Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH2:58])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:54])([F:53])[F:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH:58][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:53])([F:54])[F:52]
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propylamine hydrochloride (81 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 98 mg (73%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 3): Rt=2.03 min; m/z=498.22 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.83 (1H, d), 7.67 (1H, s), 7.50 (1H, d), 7.25 (1H, s), 4.96 (1H, d), 4.83-4.91 (m, 2H), 4.18-4.30 (2H, m), 3.92-4.01 (2H, m), 3.79-3.85 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.60 (1H, m), 1.19 (3H, d), 0.90 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[NH:25][C:24]=2[C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[NH:25][C:24]=2[C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCNC(=O)CCCc2ccc(OCc3ccccc3)cc2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCNCCCCc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a stirred solution of 4-(4-benzyloxyphenyl)-N-{2-[2-(3,5-dimethylphenyl)-5-hydroxy-1H-indol-3-yl]ethyl}butyramide (241 mg in 10 mL dry tetrahydrofuran) was added 4 mL of a 1M solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (1.4 mL) and heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 92:8) gave the title compound (234 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:30][CH3:29])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 1F, 2.30 g, 5.04 mmol) in a mixture of dichloromethane (180 mL) and methanol (45 mL) was treated at 22° C. with 4.2 mL of a 25 wt. % solution of sodium methoxide in methanol (0.2 mmol) added in one portion. More methanol (45 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched by the addition of 25 mL of 1N hydrochloric acid followed by 20 ml of saturated sodium bicarbonate. The solvent was evaporated under reduced pressure and the residue was diluted with dichloromethane (400 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel (3×10 cm, elution with dichloromethane-ethyl acetate 0-4%) gave 1.70 g (83% yield) of the title compound as a white solid. This material was recrystallized from ethyl acetate (30 mL per gram, 80% recovery) to give white needles. LC (Method D): 2.293 min. HRMS (ESI) calcd for C21H18N3O4S [M+H]+ m/z 408.1013, found 408.1024. 1H NMR (CDCl3, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37 (d, J=1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t, 1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CN(C)[C:16](=[O:18])[CH3:17].[NH4+].[Cl-]>C1CCCCC1.CCOCC>[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of 3.00 g (12.7 mmol) of 2,6-dibromopyridine in 20 mL anhydrous. Et2O at −78° C. was added dropwise over 30 min. 8.0 mL (12.8 mmol) of.1.6 M n-BuLi in cyclohexane. After stirring for 3 h at −78° C., 8.2 mL (88 mmol) of N,N-dimethylacetamide was added dropwise and the solution was stirred at −78° C. for 1 h. On warming to RT, Et2O (100 mL) and saturated aqueous NH4Cl (50 mL) were added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting yellow solid was recrystallized from hexanes to provide 1.8 g (71%) of 2-acetyl-6-bromopyridine as colorless crystals. 1H NMR (CDCl3): σ2.81 (s, 3H); 7.67-7.77 (m, 2 H); 8.22 (dd, J=6.8, 1.6 Hz, 1 H). Mass Spec.: m/e 200.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:24].[K+]>C(#N)C>[O:24]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:3]2)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCc3ccccc32)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of the Boc-piperidine (602 mg, 2 mmol) in acetonitrile (10 ml) was added potassium permanganate (KMnO4, 950 mg, 6 mmol). The reaction mixture was stirred at 70° C. for 15 hours, filtered through Celite, and the filter cake was washed with dichloromethane. The filtrate and washings were concentrated and the residue was dissolved in acetonitrile (10 ml) and reacted with KMnO4 (950 mg, 6 mmol) at 70° C. for another 24 hours. After filtration, washing and concentrating, the residue was purified by flash column chromatography (CH2Cl2/CH3CN: 1:0 to 9:1) to provide tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4). LC-MS: m/e=260.0 (M+H−tBu). Rt=3.46 min. 1H-NMR (500 MHz, CDCl3): 8.07 (dd, J=1.5, 7.8, 1H), 7.60-7.57 (td, J=7.9, 1.2, 1H), 7.50 (d, J=7.9, 1H), 7.36 (t, J=7.6, 1.0, 1H), 4.10 (br.d, J=13.2, 2H), 3.08 (t, J=13.8, 2H), 2.71 (t, J=6.7, 2H), 2.27 (t, J=6.9, 2H), 2.05 (td, J=13.4, 4.7, 2H), 1.73 (br.d, J=13.2, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10]1(N)CC1.C(N)C>>[CH:1]1([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH2:10][CH2:2]1
Reactant: CCNC(=NC#N)SC
Reactant: NC1CC1
Agent: CCN
Product: CSC(=NC#N)NC1CC1

Procedure:
1-Cyclopropyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except cyclopropylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 0.66-0.76 (m, 2H), 0.83-0.92 (m, 2H), 2.43 (s, 3H), 2.64 (br s, 1H), 6.78 (br s, 1H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35].O>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: CC(=O)c1csc2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 63.5 %

Procedure:
A solution of phenyltrimethylammonium tribromide (9.6 g) in tetrahydrofuran (20 ml) was added dropwise over 15 minutes at ambient temperature to a stirred solution of 3-acetylbenzo[b]thiophen (5 g) in tetrahydrofuran (50 ml), then the mixture was stirred at ambient temperature for 35 minutes. Water (100 ml) was added, and the resulting solid was collected by filtration, washed with water (2×50 ml) and dried in vacuo at ambient temperature to give 3-(2-bromoacetyl)benzo[b]thiophen as a white solid (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C@@H:25]1[CH2:29][NH:28][CH2:27][C@H:26]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C@@H:25]1[CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:27][C@H:26]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)[C@@H]1CNC[C@H]1c1cc2ccccc2o1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)c2cnoc2-c2ccc(C)cc2)C[C@H]1c1cc2ccccc2o1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added ethyl (±)-trans-4-(1-benzofuran-2-yl)pyrrolidine-3-carboxylate (13 mg, 0.050 mmol, 1.1 equ.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C26H24N2O5: 444.1685, found 444.1693.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1cccc(O)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2nc(Cl)ncc2Br)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 91.2 %

Procedure:
To a mixture of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 3-methoxyphenol (163.4 mg, 1.32 mmol) in DMF (5 mL) at 0° C. was added K2CO3 (363 mg, 2.63 mmol). The resulting mixture was stirred at 0° C. for 7 h. The reaction was quenched with H2O and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with H2O (5×30 mL), brine, dried and concentrated. The crude product was purified by preparative TLC using 100% of CH2Cl2 as eluting solvent to afford the title compound (380 mg, 92%). 1HNMR (CDCl3, 400 MHz): 8.57 (s, 1H), 7.37 (dd, 1H), 6.88-6.84 (dd, 1H), 6.72-6.79 (dd+d, 2H), 3.83 (s, 3H). MS (ESI) m/z: Found: 315.0 (M++1), 317.0 (M++3); Calc. 314.0 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[C:9]([F:16])[CH:10]=[CH:11][C:12]=2[F:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([F:16])=[C:8]2[C:13]=1[CH2:14][C:6]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[CH:26]=[C:27]([CH3:28])[CH3:29])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2c(F)ccc(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2c(F)ccc(F)c2C1
Temperature: 25 °C

Procedure:
4,7-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (391) (133 mg, 0.32 mmol) is dissolved in EtOH (20 mL) and set to stir at RT. To this solution was added 5M KOH (2 ml). The reaction mixture was stirred at RT. After concentration in vacuo, the residue obtained is dissolved in water (20 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The aqueous phase is washed with 100 mL EtOAc. The organic phases were collected, concentrated to dryness, and then the resulting residue is purified on an HPLC. The desired product (392) is obtained as white solid (38 mg, 28%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[O:11]([C:13]#[N:14])[K]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:13]([NH2:14])=[O:11])=[CH:5][CH:4]=1
Reactant: N#CO[K]
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: NC(=O)NNc1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 1061.3 %

Procedure:
To a solution of 1-(4-bromophenyl)hydrazine hydrochloride (25.0 g, 112 mmol) in H2O (500 mL) was added KOCN (730 mg, 9.01 mmol). The resulting solution was stirred at 40° C. overnight. After cooling to rt, the resulting solids were collected by filtration to obtain compound 11a as a grey solid (22.0 g, 84% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C7H8BrN3O: 230.0 (M+H). Found 230.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: NNc1ccc(-c2ccc(Cl)cc2)nn1
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 1.0 g. of 6-(p-chlorophenyl)-3-hydrazinopyridazine and 0.65 g. of diisopropylethylamine in 25 ml. of dioxane are placed in a flask and warmed slightly. To this is added 0.5 g. (0.45 ml.) of ethyl chloroformate and the reaction is stirred for one hour. The dioxane is removed on a rotating evaporator and ethanol is added to the residue resulting in a precipitate. This precipitate is recrystallized from ethanol giving a yellow solid, m.p. 176°-180° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:10])[CH:7]([CH3:9])[CH3:8].O>CCOCC>[CH2:6]([NH:10][C:3](=[O:4])[CH2:2][Cl:1])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CN
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: O
Product: CC(C)CNC(=O)CCl
Yield: 94.4 %

Procedure:
Chloroacetyl chloride (37.58 g) was added dropwise over 1 hour to a solution of isobutylamine (46.8 g) in ether (500 ml) maintaining the temperature below 5° C. Water (100 ml) was then added, and the organic layer was separated and washed with dilute hydrochloric acid, sodium hydroxide, and brine and dried (MgSO4). The solvent was removed in vacuo to yield N-isobutylchloroacetamide (47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)CS(=O)(=O)Nc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)CS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 34 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(2-bromophenyl)isobutylsulfonamide. MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.14 (s, 1H), 7.96 (m, 1H), 7.49 (d, J=7.0, 1H), 7.45-7.30 (m, 5H), 2.77 (d, J=6.5, 2H), 2.15-2.02 (m, 1H), 0.97 (d, J=6.7, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[CH:25]1[C:24]2[C:29](=[CH:30][C:31]3[C:36]([C:23]=2[CH2:22][N:8]2[C:9]([O:10][C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 44.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (205 mg, yield: 44.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6](Cl)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:35])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:35][C:27]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)[N:7]=1
Reactant: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Reactant: COc1cc(N)cc(OC)c1OC
Product: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Nc4cc(OC)c(OC)c(OC)c4)nc23)c1
Yield: 77.4 %

Procedure:
The target compound of Example 26 (33 mg, 77% yield) was prepared in the same manner as Step 9 of Example 1 using 3-(4-amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (30 mg, 0.085 mmol) and 3,4,5-trimethoxybenzenamine (31 mg, 0.170 mmol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:19]([O:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2CO3 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4 and concentrated to give crude methyl 3-(benzyloxy)-6-bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H)+: 322/324.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(OCC3CCN(c4ccncc4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-Butyl Ester (320 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (247 mg) in a mixture of tetrahydrofuran (15 ml) and methylene chloride (5 ml) were successively added triphenylphosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2-1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (400 mg).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:34]=[N:33][C:32]([O:31][CH3:30])=[N:37][CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: COc1ncc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cn1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-methoxy-5-pyrimidineboronic acid. The title compound was obtained in 9% yield as yellow oil. MS (m/e): 514.3 (MH+, 100%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9]2)#[N:5].C([O-])([O-])=O.[K+].[K+]>CO.ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4](=[N:2][OH:3])[NH2:5])[CH:7]=3)[C:12]2=[O:16])=[CH:18][CH:19]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Hydroxylamine hydrochloride (183 mg, 2.64 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(6-cyano-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (185 mg, 0.440 mmol) and K2CO3 (365 mg, 2.64 mmol) in MeOH (20 mL) and the mixture was stirred at room temperature for overnight. The mixture was diluted with dichloromethane (60 mL), washed with aqueous ammonium chloride (saturated, 1×20 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-(N′-hydroxycarbamimidoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.441 mmol) as an off white solid.