Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].Cl.N1CCCC1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:24]2[CH2:25][CH2:26][CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 4-bromophenethyl alcohol (2.54 mmol) and p-toluenesulfonyl chloride (2.74 mmol) in anhydrous dichloromethane (5 mL) under nitrogen was added triethylamine (2.74 mmol) dropwise by syringe at room temperature. The reaction was stirred for 16 hours at room temperature. A white precipitate formed. 1N HCl solution (5 mL) was added to the suspension and the reaction became clear. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (5 mL), dried over magnesium sulfate and concentrated in vacuo to give a white solid. To this crude product was added pyrrolidine (1 mL) under nitrogen and the reaction was stirred at 50° C. for 90 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (20 mL) and washed successively with water (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (20-100% ethyl acetate/hexanes) afforded the title compound as a white solid (80%). ESMS [M+H]+: 254.2.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 7.6 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 0.68 mmol) and 4-chloro-6,7-dimethoxyquinazoline (153 mg, 0.68 mmol) in DMF (4 mL) at rt, was added potassium carbonate (188 mg, 1.36 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (25 mg, 8%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (brs, 1H), 8.85 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.55 (s, 1H), 7.40-7.44 (m, 2H), 7.16 (m, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 482 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl.CO>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2=[O:28])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2=O

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in dichloromethane (125 cc) there was rapidly added a solution of 85% m-chloroperoxybenzoic acid (6.61 g) in methanol (125 ml). At first the solids dissolved, then after a few minutes a new solid separated out of solution. After 1 and 1/2 hours the mixture was filtered and the solid washed with dichloromethane. The title compound was thus obtained pure (8.76 g), m.p. 179°-181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([O-:7])=[O:6].[CH:13](O)=O.[OH-].[K+]>O>[Cl:12][C:9]1[C:10]2[N:11]=[CH:13][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=1
Reactant: O=CO
Reactant: Nc1cc(C(=O)[O-])cc(Cl)c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c2nc[nH]c2c1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
3,4-diamino-5-chlorobenzoate (1.2 g, 6 mmol) was added to water (10 mL) and formic acid (826 mg, 18 mmol) and heated at reflux for 4 hours. The reaction was cooled to ambient temperature and aqueous potassium hydroxide was added (21 mL, 1M). The reaction solution was washed with ethyl acetate (2×25 mL each). The aqueous layer was acidified to pH=5 with aqueous hydrochloric acid (1N) to give a precipitate which was filtered, washed with water and dried under a stream of nitrogen to give the title compound (439 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H) 8.10 (d, J=1.17 Hz, 1H) 7.77 (d, J=1.37 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(#N)C.ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNS(=O)(=O)c1ccc(F)cc1
Temperature: 4 °C
Yield: 40.9 %

Procedure:
1-(4-Aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) was dissolved in anhydrous acetonitrile (35 mL) and the solution was cooled to 4° C. A solution of 4-fluorobenzenesulfonyl chloride (0.194 g, 1.0 mmol) in anhydrous dichloromethane (10 mL) was slowly added. The reaction was allowed to slowly warm to ambient temperature over the weekend. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The layers were separated and the organic layer was concentrated to provide a pale yellow solid. This material was recrystallized from isopropyl alcohol and then further purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated. The residue was recrystallized from isopropyl alcohol to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamide as a pale yellow solid, m.p. 214-216° C. Analysis: Calculated for C26H24FN5O2S: % C, 63.79; % H, 4.94; % N, 14.30; Found: % C, 63.19; % H, 4.85; % N, 13.90. Mass spec M+1=490.2
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:18]([O-:20])=[O:19])[CH:6]=[CH:7][C:8]=2[C:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]=2)[C:3]1=[O:21].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].Cl.CCOCC>C(Cl)Cl>[CH2:24]([O:23][P:22]([C:14]1([OH:17])[CH2:15][CH2:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:18]([O-:20])=[O:19])=[C:4]3[C:9]=2[CH2:10][N:2]([CH3:1])[C:3]3=[O:21])=[CH:12][CH2:13]1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CN1Cc2c(C3=CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOP(OCC)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(O)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-methyl-7-nitro-4-(4-oxocyclohex-1-en-1-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 193D) was dissolved in DCM (10 mL), then triethyl phosphite (520 mg, 3.1 mmol) and 1N HCl/Et2O (3.1 mmol, 3.1 mL) were added at 0° C. under nitrogen. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The solvent was evaporated, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-10% MeOH/DCM) to give the title compound as a yellow solid, 470 mg, 71% yield (over two steps). 1H NMR (CDCl3): 1.39 (t, J=7.1 Hz, 6H), 2.02 (m, 1H), 2.20 (m, 1H), 2.30-2.47 (m, 2H), 2.65-2.83 (m, 2H), 3.20 (s, 3H), 4.21-4.29 (m, 4H), 4.42, 4.48 (AB, JAB=18.0 Hz, 2H), 5.86 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H). MS (ES+): m/z=425.12 [MH+]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=C(O)c1cc(NCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 77.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (2.00 g, 13.0 mmole) and 4-nitrobenzyl bromide (3.38 g, 15.6 mmole), 2.90 g (79% yield) of 5-(4-nitrobenzyl)aminosalicylic acid was obtained as a pale yellow solid.: mp 211-212° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH3:18])[C:9]=2[N:8]=[CH:7]1.[NH:19]1[CH2:24][CH:23]=[C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:22]2[CH2:23][CH2:24][N:19]([CH2:3][CH2:4][CH2:5][N:6]3[C:14]4[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH3:18])[C:9]=4[N:8]=[CH:7]3)[CH2:20][CH:21]=2)=[CH:26]1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cn1c(=O)c2c(ncn2CCCN2CC=C(c3c[nH]c4ccccc34)CC2)n(C)c1=O
Reaction time: 22 h
Yield: 98 %

Procedure:
A mixture of 5 parts of 7-(3-chloropropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione monohydrochloride, 4 parts of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 8 parts of sodium carbonate and 240 parts of 4-methyl-2-pentanone was stirred for 22 hours at reflux temperature. The whole was stirred till room temperature was reached. The product was filtered off and stirred in water. After filtration, the product was washed with water and stirred in water and an equivalent amount of acetic acid. The mixture was treated with ammonium hydroxide. The precipitated product was filtered off, washed with water and stirred in a mixture of acetonitrile and 2-propanol. The product was filtered off, washed with acetonitrile and dried, yielding 7 parts (98%) of 7-[3-[3,6-dihydro-4-(1H-indol-3-yl)-1(2H)-pyridinyl]propyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; mp. 243.2° C. (compound 17).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=C[CH:17]=2)=[CH:5]1)([CH3:3])[CH3:2].[NH2:24]C1C=C2C(C(C3C=CC(C#N)=CC=3)=CN2C(C)C)=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>[Pd].[Pt]=O>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[N:24][CH:17]=3)=[CH:5][N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(N)cc21
Agent: O=[Pt]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Product: CC(C)n1cc(-c2ccc(C#N)nc2)c2ccc(N)cc21

Procedure:
Method F This compound can be prepared from 5-(1-isopropyl-6-nitro-1H-indol-3-yl)-pyridine-2-carbonitrile (4, R1=i-Pr, R3=5-(2-cyanopyridine)) in a manner substantially similar to that described immediately above for 4-(6-amino-1-isopropyl-1H-indol-3-yl)-benzonitrile except Degussa type E101 NE/W 10% Palladium on activated carbon can be used instead of platinum (II) oxide in Method E. LRMS (API ES+)=277.0 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@:7]12[CH2:24][CH2:23][C@@:21]3([CH3:22])[C@@H:17]([CH2:18][CH2:19][C:20]3=[O:25])[C@@H:16]1[CH2:15][CH2:14][C:13]1[C@:8]2([CH3:27])[CH2:9][CH2:10][C:11](=[O:26])[CH:12]=1.[C-:28]#[N:29].[K+].O>CO>[CH3:22][C@@:21]12[C:20]([OH:25])([C:28]#[N:29])[CH2:19][CH2:18][C@H:17]1[C@@H:16]1[CH2:15][CH2:14][C:13]3[C@@:8]([CH3:27])([C:7]1([OH:6])[CH2:24][CH2:23]2)[CH2:9][CH2:10][C:11](=[O:26])[CH:12]=3
Reactant: [C-]#N
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Reaction time: 2.5 h

Procedure:
Sulfuric acid (2.07 ml) is added to 9α-hydroxyandrost-4-ene-3,17-dione (I, 21.14 g) and potassium cyanide (6.70 g) slurried in methanol (71.5 ml) and water (6.8 ml) at <5°. The mixture is allowed to warm to 15° over 0.5 hr, then warmed to 30° over 1 hr. The mixture is stirred at 30° for 2.5 hr, then cooled to 2° and sulfuric acid (0.32 ml) is added. The mixture is then stirred at 30° for 2 hr and water (13 ml) is added. Next, water (52 ml) is added over 12 hr, maintaining the mixture at 30°. The mixture is stirred 5 hr at 30°, then cooled to 0° and quenched with sulfuric acid (1 ml). Methanol (89 ml) is added and the mixture is heated to 55°. The solvent is then removed by reduced pressure until the boiling point begins to rise rapidly. The mixture is then cooled to 32° and water (105 ml) is added over 12 min. The mixture is further cooled to 0° and the the solids are collected by vacuum filtration and washed with water to give the title compound, mp 230°-233° (with decomposition). ##STR1##
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[C:29](O)(=[O:31])[CH3:30]>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: CC(=O)O
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (106 mg, 92%), MS (ISP) m/z=385.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and acetic acid.
Reaction SMILES: [NH:1]([C:8](=[O:24])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[NH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:24])[CH2:11][CH2:12]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
The product of stage 1 (0.28 g; 0.84 mmol) is stirred over night at r.t. with 10 mL 10% TFA in DCM. The solvent is removed to give 2-(4-amino-1-piperidyl)-N-phenyl-acetamide as a TFA salt (I.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11]2)[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)C(=O)NC1CCC(Oc2cccc(N)c2C#N)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCC(NC(=O)C(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 40b) and ethyl 3-oxobutanoate as a yellow solid (57%). MS 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C1(C)C=CC=CC=1.Cl[CH2:32][CH2:33][CH:34]1[O:39][CH2:38][CH2:37][CH2:36][O:35]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:32][CH2:33][CH:34]4[O:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: ClCCC1OCCCO1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(CCC2OCCCO2)CC1
Reaction time: 23 h
Yield: 64 %

Procedure:
A mixture of 2-chloro-7-fluoro-10-piperazino-10,11-dihydro-dibenzo(b,f)thiepin (10.0 g), toluene (60 ml), triethylamine (10 g) and 2-(2-chloroethyl)-1,3-dioxane (15.3 g) is refluxed under stirring for 23 hours. On cooling, the precipitate is filtered off and washed with benzene. The combined filtrates are then washed with water, dried over anhydrous potassium carbonate, filtered with a small amount of active carbon, and evaporated under reduced pressure to dryness. The residue (19.0 g) crystallizes rapidly while standing. Another crystallization from a mixture of benzene (50 ml) and petroleum ether (50 ml) yields 8.5 g (65%) of the desired base, melting at 150.5°-152° C. Repeating the crystallization from the same solvent system does not increase the m.p. any more; the product is analytically pure, and its elemental analysis corresponds to the composition C24H28ClFN2O2S. Neutralization of the base, with maleic acid in a mixture of equal amounts of benzene, acetone and ethanol, provides the neutral maleate C28H32ClFN2O6S, which crystallizes from ethanol and melts in the pure state at 184°-185° C. This salt is only very slightly soluble in water. Neutralization of base with methanesulfonic acid in ethanol gives the monomethanesulfonate C25H32ClFN2O5S2, which crystallizes from ethanol and melts at 201°-203° C. This salt is excellently water-soluble.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8](=[O:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)Cl>[Br:18][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)[C:8](=[O:15])[C:9]([CH3:13])([CH3:14])[CH2:10][CH2:11][Cl:12]
Reactant: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
136 g (0.5 mol) of 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one are dissolved in 1,000 ml of methylene chloride. 79.9 g (1 mol) of bromine are added dropwise, at room temperature, in such a manner that the solution is constantly decolourised. Thereafter, stirring is continued for 1 hour at room temperature, and the reaction mixture is concentrated by distilling off the solvent. 1-Bromo-1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one is obtained quantitatively, that is to say 177 g, and is directly reacted further. ##STR31##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[CH3:10]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1
Reactant: CI
Reactant: OCc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 66.1 %

Procedure:
To a solution of 2-chloro-5-hydroxymethyl-pyrimidine (9.0 g, 62 mmol) in 70 ml of anhydrous DMF was added methyl iodide (6 eq. 370 mmol, 23 ml). The mixture was cooled to 0° C., then NaH (2.61 g, 1.05 eq.) was added in portions over 5 mins. The resulting mixture was stirred 25 min. at 0° C., then 25 min. at rt. The reaction mixture was then cooled in ice bath, and quenched by addition of saturated NH4Cl aq. solution (200 ml), extracted with ether (150 ml×3). The combined organic layers were washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by ISCO column (330 g of silica gel) using ethyl acetate in hexane (0-90% ethyl acetate, 2500 ml, then 1000 ml of ethyl acetate) to give 6.5 g (66%) of the title compound: MS (ESI) m/z 159.2 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 2H), 4.48 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N([O-])=[O:12].[Na+].[OH-].[Na+]>O.OS(O)(=O)=O>[S:8]1[C:4]2[CH:3]=[C:2]([OH:12])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=N[O-]
Reactant: Nc1ccc2ncsc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2ncsc2c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-aminobenzothiazole (1.0 g, 6.66 mmol) in water (22 mL) and H2SO4 (16 mL) at 5° C. was added a solution of sodium nitrite (460 mg, 6.72 mmol) in water (13 mL) keeping the temperature below 5° C. The resulting solution was allowed to stir for 15 minutes. The reaction mixture was heated to 160° C. and a solution of H2SO4 (50 mL) and water (38 mL) was slowly added. The resulting mixture was allowed to stir for 1 h. The mixture was allowed to cool and an aqueous solution of 50% sodium hydroxide was added until the pH=7. The mixture was extracted with ethyl acetate and washed with brine. The combined organic was dried over MgSO4 and evaporated to yield a semi-solid. The semi-solid was purified by column chromatography (40% ethyl acetate/hexanes) to yield benzothiazo-6-ol 16 as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:38](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:38])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: CC(=O)O
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate obtained in Example 140 and 5 mg (0.17 mmol) of paraformaldehyde were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes, 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.