Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1.S(Cl)(Cl)=O.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([S:18][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=3)=[N:20][C:21]=2[CH:27]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: COc1c(C)cnc(CO)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (300 g) was charged to dichloromethane (1770 ml) and cooled to 15-20° C. Thionyl chloride (240 g) was added slowly at 15 to 20° C. and the contents were stirred at 25 to 30° C. for 1 hour. After reaction completion, water (300 ml) was added at 15 to 20° C. and allowed to attain 25 to 30° C. To this reaction mass 2-mercapto-5-methoxy benzimidazole (252 g) and tetrabutyl ammonium bromide (6 g) was added, and the pH of the reaction mass was adjusted to 10.0 to 10.5 at 5 to 15° C. using 30% sodium hydroxide solution and stirred for 2 hours at 15 to 20° C. maintaining pH 10.0-10.5. After reaction completion the dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (370 ml×2). The dichloromethane layer was then washed with water until the pH of the aqueous layer was 7.0 to 7.5, dried over sodium sulphate and partially concentrated at temperature below 50° C. under vacuum. Ethyl acetate (240 ml) was added and stripped off to remove traces of dichloromethane, further ethyl acetate (800 ml) was added and heated to 50 to 60° C., cooled to room temperature, chilled to 10 to −5° C. and maintained for 1 hour. The product was then filtered, washed with chilled ethyl acetate (200 ml). The product was then dried at 30 to 35° C. to yield 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl)thio]-1H benzimidazole form II (392 g, 80.6% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+].[C:57]([C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=1)#[CH:58]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:66][O:65][C:61]1[CH:60]=[C:59]([C:57]#[C:58][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:64]=[CH:63][CH:62]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (21 mg, 0.04 mmol), and Cs2CO3 (424 mg, 1.30 mmol) were suspended in dioxane (2 mL), and stirred for 20 minutes at room temperature. 1-Ethynyl-3-methoxy-benzene (86 mg, 0.65 mmol) was then added, and the resulting solution was stirred for 3 h at 100° C. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 160 (80 mg, 56% yield) as a light-yellow solid. LC-MS (M+H=327, obsd.=327).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5].[OH-].[Na+].C1COCC1.Cl>CO>[CH3:33][C:2]([CH3:1])([CH3:34])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)CC(=O)O)cc1)CO2
Yield: 76.4 %

Procedure:
Ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate (150 mg, 0.32 mmol) obtained in Example 182, 1 N aqueous sodium hydroxide solution (2 mL) and THF (3 mL)-methanol (3 mL) were stirred at room temperature for 16 hours. To the reaction solution was added hydrochloric acid to make the solution acidic, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 107 mg (yield: 74%) of the title compound. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:22]([NH:24][CH2:25][CH:26]([OH:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:23])[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])C1C=CC=CC=1>CO.[Pd]>[C:32]([O:31][C:29](=[O:30])[NH:28][CH2:27][CH:26]([OH:36])[CH2:25][NH:24][C:22](=[O:23])[C@@H:11]([NH2:10])[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)NCC(O)CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
38 mg (0.12 mmol) of the compound from Example 98A are dissolved in 10 ml of methanol, and 10 mg of palladium on activated carbon (10%) are added. The mixture is hydrogenated under atmospheric pressure for 2 h and filtered through kieselguhr, and the mother liquor is concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N:8]=1)[CH3:2].[CH:21](=O)[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(C(F)(F)F)=O.CC#N>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][CH2:21][CH3:22])[C:10]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CC=O
Reactant: CCOC(=O)CSc1ncc(Cc2cccs2)c(N)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNc1nc(SCC(=O)OCC)ncc1Cc1cccs1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-Amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester (0.5 mmol, 155 mg) as prepared in example 12 and acetaldehyde (0.6 mmol, 27 mg) in 1.25 ml of DMF was added acetic acid (0.25 ml) and sodium cyanoborohydride (0.6 mmol, 38 mg) and the mixture was shaken for two days at r.t. The title compound, MS: m/e=338.2 (M+H+), was obtained from the mixture by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[S:22]1[C:26]2[CH2:27][CH2:28][CH2:29][C:25]=2[N:24]=[C:23]1[NH2:30]>>[S:22]1[C:26]2[CH2:27][CH2:28][CH2:29][C:25]=2[N:24]=[C:23]1[NH:30][C:18]([C:3]1[N:4]([CH3:17])[S:5](=[O:15])(=[O:16])[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[C:2]=1[OH:1])=[O:19]
Reactant: Nc1nc2c(s1)CCC2
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nc3c(s2)CCC3)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 57 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5,6-dihydro-4H-cyclopentathiazole-2-amine with a yield of 57% of theory.
Reaction SMILES: O[C:2]1([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:20][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]=1
Reactant: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cn1ccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (800 mg) in CH2Cl2 (8 ml) was added methanesulfonyl chloride (0.44 ml) and TEA (1.6 ml) under ice bath cooling, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with aq. NaHCO2 solution and extracted with EtOAc. The organic phase was washed with brine and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by silica gel column (CHCl3:MeOH=95:5 to 90:10) to give tert-butyl 4-(1-methyl-1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (398 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH3:17][O-:18].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:11](=[NH:12])[O:18][CH3:17])[CH:8]=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: N#Cc1cccc(Cc2ccccc2Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(Cc2ccccc2Cl)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
2-(o-Chlorobenzyl)-6-cyanopyridine (5.0 g, 0.022 moles) was added to a solution of sodium methoxide in methanol [prepared by dissolving sodium metal (0.55 g, 0.024 g atoms) in methanol (50 ml)] and the mixture stirred at 20° C. for 5 hours. The methanol was evaporated, the residue taken up in dichloromethane and the precipitate filtered off through a silica bed. Removal of the solvent from the filtrate gave methyl 6-(o-chlorobenzyl)-2-picoline imidate (5.5 g, 100%) as a brown oil which was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][CH2:5][C:6]1[C:7](=O)[NH:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[C:6]([CH2:5][NH:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(=O)[nH]1
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Cl)n1
Temperature: 100 °C
Yield: 22 %

Procedure:
13.6 g (43 mmol) of crude 5-(2,6-dichloroanilinomethyl)-2-methylthio-3H-pyrimidin-4-one was treated with 120 ml of phosphorus oxychloride and the mixture heated at 100° C. for 15 minutes then cooled. The mixture was evaporated and cautiously partitioned between 200 ml of ethyl acetate and 200 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel eluting with diethyl ether/isohexane in a ratio of 1:9 to give 3.2 g (22%) of 4-chloro-5-(2,6-dichloroanilinomethyl)-2-methylthiopyrimidine as a pale yellow oil. [Mass spectrum (ESI) MH+ =334].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][C@@H:12]([NH2:14])[CH3:13].Cl[C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:43][C:26]2=[CH:27][C:28]3[C:29](=[O:42])[N:30]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:31](=[O:34])[C:32]=3[CH:33]=[C:25]2[N:24]=1>>[CH3:41][N:38]1[CH2:39][CH2:40][CH:35]([N:30]2[C:29](=[O:42])[C:28]3[CH:27]=[C:26]4[NH:43][C:23]([C:17]5[C:18](=[O:22])[NH:19][CH:20]=[CH:21][C:16]=5[NH:14][C@@H:12]([CH3:13])[CH2:11][C:3]5[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=5[F:10])=[N:24][C:25]4=[CH:33][C:32]=3[C:31]2=[O:34])[CH2:36][CH2:37]1
Reactant: C[C@H](N)Cc1c(F)c(F)cc(F)c1F
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
(S)-1-(2,3,5,6-Tetrafluorophenyl)propan-2-amine and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione were submitted to general procedure A. The isolated solid was triturated with water once and MeOH four times to give the title compound as an off-white solid, which was used directly in the next step.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[F:41].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[F:34][C:35]1[CH:36]=[C:37]([C:2]2[S:10][C:9]3[C:8](=[O:11])[N:7]([CH:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]4)[C:6](=[O:25])[N:5]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=4)[C:4]=3[CH:3]=2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)c(F)c4)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (540 mg, compound B99), (3,4-difluorophenyl)boronic acid (158 mg), dichlorobis(tricyclohexylphosphine)palladium (37 mg) and aqueous cesium carbonate solution (489 mg, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 70/30 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:29][CH:31]3[CH2:32][O:33]3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)c([N+](=O)[O-])c3)c2C1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6.4 g, 20.0 mmol) in DMF (60 mL) was treated with cesium carbonate (13.0 g, 40 mmol) and epichlorohydrin (15.6 mL, 200.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for an additional 24 h before it was diluted with ethyl acetate (350 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone/CH2Cl2) to provide 7.5 g (83%) of a light yellow powder. MS (electrospray): m/z 377.0 (377.0, calculated for C17H17ClN4O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.15-8.05 (m, 1H), 7.75-7.65 (m, 1H), 7.55-7.45 (m, 1H), 4.80-4.65 (m, 1.2H), 4.60 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2.67 (m, 3H), 2.55-2.48 (m, 1H), 2.15 (s, 1.7H), 2.10 (s, 1.3H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1)(=O)C.N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[N:10]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1ccccc1O
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=c1nc(-c2ccc(O)cc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
Salicylamide (6.85 g, 50 mmol) and 4-acetoxybenzoyl chloride (10.9 g, 55 mmol) were dissolved in 35 mL anhydrous xylene. Anhydrous pyridine (0.5 mL) was added and the reaction mixture was refluxed under nitrogen for 12 h. Water was removed by a Dean-Stark apparatus. The mixture was cooled to rt, and the xylene was removed under vacuum. Acetone (100 mL) was added and the mixture was stirred for 10 min. The solid was filtered off, washed with acetone and dried under vacuum to give the crude compound (3.0 g). The crude compound (1.5 g) was purified by column chromatography (SilicaGel 70-230 mesh; 2-5% MeOH in DCM as eluent) to give 770 mg of 2-(4-hydroxyphenyl)benzo[e][1,3]oxazin-4-one (12%) as pale yellow solid. MS (ES) m/z: 240.02; Mp. 273-275° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C2C=CC([S:35]([OH:38])(=[O:37])=[O:36])=CC=2)CCCCC1>>[CH2:1]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[S:35]([OH:38])(=[O:37])=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(O)c1ccc(C2CCCCC2)cc1
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O

Procedure:
4-dodecylbenzenesulphonic acid: 4-cyclohexylbenzenesulphonic acid;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.[Zn](C)[CH3:30]>C1COCC1.C1(C)C=CC=CC=1.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]>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1 (94 mg, 0.237 mmol) and PdCl2(dppf) (18 mg, 0.047 mmol) in THF (1 ml) at room temperature was added ZnMe2 in toluene (1.2 M, 0.4 mL). The reaction mixture was stirred at 50° C. for 2 h. A second portion of ZnMe2 (0.6 mL) and PdCl2(dppf) (18 mg) was added. The reaction was heated at 50° C. for 3 h, cooled and quenched by sat. aqueous NaHCO3. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. Purification by reverse-phase HPLC (C-18 column, 5-90% MeCN in H2O with both containing 0.05% TFA) provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.0 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.13 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.60 (d, J=7.6, 1H), 7.30 (dd, J=2.4, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 4.45 (s, 2H), 3.92-3.84 (m, 1H), 3.61-3.57 (m, 1H), 2.51 (s, 3H), 2.17-2.12 (m, 2H), 1.82-1.79 (m, 2H), 1.54-1.23 (m, 4H). HRMS (ES) [M+1]+ calcd for C23H25N3O2: 376.2020, Found: 376.2010.
Reaction SMILES: CO.[N+:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12][CH:13]=1)([O-])=[O:4].C[O-].[Li+].C(Cl)[Cl:26]>[Ti](Cl)(Cl)(Cl)Cl.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:11]1[N:12]=[CH:13][C:8]([CH2:7][C:6]([Cl:26])=[N:3][OH:4])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: ON=C(Cl)Cc1ccc(COc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a methanol (5 mL) solution of 5-(2-nitro-ethyl)-2-(pyridin-2-yloxymethyl)-pyridine (93 mg, 0.36 mmol) described in Manufacturing Example 154-1-7 was added lithium methoxide (27 mg, 0.72 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (3 mL) and methylene chloride (3 mL) was added titanium (IV) tetrachloride (87 μL, 0.79 mmol) under nitrogen atmosphere at −78° C., which was stirred for 2 hours at 0° C. More titanium(IV) tetrachloride (50 μL, 0.46 mmol) was added at −78° C., which was stirred for 3 hours at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (24 mg). This compound was used in the following reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:8]C)([O:6][CH3:7])[O:4][CH3:5].[OH-].[K+:11]>CO>[CH3:1][O:2][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O-:8].[K+:11]
Reactant: CO[Si](OC)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CO[Si]([O-])(OC)OC
Yield: 100 %

Procedure:
A solution of 91.2 gm (0.7 mol) of tetramethoxy-silane in 100 ml of methanol was mixed with a solution of 33.0 gm of 85% potassium hydroxide solution (0.5 mol KOH) in 200 ml of methanol. The mixture was heated for about 15 minutes under reflux. Subsequently methanol and excess tetramethoxy-silane were distilled off under a water jet vacuum. Instead of the theoretically expected 88.2 gm (0.5 mol) of potassium trimethoxysilanolate, 84.5 gm of solid potassium salts were obtained, that is, in addition to potassium trimethoxy-silanolate, also a small amount of oligopotassium oligomethoxy-silanolates were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:13]=3[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:28].[Br:29]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[NH4+]>C(#N)C>[Br:29][C:14]1[C:13]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20][C:12]=2[CH:11]=[C:10]2[C:15]=1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7](=[O:28])[CH2:8][CH2:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCN1C(=O)CCc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COCCCN1C(=O)CCc2cc3c(c(Br)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 109.7 %

Procedure:
To a solution of 150 mg of t-butyl 1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 4.2 ml of acetonitrile were added 107 mg of N-bromosuccinimide and 3.7 mg of ammonium nitrate, followed by stirring at room temperature for 3.5 hours. The reaction mixture was concentrated to about ¼, and ethyl acetate, an aqueous sodium thiosulfate solution, and aqueous sodium bicarbonate was added thereto. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 198 mg of t-butyl 11-bromo-1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:8](C)=[N:7][C:6](=S)[N:5]=1.[CH2:11](O)C>[Ni]>[CH3:11][C:4]1([N:5]=[CH:6][N:7]=[CH:8]1)[CH2:3][CH2:2][NH2:1]
Reactant: CCO
Reactant: CC1=NC(=S)N=C1CCN
Agent: [Ni]
Product: CC1(CCN)C=NC=N1

Procedure:
Reaction of 4-(2-aminoethyl)-5-methylimidazole-2-thione with Raney nickel in ethanol yielded 4-methylhistamine.