Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].[BrH:15]>>[BrH:15].[BrH:15].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1cn(C)c(CO)n1
Agent: Br
Agent: Cl
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1 (i) (a) gave 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.) m.p. 161°-163° (from isopropyl alcohol-methoanol).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][N:17]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15]1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Temperature: 180 °C
Yield: 93.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.274 g, 1.64 mmol) in isopropanol (10 mL) were added 4-methylpiperidine 4-carboxylic acid hydrochloric acid from step A (0.294 g, 1.64 mmol) and triethylamine (0.654 mL, 4.92 mmol). The reaction was heated to 180° C. for 1 hour under microwave conditions, concentrated, taken up with ice water, and neutralized to pH 3 with 6 N aq. HCl to precipitate the product. The product was collected by filtration and dried under vacuum overnight to give the title compound (0.42 g, 75%) as a gray solid. MS (ES+) [M+H]+=275.2.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[OH:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:59]4[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][OH:53])[CH2:57][CH2:58]4)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCCN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][CH2:45][CH:38]1[CH2:39][NH:40][CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][CH2:45][CH:38]1[CH2:39][N:40]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:21])[CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCNCC1CC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 85.4 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (0.2 g, 0.507 mmol) was combined with 3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.136 g, 0.6 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.269 g, 0.433 mmol) in 85% yield. MS m/z 602.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]=[O:14].[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16]>CC(=O)OCC>[C:19]([O:18][C:15](=[O:17])[CH2:16][CH:13]([OH:14])[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)OC(C)(C)C
Reactant: COc1ccc2nccc(C=O)c2n1
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(C(O)CC(=O)OC(C)(C)C)c2n1

Procedure:
The aldol reaction between 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (1.9 g, 10 mmol, WO 2006/032466) and tert-butyl acetate (1.2 g, 10.5 mmol) was carried out as described in the literature (J. Org. Chem. (1990), 55, 4744-4750). The title compound was isolated after chromatography on SiO2 (Hex/EA 1:1) as a beige solid (2.33 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[C:18]([OH:21])=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:20]2[CH:19]=[C:18]([OH:21])[C:17]([OH:22])=[CH:16][C:15]=2[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(O)c(O)c1
Reactant: O=[N+]([O-])c1cc(S(=O)O)ccc1Cl
Product: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
66 g (297.8 mmol) of 4-chloro-3-nitrobenzenesulphinic acid (produced by reduction of 4-chloro-3-nitrobenzenesulphonyl chloride with sodium sulphite) are condensed with 41.95 g (337.9 mmol) of 4-methyl-1,2-benzenediol in a manner analogous to that described in Example 4, yielding 4-(4-chloro-3-nitrophenylsulphonyl)-5-methyl-1,2-benzenediol in the form of crystals having a melting point of 196°-197° (from ethyl acetate/hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:15])=[O:8])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Nitrobenzoic acid (1.00 g; 5.98 mmol; 1.00 eq.) is dissolved in toluene (15 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1) (8.98 ml; 2.00 M; 17.95 mmol; 3.00 eq.) is added dropwise. The solution is stirred at RT for 1.5 h. Solvents are removed affording methyl 3-nitrobenzoate as a yellow powder (940.70 mg; 86.79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1Cl
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Product: Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3Cl)co2)s1
Yield: 83 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain 4-[2-chloro-4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 83%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 95-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:30]([CH3:54])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.4 %

Procedure:
p-Methoxyaniline (0.045 g, 0.368 mmol), triethylamine (0.037 g, 0.368 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.062 g, 0.368 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.075 g, 0.184 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.040 g, 0.0780 mmol, 42%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([S:12](=[O:16])(=[O:15])[NH:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:11][C:10]1[CH:9]=[C:8]([S:12]([NH:13][CH3:14])(=[O:16])=[O:15])[CH:7]=[C:3]([C:4]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[O:6])[C:2]=1[F:1]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Product: CNS(=O)(=O)c1cc(F)c(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared in analogy to Example BO by reaction of 2,3-Difluoro-5-methylsulfamoyl-benzoic acid and 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7]) to yield the title compound as a light yellow amorpous solid. (m/e): 462.1 (M−H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[N:5]([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](O)=[O:24].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:31][C:27]1[CH:28]=[C:29]([Br:30])[C:21]2[N:20]=[C:17]([C:4]3[N:5]([C:7]4[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:19][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1C(F)(F)F
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2C(F)(F)F)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-trifluoromethyl-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-trifluoromethyl-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3]/[CH:4]=[CH:5]/[C:6](NC1C=CC=C(NC2C=C(NC3C=CC=CC=3)N=CN=2)N=1)=[O:7].C(#N)C.Cl.CN(/C(=C\C)/C(O)=O)C.C(Cl)(=O)C([Cl:46])=O>CN(C=O)C>[CH3:1][N:2]([CH2:3]/[CH:4]=[CH:5]/[C:6]([Cl:46])=[O:7])[CH3:29]
Reactant: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Reactant: O=C(Cl)C(=O)Cl
Agent: C/C=C(/C(=O)O)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Synthesis of (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][N:10](C(=O)C(F)(F)F)[C:9]=2[CH:20]=1.[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:20]=1
Reactant: O=C(N1CCOc2ccc(Cc3cc(I)ccc3Br)cc21)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of 1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (12.0 g, 22.81 mmol) in methanol (100 mL) and THF (20 mL) was added sodium borohydride (1.73 g, 45.62 mmol) portion wise and the reaction mixture was stirred at room temperature for 1 h. The excess of sodium borohydride was quenched by adding 1N HCl. Methanol was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, and brine, then concentrated to furnish the crude product which was purified by silica gel column chromatography to provide 6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.45 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 80%), MS (ISP) m/z=314.5 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](F)[CH:35]=[CH:36][C:30]=4[S:29](=[O:39])(=[O:38])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH:35]=[CH:36][C:30]=4[S:29](=[O:39])(=[O:38])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccc(F)cc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Reactant: C1COCCN1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccc(N5CCOCC5)cc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine (100 mg, 0.16 mmol, prepared in analogy to N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine in Example 1-1 by using 2,4-dichloro-6-methylquinoline, 7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine) and morpholine (0.5 mL) was heated with stirring in a sealed 2 mL of microwave process via for 3 hours at 120° C. under microwave irradiation. The resulting mixture was concentrated in vacuo to afford 111 mg of the crude product which was used in next step without purification. MS obsd. (ESI+) [(M+H)+] 704.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([CH3:28])=[O:8])=[CH:13][CH:14]=1
Reactant: CC(=O)COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)COc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2 Trifluoroacetic acid (0.56 mL, 7.3 mmol) was added to a solution of tert-butyl 2-[4-(2-oxopropoxy)phenyl]ethylcarbamate (216 mg, 0.74 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred for 3 hr at ambient temperature, and then reaction mixture was stripped of volatiles in vacuo. The residue (143 mg) was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NCCCCNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Carbomethoxybenzoyl chloride (19.07 g, 0.096 mol) was dissolved in toluene (380 mL) in a 3-necked, 1000 mL round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel. A solution of 1,4-butanediamine in water (80 mL) was added dropwise over a period of 40 minutes while the temperature of the reaction mixture was maintained at 25° C. by a water bath. A white solid formed immediately and the reaction mixture stirred for an additional 2 hours. The solid was collected on a frit and washed with toluene, water, 5% HCl, and water. Recrystallization from DMF gave white crystals which were dried in a vacuum oven at 60° C.; yield 17.91 g (90%); m.p. 260°-261° C. 1H NMR (200 MHz, DMSO-d6) δ8.70 (2H, m), 8.05-7.93 (8H, m) 3.88 (6H, s) 3.34 (4H, s), 1.58 (4H, s); IR (nujol) 3300, 1720, 1625, 1530, 1275, 1105, 860, 730 cm-1 ; low res. MS (Cl, isobutane) 413 (MH+); 13C NMR (75 MHz, DMSO-d6) δ166.9, 165.7, 165.4, 165.2, 138.7, 131.6, 129.0, 127.5, 127.2, 52.3, 26.5.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,5-difluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:36](=[O:37])[C:35]4[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]3=[O:42])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione was prepared by the procedure of Example 5 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.2 mmol), sodium hydrogen carbonate (281 mg, 3.34 mmol) and N-ethoxycarbonyl phthalimide (732 mg, 3.3 mmol) in acetonitrile and water (4 mL each). The product was obtained as a white solid (314 mg, 22% yield): mp, 173.0-175.0° C.; 1H NMR (CDCl3); δ 1.61-2.05 (m, 8H, C5H8), 2.84 (s, 3H, CH3), 3.80 (dd, J=4.9, 14.4 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.54 (dd, J=9.9, 14.4 Hz, 1H, CHH), 4.77-4.82 (m, 1H, OCH), 5.90 (dd, J=4.9, 9.9 Hz, 1H, NCH), 6.82 (d, J=8.3 Hz, 1H, Ar), 7.09-7.17 (m, 2H, Ar), 7.69-7.75 (m, 2H, Ar), 7.81-7.86 (m, 2H, Ar); 13C NMR (CDCl3) δ 24.08, 32.77, 41.53, 48.98, 54.99, 56.03, 80.59, 111.92, 114.57, 120.37, 123.55, 129.55, 131.67, 134.20, 148.02, 150.38, 167.82; Anal Calcd for C23H25NO6S+0.1 CH2Cl2 : C, 61.38; H, 5,62; N, 3.10. Found: C, 61.05; H, 5.60; N, 2.96.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of methyl 2-aminobenzoate (50 g, 0.32 mol) in pyridine (250 mL) at 10-15° C., tosyl chloride (95 g, 0.5 mol) was added in portions. The reaction mixture was warmed to room temperature and allowed to stir for 2 h. The reaction mixture was poured on to ice and the precipitate filtered and washed with dilute hydrochloric acid (200 mL×2) followed by water (200 mL×2). The solid was dried under vacuo to afford methyl 2-(4-methylphenylsulfonamido)benzoate (100 g, 99%). 1H NMR: (400 MHz, DMDO-d6) δ: 10.41 (1H, s), 7.85 (1H, d, J=7.6 Hz), 7.69 (2H, d, J=8.0 Hz), 7.57 (1H, t, J=7.2 Hz), 7.45 (1H, d, J=8.0 Hz), 7.36 (2H, d, J=8.0 Hz), 7.18 (1H, t, J=7.6 Hz), 3.82 (3H, s), 2.25 (3H, s).