Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)#[CH:2].Cl[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH2:13]([N:14]1[CH2:15][CH2:16][CH2:17][C:1]([C:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=2)=[CH:2]1)[CH2:12][CH3:11]
Reactant: C#CC1=CC(=O)CCC1
Reactant: CCCNCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCN1C=C(C2=CC(=O)CCC2)CCC1

Procedure:
3-Ethynyl-cyclohex-2-enone (3.20 g, 26.8 mmol) (from a) above) and (3-Chloro-propyl)-propyl-amine (4.50 g, 33.2 mmol) were mixed in acetonitril (50 mL). Cs2CO3 (100 mg) and KI (200 mg) were added and the mixture was refluxed under N2 for 10 h. After cooling the mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting dark oil was purified by column chromatography (silica, ethyl acetate) to give a yellow red oil. Yield 5.1 g, 23.3 mmol (87%). IR (neat) 2932, 2871, 1589, 1538, 1157 cm−1; 1H-NMR (CDCl3) δ 6.84 (s, 1H), 5.69 (s, 1H), 3.04–3.12 (m, 4H), 2.44 (t, 2H), 2.33 (t, 2H), 2.18 (t, 2H), 1.83–2.03 (m, 4H), 1.49–1.64 (m, 2H), 0.87 (t, 3H) ppm; 13C-NMR (CDCl3) δ 197.0, 158.5, 140.1, 112.1, 102.4, 56.6, 44.3, 35.6, 23.6, 21.4, 20.2, 20.1, 19.7, 9.6 ppm; MS (CI) m/z 220 (M+1).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH2:12])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]#[C:14][Br:15]>C1(C)C=CC=CC=1>[BrH:15].[C:1]1([S:7][CH2:8][C@@H:9]2[NH:12][C:14]([NH2:13])=[N:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@@H](N)CSc1ccccc1
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: Br
Product: NC1=NC[C@H](CSc2ccccc2)N1
Reaction time: 1.5 h

Procedure:
(2R)-3-(Phenylthio)-1,2-propanediamine (0.20 g, 1.1 mmol) was dissolved in toluene (3 ml) and a solution of cyanogen bromide (0.116 g, 1.1 mmol) in toluene (1 ml) was added dropwise at room temperature. The mixture is allowed to stir for 90 min. After evaporation of the solvent the residue was dissolved in ethanol (1.5 ml). By slowly adding ethyl acetate (8 ml) a light brown solid precipitated, 0.152 g (66%), MS (ISP): 207.9 (M+H)+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37].Cl>O1CCCC1>[Br:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:36]([C:30]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Into a reaction flask, (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7, 140 mg, 0.40 mmol) is stirred in 3 mL of tetrahydrofuran and pyridine (0.3 mL, 4.0 mmol) is added, followed by 2,5-difluoro-benzenesulfonyl chloride (25, 127 mg, 0.596 mmol). The reaction is stirred at room temperature for 24 hours, then adjusted to pH 4 with addition of 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography to provide the desired compound (26, 190 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][Br:15])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][Br:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OCCBr)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCCBr)c(Br)c1
Yield: 88.7 %

Procedure:
To a stirred solution of methyl 3-bromo-4-(2-bromoethoxy)benzoate (4.0 g, 1.0 eq) in MeOH/H2O (v/v 2:1, 60 mL) was added NaOH (0.715 g, 1.5 eq). The mixture was then refluxed for 25 min, and concentrated under reduced pressure. The residue was poured into water and washed with EtOAc. To the aqueous layer was added 3 N HCl to give the desired product as a white solid (3.4 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.50 (t, J=5.6 Hz, 2H), 3.85 (t, J=5.6 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CN(C)C1CCCCC1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:32]1[C:40](=O)[C:39]2[NH:38][N:37]=[N:36][C:35]=2[N:34]=[CH:33]1.[OH-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:40]2[C:39]3[NH:38][N:37]=[N:36][C:35]=3[N:34]=[CH:33][N:32]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]cnc2nn[nH]c12
Reactant: Nc1cccc(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C1CCCCC1
Product: Cl
Product: Clc1cccc(Nc2ncnc3nn[nH]c23)c1
Temperature: 170 °C
Reaction time: 23 h
Yield: 51 %

Procedure:
To 3-chloroaniline (0.39 ml, 3.6 mmol) in dry dimethylcyclohexylamine (0.55 ml, 3.6 mmol) was added phosphorus pentoxide (0.52 g, 3.6 mmol). After heating in a 170° C. oil bath for 0.5 hours, 8-azahypoxanthine (0.50 g, 3.6 mmol) was added and stirring continued at 170° C. for 23 hours. The mixture was cooled to ambient temperature and 2M NaOH was added until basic. The solids were filtered off and washed consecutively with H2O, CH2Cl2 and methanol. The resulting solid was dried in vacuo to afford the title compound as a tan powder (0.26 g. 29%). LC-MS: 247 (MH+); anal. RP18-HPLC RT: 3.76 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:5]([O:7][CH3:8])=[O:6].[ClH:16].[CH2:17]([NH:24][CH2:25]C(O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:29](N(CC)CC)C.C=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[ClH:16].[CH3:8][O:7][C:5]([C:4]1([C:3]([O:2][CH3:1])=[O:15])[C:9]2([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:25][N:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:29]1)=[O:6]
Reactant: O=C(O)CNCc1ccccc1
Reactant: CCN(CC)CC
Reactant: COC(=O)C(C(=O)OC)=C1CCCCC1
Agent: C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)CN(Cc2ccccc2)CC12CCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
A solution of dimethyl (cyclohexylidene) malonate 2 (594 mg; 2.8 mmol), N-benzylglycine hydrochloride (1.41 g; 6.99 mmol), triethylamine (0.97 mL; 6.95 mmol), and paraformaldehyde (671 mg; 22.36 mmol) in benzene (18 mL) was slowly heated up to 125° C. (oil bath) (Dean-Stark). After stirring for 2 hours, the reaction mixture was cooled to room temperature, diluted with toluene (20 mL), and washed with brine. The aqueous phase was extracted with toluene (2×10 mL). The organic phases were combined, dried over MgSO4, and evaporated to give a brown oil which was purified on silica gel chromatography (EtOAc/heptane 1:3). The resulting pale yellow oil was diluted in diethyl ether (10 mL), and the compound was extracted with 2N HCl (2×5 mL). The aqueous phases were combined, washed with diethyl ether, and concentrated in vacuo to give 3 as a white solid (238 mg; 0.62 mmol; 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH:36]3[CH2:38][CH2:37]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCC1CC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2OCC2CC2)cc1

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting cyclopropylmethanol in place of isobutanol (yield: 0.117 g, 83%). mp 166-167° C. 1H NMR (300 MHz, DMSO d6) δ 0.22 (m, 2H), 0.46 (m, 2H), 1.10 (m, 1H), 3.31 (s, 3H), 4.30 (d, J=7 Hz, 2H), 7.36 (m, 2H), 7.66 (m, 2H), 7.96 (m, 2H), 8.07 (m, 2H), 8.20 (s, 1H). MS (DCI/NH3) m/z 415 (M+H)+, 432 (M+NH4)+. Anal. calc. for C23H25ClN2O4S: C, 60.86; H, 4.62; N, 6.76. Found: C, 60.76; H, 4.72; N, 6.61.
Reaction SMILES: [F:1][C:2]1([F:17])[CH:10](O)[C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:17][C:2]1([F:1])[CH2:10][C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(O)C(F)(F)CC2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c([nH]1)CC(F)(F)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
Into a 500-mL 3-necked round-bottom flask was placed a solution of 113k (18 g, 73.40 mmol, 1.00 equiv) in dichloromethane (200 mL) and CF3COOH (41.9 g, 367.48 mmol, 5.00 equiv), followed by the addition of triethylsilane (25.6 g, 220.16 mmol, 3.00 equiv) dropwise with stirring at 0° C. over 20 min (FIG. 14). The resulting solution was stirred at room temperature for 4 h, adjusted pH to 7 with saturated aqueous sodium bicarbonate and extracted with 1×200 mL of dichloromethane. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC to afford 10 g (59%) of 113l as a white solid.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][CH2:17]2)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C1CCNCCN1CCCN1CCC2(CC2)[C@H](O)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)CCN1CCCN1CCC2(CC2)[C@H](O)C1

Procedure:
In analogy to the procedure described in example 5, 4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride (US 2007249589, described as 4-[3-((−)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one dihydrochloride) and 3,4-dichlorophenyl isocyanate gave after separation with flash chromatography (silicycle SiO2, dichloromethane/methanol 95:5 to 4:1) 43% of the title compound as white solid. MS: 469.3 (MH+, 2Cl).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([S:13](/[CH:16]=[CH:17]/[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([S:13]([CH:16]2[CH:17]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:3]3[CH2:4][CH2:5][CH:6]2[CH:1]=[CH:2]3)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(/C=C/S(=O)(=O)c1ccccc1)c1ccccc1
Reactant: C1=CCCC=C1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)C1C2C=CC(CC2)C1S(=O)(=O)c1ccccc1
Yield: 104.4 %

Procedure:
A mixed solution of 3.16 g (39.5 mmol) of 1,3-cyclohexadiene, 10.5 g (34.1 mmol) of trans-1,2-bis(phenylsulfonyl)ethylene and 200 ml of toluene was refluxed for 7 hours, then cooled and concentrated under reduced pressure to give a reaction mixture. This reaction crude product was made to recrystallize, thereby giving 5,6-bis(phenylsulfonyl)-bicyclo[2.2.2]octa-2-ene (13.8 g, 35.6 mmol, yield 90%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.Cl[CH2:20][CH:21]1[CH2:23][CH2:22]1.[BrH:24].CCOCC>CN(C)C=O.CCOCC>[BrH:24].[CH:21]1([CH2:20][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH2:23][CH2:22]1
Reactant: ClCC1CC1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(CC3CC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a stirred mixture of 1.19 g of sodium hydride (50% oil dispersion) in 65 ml of dimethylformamide was added, dropwise, 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 20 ml of hot dimethylformamide. The mixture was stirred for 1 hr at ambient temperature and then 1.40 g of chloromethylcyclopropane in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 21/2 days at ambient temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and saturated hydrogen bromide/ether solution was added dropwise to precipitate a salt. The salt was recrystallized from toluene and ethyl acetate to yield 2.8 g (32%) of product, mp 177°-179° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]=[C:11]=[O:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N+:13](=[C:15]1[N:19]=[CH:18][N:17]=[C:16]1[C:20]([NH2:22])=[O:21])=[N-:14].CCOCC>CCOC(C)=O.CS(C)=O>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:11](=[O:12])[N:19]2[CH:18]=[N:17][C:16]([C:20](=[O:21])[NH2:22])=[C:15]2[N:13]=[N:14]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CCOP(=O)(CN=C=O)OCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOP(=O)(Cn1nnc2c(C(N)=O)ncn2c1=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Isocyanatomethyl-phosphonic acid diethyl ester (953 mg, 6.95 mmol) in EtOAc (10 mL) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (10 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into Et2O and the resultant collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a solid (1.14 g, 50%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.91 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 4.85 (2H, t, J=11.2 Hz), 4.12 (4H, m), 1.25 (6H, t, 7.2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31][C:30]=2[CH:37]=1.C(O)(C)C.Cl>O1CCOCC1.C(N(CC)CC)C>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:7][C:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31][C:30]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2OCCN2CCOCC2)n1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCCN4CCOCC4)n3)cc2N1
Temperature: 120 °C

Procedure:
Into a microwave vial, (2,5-dichloro-pyrimidin-4-yl)-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-amine (100.0 mg, 0.2708 mmol), 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (61.2 mg, 0.348 mmole), isopropyl alcohol (2.00 mL, 26.1 mmol) and 4 M of hydrogen chloride in 1,4-dioxane (0.20 mL) were added, respectively. The reaction was heated in the microwave on 300 watts, 120° C. for 20 minutes. Triethylamine (0.2 mL) was added. The reaction was concentrated to dryness. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (10% methanol). The resulting solid was triturated with diethyl ether to afford 8-{5-Chloro-4-[2-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white solid (42 mg, 30%). 1H-NMR (DMSO-D6, 400 MHz): δ 9.42 (s, 1H), 9.32 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.10 (bs, 1H), 7.35 (d, 1H), 7.27 (s, 1H), 7.12 (s, 2H), 7.0 (d, 1H), 6.85-6.95 (m, 1H), 4.16 (t, 2H), 3.50 (t, 4H), 2.55-2.70 (m, 4H), 2.40 (s, 4H), 2.00-2.20 (m, 4H). LC/MS (ESI+) 509 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:33])[NH:16][C:17]2[S:18][C:19]3[CH2:25][C@H:24]([NH:26]C(=O)C(F)(F)F)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:10]=1)=[O:6].O.C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C>[NH2:26][C@@H:24]1[CH2:23][CH2:22][C:20]2[N:21]=[C:17]([NH:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:2]([Cl:1])[CH:3]=3)=[O:33])[S:18][C:19]=2[CH2:25]1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](NC(=O)C(F)(F)F)CC4)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N)CC4)c2)cc1Cl
Temperature: 55 °C
Yield: 77.2 %

Procedure:
Dissolved 3-chloro-4-methoxy-N-{3-[(R)-6-(2,2,2-trifluoro-acetylamino)-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl]-benzyl}-benzamide (520 mg, 0.92 mmol) in 5 mL of MeOH and added 5 mL of H2O. To this was added K2CO3 (500 mg, 3.62 mmol) and the mixture was heated overnight at 55° C. LC-MS analysis indicated the desired material. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-70% CH3CN/H2O) to give 334.6 mg of N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3-chloro-4-methoxy-benzamide. MS, electrospray 471.2 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25]([N:26]=[CH:27][C:28]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:29]3)=[CH:24][CH:23]=2)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25](=[CH:24][CH:23]=2)[N:26]=[CH:27][C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29]3)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1F
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
Benzylamine (336 mg, 3.1 mmol) and potassium carbonate (865 mg, 6.2 mmol) were added to a solution of 7-(4-fluoro-3-nitrophenyl)-2-(morpholin-4-yl)quinoxalin (1.1 g, 3.1 mmol) in DMF (100 mL). The mixture was stirred 24 h at room temperature and then diluted with EtOAc. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over sodium sulphate. After filtration and subsequent removal of solvent, the residue was purified by chromatography (silica gel, Hexane/EtOAc: 20%->100% EtOAc) giving rise to 1.29 g (93%) of the desired product.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].F[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[N+:22]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:11]=1[N:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9])[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:24])=[O:23]
Reactant: O=C1CSCCN1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCSCC2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
Sodium hydride (60%, 171 mg, 4.27 mmol) was suspended in tetrahydrofuran (10 ml), and thiomorpholin-3-one (500 mg, 4.27 mmol) prepared in the Step 40-1-1 was added thereto. The mixture was stirred at a room temperature for 5 minutes, and a solution (10 ml) of ethyl 4-fluoro-3-nitrobenzoate (910 mg, 4.27 mmol) prepared in the Step 1-1-1 in tetrahydrofuran was slowly added to the mixture. The resulting mixture was stirred at a room temperature for 4 hours. The mixture was concentrated, and chloroform was added thereto. The resulting mixture was washed with a saturated sodium bicarbonate solution. The washed product was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) and washed with methanol to give the title compound (360 mg, 27%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1Cl
Temperature: 120 °C
Yield: 20.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 90 mg, 0.261 mmol), 3-Chloro-4-methoxyphenylboronic acid (97 mg, 0.522 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 21 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.5 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 120° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (24 mg, 20%). 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.90-8.17 (m, 4H), 7.54-7.73 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 1H), 3.99 (s, 3H), 2.42 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][NH2:9])[CH2:4][CH3:5])[CH3:2].Cl[C:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[O:26][CH3:27])[S:16][C:15]=2[C:14]([N+:28]([O-:30])=[O:29])=[CH:13][CH:12]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:11]2[CH:12]=[CH:13][C:14]([N+:28]([O-:30])=[O:29])=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[C:22]=4[C:23]([C:24]=23)=[N:9]1)[CH3:2]
Reactant: COc1cccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c12
Reactant: CCN(CC)CCNN
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1cccc(OC)c1-2
Yield: 51.7 %

Procedure:
Reaction of a mixture of 2.5 g (0.0192 mol) of 2-(diethylaminoethyl)hydrazine, 4.2 g (0.0131 mol) of 1-chloro-8-methoxy-4-nitro-9H-thioxanthen-9-one in 110 ml of DMF as described in Example 53 gave 2.7 g of product.