Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=1)=[CH:16][CH:15]=3.I[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][O:26][CH2:33][CH3:34])[N:24]=1)=[CH:16][CH:15]=3
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Product: CCOCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 101 above, with the compound from Example 95 above, 3-(2,4-dichlorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](SC)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].C(O)C.O>O1CCOCC1.[Ni]>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Agent: [Ni]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cncnc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Yield: 21.8 %

Procedure:
((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine (400 mg, 0.728 mmol) was dissolved in dioxane (10 ml), ethanol (2 ml) and water (2 ml) and treated with 2 g of Raney Nickel (2000). This was refluxed for 16 hours. The reaction was filtered, evaporated and purified by silica gel chromatography (5% methanol/methylene chloride to give ((S)-1-methanesulfonyl-piperidin-3-yl)-{5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine (˜80 mg). MS (ES+): 504.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(C(Cl)=O)=O.[I:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH:27]C(=O)OC(C)(C)C)[N:20]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH3:42])=[CH:37][CH:36]=2)[N:19]=1.C(O)(C(F)(F)F)=O>C(#N)C.CN(C=O)C.C(Cl)Cl>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C:35]3[CH:36]=[CH:37][C:38]([N:41]([CH3:42])[C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])=[CH:39][CH:40]=3)[N:19]=[C:18]([I:17])[C:26]=12
Reactant: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)cc1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride salt (5) (66 mg, 0.4 mmol) in acetonitrile (5 mL) was added 1 drop of DMF before introducing (COCl)2 (66 mg, 0.52 mmol). The resulting mixture was stirred at RT for 2 h and then concentrated. The residue was dissolved in DCM (2 mL) before adding a solution of tert-butyl 3-iodo-1-(4-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (30) (170 mg, 0.438 mmol) in DCM (2 mL). The resulting solution was stirred at RT overnight before adding TFA (10 mL). The reaction mixture was stirred for 3 hr. The reaction mixture was concentrated and quenched with sat. aqueous NaHCO3. The mixture was extracted with 85% DCM/IPA (3×). The organic solution was dried over Na2SO4 and concentrated to provide (E)-N-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (32) (170 mg, 100%) which was used in the next step directly without purification. LC-MS (ESI): m/z (M+1) 478.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([CH3:10])[N:3]=1.Cl[C:12]1C(CCl)=CC=C(Cl)[N:13]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:13][CH3:12])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CCl)cc(C)n1
Reactant: ClCc1ccc(Cl)nc1Cl
Product: CNCc1cc(C)nc(C)c1

Procedure:
The reaction according to Reference Example 11 was carried out using (2,6-dimethyl-4-pyridyl)methyl chloride in lieu of 2,6-dichloro-3-pyridylmethyl chloride to give the title compound as oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][CH:22]1[C:23]([O:66]C(OCC)C)([CH3:65])[CH2:24][CH2:25][CH:26]([O:58][C:59](=[O:64])[CH2:60][O:61][CH2:62][CH3:63])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:57])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:56])[CH2:41][CH:42]2[O:55][CH:43]2[CH:44]([CH3:54])[CH:45]([O:48]C(OCC)C)[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]>CO.C(OCC)(=O)C>[C:18]([O:21][CH:22]1[C:23]([OH:66])([CH3:65])[CH2:24][CH2:25][CH:26]([O:58][C:59](=[O:64])[CH2:60][O:61][CH2:62][CH3:63])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:57])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:56])[CH2:41][CH:42]2[O:55][CH:43]2[CH:44]([CH3:54])[CH:45]([OH:48])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]
Reactant: CCOCC(=O)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOCC(=O)OC1CCC(C)(O)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(O)CC)OC(=O)C1
Agent: CCOCC(=O)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCC(=O)OC1CCC(C)(O)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(O)CC)OC(=O)C1
Reaction time: 15 h

Procedure:
Pyridinium p-toluenesulfonate (9.8 mg, 0.039 mmol) was added to a solution of (8E,12E,14E)-7-acetoxy-3-ethoxyacetoxy-6,21-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (6.0 mg, 0.0078 mmol) in methanol (1.0 mL) at room temperature, followed by stirring at the same temperature for 15 hours. The reaction mixture was diluted with 15 mL of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by thin layer chromatography (MERCK Silicagel 60 F254, 0.2 mm, developing solution; ethyl acetate) to obtain the title compound (1.7 mg, 35%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=[C:7]2[CH2:6]1)=[O:4]>O=[Mn]=O>[F:29][C:24]1[CH:23]=[C:22]([NH:21][C:11]2[N:8]3[C:7]([CH:6]4[NH:1][C:2]([CH3:31])([CH3:30])[C:3](=[O:4])[N:5]4[CH2:10][CH2:9]3)=[N:13][C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(N)C(=O)N1CCn2c(nc(-c3ccc(F)cc3)c2Nc2ccc(F)c(F)c2)C1
Agent: O=[Mn]=O
Product: CC1(C)NC2c3nc(-c4ccc(F)cc4)c(Nc4ccc(F)c(F)c4)n3CCN2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Example 646 was prepared from Example 29 by the following method: to a stirred solution of Example 29 (12 mg, 0.03 mmol) was added MnO2 (52 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC/MS test showed that Example 29 was almost gone and the desired product ([M+1]=528) was detected as one of the major peaks. Solid was filtered off and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give Example 646.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3ccc(F)cc3c(N[C@H]3CCNC3)n2)[nH]1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a mixture of (S)-3-(7-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 0.35 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (122 mg, 1.15 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (45 mg, 0.49 mmol) was added dropwise and the reaction mixture was stirred at −40° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (79 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 11.70 (s, 1H), 8.25-8.22 (d, J=10.8 Hz, 1H), 7.97-7.96 (m, 1H), 7.63-7.60 (m, 2H), 7.55-7.54 (m, 1H), 6.59-6.57 (m, 1H), 6.21-6.15 (m, 1H), 5.68-5.65 (dd, J1=10.4 Hz, J2=2.4 Hz, 1H), 5.20-5.18 (m, 1H), 4.19-4.15 (m, 0.5H), 3.70-3.67 (m, 2H), 3.69-3.45 (m, 1.5H), 3.25 (m, 0.5H), 2.26-2.24 (m, 1H), 2.08-2.03 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Li]CCCC.[Br:15][C:16]1[N:17]=[C:18]([CH:40]=[O:41])[N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1>C1COCC1>[Br:15][C:16]1[N:17]=[C:18]([CH:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=2)[OH:41])[N:19]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1
Reactant: CCc1cccc(Br)c1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (266 mg, 1.44 mmol) in 7 mL THF at −78° C., was added BuLi (1.6 M in hexanes, 0.99 mL, 1.58 mmol). The mixture was stirred at −78° C. for 10 min, then a solution of Intermediate 175.1 (600 mg, 1.44 mmol) in 3 mL THF was added. The mixture was stirred at −78° C. for 1 h, then was removed from the cooling bath and stirred 20 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 585 mg of Intermediate 175.2 as a colorless solid. LCMS (4 min gradient, 50 to 100% B, A=95% H2O/5% CH3CN/0.1% TFA, B=95% CH3CN/5% H2O/0.1% TFA) RT=3.65 min, 523.10 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:7][CH:6]=1.Cl>CO.[OH-].[Na+]>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(OC)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCCOc2ccc(C(=O)C(=O)O)cc2)cc1OC
Yield: 93.6 %

Procedure:
A mixture of 4-[[2-(3,4-dimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in methanol and 0.5N sodium hydroxide (8 mL) was heated on the steam bath for 0.5 hours and cooled. 2N hydrochloric acid (5 mL) was added and the resulting solids were filtered and washed with water. The solids were dried by boiling in benzene (20 mL), filtered, hexane (5 mL) was added, and the resulting mixture was chilled to give 0.63 g of colorless 4-[[2-(3,4-dimethoxyphenoxy)ethyl]oxy]-alphaoxobenzeneacetic acid, mp 140°-141° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[CH3:20][S:17]([CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)(=[O:18])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)CCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Hydrochloric acid (42 mL, 168 mmol, 4 M in 1,4-dioxane) was added to a cooled solution of 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine (2.29 g, 7.8 mmol) in 1,4-dioxane (42 mL). The mixture was stirred at room temperature overnight then concentrated to give 1-(2-methanesulfonylethyl)piperazine bishydrochloride as a white solid (2.05 g).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:60](Cl)(=[O:67])[C:61]1[CH:66]=[CH:65][CH:64]=[N:63][CH:62]=1>>[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:53][CH2:54][N:55]([C:60]([C:61]5[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=5)=[O:67])[CH2:56][CH2:57]4)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]3=[O:49])=[O:40])=[CH:58][CH:59]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=C(Cl)c1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(C(=O)c5cccnc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 85 %

Procedure:
Following a procedure analogous to that used in reaction (10), the material from example 8 was reacted with nicotinoyl chloride overnight to provide the title compound (13 mg, 85%). MS found: (M+H)+=622.5.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:4][CH2:1][C:2]#[CH:3]
Reactant: BrCCCCCCBr
Reactant: C#CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCOCCCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
A mixture of propargyl alcohol (5.6 g), 1,6-dibromohexane (73.2 g), tetrabutylammonium bisulphate (0.5 g), and aqueous sodium hydroxide (50%, w/v, 27 ml) was stirred at room temperature for 20 h, diluted with water (50 ml), and extracted with diethyl ether (2×100 ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385) eluting with cyclohexane followed by cyclohexane-diethyl ether (19:1) to give the title compound as a colourless oil (15.0 g), t.l.c. (cyclohexane-diethyl ether 9:1) Rf 0.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]C)C.[F:6][C:7]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:8]=1[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>O1CCCC1.C(Cl)Cl>[CH3:1][N:3]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][C:8]1[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:7]=1[F:6])[CH3:4]
Reactant: CCNCC
Reactant: Fc1ccc(Br)cc1COCCCCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethylamine (17.6 ml, 35.3 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml). The resulting mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]2[C:24]3[C:11]([O:10][CH3:9])=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: COc1cccc2c1C(C(=O)Cl)c1ccccc1O2
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3cccc(OC)c32)n1

Procedure:
The title compound, white solid, m.p. 259-260° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-1-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:5][CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O.O>[N:19]([CH2:3][C:4]1[NH:5][CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:10])[CH:9]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(CCl)[nH]cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
A mixture of 2-(chloromethyl)-5-(phenylmethoxy)-4(1H)-pyridinone, monohydrochloride (3.59 g, 12.54 mmole), sodium azide (4.08 g, 62.7 mmole) and diisopropylethylamine (2.19 ml, 12.54 mmole) in 70 ml of dimethylformamide was stirred at room temperature under argon for 3.5 days. An additional 4.08 g of sodium azide was added and the mixture was heated at 45°-50° C. for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water, producing an insoluble white solid. The pH of the supernatant liquid was lowered from 8.5 to 7.5 with dilute hydrochloric acid, and the white solid was filtered. After washing with water, acetone, and hexane the solid was dried in vacuo. The yield of the title compound was 2.81 g.
Reaction SMILES: [NH2:1][C:2]([NH:4][NH:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[S:3].[O-]CC.[Na+]>C(O)C>[SH:3][C:2]1[NH:4][N:5]=[C:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:1]=1
Reactant: CCOC(=O)CC(=O)NNC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1n[nH]c(S)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A suspension of ethyl 3-[2-(aminocarbonothioyl)hydrazino]-3-oxopropanoate (14.0 g, 68.2 mmol) and sodium ethoxide (9.52 g, 140 mmol) in ethanol (200 mL) was stirred at 80° C. for 15 hr. The mixture was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as an orange powder (12.2 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10][C:9]2=[O:18])=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]2=[O:18])=[CH:6][CH:7]=1
Reactant: O=C1CNc2ccccc2N1c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=c1cnc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoxalin-2-one (8.2 g) in dichloromethane (50 ml) was stirred with manganese dioxide (10.0 g) for 4 hours. The mixture was filtered, evaporated, and the residue was recrystallised from ethanol giving the title compound mp 169°-171° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[C:8]([CH:19]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:21]([NH:20][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[O:10])=[O:22])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide (0.48 g, 0.96 mmol) in methanol (20 mL),was added sodium borohydride (36 mg, 0.96 mmol). The reaction was stirred at room temperature for 5 min, treated with water, and concentrated in vacuo. The residual mixture was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.47 g (98%) of a white foam.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:17][CH3:18])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH2:17]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:14][CH:15]=1)[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6.00 g (20.3 mmol) of 4-[3-(diethylamino)propoxy)benzenamine dihydrochloride in 50 mL of pyridine under a nitrogen atmosphere and cooled to ca -10° C. add 2.0 mL (25.4 mmol) of methanesulfonyl chloride dropwise. Maintain the temperature below 0° C. during the addition. Stir the reaction mixture at ambient temperature for 5 h then add 10 mL of H2O. Evaporate the solvent in vacuo and dissolve the residue in 50 mL of H2O (pH=ca. 3). Extract the aqueous solution with 2×100 mL of diethyl ether. Adjust the pH of the aqueous solution to pH=13 with 20% aqueous sodium hydroxide solution and extract this solution with 3×50 mL of methylene chloride. Adjust the pH of the aqueous solution to pH=8.5 with concentrated hydrochloric acid and saturate the solution with sodium chloride. Extract the mixture with 3×100 mL of methylene chloride. Wash the organic extracts with 25 mL of saturated aqueous sodium chloride solution, combine the extracts and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][NH2:11].[BH4-].[Na+]>CO>[CH3:10][NH:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: CN
Reactant: Cc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 2-methylbenzaldehyde (10.0 g, 83.23 mmol) in MeOH at 25° C. was added methylamine (40 % in H2O, 25.85 g, 332.9 mmol). The reaction mixture was stirred at 25° C. for 30 min after which time it was cooled to 0° C. and NaBH4 (6.30 g, 166.5 mmol) was added portion-wise. The reaction mixture was then warmed to 25° C. and stirred for an additional 1 hr. The solvent was removed under reduced pressure and water and CH2Cl2 were added. The organic layer was separated and washed with saturated NaHCO3 and brine. After drying over Na2SO4, organic phase was concentrated to afford desired methyl-(2-methyl-benzyl)-amine (10.49 g, 93.2%) as an oil of sufficient purity for use in the next reaction: MS(APCI+) 136.3 m/z (M+H); H-NMR (CDCl3) δ 7.35-7.08 (m, 3 H), 3.73 (s, 2 H), 2.49 (s, 3 H), 2.34 (s, 3 H).