Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CNS(=O)(=O)c1ccc(Cl)cc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 2.2 %

Procedure:
(Step 2) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g), 2-(aminomethyl)-4-chloro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (0.81 g) and potassium carbonate (0.88 g) were stirred in ethanol (10 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (10 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCn1c(C)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 2-methylbenzimidazole (1.32 g, 0.01 mol), 1-bromobutane (1.21 g, 0.01 mol), 50% aqueous sodium hydroxide (5 ml), toluene (20 ml) and 0.5 mmol of compound 1 was stirred at 80°-85° C. for 3 hours. After that time, the resulting mixture was allowed to cool to room temperature and the organic layer was separated, extracted with concentrated hydrochloric acid (3×20 ml). The acidic solution was neutralized with 20% sodium hydroxide, extracted with toluene (3×15 ml), dried over magnesium sulphate and evaporated to give a residue which was distilled at reduced pressure (0.4-0.5 mm 162°-6° C.) to give 1-n-butyl-2-methylbenzimidazole. Yield: 65%.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)([CH3:11])[C:8](=[O:10])[CH:9]=1)=[O:4].O[Li].O>C1COCC1.CO>[C:12]1([C:7]2([CH3:11])[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]2=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: COC(=O)C1=CC(=O)C(C)(C2=CCCCC2)O1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C2=CCCCC2)OC(C(=O)O)=CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To a solution of 5-cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester (47 mg, 0.2 mmol) in THF/MeOH (1/1, 2 mL) was added LiOH.H2O (8.4 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. After concentration, the residue was dissolved in H2O (4 mL), washed with ethyl ether (2×5 mL). The separated aqueous layer was acidified to pH 2. This acidified solution was extracted with ethyl ether (3×5 mL). The extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified with a silica gel column using EtOAc/AcOH (20/1) providing 35 mg (79%) of racemic 5-cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid: LC-MS m/z 221 (M−1); 1H NMR (400 MHz, CDCl3) δ 6.30 (s, 1H), 5.90 (m, 1H), 2.16-2.06 (m, 3H), 1.79-1.70 (m, 1H), 1.67-1.51 (m, 4H), 1.58 (s, 3H).
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.ClCI.[C:15]12([CH2:25][CH2:26][N:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]([NH:30][CH2:31]/[CH:32]=[CH:33]\[C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:29])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.[Cl-].[NH4+]>ClCCCl.C(OCC)(=O)C>[C:15]12([CH2:25][CH2:26][N:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]([NH:30][CH2:31][C@@H:32]3[CH2:1][C@@H:33]3[C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)=[O:29])[CH2:16][CH:17]3[CH2:18][CH:19]([CH2:20][CH:21]([CH2:23]3)[CH2:22]1)[CH2:24]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NC/C=C\c1ccncc1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCCCCC
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NC[C@@H]1C[C@@H]1c1ccncc1
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A 1.0 M solution of diethylzinc in hexane (3.1 ml, 3.1 mmol) and chloroiodomethane (0.44 ml, 6.1 mol) were added to a solution of (Z)-1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)-2-propenyl]urea (Compound No. 1-111) in anhydrous 1,2-dichloroethane (3 ml) under a nitrogen atmosphere and ice-cooling, and the mixture was stirred for one hour. A saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture under ice-cooling, and the whole was stirred at room temperature for 20 minutes and distributed with ethyl acetate (20 ml) and a saturated aqueous ammonium chloride solution (10 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 9.0 mg (3.5%) of the titled compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7](I)[C:6]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[B:35](OC)([O:38]C)[O:36]C.C(=O)=O.CC(C)=O.Cl>C(OCC)C>[F:19][C:18]([F:21])([F:20])[CH2:17][O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:7]=1[B:35]([OH:38])[OH:36]
Reactant: CC(C)(C)c1cc(I)c(OCC(F)(F)F)c(C(C)(C)C)c1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(B(O)O)c(OCC(F)(F)F)c(C(C)(C)C)c1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
1,5-Di-tert-butyl-3-iodo-2-(2,2,2-trifluoro-ethoxy)-benzene (3.17 g, 7.7 mmol) was dissolved in anhydrous diethyl ether (75 mL) in an oven-dried flask under nitrogen. N,N,N′,N′-Tetramethyl ethylenediamine (1.73 mL, 11.5 mmol) was added and the reaction cooled in a dry ice/acetone bath. At −76° C. to −73° C. was added over 5 min n-butyl lithium (4.6 mL, 11.5 mmol, 2.5M in hexane). The reaction was stirred at −75° C. for 15 min and then treated slowly with trimethyl borate (2.6 mL, 23 mmol). The reaction was stirred at −75° C. for 1 h. The dry ice/acetone bath was replace with an ice bath and the reaction was allowed to warm to 0° C. over 40 min. 1N hydrochloric acid (50 mL) was added and after 5 min the ice bath was removed and stirring allowed to continue for 1 h. The aqueous and organic layers were separated and the aqueous layer was washed with ethyl acetate (2×75 mL). The combined organic portion was washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide a yellow gum. The material was purified by flash chromatography using (9:1) hexane:ethyl acetate and then (4:1) hexane:ethyl acetate to give 1.28 g (50%) of an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:3]#[C:4][CH2:5][O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:10][C:9]([CH3:11])=[CH:8][CH2:7][O:6][CH2:5][C:4]#[C:3][C:2]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=[O:1]
Reactant: CC(C)=CCOCC#CC(O)c1ccc2c(c1)OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)=CCOCC#CC(=O)c1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
A solution of 34.2 g (125 mmol) of 1-hydroxy-4-[(3-methyl-2-butenyl)oxy)-1-(3,4-(methylenedioxy)phenyl]-2-butyne in 350 ml of methylene chloride was added dropwise at 0° to a suspension of 163 g (1.87 mol) of manganese dioxide in 500 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. The crude product was recrystallized from ether/hexane at -50°. There was obtained 4-[(3-methyl-2-butenyl)oxy]-1-[3,4-(methylenedioxy)phenyl]-2-butyn-1-one as pale yellow crystals which melt at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:29]1[C:34]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)=[CH:33][CH:32]=[CH:31][N:30]=1>C1COCC1>[CH3:60][O:59][C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:42]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)[C:37]2[N:36]=[C:35]([C:34]3[C:29]([NH:15][C:13]4[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=5)[CH:14]=4)=[N:30][CH:31]=[CH:32][CH:33]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:58][CH:57]=1
Reactant: COc1ccc(COc2cc(N)ccn2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Nc3ncccc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 2-(4-methoxybenzyloxy)pyridin-4-amine (0.500 g, 2.171 mmol) in THF (10 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (6.51 mL, 6.51 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. 4-(2-Fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.161 g, 2.61 mmol) was added to this reaction mixture. After the addition, the resulting mixture was stirred at 0° C. for 10 min and then removed from the ice bath and stirred for 2 h at rt. The reaction was quenched with water. The resulting mixture was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 20% to 30% EtOAc in hexanes) to give the product as a white solid (0.950 g). m/z (ESI, +ve ion) 656.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.36 (s, 1H); 8.85 (d, J=7.75 Hz, 1H); 8.40 (d, J=4.38 Hz, 1H); 7.98 (d, J=5.41 Hz, 1H); 7.50 (s, 1H); 7.43 (d, J=8.33 Hz, 2H); 7.21 (d, J=8.18 Hz, 4H); 7.02 (d, J=4.38 Hz, 1H); 6.73-6.98 (m, 7H); 5.32 (s, 2H); 4.85 (br. s., 4H); 3.69-3.96 (m, 9H); 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][CH2:25][Cl:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][CH2:25][Cl:26])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(CCl)CCCl
Solvent: C1CCOC1
Product: ClCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,4-dichloro-2-butanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(2-chloroethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: CO[C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl.[CH3:30][NH2:31].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:7]1[N:8]=[C:3]([NH:31][CH3:30])[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CN
Reactant: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)N=C(NC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
A solution of 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (3.71 g crude) in dimethylformamide (15 ml) was treated with methylamine hydrochloride (1.01 g, 15.0 mmoles) and sodium acetate (1.49 g, 17.0 mmoles). The reaction was allowed to stir at room temperature for 48 hours. It was then diluted with ethyl acetate and filtered. The filtrate was washed with water, sodium bicarbonate, brine and was dried over anhydrous magnesium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (5-7% ethyl acetate, dichloromethane). The product was crystallized from dichloromethane-isopropyl ether-hexanes to provide the title compound as yellow crystals (1.91 g), melting point 112.5°-114.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:19])[CH2:17][CH3:18])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and propionyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC(Cl)=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[O:31][N:30]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
3-(6,7-Dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.302 mmol) and 4-chlorophenyl 5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate from the previous step (90 mg, 0.302 mmol) were reacted according to the procedure described in Example 122B, except the reaction mixture was stirred at room temperature for 3 h. The crude material was purified via silica gel chromatography (0%-10% methanol in dichloromethane) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-fluoropropan-2-yl)isoxazol-3-yl)urea as a colorless solid (37 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (brs, 1H), 9.04 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.40-7.41 (m, 2H), 7.29 (m, 1H), 7.00 (m, 1H), 6.86 (s, 1H), 4.00 (s, 6H), 1.72 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[CH3:34][S:35]([N:15]1[CH2:16][C@@H:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][C@H:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13])(=[O:37])=[O:36]
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To an ice-cooled solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (29 mg, 0.08 mmol) in THF (0.8 mL) with Et3N (60 μL, 0.4 mmol) was added methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (31 mg, 87%). MS (ESI): mass calcd. for C21H30FN3O4S, 439.19; m/z found, 440.5 [M+H]+. 1H NMR (CDCl3): 7.00-6.94 (m, 2H), 6.83-6.78 (m, 2H), 4.94-4.89 (m, 1H), 4.86 (ddd, J=8.8, 4.4, 4.4 Hz, 1H), 4.10-4.03 (m, 1H), 3.78-3.40 (m, 5H), 3.08 (d, J=4.0 Hz, 3H), 2.84 (dd, J=16.2, 7.8 Hz, 1H), 2.75-2.66 (m, 1H), 2.57-2.26 (m, 4H), 2.25-2.14 (m, 1H), 2.07-1.97 (m, 2H), 1.97-1.71 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:15]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:14][C:13]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:6][C:5]=1[O:38]C(=O)C.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CO.C1COCC1>[C:24]([C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[C:5]([OH:38])[CH:6]=2)=[C:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(COc2c(-c3ccccc3)cc(C(=O)c3ccccc3)cc2-c2ccccc2)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OCc2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
At ambient temperature, to a stirred solution of 4-(5'-benzoyl-[1,1';3',1"]terphenyl-2'-yloxymethyl)-2-acetoxy-benzoic acid methyl ester (0.527 g, 0.946 mmol) in MeOH:THF (1:1,15 mL) was added K2CO3 (0.261 g, 1.89 mmol). After 1 h, to the reaction was added 1N NaOH (5 mL) and the reaction was heated at 100° C. for 4 h. The reaction was cooled to ambient temperature, acidified with 1N HCl and extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated. Recrystallization from ether/pet. ether gave 0.261g (55%) of the title compound as a white solid, mp 217-220'C. 1H NMR (DMSO-d6) δ 4.25 (s, 2H), 6.29 (dd, 1H), 6.34 (d, 1H), 7.38-7.48 (m, 6H), 7.53-7.69 (m, 8H), 7.72 (s, 2H), 7.82 (d, 2H). IR (KBr) 3050, 1675, 1620, 1575 and 1210 cm-1. mass spectrum (EI) m/z 500 (M+). Anal. Calcd. for C33H24O5H2O: C,76.43; H,5.05; N,0.00. Found: C,76.75; H,4.82; N,0.03.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6])(=[O:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.O>C1C=CC=CC=1>[Cl:15][C:4]1([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6]
Reactant: CCC1CC(C(C)=O)C(=O)O1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCC1CC(Cl)(C(C)=O)C(=O)O1
Temperature: 25 °C

Procedure:
Into a solution of 58.2 g (0.37 moles) of α-acetyl-γ-ethyl-γ-butyrolactone [prepared according to J. Pharm. Sci. 52, 733 (1963)] in 60 cm3 benzene 50 g of (0.37 moles) of sulphuryl chloride are added dropwise under stirring and cooling in 2 hours, keeping the temperature of the reaction mixture between 5 and 10° C. After completing the addition the reaction mixture is let to warm to room temperature and stirred at this temperature until the gas formation ceases. Then it is poured into 400 cm3 of water, the phases are separated and the water is extracted with 200 cm3 of benzene. The benzene containing solution is washed with 100 cm3 of 5% sodium hydrogencarbonate solution. After evaporation the residual oil is distilled in vacuo. The title compound is obtained in the form of a colourless liquid in an amount of 58.9 g (82.5%), its boiling point is 91° C. at a pressure of 80 Pa, nD20 =1,4623.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.O.[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:23]([N:1]1[CH2:2][CH2:3][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:5][CH2:6]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29]
Reactant: c1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1

Procedure:
Dissolve 13.8 g of 11-(4-piperidylidene)-6,11 dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (Compound IC) prepared according to Villani et. al., J. Med. Chem. 15, 750 (1972) in 250 ml of dry tetrahydrofuran. With stirring, add in one portion 12 g of di-t-butyl carbonate and stir at room temperature overnight. The mixture is poured into water, is extracted with ether, is washed with water and the solvent removed. Recrystallize the residue from isopropyl ether. The melting point is 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:30])[CH:27]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1S(=O)(=O)n1ccc2c(CN(C)C)c(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 5-bromo-2-methoxybenzenesulphonyl chloride (31 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (9 mg, 27%) as a white solid. MS (ESI+) for C19H21BrN2O4S m/z 454 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([O:25]C)[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:8])[CH3:7].S([O-])([O-])(=O)=O>O>[CH:6]([NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([OH:25])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:8])[CH3:7]
Reactant: COc1cccc2c1C(=O)c1cccc(NC(C)C)c1C2=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)Nc1cccc2c1C(=O)c1cccc(O)c1C2=O
Yield: 90 %

Procedure:
This press cake is introduced with intensive stirring into 34.7 parts of 90% strength sulphuric acid, the solution is warmed to 120°-125° until no further 1-isopropylamino-5-methoxy-anthraquinone is chromatographically detectable in a worked-up sample (about 3 hours are required) and is diluted with 18 parts of water at 50°-80°, the mixture is stirred overnight in the cold, and the sulphate which has precipitated in large boat-shaped plates is filtered off, washed with 50% strength sulphuric acid, decomposed with water, and the product washed until neutral and dried. 12.9 parts (90% of theory) of 1-isopropylamino-5-hydroxy-anthraquinone are obtained.