Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]([CH3:23])([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]([CH3:13])([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH3:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC=C(C(C)(C)c2ccc(N)cc2)CC1
Reaction time: 72 h

Procedure:
4-[1-Methyl-1-(4-nitro-phenyl)-ethyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester was dissolved in EtOH (150 mL) and suspended with Pd/C (10%, 1 g). The reaction flask was equipped with a balloon filled with H2. The hydrogenation was continued for 3 days. The mixture was filtered through a layer of Celite® and concentrated in vacuo to provide the desired compound as a light brown oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:15]1[S:14][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:12]([CH3:11])[CH:16]=1)=[O:10]
Reactant: Cc1ccsc1-c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C=O)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.35 mol (32 mL) of POCl3 was added at 0° C. to a 1.0 mol (77 mL) of DMF (excess of DMF used as solvent). At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 3-methyl-2-phenylthiophene (60 g, 0.35 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water, added of sodium acetate and extracted with CHCl3 (3×150 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated off to dryness. The residue was crystallized. Yield 60.2 g (85%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:41]=[C:42](C)[CH2:43][O:44][C:45](=[O:47])[CH3:46]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][C:42]([CH2:43][O:44][C:45](=[O:47])[CH3:46])=[O:41])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CC(=O)COC(C)=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.12 gms, 0.338 mmole), 1-hydroxybenzotriazole (0.07 g, 0.507 mmol) ethylcarbodiimide (0.10 g, 0.507 mmol), triethylamine (0.3 mL, 2.0 mmol) and acetic acid 2-oxo-propyl ester (0.05 g, 0.40 mmol) were dissolved in 10 mL methylene chloride. The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water, and the entire mixture was absorbed on to silica gel and medium pressure chromatography, and eluted with ethyl acetate//hexanes (3:1) to give 0.1 g of acetic acid {[(R)-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.20 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Reactant: Clc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(Oc2nccs2)cc1
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
A mixture of 2-chlorothiazole (5.0 g), ethyl 2-(4-hydroxyphenyl)propionate (8.1 g), potassium carbonate powder (8.65 g) and dimethylformamide (80 ml) is stirred at 150°-155° C. for 2.5 hours. The solvent is distilled out under reduced pressure. To the residue is added water and extracted with ether. The extract is washed with a 10% aqueous solution of sodium hydroxide and water and dried. The ether is evaporated. The residue is subjected to chromatography using silica gel and eluted with 50% benzene-hexane, benzene and 10% ether-benzene to yield ethyl 2-[4-(2-thiazolyloxy)-phenyl]propionate (5.8 g). IR νmaxCCl4 1740, 1240, 700 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)=[N:7]2.[CH3:27][NH2:28]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH2:14][CH2:13]1)=[N:7]2
Reactant: CN
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3c(Cl)cccc3n2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2ccc3c(Cl)cccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 6.40 g (17.12 mmol) of 3-{2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 15.3, and 60 ml (119.84 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 96/4 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 5.14 g of product are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27]2.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2
Reactant: COc1cc2c(Oc3ccc4c(c3)CCCN4C(=O)OC(C)(C)C)ncnc2cc1OCCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4c(c3)CCCN4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To 6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)quinazoline (110 mg, 0.2 mmol) in solution in dichloromethane (3 ml) was added TFA (0.3 ml) and the mixture stirred for 1 hour at ambient temperature. The solvents were evaporated and the remaining oil was diluted with dichloromethane and the pH adjusted to 9 with a saturated solution of sodium hydrogen carbonate. The organic phase was washed with, brine, dried (MgSO4), filtered and the solvent evaporated to give 6-methoxy-7-(3-morpholinopropoxy)-4-(1,2,3,4-tetrahydroquinolin-6-yloxy)quinazoline (84 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isobutyl-pyrrolidin-3-yl-amine (0.16 g, 0.6 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction was concentrated, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.80 (6H, d), 1.55(6H, s), 1.60–1.90 (4H, m), 2.15 (1H, d), 2.20–2.60 (6H, m), 3.25–3.60 (2H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.15–7.30 (6H, m), 7.40 (1H, d), 7.55 (1H, dd), 8.45 (1H, dd). ESI-MS m/z: 560 (M+1), UV retention time: 1.66 min.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@H:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl>Br>[ClH:1].[ClH:1].[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:12]2[C@@H:13]3[C@@H:9]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([OH:3])[C:16]=4[CH2:15][CH2:14]3)[CH2:10][CH2:11]2)[CH2:20][CH2:21]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCOCC1
Agent: Br
Agent: Cl
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 165.5 %

Procedure:
6.28 g (0.016 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-morpholinoethyl)-1H-benzo[e]indole hydrochloride were dissolved in 0.51 of 48 percent aqueous HBr, boiled under reflux for 4 hours and then concentrated, whereupon the residue was dissolved in water. The solution was neutralized by adding firstly solid Na2SO3 and then saturated aqueous NaHCO3 solution. The mixture was extracted three times with CH2Cl2, the organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered, the filtrate was concentrated and the residue was chromatographed over 0.27 kg of silica gel with methylene chloride/methanol (4:1). The product (4.8 g) was dissolved in 150 ml of ethanol. 6 ml (0.035 mol) of 21 percent ethanolic HCl solution were added dropwise thereto and the mixture was stirred at room temperature for 4 hours, whereby crystals separated. Recrystallization from ethanol gave 4.97 g (82%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(2-morpholinoethyl)-1H-benzo[e]indol-6-ol dihydrochloride as white crystals with m.p. 230°-275° (dec.).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH3:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[C:21]([S:28][CH3:29])[N:20]=1.C(=O)([O-])O.[Na+]>O>[CH3:18][C:19]1[C:24]([C:25]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:26])=[CH:23][N:22]=[C:21]([S:28][CH3:29])[N:20]=1
Reactant: CSc1ncc(C(=O)O)c(C)n1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To 40 ml of N,N-dimethylformamide were dissolved 4.00 g (20 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 4.00 g (22 mmol) of 4-methyl-2-(methylthio)pyrimidine-5-carboxylic acid, followed by the addition of 3.70 g (44 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 5.30 g (yield: 92%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(methylthio)-pyrimidine-5-carboxylate.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1)[CH3:6]>C(O)C>[CH2:5]([C:7]1[N:8]=[C:9]([Cl:17])[C:10]([N+:14]([O-:16])=[O:15])=[C:11]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1)[CH3:6]
Reactant: NC1CC1
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: CCc1nc(Cl)c([N+](=O)[O-])c(NC2CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
28.6 g (0.5 mole) of cyclopropylamine are added dropwise ar -50° C to 55.5 g (0.25 mole) of 2-ethyl-4,6-dichloro-5-nitro-pyrimidine in 1 liter of ethanol. The reaction mixture is stirred for 3 hours at room temperature and then cooled to -40° C. The crystalline precipitate that has formed is filtered off and dried. Yield: 21 g of 2-ethyl-4-chloro-5-nitro-6-cyclopropylamino-pyrimidine of m.p. 61°-62° C. A Further 22 g of 2-ethyl-4-chloro-5-nitro-6-cyclopropylamino-pyrimidine of m.p. 61°-62° C are obtained by evaporating the filtrate, suspending the residue in water, extracting with ether, drying the ethereal extracts over MgSO4 and evaporating them.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:30]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:9]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:11]=[C:12]1[Br:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(Br)cc(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1-tert-butyloxycarbonyl-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)pyrrole (13.5 g, 0.032 mole) in 100 ml N,N'-dimethylformamide was treated with a solution of N-bromosuccinimide (5.7 g, 0.032 mole) in 50 ml N,N'-dimethylformamide. The mixture was stirred for four hours at room temperature and poured into a mixture of 500 ml 5% sodium bicarbonate and 500 g of ice. The resulting solid was collected by filtration, washed with water, and dried. The crude product was recrystallized from diethyl ether/hexanes to yield 11.0 g (68%); m.p. 121° dec.
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([N:55]([CH3:72])[C@H:56]([C:61]([NH:63][C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([N:55]([CH3:72])[C@H:56]([C:61]([NH:63][C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 64 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.65 g.) and HDTrp-MeLeu-MetNH2 (1.34 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 (1.70 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-MeLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 67% yield.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[CH:4][N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1cn2c(=O)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford the 600 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 0.84-0.86 (s, 1H), 2.42 (s, 1H), 3.74-3.76 (m, 2H), 3.79 (s, 3H), 6.25 (s, 1H), 7.00-7.16 (m, 2H), 7.31-7.33 (m, 1H), 7.80 (s, 1H), 8.06-8.11 (m, 1H); ESI-MS (m/z) 369.24 (M+H)+.
Reaction SMILES: C(OC([N:6]=[S:7]([CH2:35][CH3:36])([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C@H:23]([CH2:28][OH:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)=[CH:18][N:17]=2)=[CH:11][CH:10]=1)=[O:8])=O)C.CC[O-].[Na+]>>[CH2:35]([S:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C@H:23]([CH2:28][OH:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)=[CH:18][N:17]=2)=[CH:13][CH:14]=1)(=[NH:6])=[O:8])[CH3:36]
Reactant: CCOC(=O)N=S(=O)(CC)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCS(=N)(=O)c1ccc(Nc2ncc(-c3ccsc3)c(N[C@H](CO)CC(C)C)n2)cc1
Yield: 34 %

Procedure:
In the reaction of (RS)—N-(ethoxycarbonyl)-S-ethyl-S-(4-{[4-{[(S)-1-(hydroxy-methyl)-3-methylbutyl]amino}-5-(3-thienyl)pyrimidine-2-yl]amino}phenyl)-sulfoximide (265 mg, 0.50 mmol) with sodium ethylate (70 mg, 1.0 mmol) according to procedure 14, the desired product is obtained in 34% yield (77 mg) after chromatographic purification (silica gel, dichloromethane/methanol (9/1)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12].CO>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC(=O)Nc1ccccc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
1128.6 g of o-toluidine were initially charged in 500 ml of toluene and heated to 90° C. 134.3 g of butyryl chloride were added dropwise within 2 hours. After completed addition, the mixture was heated to reflux and stirring continued at this temperature until the end of gas formation. The mixture was cooled to 70° C., 12 ml of methanol were added and stirring was continued for an hour. To remove the methanol, the mixture was heated and 70 ml were distilled off. 300 ml of toluene were then distilled off and 400 ml of cyclohexane were added. The mixture was cooled to 10° C. and filtration gave 199.5 g (92% yield) of the product in 98% purity after drying.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([C:15]1[C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].Cl>ClC(Cl)C>[C:1]([C:23]1[CH:24]=[CH:25][C:26]2[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[C:12](=[O:14])[CH3:13])[CH2:20][C:21]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2c1-c1ccccc1C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)Cc1cccc(C(C)=O)c1-2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (17.7 g.) was added to a stirred suspension of aluminium chloride (64 g.) in dichloroethane (100 ml.). The resulting solution was cooled to 0° C and treated dropwise with stirring, below 10° C, with a solution of 4-acetylfluorene (27.86 g.) in dichloroethane (100 ml.). The mixture was stirred at room temperature for 1 hour and then at 40° C for 3 hours, and finally cooled to 0° C and decomposed with 2N hydrochloric acid (200 ml.). The dichloroethane solution was separated and the aqueous portion was extracted with chloroform. The combined organic solution was washed with water and with aqueous sodium bicarbonate, dried over sodium sulphate and evaporated under reduced pressure. The residual solid was twice recrystallised from ethanol to give pure 2,5-diacetylfluorene, m.pt. 128°-129°. A solution of sodium hydroxide (27.2 g.) in water (500 ml.) was cooled to 0° C, stirred, and treated dropwise with bromine (14.8 ml.). 2,5-Diacetylfluorene (5g.) was added, the temperature was raised to 60° C over 3 hours and kept at 60° C for 3 hours. The mixture was cooled and filtered and the filtrate was warmed to 60° C, treated with sodium acetate (230 g.) and then cooled to 0° C for 1 hour. The resulting yellow precipitate was dissolved in water (200 ml.) and the solution was acidified with concentrated hydrochloric acid. After heating on the steam bath for 1 hour the solid was filtered, washed with water and dried in vacuo to give fluorenone-2,5-dicarboxylic acid m.pt. 300° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(ethyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C5) (3.0 g, 9.09 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (2.64 g).