Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]([F:29])[O:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:16]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:29][CH:3]([F:2])[O:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:24][CH2:25][N:26]([CH3:32])[CH2:27][CH2:28]3)[CH:16]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C)CC1

Procedure:
The compound was prepared by reaction of 3-difluoromethoxy-N-[4-methoxy-3-(piperazin-1-yl)-phenyl]-benzenesulfonamide hydrochloride (compound of example 1) with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][C@@:23]12[C:31](=[O:32])[CH2:30][CH2:29][C@H:28]1[C@@H:27]1[CH2:33][CH:34]=[C:35]3[CH2:40][C@@H:39]([O:41]S(O)(=O)=O)[CH2:38][CH2:37][C@:36]3([CH3:46])[C@H:26]1[CH2:25][CH2:24]2>>[CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][C@@:23]12[C@@H:31]([OH:32])[CH2:30][CH2:29][C@H:28]1[C@@H:27]1[CH2:33][CH2:34][C:35]3[C@@:36]([CH3:46])([C@H:26]1[CH2:25][CH2:24]2)[CH2:37][CH2:38][C:39](=[O:41])[CH:40]=3
Reactant: C[C@]12CC[C@H](OS(=O)(=O)O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
Dehydroepiandrosterone (DHEA) [(3β-hydroxy-5-androsten-17-one)] is a weak androgen synthesized by the adrenal cortex. It has a short plasma half-life and is usually converted to dehydroepiandrosterone sulfate (DHEA-S). Excessive DHEA secretion can produce acne, hirsutism and virilization via conversion to testosterone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH2:35][C@@H:36]([CH3:49])[CH2:37][O:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:35][C@@H:36]([CH3:49])[CH2:37][O:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OC[C@H](C)N)cc1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (505 mg, 1.05 mmol), methyl (S)-4-(2-amino-1-propoxy)benzoate (220 mg, 1.05 mmol), and Et3N (0.220 mL, 1.58 mmol) in DMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from MeOH—CHCl3-n-hexane to give 290 mg (55%) methyl (S)-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a white crystalline powder. 1H-NMR (DMSO-d6) δ1.18 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.36 (s, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 3.93-4.03 (m, 2H), 4.09-4.14 (m, 1H), 6.75-8.57 (series of m, total 13 H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:23][S:20]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=1)(=[O:22])=[O:21])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and acetyl chloride, gave N-acetyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17]([C:20]([CH3:33])([CH3:32])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C)[CH2:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:34](N(CC)CC)C>ClCCl>[C:11]1([S:17]([C:20]([CH3:33])([CH3:32])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][S:7]([C:1]3([CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]3)(=[O:9])=[O:8])[CH2:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CNC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Solvent: ClCCl
Product: CC1(S(=O)(=O)NC2CCCN(CCCC(C)(C)S(=O)(=O)c3ccccc3)C2)C=CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Benzenesulfonyl chloride (90 μL, 0.7 mmol) was added to a solution of 1-(4-benzenesulfonyl-4-methylpentyl)-3-(methylamino)piperidine (0.22 g, 0.65 mmol) and triethylamine (180 μL, 1.3 mmol) in dichloromethane (5 ml). The reaction was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and washed with water (×2). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2–5% methanol/dichloromethane, to give the title compound (220 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CC2)nc1
Yield: 88 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (81 mg, 88%), which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]1=[O:23])(=[O:35])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CCNCC2)c2ccccc2n1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid t-butyl ester (64 mg, 0.2 mmol) in CH2Cl2 at room temperature is treated with 2-naphthylsulfonyl chloride (50 mg, 0.2 mmol) followed by diisopropylethylamine (174 uL, 1.0 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol), stirred at 60° C. for 16 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with HCl in dioxane (4 N) (1 mL), stirred for 4 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 24 mg, [M+H] 408, retention time (RT) 1.89 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15](C=O)[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27][CH2:28][CH3:29])=[O:26].[CH:50]1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15](/[CH:50]=[CH:30]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=O)oc12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccccc1
Product: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(/C=C/C(=O)OCC)oc12

Procedure:
A solution of 7-benzyloxy-4-oxo-8-n-propyl-4H-1-benzopyran-2-carboxaldehyde (1.0 g) in dry benzene (30 ml) was added to a stirred solution of carbethoxymethylene-triphenylphosphorane (1.1 g) in dry benzene (50 ml). After 1 hour the solvent was evaporated and the remaining white solid was extracted several times with ether. The combined and concentrated ether washings were chromatographed over silica gel (100 g). Elution with ether afforded a white solid which was crystallised from ether to yield trans ethyl 3-(7-benzyloxy-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl)acrylate (0.45 g) mp 140° C., a compound of the invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]2[CH2:23][NH:24][C:25]([O:27]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:23][NH:24][C:25]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1COCCN1
Product: Cl
Product: O=C(NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1)N1CCOCC1

Procedure:
Using tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(4-nitrophenoxy)carbonylamino]methyl}-1,4-oxazepane-4-carboxylate and morpholine, and by a method similar to that in Example 158, steps B and C, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:27]1[CH:32]=[N:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>CN(C)C=O>[CH2:33]([C:30]1[N:31]=[CH:32][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:28][CH:29]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Reactant: CCc1cnc(Br)cn1
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)cn1

Procedure:
The title compound is prepared from 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-bromo-5-ethylpyrazine in N,N-dimethylformamide following a procedure analogous to that described in Example 10. LC (method 5): tR=1.25 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.C(OCC)(=O)C.O>[C:6]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([I:1])=[N:3]1)([CH3:7])([CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1I
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (1.10 g, 3.91 mmol) in tert-butanol (5 mL) was added sulfuric acid (0.40 mL, 4.18 mmol, 18 M). The reaction was heated to 100° C. and stirred for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (25 mL). The pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The layers were separated and the organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave 2 regioisomeric products.
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([O:40][CH2:41][CH3:42])[CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:37]([C:34]3[CH:35]=[C:36]4[C:31]([CH:30]=[CH:29][N:28]4[CH:25]4[CH2:27][CH2:26]4)=[C:32]([O:40][CH2:41][CH3:42])[CH:33]=3)=[O:38])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc2c1ccn2C1CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N-Carbamoylmethyl-4-oxospiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (389 mg), 1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (245 mg), WSC hydrochloride (230 mg), HOBT (183 mg) and triethylamine (0.209 mL) were suspended in DMF (8 mL), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed successively with water, 1 N hydrochloric acid, aqueous saturated sodium bicarbonate and saturated saline water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to afford the title compound as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.78-8.71 (1H, m), 8.32-8.30 (1H, m), 8.08 (1H, dd, J=8.7, 2.3 Hz), 7.34 (1H, s), 7.28 (1H, d, J=3.4 Hz), 7.22-7.16 (2H, m), 6.99 (1H, s), 6.56 (1H, s), 6.38 (1H, d, J=3.4 Hz), 4.27-4.15 (1H, br m), 4.15 (2H, q, J=7.0 Hz), 3.77 (2H, d, J=5.9 Hz), 3.46-3.25 (3H, br m), 3.45-3.39 (1H, m), 2.95 (2H, s), 2.09-1.75 (4H, br m), 1.38 (3H, t, J=7.0 Hz), 1.08-1.01 (2H, m), 0.95-0.90 (2H, m); MS [M+H]+=545.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12](=[O:27])[CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)=[O:15])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:31]([CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C.C1COCC1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:37][CH2:38][CH2:39][CH2:40][CH:13]([C:14](=[O:15])[NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)[C:12](=[O:27])[NH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:36]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: O=C(CC(=O)Nc1cccc2cccnc12)Nc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(C(=O)Nc1cccc2cccnc12)C(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of N,N′-di-quinolin-8-yl-malonamide (10.3 g, 28.8 mmol) in dry DMF (200 mL) and dry THF (85 mL) at 0° C. was added NaH (60% disp./1.27 g, 31.7 mmol) portion-wise. The resultant solution was allowed to warm to RT for 10 min. The solution was cooled to 0° C. and ethyl bromohexanoate (5.6 mL, 31.7 mmol) was added dropwise. The mixture was stirred overnight. The solvent was removed, and the residue was diluted with EtOAc (250 mL), and washed with H2O (100 mL). The organic fraction was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the desired material (10 g, 69.6%). ESIMS calcd 499 (M++H), found 499 (M++H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19]C5CCCC=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH2:40][CH:41]([CH3:43])[CH3:42]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:40]([CH:41]([CH3:43])[CH3:42])=[C:39]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)CC(=O)c1ccccc1
Product: CC(C)c1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert isovalerophenone (0.484 g, 2.98 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.5-11.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-isopropyl-4-phenyl-1,3-thiazol-2-amine as a pink powder (0.060 g, 0.099 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.82 min;
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[O:8][CH3:9])=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Nc1ccc(COc2ccc3c(c2)CCC(CN(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
o-Anisoyl chloride (0.15 ml) was added dropwise to pyridine solution (4 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (200 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; THF), and recrystallized (ethyl acetate-hexane) to give the titled compound (200 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.S1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31].[N:34]1C=CC=C[CH:35]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([C:26]4[CH:35]=[N:34][CH:29]=[CH:28][CH:27]=4)(=[O:32])=[O:31])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccncc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccnc3)cc2)c2ccc3ccccc3c2N1
Yield: 61 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-thiophenesulfonyl chloride (26 mg, 0.14 mmol) were treated by heating in pyridine (3 mL). A post-treatment was performed in a conventional manner to obtain the title compound (27 mg, yield 61%) as white amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:4]([O:19][CH3:20])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(C2(C)CC2)c(Cl)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of ethyl 2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetate (630 mg, 2.12 mmol) in THF (15 mL) and water (5 mL), LiOH.H2O (889 mg, 21.2 mmol) was added and the resulting mixture was stirred at RT for 2 h. The mixture was washed with 20% ethyl acetate/petroleum ether. The aqueous layer was acidified with aqueous HCl (1N) to adjust pH to 3-4 and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (200 mg, 33% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][C:18]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[C:25]2[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=2)[N:19]=1.O>CN(C)C=O>[C:10]1([N:9]([CH2:17][C:18]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=3)[C:25]3[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=3)[N:19]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN(c3ccccc3)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.9 %

Procedure:
Sodium hydride (oily, 60%, 0.129 g) was added to a solution of diphenylamine (0.497 g) in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 20 minutes. Then, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.0 g) was added, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:1, v/v) gave 2-(N,N-diphenylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.27 g, 20%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 215°-216° C.
Reaction SMILES: C=O.[ClH:3].[CH3:4][C:5]1[S:6][C:7]([Cl:11])=[CH:8][C:9]=1[Cl:10].[C:12](O)(=O)C>>[Cl:3][CH2:12][C:8]1[C:9]([Cl:10])=[C:5]([CH3:4])[S:6][C:7]=1[Cl:11]
Reactant: Cc1sc(Cl)cc1Cl
Reactant: CC(=O)O
Reactant: Cl
Agent: C=O
Product: Cc1sc(Cl)c(CCl)c1Cl
Temperature: 70 °C

Procedure:
8.6 G. (0.107 mol) of formalin and 90 ml. of concentrated hydrochloric acid were added to a solution of 10.87 g. (0.065 mol) of 2-methyl-3,5-dichlorothiophene in 45 ml. of acetic acid. The resulting mixture was heated to 70° C. for 18 hrs., cooled, poured into ice water and extracted with ether. The organic solution was washed with water, sodium bicarbonate and water, dried and evaporated to yield 3-chloromethyl-2,4-dichloro-5-methylthiophene as a crude oil.