Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 97 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (450 mg, 1.45 mmol) was converted using thiomorpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 560 mg, 97%) which was obtained as a white solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:41](=[O:42])[NH:11][N:10]=2)[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NN)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3n[nH]c(=O)o3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (122 mg, 0.252 mmol) and CDI (49.1 mg, 0.303 mmol) were taken up in 1,4-dioxane (3.0 ml). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was loaded onto silica gel and purification by MPLC 0-50% EtAOc/hexanes gave 5-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-one (53B). MS: [M+H]+ m/z 510.
Reaction SMILES: Cl.N[C@H](C)CSC1SC2C=CC(Cl)=CC=2N=1.ClC1C=CC2SC(S)=NC=2C=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:60][C@@H:61]1[C@H:65]([O:66]C(=O)C)[C@@H:64]([CH2:70][O:71]C(=O)C)[O:63][C@H:62]1[N:75]1[C:98]2[N:97]=[C:96]([Cl:99])[N:95]=[C:79]([NH:80][C@H:81]([CH3:94])[CH2:82][S:83][C:84]3[S:85][C:86]4[CH:92]=[CH:91][C:90]([Cl:93])=[CH:89][C:87]=4[N:88]=3)[C:78]=2[N:77]=[CH:76]1)(=O)C.C[O-].[Na+]>CO>[Cl:93][C:90]1[CH:91]=[CH:92][C:86]2[S:85][C:84]([S:83][CH2:82][C@H:81]([NH:80][C:79]3[C:78]4[N:77]=[CH:76][N:75]([C:98]=4[N:97]=[C:96]([Cl:99])[N:95]=3)[C@@H:62]3[O:63][C@H:64]([CH2:70][OH:71])[C@@H:65]([OH:66])[C@H:61]3[OH:60])[CH3:94])=[N:88][C:87]=2[CH:89]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5cc(Cl)ccc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1nc2cc(Cl)ccc2s1
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1nc2cc(Cl)ccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 46 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]-5-chlorobenzothiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1] with 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (1.75 g, 10 mmol) and 5-chloro-2-mercaptobenzothiazole (2.02 g, 10 mmol) followed by acidic hydrolysis! (0.5 g, 1.5 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.54 g, 1.2 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title N-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]2-chloroadenosine (0.30 g, 46%) as a solid, mp 145° C. (following column chromatography), 1H NMR (DMSO-d6) δ1.39 (3H, d, --CHCH3), 3.45-3.78 (4H, m, H-5'a and H-5'b and --CH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, t, H-3'), 4.52 (1H, t, H-2'), 4.72 (1H, m, --CH), 5.84 (1H, d, H-1'), 7.41 (1H, dd, Ar--H), 7.94 (1H, s, Ar--H), 8.02 (1H, dd, Ar--H), 8.42 (1H, s, H-8), 8.52 (1H, d, N--H). HPLC retention time 23.58 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1.N12CCN(CC1)CC2.ClN1C(=O)CCC1=O.CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:7]1[NH:6][C:14]2[C:9]([C:8]=1[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: OCCCCl
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
Method C A solution of 3-chloropropanol (142.47 g, 1.51 mol) in dichloromethane (1200ml) was cooled to -20° C. In a second vessel dichloromethane (1300 ml), methyl indole-3-carboxylate (240.0 g, 1.37 mol) and 1,4-diazabicyclo[2.2.2]octane (84.52 g 0.75 mol) were cooled to 0° C. N-Chlorosuccinimide (201.22 g 1.51 mole) was added to the second vessel and stirred at 0° C. for 10 minutes. In the meantime methane sulfonic acid (10.56 ml) was added to the first vessel. The solution in the second vessel was added to the first vessel keeping the temperature below about 0° C., and the resulting mixture stirred for a further 2.5 hours at -5 to 0° C. 10% Sodium carbonate solution (1250 ml) was added and the mixture stirred for about 30 minutes. The organic layer was separated and washed once more with 10% sodium carbonate solution (1250 ml) and once with water (1250 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was triturated with toluene (400 ml) and the mixture stirred at 0° C. for about 1 hour. The resulting solid was filtered, washed with toluene and dried in vacuo to give methyl 2-(3-chloropropoxy)-indole-3-carboxylate (245.5 g) as a white crystalline solid in 67% yield.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][C:6]3[N:18]([CH3:19])[CH:17]([CH3:20])[C:16]([CH3:22])([CH3:21])[C:7]=3[CH:8]=2)[NH:3]1.P(OC)(OC)(O[CH3:26])=O>>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]2[C:4](=[CH:5][C:6]3[N:18]([CH3:19])[CH:17]([CH3:20])[C:16]([CH3:21])([CH3:22])[C:7]=3[CH:8]=2)[N:3]1[CH3:26]
Reactant: COP(=O)(OC)OC
Reactant: CC1N(C)c2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2C1(C)C
Product: CC1N(C)c2cc3c(cc2C1(C)C)c(C(F)(F)F)cc(=O)n3C

Procedure:
refluxing said 7-oxo-1,2,3,3-tetramethyl-5-trifluoromethyl-2,3,7,8-tetrahydro-1H-pyrrolo [3,2-g] quinoline with trimethyl phosphate to yield 7-oxo-1,2,3,3,8-pentamethyl-5-trifluoromethyl-2,3,7,8-tetrahydro-1H-pyrrolo [3,2-g] quinoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]3[N:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]([C:15]4[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=4[C:17]([NH:19][NH2:20])=[O:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[N:36]#[C:37]Br>O1CCOCC1.O>[NH2:36][C:37]1[O:18][C:17]([C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[C:13]2[N:12]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:11]3[CH:29]=[CH:30][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:14]=2)=[N:19][N:20]=1
Reactant: N#CBr
Reactant: CC(C)(C)n1c(-c2ccccc2C(=O)NN)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2nnc(N)o2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a vial is added 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid hydrazide (43 mg, 0.107 mmol) in 1,4-dioxane (2 mL), followed by the addition of NaHCO3 (13 mg, 0.155 mmol) in water (0.5 mL), then cyanogen bromide (13 mg, 0.123 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is loaded to a silica gel column. The column is eluted with 0-8% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (30 mg, 66%) as an off-white solid. LCMS (ESMS): m/z 427.76 (M++1)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O-]CC.[Na+].Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cncn1
Temperature: 0 °C
Reaction time: 60 h
Yield: 88.2 %

Procedure:
34.53 gms of 1,2,4-triazole were added to 250 mls of ethanol along with 34.0 gms of sodium ethoxide. The system was placed under an argon atmosphere and cooled to about 0° C. After cooling, 107.28 gms of t-butyl bromoacetate were dropwise added to the system. The system was then allowed to come to room temperature and stirred there for 60 hours. The reaction was stopped and the system filtered. The solvent was removed by stripping and the residue was dissolved in hot ether and then filtered. The ether was removed by stripping and the resulting solid triturated with hexane and dried to yield 80.81 gms of the title compound as a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[H][H]>CC(O)C>[C:7]1([C@H:5]([OH:6])[CH2:4][CH2:3][N:2]([CH3:13])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CN(C)CCC(=O)c1ccccc1
Solvent: CC(C)O
Product: CN(C)CC[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
Chiral hydrogenation of 3-(dimethylamino)propiophenone was carried out (see formula (13) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex synthesized in Example 2 and using 3-(dimethylamino)propiophenone(886 mg; 5.0 mmol) as the substrate and 2-propanol (5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 250° C., and the reaction time was set to 12 hours. As a result, (R)-1-phenyl-3-(dimethylamino)propane-1-ol was obtained at a conversion rate of 100%, isolation yield of 89% (796 mg; 4.45 mmol), and enantiomeric excess of 97%. HPLC (column: CHIRALCEL OD; size: 4.6 mm×250 mm; made by Daicel Chemical Industries Ltd.; solvent: 9:1 hexane/2-propanol; temperature: 30° C.; UV wavelength: 254 nm; flow rate: 0.5 ml/minute; tR of (R)-1-phenyl-3-(dimethylamino)propane-1-ol: 14.4 minutes (98.4%); tR of S alcohol: 20.4 minutes (1.6%)); [α]26D+31.8° (c: 1.67; CH3OH); absolute structure: R; literature value: [α]D+27.6° (c:1.61; CH3OH),(R).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:15]=3)[N:10]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1>CS(C)=O>[CH3:20][N:19]([CH3:21])[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[N:9]=[C:8]2[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]2)[N:7]=1)=[O:18]
Reactant: CN(C)C(=O)c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc2c(c1)c(-c1ccnc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)nn2C1CCCCO1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 3-(2-chloropyrimidin-4-yl)-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (0.5 g, 1.29 mmol) in DMSO (5 mL) was added tert-butyl piperidin-4-ylcarbamate (0.311 g, 1.54 mmol) and the reaction was stirred for 12 h at 100° C. The reaction was quenched with ice cold water (5 mL) to give the off white precipitate. The suspension was filtered, washed with ice cold water and dried to give tert-butyl (1-(4-(5-(dimethylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)carbamate (0.4 g, 48%) as a off white solid. MS (ESI, pos. ion) m/z: 550.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.45 (d, 1 H, J=5.1 Hz), 7.90 (d, 1 H, J=8.8 Hz), 7.35-7.65 (m, 1H), 7.28 (d, 1 H, J=5.1 Hz), 6.89 (d, 1 H, J=7.7 Hz), 6.01 (dd, 1 H, J=7.4, 2.0 Hz), 4.64 (d, 2 H, J=12.9 Hz), 3.90-4.04 (m, 1H), 3.76-3.82 (m, 1H), 3.60 (s, 1H), 3.16 (t, 2 H, J=11.8 Hz), 3.02 (s, 6H), 2.03-2.06 (m, 2H), 1.82-1.86 (m, 3H), 1.62 (bs, 2H), 1.23 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2)N1CCOCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a suspension of 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl chloride (0.027 g, 72.6 μmol) in DCE (1 mL) was added morpholine (15.97 μL, 182 μmol) and pyridine (350 μL). The reaction was heated to 70° C. and stirred at that temperature for 16 hours. LCMS analysis of the reaction mixture indicated complete consumption of starting material. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 0-60% EtOAc to provide (4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)(morpholino)methanone (21.8 mg, 49.3 μmol, 88% yield for 2 steps) as off-white solid. LCMS (+ESI) m/z=423.5 [M+H]−.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:13])[CH3:10]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([Br:1])[CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(=O)C(Br)C1
Yield: 140.8 %

Procedure:
To a stirred solution of N-bromosuccinimide (1.11 g, 6.274 mmol), PTSA (0.108 g, 0.627 mmol) in toluene (15 mL) was added 4-oxocyclohexanecarboxylic acid ethyl ester (1.068 g, 6.274 mmol) under nitrogen atmosphere and the reaction was refluxed for 2 hrs. Toluene was evaporated under reduced pressure and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated; the organic layer was washed with sat. sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get title the compound (2.2 g) which was carried without purification for the next step.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:25])[C:18](=O)[NH:19]2.FC1C=C2C(=CC=1)NC(=O)C2=O>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:25])[C:18]1[N:19]2[C:7](=[O:8])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:13]=2)[N:11]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2c(Cl)cccc2-n2c1nc1ccccc1c2=O
Yield: 16 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 4-chloroisatin for 5-fluoroisatin gave the title compound in 16% yield: mp 294°-295.7° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H) 8.33 (d, 1H) 7.97 (d, 2H) 7.81-7.90 (m, 1H) 7.72-7.80 (m, 1H) 7.52 (d, 1H); MS (M+H)+ 283.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)=[O:4].[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[NH2:8][CH2:7][CH2:6][N:5]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:3](=[O:4])[C:2]([F:22])([F:1])[F:21]
Reactant: CC(C)(C)OC(=O)NCCN(CC(F)(F)F)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCN(CC(F)(F)F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
The compound (3.05 g, 9.02 mmol) obtained in step C was dissolved in ethyl acetate (20 ml), 4N hydrochloric acid-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 6 hr. The precipitated solid was collected by filtration, and the obtained solid was washed with ethyl acetate, and dried under reduced pressure to give the title compound (1.51 g, yield 61%) as a pale-bistered solid.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:8][C:9](=[O:13])/[CH:10]=[CH:11]/[I:12])[CH2:7][CH2:6][CH2:5][CH2:4]1>C1C=CC=CC=1>[CH:3]1([CH2:8][CH:9]([OH:13])/[CH:10]=[CH:11]/[I:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(/C=C/I)CC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: OC(/C=C/I)CC1CCCC1

Procedure:
To a solution of 7.1 g. of sodium borohydride in 60 ml of absolute alcohol, stirred in an ice bath under nitrogen atmosphere, is added dropwise, over a period of about 2 hours, a solution containing 7 g. of 4-cyclopentyl-1-iodo-1-trans-buten-3-one (Example 116) in 160 ml. of absolute alcohol. The temperature is maintained at 5°-10° C. The solution is poured into 850 ml. of iced water and the resulting mixture is extracted three times with ether. The combined extracts are washed with dilute sodium bisulfite solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 81 g. of yellow oil. Column chromatography on a column of 1 kg. of silica gel using benzene gives 75 g. (88%) of oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=O)[C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.[NH2:19][OH:20].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]=[N:19][OH:20])[C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(-c2ccc(O)cc2)cc2ccoc12
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: ON=Cc1cc(-c2ccc(O)cc2)cc2ccoc12
Temperature: 68 °C
Reaction time: 0.08 h

Procedure:
To a 10 ml round bottom flask was added 5-(4-hydroxyphenyl)-benzofuran-7-carbaldehyde (76 mg, 0.32 mmol), hydroxylamine hydrochlorode (44.4 mg, 0.64 mmol), anhydrous MeOH (2 ml), and anhydrous pyridine (0.06 ml, 0.67 mmol). The reaction was then heated to 68° C. and the reaction was done in 5 minutes. The reaction was then cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 20 mg (25%) of product as a yellow solid: 1H NMR (300 MHz, DMSO-d6): δ 6.86 (2H, d, J=8.5 Hz), 7.03 (1H, d, J=2.1 Hz), 7.51 (2H, d, J=8.5 Hz), 7.73 (1H, d, J=1.4 Hz), 7.84 (1H, d, J=1.6 Hz), 8.08 (1H, d, J=2.1 Hz), 8.45 (1H, s) 9.56 (1H, s), 11.57 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[C:11]2[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[C:11]2[C:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:9][S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2scc(CCc3ccccc3)c12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc2scc(CCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 4-methoxy-3-(2-phenylethyl)benzo-[b]thiophene (0.77 g) in dichloromethane (25 mL) was added boron tribromide (0.54 mL) at −78° C., and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with diethylether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (0.66 g).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([O:73][CH3:74])[CH:68]=2)[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[C:69]([O:73][CH3:74])[CH:68]=4)[C:56]=3[CH3:75])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)ccn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 2,5-dimorpholinopyridin-3-amine (0.099 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.075 g, 0.78 mmol) in toluene (3.1 mL) at 120° C. for 3.2 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.33 (1H, dd, J=5.2, 0.7 Hz), 7.72 (1H, d, J=11.0 Hz), 7.66 (1H, d, J=2.7 Hz), 7.60 (1H, m), 7.07-7.01 (2H, m), 6.91 (1H, s), 6.32 (1H, d, J=2.3 Hz), 4.02 (3H, s), 3.91 (4H, t, J=4.7 Hz), 3.83 (4H, app t, J=4.7 Hz), 3.25 (4H, br. s), 3.03 (4H, app t, J=4.9 Hz), 2.13 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 80 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 3.12-3.21 (m, 4H), 3.77-3.84 (m, 3H), 4.11-4.15 (m, 4H), 6.95-7.10 (m, 4H), 7.20-7.45 (m, 3H), 7.65-7.82 (m, 1H).