixture of methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g), 4-(2-propoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (3 ml), ethanol (3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere overnight, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.26 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=3)=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A mixture of tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.015 g, 0.030 mmol), nicotinoyl chloride hydrochloride (0.007 g, 0.039 mmol), and triethylamine (0.013 ml, 0.091 mmol) in dichloromethane (1 ml) was stirred at ambient temperature for 1 hour. The reaction was loaded onto a silica gel sample and the product was eluted using a gradient system of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to provide tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetate (0.005 g, 275%).
Reaction SMILES: [W:1].[CH3:2][SiH:3]=C>>[C-:2]#[W:1].[Si:3].[Si:3].[Si:3].[W:1].[W:1].[W:1].[W:1].[W:1]
Reactant: C=[SiH]C
Agent: [W]
Product: [C-]#[W]
Product: [Si]

Procedure:
The polycarbosilane reacted with molybdenum yielded a molybdenum silicide and molybdenum carbide. With ammonia pretreatment, a substantial carbon removal was seen with molybdenum silicides being formed. Tungsten reacted with the polycarbosilane yielding tungsten carbide and tungsten silicide.
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[O:12]CC(C)(C)N=1.Br[CH2:19][CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1.[Mg]>>[CH3:10][O:9][C:8]1[C:3]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCc1ccsc1
Reactant: COc1cccc(C2=NC(C)(C)CO2)c1OC
Agent: [Mg]
Product: COc1cccc(CO)c1CCc1ccsc1

Procedure:
Using the method of example 44, steps 1-3, with 2-(2,3-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem. 43, 1372 (1978) and the Grignard reagent prepared from 1-bromo-2-(3-thiophenyl)ethane and magnesium the title compound was prepared and the structure confirmed by NMR spectroscopy. 4. 3-[2-(2-Bromomethyl-6-methoxy-phenyl)-ethyl]-thiophene