Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1(OC)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:24]3([O:23][CH3:22])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]4[C:36]3=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1(OC)c2ccccc2-c2ccccc21
Product: COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)c2ccccc2-c2ccccc21
Yield: 21.1 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 9,9-dimethoxyfluorene (2.26 g, 10 mmol) in the same manner as the example 20 to give the compound 43 (114 mg, 21.2%). Mp 130-131° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 7 Hz, (CH3)2C), 3.20 (3 H, s, CH3O), 3.02 (2 H, m, CH2 -Im), 3.11 (1 H, m, (CH3)2CH), 3.42 (3 H, s, NCH3), 3.85 (2 H, t, J 6.2 Hz, OCH2), 6.8-7.6 (8 H, m, arom-H) Elementary analysis (for C29H28N2O2Cl2S) Calcd.: C, 64.56% H, 5.23% N, 5.19% S, 5.94% Cl, 13.14% Found: C, 64.65% H, 5.25% N, 5.10% S, 5.95% Cl, 12.89%
Reaction SMILES: C(N(CC)CC)C.[Br:8]N1C(=O)CCC1=O.[C:16]([NH:24][CH:25]1[C:41](=[O:42])[N:27]2[C:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:29]([CH3:33])[CH2:30][S:31](=[O:32])[C@H:26]12)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.[W]>[C:16]([NH:24][CH:25]1[C:41](=[O:42])[N:27]2[C:28]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])=[C:29]([CH3:33])[CH:30]([Br:8])[S:31](=[O:32])[C@H:26]12)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Agent: [W]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1Br
Yield: 112.9 %

Procedure:
4.2 ml (30 mmoles) of triethylamine and 3.28 g (24 mmoles) of N-bromosuccinimide were sequentially added to a solution of 7.8 g (20 mmoles) of t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 150 ml of methylene chloride under nitrogen and cooled in an ice bath and the mixture was irradiated with a 150 W tungsten lamp for 15 minutes. The dark-brown reaction mixture was washed with a dilute hydrochloric acid solution (pH 1) and then twice with 250 ml portions of water. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to obtain 10.6 g (70% yield-purity 62%) of t-butyl 7-benzamido-2-bromo-3-methyl-3-cephem-4-carboxylate 1-oxide.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])#[N:2].CO>[Pt](=O)=O.C(Cl)(Cl)Cl>[NH2:2][CH2:1][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CC#N)cc2s1
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Reaction time: 48 h
Yield: 121.5 %

Procedure:
A suspension of 1-(6-(2-cyanoacetyl)-2-benzothiazolyl)-3-ethylurea (0.56 g, 1.94 mmol) and platinum (IV) oxide (0.176 g, 0.78 mmol, 0.40 eq) in 50 mL of 2/3 mixture of MeOH and chloroform was purged and bubbled with hydrogen gas. It was stirred under hydrogen gas for about 2 days. The mixture was filtered and concentrated to give 0.689 g (quantitative yield) desired compound. LC/MS 292.9 (M+1); LC retention time 1.80 min. HPLC purification gave corresponding acetic acid salt. LC/MS 292.9 (M+1); LC retention time 1.80 min. In a similar reaction, compound as an acetate salt form was obtained after HPLC purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>ClCCl>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: NCC1(O)CC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of 1-(aminomethyl)cyclopropanol (approximately 36.7 mmol, prepared as described by Lysenko, I. L. and Kulinkovich, O. G. Russ. i J. Org Chem. 2001, 17, 1238-1243) and triethylamine (6.30 mL, 45.4 mmol) in dichloromethane (120 mL) was added a solution of 4-chloro-3-nitroquinoline (7.28 g, 34.9 mmol) in dichloromethane (30 mL). The suspension was stirred at room temperature over the weekend. The dichloromethane was removed under reduced pressure and the residue was suspended in water (150 mL) and stirred at room temperature for 3 hours. A solid was isolated by filtration and dried in a vacuum oven to afford 8.99 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol as a yellow solid.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])(=O)C.O.[BrH:16]>>[Br:16][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: CC(=O)OCCCCC(C)(C)C(=O)O
Reactant: Br
Solvent: O
Product: CC(C)(CCCCBr)C(=O)O
Temperature: 130 °C
Yield: 91 %

Procedure:
6-Acetoxy-2,2-dimethylhexanoic acid (4.5 g) was dissolved in 47% aqueous hydrobromic acid (25 ml), and the solution was heated at 130° C. for 4 hours. After the completion of the reaction, water (100 ml) was added to the solution, and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development with isopropyl ether yielded 6-bromo-2,2-dimethylhexanoic acid (4 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22]COC)[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)=[C:5]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:4]=1[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)ccc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)c(O)c1

Procedure:
Then, 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone was dissolved in 7.5 ml of methanol, and 7.5 ml of hydrochloride acid/methanol was added to the solution and the mixture was heated and refluxed. After the reaction, the solvent was removed from the reaction mixture by distillation and the obtained residue was dissolved in a small amount of ethyl acetate and crystallized from ether/hexane to obtain 3.5 g (yield=of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-hydroxy-4-methoxyphenyl)-1-propanone in the form of a colorless transparent rectangular crystal.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[S:16]([CH3:19])(=[O:18])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][Br:20])[CH:12]=[CH:11][C:10]=1[S:16]([CH3:19])(=[O:18])=[O:17])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1cc(CBr)ccc1S(C)(=O)=O

Procedure:
A solution of 46 g (0.152 mol) of N-tert-butyl-2-methanesulfonyl-5-methyl-benzenesulfonamide in 450 ml of CCl4 is, after the addition of 27.0 g (0.152 mol) of NBS (N-bromosuccinimide) and 1 g of AIBN (azobisisobutyronitrile), heated under reflux for 7 h using a daylight lamp. The reaction mixture is then filtered and washed successively with NaHSO3 solution, NaHCO3 solution and water, dried over MgSO4 and completely concentrated in vacuo. 51.2 g of a crude mixture containing 55% by weight of N-tert-butyl-5-bromomethyl-2-methanesulfonylbenzenesulfonamide are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH3:31])=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH3:31])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: CCN=C=S
Product: CCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)COC
Yield: 52 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and isothiocyanatoethane (50 mg) to give the title compound as beige solid (42 mg, 52%). LCMS (formate) Rt 0.78 min, MH+ 410
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C-:9]#[N:10].[Na+]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:9]#[N:10])=[O:7]
Reactant: [C-]#N
Reactant: O=C(Cl)c1cccs1
Agent: [Na+]
Solvent: ClCCl
Product: N#CC(=O)c1cccs1

Procedure:
A process for preparing thienylglyoxamide which comprises reacting thiophene carboxylic acid chloride with aqueous sodium cyanide in methylene chloride solvent and in the presence of a phase transfer catalyst to form thiophene carboxylic acid cyanide and reacting said thiophene carboxylic acid cyanide with concentrated hydrochloric acid at a temperature and for a time sufficient to form thienylglyoxamide.
Reaction SMILES: S(=O)(=O)(O)O.[SH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10]>C1(C)C=CC=CC=1>[CH3:9][C:8]1[C:12]2[C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:6][C:13]=2[CH:14]=[CH:15][CH:7]=1
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc2sc3ccccc3c(=O)c12
Reaction time: 8 h

Procedure:
To a stirred mixture of concentrated sulphuric acid (300 ml) and toluene (46 ml), o-mercaptobenzoic acid (30 g) was added slowly. The mixture was stirred for 8 hrs. and allowed to stand for a further 10 hrs. After 1 hr. heating on the steam bath the dark red solution was cooled and poured on to ice. The gummy yellow precipitate was filtered off and triturated with 2N aqueous sodium hydroxide. The solid isomer-mixture was filtered off, washed with water, and dried at room temperature in vacuo, m.p. 107°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:20][CH2:19]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using di(4-fluorophenyl)methyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(4-fluorophenyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][O:13][S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCOc1ccc(-n2ccnc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)OCCOc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.0 g (0.074 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol in 100 mL of N,N-dimethylformamide (DMF) was added 3.8 g (0.1 mol) of sodium hydride (60% oil dispersion) portionwise and the mixture was stirred at ambient temperature for 3 h. To this mixture was added 13.7 g (0.1 mol) of dimethylsulfamoyl chloride and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 1.2 L of water and its pH was adjusted to 10 with sodium carbonate. The mixture was extracted with three 400-mL portions of ethyl acetate. The combined organic layers were washed twice with 400-mL portions of water, dried (MgSO4), and the solvent was evaporated under reduced pressure to give a viscous residue. The residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPAK 500 silica; ethyl acetate; flow rate 150 mL/min). Fractions containing the product were combined and the solvent was evaporated under reduced pressure to give the title compound, a viscous oil. The oil was converted to the hydrochloride (2-propanol; ethereal HCl) and the white solid was collected by filtration to yield 5.9 g (26%), mp 120°-123° C.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(=O)/C=C\C(O)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:27]=[CH:26]2>>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][CH:2]3[CH2:6][CH2:5][NH:4][CH2:3]3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1)=[O:37]
Reactant: CC(C)(C)C(=O)n1ncc2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: O=C(O)/C=C\C(=O)O
Product: CC(C)(C)C(=O)n1ncc2cc(NC3CCNC3)ccc21

Procedure:
Reaction of tert-butyl 3-oxopyrrolidine-1-carboxylate and 1-(5-amino-1H-indazol-1-yl)-2,2-dimethylpropan-1-one maleate salt using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:32](Cl)(=[O:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:32](=[O:34])[CH3:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (6-methoxy-2′-phenylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[F:15][CH:16]([C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[C:25]=1[CH3:34])[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[CH2:35]([OH:37])[CH3:36]>>[F:15][CH:16]([C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[C:25]=1[CH3:34])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:14][CH:12]([OH:13])[C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[CH2:20][CH2:19]1.[CH2:35]([O:37][CH:16]([C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[C:25]=1[CH3:34])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:14][CH:12]([OH:13])[C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[CH2:20][CH2:19]1)[CH3:36]
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(F)CN2CCNCC2)ccc2c1COC2=O
Reactant: CCO
Product: CCOC(CN1CCN(CC(O)c2ccc3c(c2C)COC3=O)CC1)c1ccc2c(c1C)COC2=O
Product: Cc1c(C(O)CN2CCN(CC(F)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
4-Methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (75 mg, 0.394 mmol, 1.2 mmol) and 5-(1-fluoro-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one (90 mg, 0.323 mmol, 1.0 eq) were suspended in ethanol (30 ml). The mixture was heated to 150° C. for 30 min under microwave irradiation. The mixture was concentrated and purify by flash column chromatograph (0-10% MeOH/DCM) to afford the expected product 5-(1-fluoro-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one as well as byproduct 5-(1-(ethyloxy)-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[C:14](=[S:15])[NH:13][N:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH3:17].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH:11]=[N:12][N:13]=[C:14]2[S:15][CH3:19])[CH:7]=[CH:6][C:5]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc(-n2cn[nH]c2=S)ccc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(-n2cnnc2SC)ccc1OC
Yield: 72 %

Procedure:
Treat a stirred mixture of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid methyl ester (3.80 g, 14.38 mmol), potassium carbonate (2.19 g, 15.8 mmol) and anhydrous acetone (60 mL) with methyl iodide (1.07 mL, 17.25 mmol) added dropwise via syringe. Reflux the stirred mixture for 2.5 hours, cool, filter and wash the filter cake twice with acetone. Combine the acetone phases, concentrate in vacuo, dissolve the residue in ethyl acetate and wash with NaHCO3 solution. Extract the combined aqueous phases three times with ethyl acetate. Combine the ethyl acetate phases, wash with saturated NaHCO3 and brine, dry (MgSO4), filter and concentrate in vacuo to afford an oil. Purify the oil by flash chromatography (silica gel, 5.5×15.2 cm) eluting with ethyl acetate and then with 5% methanol in dichloromethane after elution of the starting material. Concentrate the appropriate fractions to afford 2.89 g of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:13])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH3:10])[C:5]([CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)c[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncc(Br)c(Cl)c1C

Procedure:
5-bromo-2,3-lutidine-N-oxide (30.31 g) was added in portions to phosphorus oxychloride (41.3 ml) at 30°-40°. The mixture was heated to 50°, when an exothermic reaction raised the temperature to reflux. After 30 minutes the solution was cooled and poured onto ice to give a white solid, which was filtered off and discarded. The filtrate was extracted with ether then treated with 40% aqueous sodium hydroxide to pH 7, and extracted again with ether. The latter extract was dried (MgSO4) and stripped to give 5-bromo-4-chloro-2,3-lutidine, 12.0 g as a low melting solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH3:10][N:11]([CH3:17])[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15].C(C1C([OH:28])=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[OH-].[Na+]>O>[CH3:15][C:14]([NH:4][C:1](=[O:28])[CH:2]=[CH2:3])([CH3:16])[CH2:13][CH2:12][N:11]([CH3:17])[CH3:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)=CCN(C)C
Reactant: C=CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)NC(C)(C)CCN(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A resin flask is cooled to 0°C. and 450 grams (8.5 moles) of acrylonitrile, 1020 grams (10 moles) of sulfuric acid and 37 grams of water are added. To this mixture are then added 475 grams (4.2 moles) of the 1-dimethylamino-3-methyl-2-butene prepared as described above, and 8.5 grams of 2,6-di-t-butyl-p-cresol. The mixture is stirred at 68°C. for about 1 hour and is then neutralized with about 30% sodium hydroxide. The organic layer is separated, diluted with 2050 ml. of methanol and neutralized with ammonia. An additional 1000 ml. of methanol is added and the solution is filtered. The methanol is stripped from the filtrate and the residue is distilled. There is obtained 400 grams (64.5% of the theoretical amount) of the desired N-(1,1-dimethyl-3-dimethylaminopropyl)acrylamide boiling at 75°-92°C./0.25- 0.9 mm. The nitrogen analysis is 15.4%, as compared with theoretical value of 15.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]([OH:26])[C:13]([NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:27]1[CH2:31][O:30]CC1.C[OH:33].[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][C@H:10]([N:12]([OH:26])[C:13](=[O:14])[NH:15][CH2:27][C:31]([OH:33])=[O:30])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)N(O)[C@H]2C[C@@H](c3ccc(F)cc3)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNC(=O)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reaction time: 8 h

Procedure:
To a stirred solution of the compound prepared in Example 71, above (1.03 g, 3.32 mmol), in a THF/MeOH (5 ml/5 ml) solution was added dropwise KOH (0.285 g, 4.32 mmol) in H2O (7 ml). After stirring overnight, the volatiles were removed in vacuo, an Et2O/H2O (40 ml/30 ml) mixture was added, the aqueous layer was separated and acidified with 10% aqueous HCl and the whole was extracted with ethyl acetate (2×50 ml), washed with water and brine, then dried over MgSO4 and evaporated in vacuo. The resulting solid was triturated with an Et2O/n-hexane mixture to afford 0.74 g of desired product as a colorless solid, m.p. 137-139° C. (dec.).