Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[CH:27]1[C:32]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=[C:29]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])[CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(O)(=O)C>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][O:14][C:36]([CH2:35][CH2:34][CH2:33][C:32]3[CH:27]=[CH:28][C:29]([N:39]([CH2:40][CH2:41][Cl:42])[CH2:43][CH2:44][Cl:45])=[CH:30][CH:31]=3)=[O:37])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To 250 ml CH2Cl2 is added with stirring 36 g prednisolone (0.10 mol), 31.3 g chlorambucil (0,103 mol), 1.2 g DMAP (0,01 mol) and 1.1 g pTSA (0,06 mol). The reaction mixture is cooled to 0° C. and with continued stirring at this temperature a solution of 22.7 g DCC (0,11 mol) in 50 ml CH2Cl2 is slowly added. The reaction mixture is then kept at 0° C. with stirring for 20 h. 3 ml acetic acid is added and precipitated urea filtered off. The filtrate is evaporated in vacuo and the residue recrystallized from ethanol to give 58.9 g of TLC pure prednimustine (91% yield) without any discolouration. M.P. 165°-166° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[CH2:15][NH:16][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:26])[CH2:15][NH:16][C@@H:17]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][CH2:18]4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CN[C@H]1CCc2ccccc21
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CN[C@H]4CCc5ccccc54)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((S)-indan-1-ylamino)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>CCO.C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3ccccc23)cn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3c2CCCC3)cn1
Reaction time: 16 h

Procedure:
A solution of the acid 3-5 (150 mg, 0.34 mmol) in EtOH (30 mL) and acetic acid (4 mL) was degassed with argon. PtO2 (25 mg) was added and the mixture placed under an atmosphere of hydrogen gas (balloon) for 16 hours. The mixture was filtered through celite, the solvent removed and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 3-6 was obtained as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28]C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCCOC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCCCCBr)ccc21
Product: COCCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 7.2, 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and methoxyethyl-ethylamine were converted to yield 5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless oil, MS: 379 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[C:15]#[N:16].[CH2:17](O)[CH2:18][OH:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:15]([CH:10]1[CH2:11][CH2:12][C:13]2([O:19][CH2:18][CH2:17][O:14]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])#[N:16]
Reactant: OCCO
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: N#CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.), ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene (160 ml.) was heated to reflux for 31/2 hours with continuous removal of water. The mixture was cooled to ambient temperature, anhydrous sodium carbonate was added, and after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p. 166°-182° C./0.1 mm.Hg. This material was used as a starting material in the next stage, an aliquot being redistilled to b.p. 177°-179° C./0.1 mm.Hg for elemental analysis:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[C:8]([C:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH2:13][CH3:14])[CH2:11]Br)#[N:9].O>CS(C)=O>[C:8]([C:10]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)([CH2:13][CH3:14])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)#[N:9]
Reactant: CCC(C#N)(CBr)c1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C#N)(Cn1cncn1)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
2.2 g (0.032 Mol ) of 1,2,4-triazole and 1.3 g (0.032 mol) pulverised NaOH in 30 ml of dimethylsulfoxide are heated at 110°. To this mixture are added, within a few minutes, at 110° a solution of 2-cyano-2-(4-bromophenyl)butylbromide in 10 mol of dimethylsulfoxide. The reaction mixture is stirred at 110° for another 90 minutes, poured into 600 ml of water and extracted several times with diethylether. The united ether phases are washed with water and dried with magnesiumsulfate. Thereafter the ether is evaporated at the water jet and residues of dimethylsulfoxide at high vacuum to give the title compound (solid; m.p. 68°-70°, Rf=0.45 employing CH2Cl2 /CH3OH 95:5 as eluant).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1.CO[CH:27](OC)[N:28](C)C.Cl.NO>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:28]=[CH:27][C:15]=2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCSCc1ccc(C(=O)CC(=O)OC(C)(C)C)cc1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Product: COC(=O)CCSCc1ccc(-c2oncc2C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To tert-butyl 3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)-3-oxopropionate (472 mg, 1.34 mmol) was added N,N-dimethylformamide dimethylacetal (5 ml), and the mixture was stirred at 100° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethanol (10 ml). Hydroxylamine hydrochloride (280 mg, 4.03 mmol) was added, and the mixture was stirred at 70° C. for 2 hours. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (330 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C1C=CC=CC=1.Cl.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: COC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC1(c2ccc(OC(C)=O)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 3 h
Yield: 52.7 %

Procedure:
3,4-Dihydro-2-(4-hydroxyphenyl)-2-methoxy-4-methyl-3-oxo-2H-1,4-benzothiazine (0.2 g, compound No. 5) is dissolved in a mixture of acetic anhydride (2 ml) and pyridine (5 ml). The mixture is standed for 3 hours at room temperature, and then poured into a mixture of benzene and dilute hydrochloric acid. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 0.1 g (52.7%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N(C[CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:34][N:35]([CH3:37])[CH2:36][CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CN(C)CCNN
Product: CN(C)CCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=4.6, 1.7, Hz, 2H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.15 (d, J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.82 (t, J=6.6 Hz, 2H), 2.28 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: [O:1]=[C:2]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1.Cl[CH:24]([C:27]1([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][CH:34]=[CH:33]3)[CH2:29][CH2:28]1)[CH:25]=O>C(O)(C)C.CO>[O:1]=[C:2]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:24]([C:27]4([C:30]5[CH:31]=[C:32]6[C:37](=[CH:38][CH:39]=5)[N:36]=[CH:35][CH:34]=[CH:33]6)[CH2:29][CH2:28]4)=[CH:25][N:17]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(OCC(=O)N3CCCC3)cc2)cn1
Solvent: CO
Solvent: CC(C)O
Product: O=C(COc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)N1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 5-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-2-amine (23.9 mg, 0.08 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (19.6 mg, 0.08 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. overnight. The mixture was diluted with methanol, and purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=490.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([OH:23])CCC.[OH-].[K+]>Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:23])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCO
Reactant: CC(CC#N)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(CC(N)=O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a solution of 3-(2-fluoro-biphenyl-4-yl)butyronitrile in tent-butyl alcohol was added 1.87 g of finely powdered potassium hydroxide. The resulting suspension was stirred and heated to 70° C. for 2.5 hours and cooled to room temperature. The reaction suspension was diluted with 1.0 N HCl solution (100 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with 5% bicarbonate solution (100 mL) and then with H2O (100 mL). The organics were then dried over MgSO4, and concentrated to a white solid which was re-crystallized several times with EtOAc/Hex to give white flaky prisms (1.62 g, 75% yield).
Reaction SMILES: [S:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)([OH:4])(=[O:3])=[O:2].[OH-].[K+].C(O)C.Cl>O>[S:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([OH:4])(=[O:3])=[O:2]
Reactant: CCOC(=O)c1ccc(NCCS(=O)(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCS(=O)(=O)O)cc1

Procedure:
A mixture of 4.4 g. of ethyl 4-(2-sulfoethylamino)benzoate, 2.3 g. of potassium hydroxide, 10 ml. of water, and 90 ml. of ethanol is stirred under reflux for 8 hours, allowed to cool, diluted with water, and brought to pH 4 with concentrated hydrochloric acid. The precipitate is collected by filtration, dried, and recrystallized from acetic acid to yield 4-(2-sulfoethylamino)benzoic acid as a white solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Yield: 47 %

Procedure:
Cyclopropylamine (1.8 ml) and N,N-diisopropylethylamine (6.6 ml) were dissolved into 75 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (5.0 g) in dichloromethane (15 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 40 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (2.6 g) in a yield of 47%. 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 7.35 (s, 1H), 3.84 (m, 1H), 1.36 (m, 4H) ppm.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)=[O:13])[CH3:10].CI>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH3:2])[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of LDA (7.0 mL, 14 mmol, 2M solution in THF/ethylbenzene) in THF (10 mL) was added a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (Compound 282H, 2.14 g, 9.99 mmol) in THF (5 mL) at −78° C. under nitrogen. The resulting mixture was stirred at this temperature for 30 min, then a solution of methyl iodide (1.98 g, 14.0 mmol) in THF (5 mL) was added. The resulting mixture was slowly warmed to rt overnight. The reaction was quenched with sat. aq. NH4Cl (20 mL) and diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure to give the desired compound as a light-yellow oil, 2.30 g, 100% yield. The material was used in next step without further purification. 1H NMR (CDCl3): 1.20 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.52-1.68 (m, 6H), 2.12-2.17 (m, 2H), 3.94 (s, 4H), 4.15 (q, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C#N)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C#N)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-cyanoanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-cyanoanilino)acetaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH2:14])[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[CH2:15]1[O:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[OH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12][C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1cc(CCN)cc(C)c1OC
Solvent: C1CCOC1
Product: COc1cc(CCNCC(O)c2ccccc2)cc(C)c1OC

Procedure:
1-Phenyl-7,8-dihydroxy-9-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is obtained by treating 2-(3,4-dimethoxy-5-methylphenyl)ethylamine in tetrahydrofuran with styrene oxide for 12 hours as described above to give N-[(2-hydroxy-2-phenylethyl)]-2-(3',4'-dimethoxy-5-methylphenyl)ethylamine which on cyclization gives the 7,8-dimethoxy benzazepine. Cleavage of this as described gives the desired 6-methyl compound as the hydrobromide which may be converted via the free base to the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([OH:11])=[O:10].[C:13]([C@@H:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)#[N:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([O:11][C@H:15]([C:13]#[N:14])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)=[O:10]
Reactant: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Yield: 79 %

Procedure:
Using the procedure of Example 1, 0.6 g of the acid of Step C of Example 27 and 0.73 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 1.0 g of (S)α-cyano-3-phenoxybenzyl (1R,trans) 2,2-dimethyl-3-(3-chloro-1,2-propadienyl)cyclopropane-carboxylate with a specific rotation of [α]D20 =+26°±2° (c=0.75% in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=S(=O)(Nc1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
To a mixture of 4-fluoro-N-(4-fluoro-phenyl)-benzenesulfonamide (1.0 g, 3.7 mmol) and K2CO3 (1.03 g, 7.4 mmol) in dimethylformamide (5 mL) was added 1-bromo-2-methylpropane (1.21 mL, 11.2 mmol). The mixture was heated at 100° C. in a microwave reactor for 3 hours. Water was added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated. The crude product was re-dissolved in cyclohexane then concentrated to give 4-fluoro-N-(4-fluoro-phenyl)-N-isobutyl-benzenesulfonamide (1.05 g, 86%). 1H NMR (300 MHz, CDCl3): δ 7.56-7.57 (m, 2H), 7.12-7.13 (m, 2H), 7.00 (d, 4H), 3.28 (d, 2H), 1.54 (m, 1H), 0.91 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:18](=[O:20])[CH3:19])[CH2:11][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CNc1ccccc1CO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2cc(Cl)ccc2OCc2ccccc21
Temperature: 80 °C
Yield: 55 %

Procedure:
To a stirred solution of 2-Chloro-11,12-dihydro-6H-5-oxa-11-aza-dibenzo[a,e]cyclooctene Example 348C (43 mg, 0.18 mmol) and DMAP (4.27 mg, 34.9 μmol) in toluene (1.25 mL) was added acetic anhydride (36.0 μL, 0.39 mmol) and pyridine (13.9 mg, 0.18 mmol). This reaction mixture was heated at 80° C. for 50 min, cooled to room temperature and concentrated in vacuo. This was purified by a Shimadzu auto prep HPLC, employing 20% to 100% 10 min gradient elution with 0.1% TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 27.7 mg of desired 1-(2-Chloro-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348D in 55% yield. HPLC Rt=3.09 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=288
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C2C(=CC=CC=2)C=CC=1>[C:12]1([S:18][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[CH3:11])[C:5]([OH:7])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1Br
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc(C(=O)O)cc1Sc1ccccc1
Yield: 95 %

Procedure:
Reaction of 3-bromo-4-methylbenzoic acid 1 with thiophenol and cuprous oxide in quinoline at 180° C produces 3-phenylthio-4-methylbenzoic acid 5 in 95-96% yield. Generation of the dianion of 5 is ccomplished by sequential treatment with sodium ydride and then lithium diisopropylamide in a olvent mixture of tetrahydrofuran and 1,3-dimethylmidazolidinone at -20° C. Carboxylation at -15° with carbon dioxide at a pressure of one atmosphere produces the diacid 6 in 90% yield.