Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:34]4[CH2:35][CH2:36][N:31]([C:25]5[CH:26]=[CH:27][CH:28]=[C:29]6[C:24]=5[N:23]=[CH:22][C:21]([C:20]([F:39])([F:38])[F:19])=[CH:30]6)[CH2:32][CH2:33]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=C1CCN(c2cccc3cc(C(F)(F)F)cnc23)CC1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCN(C3CCN(c4cccc5cc(C(F)(F)F)cnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-methoxy-8-piperazinoquinoline (Example A, Step 4; 0.0825 g) and 1-[3-(trifluoromethyl)quinolin-8-yl]piperidin-4-one (0.1 g) in methanol (5 mL) was treated with sodium cyanoborohydride (Step 4, 0.032 g). The resulting mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator. The residue was taken up in CH2C2, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give the desired product, which was converted to its dihydrochloride salt in using 1N HCl/Et2O to yield 0.035 g as a yellow solid; MS (ES) m/z (relative intensity): 522 (M+H)+ (100).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.N1C(C)=CC=CC=1C.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C1C=CC(O)OC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)CO1
Temperature: -78 °C
Yield: 54.9 %

Procedure:
6-Hydroxy-2H-pyran-3(6H)-one (9 g, 79 mmol) was dissolved in DCM (250 mL), placed under a nitrogen atmosphere, and cooled to −78° C. 2,6-Lutidine (13.78 mL, 118 mmol) was then added in one portion, followed by slow addition of t-butyldimethylsilyltrifluoromethanesulfonate (21.74 mL, 95 mmol). The reaction was allowed to slowly warm to 0° C. over 4 h. The reaction was quenched by addition of ˜20 mL of water. The solution turned pale yellow upon quenching. After transferring to a separatory funnel, the organic phase was washed successively with 10% citric acid and brine. The organic layer was then dried over sodium sulfate, filtered and condensed to give a yellow oil. The crude material was purified on a 340G SNAP Biotage column (0-20% ethyl acetate in hexane) to give 6-(tert-butyldimethylsilyloxy)-2H-pyran-3(6H)-one (9.90 g, 43.4 mmol, 55.0% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (dd, J=10.54, 3.12 Hz, 1H), 6.08 (d. J=10.15 Hz, 1H), 5.53 (d, J=3.12 Hz, 1H), 4.51 (d, J=16.79 Hz, 1H), 4.08 (d, J=16.79 Hz, 1H), 0.92 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=[O:14]>O1CCCC1>[Cl:22][C:18]1[CH:17]=[C:16]([N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(Cl)c2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
3-Methylphenyl isocyanate (0.6 g) is added at a temperature in the region of 20° C. to a solution of tert-butyl 2-[2-amino-N-(3-chlorophenyl)acetamido]-acetate (1.25 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 4 hours at a temperature in the region of 20° C and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2 cm in diameter [eluent: ethyl cyclohexaneacetane [sic] (75:25 by volume)], collecting 20 cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After crystallisation in diisopropyl ether, tert-butyl 2-{N-(3-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.8 g), m.p. 110° C. is obtained
Reaction SMILES: [C:1]1(Br)[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3].C([Li:17])CCC>C1(C)C=CC=CC=1>[C:1]1([Li:17])[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Reaction time: 2 h

Procedure:
1.53 mL (0.0123 mole) of C6F5Br was put in toluene in 50 omL flask. Then, 7.67 mL (0.0123 mole) of n-butyl lithium was taken with syringe and, added dropwisely in dry ice acetone bath at −78° C., and agitated for 2 hours to obtain C6F5Li. 0.64 g (0.002 mole) of Cl2B(C6F4)BCl2 was dissolved in 40 mL of toluene, added slowly to the agitating flask at −78° C. with syringe, and the reaction was performed continuously for 12 hours by elevating the temperature to the room temperature. The remaining solvent was removed under vacuum to produce salts of (Li+)2[(C6F5)3B—C6F4—B[(C6F5)3]2−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)([O:12][CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:38]=[N+:39]=[N-:40].[Na+]>C(OCC)(=O)C.O>[N:38]([CH2:14][CH2:13][O:12][C@:8]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][CH3:11])=[N+:39]=[N-:40]
Reactant: CCC[C@](OCCOS(C)(=O)=O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@](OCCN=[N+]=[N-])(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
(R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methylsulfonyloxy)ethoxy)butyl)piperidine-1-carboxylate (900 mg, 1.82 mmol) was dissolved into anhydrous DMF (15 mL), solid NaN3 (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and then was diluted with ethyl acetate (110 mL), and water (30 mL), the organic phase was washed with water (3×20 mL), dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((R)-1-(2-azidoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (790 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(C)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
3,5-Dimethylphenol, 12.2 g (100 mmole), 10.8 ml (125 mmole) of allyl bromide, and 16.56 g (120 mmole) of potassium carbonate was dissolved and then refluxed in 50 ml acetone, with stirring, under nitrogen for 18 hours. The reaction was cooled, the insoluble inorganics were filtered off and stripped to give 16.2 g (100%) of subtitled product, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Reactant: OB(O)c1cccnc1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3cccnc3)c2)C(=O)O1

Procedure:
The title compound was prepared from 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-pyridylboronic acid following procedures analogous to those in Example 1 Step 2. LC-MS Method 2, tR=1.819 min, m/z=345.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.45-2.65 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H), 7.30-7.60 (m, 8H), 7.85 (m, 1H), 8.40 (m, 1H), 8.75 (m, 1H), 9.00 (m, 1H), 9.30-9.50 (b, 2H).
Reaction SMILES: O1C2C=CC(O)=CC=2OC1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[CH2:13][CH2:12]1.C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:37]1([CH:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=[O:53])[C:45]2=[O:54])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:55]1([CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([OH:53])([C:17]3[C:18]([OH:20])=[CH:19][C:14]4[CH2:13][CH2:12][O:11][C:15]=4[CH:16]=3)[C:45]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)CCO2
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCO2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-5-ol, (Alabaster, R. J., et al.; Synthesis (1988), 12:950-2) and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained: MS (ES+) m/z 472.2 (M+23).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[N:17]=3)[C:10]([C:13]#[N:14])=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[NH2:30][OH:31]>CCO>[OH:31]/[N:30]=[C:13](/[C:10]1[N:9]2[CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:17]=[C:8]2[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:11]=1)\[NH2:14]
Reactant: N#Cc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12

Procedure:
A mixture of compound 55a (100 mg, 0.26 mmol) and hydroxylamine (50% wt, 0.086 mL, 1.4 mmol) in EtOH (2 mL) was heated to 90° C. for 5 h. The precipitate obtained was collected by filtration, washed with EtOH, and dried to give compound 55b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H21N7O3: 420.2 [M+H]. found 420.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH3:61][O:62][C:63]1[CH:64]=[C:65]([CH:67]=[CH:68][CH:69]=1)[NH2:66]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OC(=O)C)C.O.C1(C)C=CC=CC=1>[CH:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:66][C:65]4[CH:67]=[CH:68][CH:69]=[C:63]([O:62][CH3:61])[CH:64]=4)[CH:3]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:15][C:16]=1[CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cccc(N)c1
Reactant: Cc1cc(C2(c3cccc(Br)c3)COC(N)=N2)ccc1OC(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2cccc(C3(c4ccc(OC(C)C)c(C)c4)COC(N)=N3)c2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with 4-(3-bromo-phenyl)-4-(4-isopropoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block L, 181 mg, 0.467 mmol, 1.0 eq), sodium tert-butoxide (89 mg, 0.933 mmol, 2.0 eq.), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (18 mg, 0.042 mmol, 0.042 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.012 mmol, 0.025 eq.) and 3-methoxyaniline (115 mg, 0.933 mmol, 2.0 eq.). After three vacuum-nitrogen cycles, toluene was introduced (1 mL), the tube was sealed and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethylacetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2 M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 99 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][C:16](=O)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][CH:16]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: C1CCNC1
Reactant: Cn1cc(-c2ccc3nc(N4CC(=O)C4)sc3c2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc3nc(N4CC(N5CCCC5)C4)sc3c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-one (Reference Example 4, 17 mg, 0.06 mmol), pyrrolidine (0.015 mL, 0.18 mmol), and a catalytic amount of acetic acid (0.005 mL) in toluene (0.4 mL) was stirred at room temperature for 5 minutes, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 1 M aqueous K3PO4 (0.4 mL), and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (60:40 dichloromethane/acetonitrile to 56:40:4 dichloromethane/acetonitrile/methanol) to give 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.84-1.90 (m, 4H), 2.59-2.66 (m, 4H), 3.59-3.68 (m, 1H), 3.92 (s, 3H), 4.06-4.12 (m, 2H), 4.26-4.32 (m, 2H), 7.45 (dd, J=1, 8 Hz, 1H), 7.50 (dd, J=2, 8 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.85 (d, J=2 Hz, 1H), 7.92 (d, J=1 Hz, 1H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][NH:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1.Cl.O1CCOCC1.Cl>C(O)(C)C>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][NH:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)CNC(=O)NC2
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)NC3)ncc1Cl
Yield: 1 %

Procedure:
A solution of 7-amino-1,2,4,5-tetrahydro-(2,4)-benzodiazepin-3-one (75.0 mg, 0.42 mmol) in isopropanol (3 mL) was treated with N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (140.2 mg, 0.42 mmol) and 4N HCl/Dioxane (0.106 mL, 0.50 mmol). The reaction mixture was irradiated at 130° C. for a total of 60 minutes. The reaction mixture was then reduced en vacuo and the product was purified and isolated flash column chromatography (0% MeOH/DCM-15% MeOH/DCM) to afford 1.98 mg of N-{2-[5-Chloro-2-(3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,3]diazepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide as the HCl salt. The compound was isolated as a foam, LC/MS (ESI)=480.35 (M+H). 1H NMR (400 MHz, MeOD, d4) δ 7.68 (m, 2H), 7.46 (m, 1H), 7.29 (m, 2H), 7.06 (m, 4H), 6.62 (m, 1H), 4.31 (m, 2H), 4.19 (m, 2H), 3.47 (s, 1H), 3.12 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: Cl[CH2:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:2]([S:3]([N:6]3[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]3)(=[O:5])=[O:4])=[CH:20][C:19]=2[CH:22]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=CN1CCN(S(=O)(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CN1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 12.4 %

Procedure:
A mixture of 1-(chloromethanesulfonyl)-4-formylpiperazine (2.26 g), 5-chlorosalicylaldehyde (1.56 g) and potassium carbonate (1.38 g) in DMF (30 ml) was stirred at 100° C. for 48 hours. The reaction solution was concentrated, and to the residue was added ethyl acetate. The organic layer was washed with water and brine, dried, concentrated and purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of 1-(5-chlorobenzofurane-2-sulfonyl)-4-formylpiperazine (406 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[C:5]([F:9])=[C:6]([NH:7][C:20]([NH:19][C:17](=[O:18])[C:16]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=2[F:14])=[O:21])[CH:8]=1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1F
Yield: 69.2 %

Procedure:
The product was prepared from 5-chloro-2-fluoro-3-trifluoromethylaniline (0.5 g) and 2,6-difluorobenzoylisocyanate (0.4 g) by operating according to the process of Example 1 to obtain the product 0.6 g. (m.p. 187°-189° C.)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1[NH:22][C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:23]4[NH:22][N:21]=[CH:25][N:24]=4)=[CH:34][CH:33]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-c2ncn[nH]2)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(-c2ncn[nH]2)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-4-(2H-[1,2,4]triazol-3-yl)-benzamide was prepared starting from intermediate D and 4-(2H-[1,2,4]triazol-3-yl)-benzoic acid. MS calcd. for C25H18ClN5O2 [(M+H)+] 455.9, obsd. 456.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.C1C2C=CC3C(=CC([CH:38]=[O:39])=C4C=3C=CC=C4)C=2C=CC=1>CCOC(C)=O>[Cl:1][C:2]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH:38]=[O:39])[CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: Clc1cc2c3ccccc3ccc2c2ccccc12
Solvent: CCOC(C)=O
Product: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) was formylated according to the procedure outlined in 1A, except that Ch2Cl2 (2.5 L) was used as the reaction solvent. Chromatography on a plug of SiO2 (1 kg) using EtOAc as the eluting solvent afforded after removal of solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehyde mp 255°-257°, (EtOAc).
Reaction SMILES: C1(CC(O)=O)C2C(=CC=CC=2)C=NN=1.C([O:17][C:18](=[O:46])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]([CH2:31][C:32]([NH:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2[Br:45])=[S:33])[N:21]=1)C>>[Br:45][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:42])[F:43])=[CH:40][C:35]=1[NH:34][C:32](=[S:33])[CH2:31][N:22]1[C:23](=[O:30])[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([CH2:19][C:18]([OH:46])=[O:17])=[N:21]1
Reactant: CCOC(=O)Cc1nn(CC(=S)Nc2cc(C(F)(F)F)ccc2Br)c(=O)c2ccccc12
Agent: O=C(O)Cc1nncc2ccccc12
Product: O=C(O)Cc1nn(CC(=S)Nc2cc(C(F)(F)F)ccc2Br)c(=O)c2ccccc12

Procedure:
This compound was prepared according to Example 3, starting with 1-phthalazine acetic acid, 3-[2-[N-[2-bromo-5-(trifluoromethyl) phenyl]amino]-2-thioxoethyl]-3,4-dihydro-4-oxo-, ethyl ester (0.15 g) [the final product of Example 5]. The title compound melted at 176°-177° C. (yield, 0.12 g) .
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[C:5]([Cl:11])=[CH:4][N:3]=1.O=S(Cl)[Cl:14].ClC1C=NC=C(Cl)C=1CCl>>[Cl:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Cl:11])[C:6]=1[CH2:9][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncc(Cl)c(CO)c1Cl
Agent: ClCc1c(Cl)cncc1Cl
Product: Nc1ncc(Cl)c(CCl)c1Cl

Procedure:
(2-Amino-3,5-dichloro-pyridin-4-yl)-methanol (7 mg, 0.036 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 211.0 [M+H+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=O)[CH3:11])=[N:2]1.Cl.[NH2:14][OH:15].N1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:14][OH:15])[CH3:11])=[N:2]1
Reactant: CC(=O)c1noc2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=NO)c1noc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.4 g of 1-(1,2-benzisoxazol-3-yl)ethanone, 0.7 g of hydroxylamine hydrochloride and 10 ml of pyridine is refluxed for 1 h. The reaction mixture is then poured onto a mixture of ice/water and the precipitated product is isolated by filtration. The product is dissolved in ethyl acetate, the solution is washed once with water, then twice with a saturated solution of sodium chloride and finally dried over sodium sulfate. The solvent is stripped off under vacuum, to give pure 1-(1,2-benzisoxazol-3-yl)ethanone oxime having a melting point of 193°-195° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]2[S:10][C:9]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])=[N:8][C:7]=2[CH:21]=1.[BH4-].[Na+]>CS(C)=O.O.Cl>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:9]1[S:10][C:6]2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]([CH3:2])=[CH:21][C:7]=2[N:8]=1
Reactant: Cc1cc(C)c(Nc2nc3cc(CCl)cc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(Nc2nc3cc(C)cc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (120 mg, 0.332 mmol) in dimethyl sulfoxide (DMSO) (2 ml) was added sodium borohydride (25 mg, 0.663 mmol). The mixture was stirred at room temperature for 3 h and diluted with water and neutralized with 1N HCl solution. The aqueous solution was extracted with AcOEt.