Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13]O)[CH:4]=1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>ClCCl>[Cl:26][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COc1cc(CO)cc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCl)cc2ccccc12
Temperature: -5 °C
Reaction time: 23 h

Procedure:
15.0 g (79.7 mmol) of (4-methoxy-naphthalen-2-yl)-methanol [Chem. Pharm. Bull. 19(6), 1245-1256 (1971)] were dissolved in 100 ml of dichloromethane, the solution treated with 20 ml of triethylamine, cooled to −5° C. and treated slowly with 9.3 ml (119.5 mmol) methanesulfonyl chloride. Then, the reaction mixture was stirred at room temperature for 23 hours, concentrated in a water-jet vacuum, redissolved in 80 ml of tetrahydrofuran, treated with 11.25 g of sodium hydrogen carbonate and stirred for another 2 hours. The suspension was then diluted with 500 ml of water and extracted three times with 300 ml of ethyl acetate, the organic phases were washed once with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with pentane/dichloromethane (4/1). There were thus obtained 11.9 g (57.5 mmol), 72.5% 3-chloromethyl-1-methoxy-naphthalene as a colorless solid; MS: 206 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].[Cl:33]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[Cl:33][CH2:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CN(c1cc(CCl)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1

Procedure:
The product of step (v) (0.5 g) in tetrahydrofuran (20 ml) was treated with triphosgene (0.114 g) then pyridine (0.183 g). After 16 hours the reaction was evaporated and purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.4 g.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:14]
Reactant: NO
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of 3-formyl-5-methylindole (0.50 g), hydroxylamine hydrochloride (0.44 g) and sodium acetate (0.52 g) in acetic acid (5 ml) was stirred for 2 hours, then acetic anhydride (2.5 ml) was added to the mixture and allowed to react under reflux for 0.5 hour. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. After filtration of insoluble materials, the filtrate was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 3-cyano-5-methylindole (109 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][CH2:9][O:8][C:4]1[C:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:28])[CH3:27]
Reactant: Cn1nc(OCCO)c(C(=O)OC(C)(C)C)c1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCOc1nn(C)c(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 5-amino-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-4-carboxylate (Preparation 11) (60 g) in tetrahydrofuran (500 ml), under nitrogen and at room temperature, was added triethylamine (41.7 ml), 4-dimethylaminopyridine (400 mg) followed by acetic anhydride (28.6 ml) dropwise. The reaction was stirred at room temperature overnight and was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 ml) and washed with brine (2×100 ml). The organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as white solid (71 g).
Reaction SMILES: O1C=CC=C1[C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)/[CH:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[NH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:17]\1=2.[C:25]([O:28][CH2:29][CH3:30])(=O)[CH3:26]>[Pd]>[O:28]1[CH2:29][CH2:30][CH:26]([C:6]2[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=2)[CH2:9][CH:10]2[C:17]3[CH:16]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:25]1
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(-c2ccco2)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C2CCOC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(E)-Methyl 4-(3-(furan-2-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.066 g, 0.207 mmol) was dissolved in ethyl acetate (5 mL). Then palladium on carbon (5%) was added and the reaction placed under a hydrogen atmosphere using a balloon, stirred at room temperature for 5 h, then filtered through celite. The filtrate was concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane affording the title compound. 0.028 g.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:56][O:57][C:58]1[CH:59]=[C:60]([CH:63]=[C:64]([O:68][CH3:69])[C:65]=1[O:66][CH3:67])[CH2:61][NH2:62]>CN(C)C=O>[CH3:69][O:68][C:64]1[CH:63]=[C:60]([CH:59]=[C:58]([O:57][CH3:56])[C:65]=1[O:66][CH3:67])[CH2:61][NH:62][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:23]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Reactant: COc1cc(CN)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)C2CCCC(n3c(=O)c4c(C)onc4c4ccncc43)C2)cc(OC)c1OC
Yield: 86.9 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol) and 3,4,5-trimethoxy benzylamine (33 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and chromatograph over silica gel to give 66 mg (85%) of the desired product as a white solid. MS(ES): (M+1)+ 507.2, 508.2, 509.2 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Zn]>[NH2:20][C:19]([C:15]1([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][CH2:18]1)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:7]
Reactant: CCOC(=O)CBr
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 0.25 h

Procedure:
A suspension of zinc dust (25.5 g) (which had been activated by treatment with excess 3N hydrochloric acid followed by washing with water, ethanol and ether and drying) in dry tetrahydrofuran (250 ml) was stirred and heated under reflux while ethylbromoacetate (5 ml) was added dropwise. Stirring was continued for 15 minutes and 1-(4-chlorophenyl)cyclobutanecarbonitrile (15 g) was added. The mixture was heated under reflux and ethyl bromoacetate (60 g) was added over a period of 1 hour and the heating continued for a further 15 minutes. The mixture was then cooled and tetrahydrofuran (700 ml) and 25% aqueous potassium carbonate solution (300 ml) were added and the mixture was stirred for 15 minutes. The aqueous phase of the reaction mixture was separated, extracted with ether and the extracts combined with the organic phase of the reaction mixture, washed with brine and dried. Removal of the solvents gave an oil which was extracted with petroleum ether (b.p. 40°-60° C.). Removal of the solvent by evaporation gave ethyl 3-amino-3-[1-(4-chlorophenyl)cyclobutyl]acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54]C)=O)=O.[NH2:56][NH2:57]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]1[NH:50][CH2:51][C:52](=[O:54])[NH:57][N:56]=1
Reactant: NN
Reactant: COC(=O)CNC(=O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: CO
Product: O=C1CNC(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)=NN1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of methyl 2-(2-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)acetamido)acetate (compound 54, 1.1 g, 1.44 mmol) in MeOH (20 ml) was added hydrazine anhydrous (2 ml) at room temperature. Then, the reaction temperature was raised to 60° C., and maintained for overnight. After reaction complete, the solution was evaporated in vacuo, and the residue was dissolved in acetic acid (10 ml) with ammonium acetate (1 g). The reaction solution was refluxed for 1 day. The resulting solution was cooled to room temperature, and then evaporated under reduced pressure. The residue was purified with column chromatography (Hx/EtOAc=1/1) to afford to title compound (826 mg, 77% overall yield) as white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[C:15]([CH3:20])[C:14]=1[O:21][CH3:22]>C1COCC1>[CH3:22][O:21][C:14]1[C:15]([CH3:20])=[N+:16]([O-:19])[CH:17]=[CH:18][C:13]=1[O:1][CH2:2][C:3]1([CH3:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1
Reactant: CC1(CO)COCOC1
Reactant: COc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(OCC2(C)COCOC2)cc[n+]([O-])c1C
Yield: 24.1 %

Procedure:
A deareated solution of 5-(hydroxymethyl)-5-methyl-1,3-dioxane (1.19 g, 9 mmol) in 125 ml dry THF was treated with NaH (0.79 g 55% dispersion in oil, 18 mmol) for 20 min. 4-Chloro-3-methoxy-2-methylpyridine-N-oxide (1.04 g, 6 mmol) was added and the mixture was refluxed for 26 h. Excess NaH was quenched with 10 ml of H2O and the solvent evaporated. The residue was partitioned between 150 ml CH2Cl2 and 50 ml 5% Na2CO3. The organic layer was passed through a phase separation paper and evaporated leaving 1.83 g enriched product. Chromatography (SiO2CH2Cl2 /MeOH, 95/5) afforded 0.39 g (24%) pure title compound as a tanned oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:34][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCF)c3)nc2c1

Procedure:
This compound was prepared in the same manner as described in example 81 starting from 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (250 mg, 0.559 mmol) and toluene-4-sulfonic acid fluoromethyl ester (171 mg, 0.838 mmol). White solid (10 mg, 4%). LC-MS: m/z=480.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:37][C:38](=[NH:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1>CN(C)C=O>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:9][N:47]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=3)[N:37]=2)=[CH:10][CH:11]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(-c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-trifluoromethylbenzoic acid (6 g, 0.032 mol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (6.05 g, 0.0315 mol) and 1-hydroxy-benzotriazole hydrate (4.82 g, 0.032 mol) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 30 minutes. N-Hydroxy-4-hydroxymethylbenzamidine (6.97 g, 90%, 0.038 mol) is added and the reaction mixture is heated at reflux for 3 hrs, then allowed to come to room temperature and solvent is removed under reduced pressure. An aqueous solution (100 mL) of sodium bicarbonate is added to the residue and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 65:35) to give 4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]phenylmethanol.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.[CH:24]([C:26]1[CH:30]=[C:29](I)[S:28][C:27]=1[CH2:32][OH:33])=[O:25]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCCC1>[CH:24]([C:26]1[CH:30]=[C:29]([C:6]2[S:10][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:7]=2)[S:28][C:27]=1[CH2:32][OH:33])=[O:25]
Reactant: O=Cc1cc(I)sc1CO
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2cccs2)s1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(-c3cccs3)s2)sc1CO
Yield: 37.6 %

Procedure:
In a two-necked round bottomed flask was added 5-tributylstannyl-2,2'-bithiophene (2.04 g), bis(triphenylphosphine)palladium (II) chloride (0.19 g), 3-formyl-2-hydroxymethyl-5-iodo-thiophene (1.0 g) and tetrahydrofuran (20 ml). The reaction mixture was refluxed for 16 hours. Extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (9:1→1:1 gradient) to give brownish solid product (0.43 g, 38%), melting point 108°-110° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1C(OC)=O.[H][H]>CO.[Pd]>[OH:1][CH2:2][C@@H:3]1[CH2:4][N:5]2[CH2:13][CH2:12][CH2:11][C@H:6]2[C:15](=[O:17])[NH:14]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCCN1C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1N[C@H](CO)CN2CCC[C@@H]12
Yield: 84.9 %

Procedure:
A solution of methyl 1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50 wt. % in water) in methanol and treated with hydrogen at 40 psi for 1 h. The mixture was filtered and the filtrate was brought to reflux briefly and then cooled and concentrated in vacuo to afford (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a colorless solid (1.50 g, 8.83 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.28-7.22 (m, 1H), 3.83-3.75 (m, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H), 3.31 (t, 1H), 3.08 (dd, 1H), 2.92 (dt, 1H), 2.76-2.70 (m, 1H), 2.66 (dd, 1H), 2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (EI) for C8H14N2O2: 171 (MH+).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>CCOCC>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:27]
Reactant: COC1CCCCC1=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COC1CCCCC1(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2.5M n-butyllithium in hexane (13.2 ml, 33 mmol) at -78° C. was added diethyl ether (15 ml) followed by a solution of 3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10 minutes. After 1 hour at -78° C. a solution of (±)-2-methoxycyclohexanone (3.84 g, 30 mmol) in ether (20 ml) was added dropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at 0° C. the reaction mixture was warmed to 20° C. and then poured onto ice (150 g). The mixture was extracted with ether (2×50 ml) and then the combined organic extracts were extracted with 1N hydrochloric acid (50 ml). This aqueous extract was washed with ether (20 ml) and then treated with 2M sodium hydroxide solution (25 ml) and extracted with ether (3×100 ml). The organic extracts were combined, washed with brine then dried over anhydrous sodium sulphate. Concentration in vacuo afforded (±)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1 mixture of cis and trans isomers;
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+].[OH-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:19])=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)O
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the commercially available 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (CAS No. 950-81-2) (51.6 g) in tetrahydrofuran (THF) (1 L) at 0° C. was added a solution of sulfamic acid (48.5 g) in water (640 mL). A solution of sodium chlorite (43.7 g) in water (500 mL) was added slowly maintaining the temperature below 8° C. The reaction mixture was allowed to warm to room temperature. After 5 hours, the pH of the reaction was adjusted to 8 with a 6 N aqueous solution of sodium hydroxide (NaOH). The mixture was extracted with ethyl acetate (EtOAc). The aqueous layer was acidified to pH 4 with a 6N solution of hydrochloric acid (HCl) and extracted with dichloromethane (DCM). The combined DCM extracts were washed sequentially with 5% aqueous sodium sulfite and saturated brine, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude solid was triturated with methanol (MeOH) to give the title compound (17 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(C)C>[N:21]1([C:2]2[C:3]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1C
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: COc1ccc(-c2ccc3ncnc(N4CCNCC4)c3n2)cc1C
Temperature: 80 °C
Yield: 78 %

Procedure:
To a suspension of 4-chloro-6-(3-methyl-4-methoxyphenyl)-pyrido[3,2-d]pyrimidine (0.99 mmole) in isopropanol (40 ml) was added piperazine (1.99 mmole). The reaction mixture was heated at 80° C. for 2 hours. The solvents were evaporated in vacuo. The crude residue was purified by silica gel flash chromatography (the mobile phase being a mixture of methanol and dichloromethane with an 0.5% aqueous NH3 solution (in a ratio gradually ranging from 2:98 to 3:97), resulting in the pure title compound (259 mg, yield 78%) which was characterized by its mass spectrum as follows: MS (m/z): 336 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][C:4]=1[F:15].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][C:4]=1[F:15])[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(CCN)c[nH]c2cc1F
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 0.75 grams (3.6 mmole) of the tryptamine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was prepared. Acetic anhydride (1.0 ml.) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvents then were removed in vacuo with moderate heating. The resulting crystalline residue was dissolved in a 1:1 mixture of warm ethyl acetate and chloroform. The solution was washed with water, then with sodium chloride solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The crystalline residue was boiled in benzene for a few minutes. The mixture was allowed to stand at room temperature for several hours, and the resulting product was collected by filtration and dried to obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, m.p. 158°-159° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
tert-Butyl (E)-3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]acrylate (0.14 g, 0.44 mmol) was dissolved in trifluoroacetic acid (2.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.088 g, 64%) as white crystals.