Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.Cl.Cl.Cl.[NH2:14][C:15]1[C:20]2=[C:21]([C:39]3[S:40][C:41]4[C:47]([O:48][CH3:49])=[CH:46][C:45]([CH3:50])=[CH:44][C:42]=4[CH:43]=3)[C:22]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][C:34](=[O:38])[CH2:33]3)=[C:23]([CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:19]2[N:18]=[CH:17][N:16]=1>ClCCl.N1C=CC=CC=1.CO>[NH2:14][C:15]1[C:20]2=[C:21]([C:39]3[S:40][C:41]4[C:47]([O:48][CH3:49])=[CH:46][C:45]([CH3:50])=[CH:44][C:42]=4[CH:43]=3)[C:22]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][C:34](=[O:38])[CH2:33]3)=[C:23]([CH2:24][N:25]3[CH2:26][CH2:27][N:28]([CH:1]=[O:3])[CH2:29][CH2:30]3)[N:19]2[N:18]=[CH:17][N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Agent: Cl
Solvent: O=CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCN(C=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid anhydride (498 μl, 5.17 mmol) and formic acid (237 μl, 6.28 mmol) were stirred first 2 h at 50° C. and then overnight at rt. Subsequently, the mixture was diluted with dichloromethane (5.1 ml), and 1.16 ml of this solution were added to a solution of Example 49 (233 mg, 370 μmol) in pyridine (89 μl). After stirring at rt for 2 h, the mixture was diluted with methanol and then evaporated. The residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 77 mg (35% of th.) of title compound.
Reaction SMILES: CO[CH:3]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6].[C:11]([NH2:14])(=[NH:13])[CH3:12]>>[CH3:12][C:11]1[N:14]=[C:5]([NH2:6])[C:4]([CH2:7][NH:8][CH:9]=[O:10])=[CH:3][N:13]=1
Reactant: COC=C(C#N)CNC=O
Reactant: CC(=N)N
Product: Cc1ncc(CNC=O)c(N)n1

Procedure:
The α-methoxymethylene-β-formylaminopropionitrile solution and the acetamidine solution are combined. The mixture is reacted at 25°C for 10 minutes. The reaction mixture is subjected to concentration at not higher than 40°C to give crystals. The produced crystals are washed with 50 parts by volume of ethanol, whereby 24.8 parts of 2-methyl-4-amino-5-formylaminomethylpyrimidine is obtained as crystals (Purity: 93 %). The ethanol washing is concentrated to give 16 parts of 2-methyl-4-amino-5-formylaminomethylpyrimidine as crystals (Purity: 47.5 %).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][NH:10][CH:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][N:14]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH2:15]2.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:14]2[CH2:15][CH:16]3[CH:11]([N:10]([CH3:9])[S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])[CH:12]([CH2:18][CH2:17]3)[CH2:13]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCCCS(=O)(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution of 1-butanesulfonyl chloride (39.1 mg, 0.25 mmol) in MeCN (2 mL) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Preparation G; 74.6 mg, 0.25 mmol) in CHCl3 (0.5 mL). K2CO3 was added and the mixture was stirred at rt for 24 h. The mixture was filtered through a silica plug (500 mg), which plug was then eluted with MeCN:CHCl3 (80:20; 3×2.5 mL), followed by CHCl3:MeOH (95:5), to give the title compound in 35% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[O:27]
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Reactant: COc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)Cc2ccccc2OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-methoxyphenylpiperazine (0.062 g, 0.32 mmol) and 2-(2,2,2-trifluoroethoxy)phenylacetic acid (0.075 mg, 0.32 mmol) in DMF (1 mL) was added EDC (0.115 g, 0.40 mmol), HOBT (0.049 g, 0.32 mmol), and DIEA (0.055 mL, 0.32 mmol). The mixture was stirred at ambient temperature for 18 h. The DMF was removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC using 1:1 EtOAc:hexane as eluant. The title compound was obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH3:9])[C@H:5]([OH:10])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C@@H:5]([OH:10])[C@H:6]([N:8]([CH3:9])[C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH2:7]1)[CH3:2]
Reactant: CCN1C[C@@H](O)[C@H](NC)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 17.0 g. (118 mmoles) of trans-1-ethyl-4-methylamino-3-pyrrolidinol in 180 ml of methylene chloride was mixed with 15 g of powdered anhydrous potassium carbonate and cooled to -5°. The mixture was kept at or below 0° C. while a solution of 22.0 g (118 mmoles) of p-nitrobenzoyl chloride in 100 ml of methylene chloride was added dropwise. After the mixture was stirred at ambient temperature for 18 hr, it was poured into 100 ml of water. The organic layer was separated, dried, and concentrated. The residue was crystallized from benzene to give 30 g (87%) of white crytals; m.p. 104°-108° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH:24]1[CH2:25][NH:26][CH2:27]2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([CH:25]3[NH:26][CH2:27][CH:28]4[N:23]([CH3:22])[CH:24]3[CH2:30][CH2:29]4)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CN1C2CCC1CNC2
Agent: Cl
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C3NCC4CCC3N4C)c(F)c21
Temperature: 25 °C
Reaction time: 22 h
Yield: 44.5 %

Procedure:
A mixture of 1.40 g (5.0 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.0 g (8 mmole) of 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 2.0 ml (13.3 mmole) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 75 ml of acetonitrile was heated under reflux for 1.5 hr and then stirred at room temperature for 22 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from 2-propanol to give 0.84 g of the title compound, mp 184°-187° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:30][CH3:31])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: COc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(OC)ccc1-n1c(C)c(C(C)=O)c(C(C)=O)c1C

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(2-ethoxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 330 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (60 mg) and hydrazine (50 μL) reacted to give 6-(2-ethoxy-4-methoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.04 (d, 1H), 6.68 (s, 1H), 6.64 (d, 1H), 4.15 (q, 1H), 3.78 (s, 3H), 2.81 (s, 6H), 2.40 (s, 6H), 1.51 (t, 3H); MS (ESI) 326 (M+H)+.
Reaction SMILES: Br[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Br)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[C:32]3[S:31][CH:30]=[CH:34][CH:33]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1cccc2c1Sc1c(Br)cccc1S2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1csc(-c2cccc3c2Sc2c(cccc2-c2cccs2)S3)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 103 %

Procedure:
An airfree tube containing 1,9-dibromothianthrene (187 mg, 0.5 mmole) and Pd(PPh3)2Cl2 (35 mg, 0.05 mmole) was flame dried and filled with Ar. DMF (5 mL) was added to the tube and the tube was heated to 70° C. Tributylstannylthiophene (580 mg, 1.5 mmole) was added and the solution turned black. The reaction mixture was stirred for 2 days and then cooled down to room temperature. It was poured into dichloromethane (50 mL) and the organic layer washed by water twice, dried by MgSO4. The solvent was removed in vacao. The crude product was further purified by column chromatography (hexane/dichloromethane 6/1) and yield white crystal (196 mg, 92%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[NH3:15]>C(O)C>[NH2:15][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3
Reactant: N
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Solvent: CCO
Product: NC1=NC2CCCc3cccc(c32)N1

Procedure:
62 g (0.3 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine in 400 ml of ethanol and 150 ml of liquid ammonia are heated to 150° in an autoclave for 6 hours. The pressure thereby increases to a maximum of 30 bars. After cooling, the reaction mixture is evaporated to dryness. The residue is dissolved in water, the solution is filtered through active charcoal and the 2-amino-3a,4,5,6-tetrahydroperimidine formed is precipitated by adding aqueous ammonia. After filtering off and drying the product, 40 g (71% of theory) of melting point 230°-232° are obtained. Preparation of 2-chloro-3a,4,5,6-tetrahydro-perimidine:
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])[CH2:3][CH3:4].C[Si]([C:17]#[N:18])(C)C>>[F:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[CH:2]([CH2:3][CH3:4])[C:17]#[N:18]
Reactant: CCC(Br)c1cc(F)ccc1F
Reactant: C[Si](C)(C)C#N
Product: CCC(C#N)c1cc(F)ccc1F

Procedure:
rac-2-(2,5-Difluoro-phenyl)-butyronitrile was prepared from rac-2-(1-bromo-propyl)-1,4-difluoro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:16])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
Starting material (10(c)) was prepared as follows. Pyridine 2,5-dicarboxylic acid 2-methyl ester (10(a)) (9.0 g; 0.05 mole) was added to stirring thionyl chloride (25 mL) and the mixture refluxed gently for 2.5 hours. The excess thionyl chloride was removed in vacuo and the residual solid azeotroped with toluene (2×25 mL) to give 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester (10(b)) which was used crude in the next reaction.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1[C:52]2[C:47](=[N:48][CH:49]=[CH:50][CH:51]=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.N1CCCCC1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:48]5[CH2:49][CH2:50][CH2:51][CH2:52][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.013 g (0.15 mmole) piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.042 g of 9-cyclopentyl-7,7-difluoro-2-[2-methoxy-4-(piperidine-1-carbonyl)-phenylamino]-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-126) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:34])[CH2:17][CH2:18][C:19](=[O:33])[CH:20]([CH3:32])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=CCO>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH:2]=[C:9]([CH3:8])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:34])[CH2:17][CH2:18][C:19](=[O:33])[CH:20]([CH3:32])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCO
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a mixture of acetic anhydride (8.1 g) and pyridine (3.2 g), 3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-on-1-ol (15 g) is added, and stirring is continued while cooling with ice for 3 hours. The reaction mixture is poured into ice water and extracted with ether. The ether extract is washed with water, dired and evaporated to give 1-acetoxy-3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-one (15 g). IR: 1740, 1710, 1675 cm-1. NMR (carbon tetrachloride): δ 1.01 (d), 1.56 (s), 1.65 (s), 1.90 (s), 1.97 (s), 2.05-2.71 (m), 4.43 (d), 4.70-5.39 (m).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][O:6][CH3:7].[SH:8][CH2:9][C:10]([OH:12])=[O:11]>>[CH3:7][O:6][CH2:5][CH2:4][O:3][CH2:2][S:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COCCOCCl
Reactant: O=C(O)CS
Product: COCCOCSCC(=O)O
Yield: 58 %

Procedure:
In a similar manner, 2-methoxyethyl chloromethyl ether (4d) was reacted with mercaptoacetic acid to give S-(methoxy-ethoxy)methylmercaptoacetic acid (5d) in 58% yield as an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][C@H:15]([CH3:17])[O:14][C@H:13]([CH3:18])[CH2:12]2)=[CH:7][CH:6]=1)C.CO.O1CCCC1.O.[NH2:28][NH2:29]>C(OCC)(=O)C.O>[CH3:18][C@H:13]1[O:14][C@@H:15]([CH3:17])[CH2:16][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([NH:28][NH2:29])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1
Reactant: NN
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)O[C@@H](C)C2)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(C(=O)NN)cc2)C[C@H](C)O1
Temperature: 25 °C

Procedure:
To a solution of 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid ethyl ester (0.55 g) in a mixed solvent of methanol (3 ml) and tetrahydrofuran (6 ml) was added hydrazine monohydrate (1.6 ml). The solution was refluxed for 20 hours, during which period additional hydrazine monohydrate (1.6 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was washed with sodium chloride solution. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid hydrazide (489.7 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]1[O:15][CH2:14]1>CO>[OH:15][CH2:14][CH2:13][N:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][CH:6]([CH2:8][OH:9])[CH2:7][C:2]1([CH3:12])[CH3:1]
Reactant: C1CO1
Reactant: CC1(C)CC(CO)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(CO)CC(C)(C)N1CCO
Temperature: 120 °C
Reaction time: 6 h

Procedure:
25 g of 2,2,6,6-tetramethyl-4-hydroxymethyl-piperidine of Example 1 (0.146 moles) were dissolved in 50 cc of methanol and added with 8 g (0.18 moles) of ethylene oxide. The solution was introduced into a steel autoclave and heated under stirring during 6 hours at 120° C. Then the solvent was evaporated and the residue was crystallized from acetonitrile. 30 g of product having a M.P. of 81°-83° C. were obtained, the product being characterized by N.M.R. and I.R. analyses and recognized as the product intended to be obtained.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:13](N)=[O:14]>O>[CH:13]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[CH2:9]1)=[O:14]
Reactant: NC=O
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Solvent: O
Product: O=CN1CCc2cc(O)ccc2C1
Temperature: 100 °C

Procedure:
46.0 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline-hydrobromide are reacted with 85 ml of formamide for 1 hour at 140° C. with stirring. After cooling to 100° C., 216 ml of water are added, whereby the reaction product crystallizes. 34.0 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline are obtained. m.p. = 185.5° - 186° C. (ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([CH2:20][CH2:21][CH:22]2OCC[O:23]2)[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1.O1CCCC1>Cl.C(OCC)C>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([CH2:20][CH2:21][CH:22]=[O:23])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2CCC2OCCO2)c(Cl)c1OC(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1nc(-c2c(F)cc(Cl)c(=O)n2CCC=O)c(Cl)c1OC(F)F
Reaction time: 8 h
Yield: 64.1 %

Procedure:
0.40 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-1-(2-[1.3]-dioxolan-2-ylethyl)-5-fluoro-[1H]-pyridin-2-one is stirred overnight at 22° C. in a mixture of 6 ml of 2N hydrochloric acid and 6 ml of diethyl ether. The next day, the same amount of the mixture together with 2 ml of tetrahydrofuran are added and the mixture is again stirred overnight. The mixture is subsequently diluted with diethyl ether and washed three times with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. 0.23 g of the desired compound (crude) is obtained in the form of a yellow oil.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:9]([S:16][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1cccnc1SCc1ccccc1

Procedure:
A solution of 34.0 g (0.15 mol) of 2- fluoro-3-iodopyridine and 18.6 g (0.15 mol) of benzylmercaptan in 250 ml of acetonitrile is heated under reflux with 22.8 g (0.165 mol) of potassium carbonate for 8 h. The mixture is cooled, the solvent is removed on a rotary evaporator, the residue is taken up in dichloromethane and the organic phase is washed with water. After drying with sodium sulfate, evaporating and distilling the oily residue in vacuo, 37.3 g (76% of theory) of 2-benzylthio-3-iodopyridine of boiling point 150°-153° C. at 0.1 mbar are obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN)cc1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of methyl 4-(2-azidomethyl-5-chlorophenoxymethyl)benzoate (389 mg; prepared in Reference Example 49.) in THF (4.0 ml), triphenylphosphine (462 mg) was added at room temperature. The mixture was stirred for 3 hours. After stirring, water was added thereto. The mixture was stirred for 15 hours. The reaction mixture was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (CHCl3:MeOH=50:1→10:1) to give the title compound (339 mg) having the following physical data.
Reaction SMILES: C([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[C:12]([C:25]2[C:33]3[C:28](=[C:29]([O:34][CH3:35])[N:30]=[CH:31][CH:32]=3)[N:27]([CH3:36])[CH:26]=2)[CH:11]=1)C1C=CC=CC=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][C:12]=1[C:25]1[C:33]2[C:28](=[C:29]([O:34][CH3:35])[N:30]=[CH:31][CH:32]=2)[N:27]([CH3:36])[CH:26]=1
Reactant: COc1nccc2c(-c3cc(CNCc4ccccc4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nccc2c(-c3cc(CN)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A solution of Example 106A (78 mg, 0.161 mmol) in tetrahydrofuran (10 mL) was added to 20% palladium hydroxide on carbon (16 mg, 0.012 mmol) in a 50 mL pressure bottle and the mixture was stirred for 16 hours under a hydrogen atmosphere (30 psi). The mixture was filtered through a nylon membrane and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% 7N methanolic ammonia in dichloromethane) to afford the title compound (57 mg, 90% yield).