Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH3:11])[CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester as yellow viscous oil, MS: 405 (MH+, 1Cl).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C([C:32]#[N:33])=CN=1.NC1C=CC([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=CC=1>>[CH2:45]([O:44][C:42]([CH2:41][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:18][CH:17]=3)[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=[CH:3][CH:2]=1)=[O:43])[CH3:46]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Product: CCOC(=O)Cc1ccc(Nc2ncc(C#N)c(Nc3ccc(CC(=O)OCC)cc3)n2)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenylacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.29 (bs, 1H), 7.46 (2d, 4H, J=7.8 Hz), 7.28 (d, 2 h, J=8.1 Hz), 7.19 (d, 2H, J=8.1 Hz), 4.16 (2q, 4H, J=6.3 Hz), 3.64 (s, 2H), 3.59 (s, 2H), 1.30-1.23 (m, 6H); LCMS: ret. time: 29.29 min.; purity: 93%; MS (m/e): 461 (MH+).
Reaction SMILES: [OH-:1].[Na+].[C:3]1(=[O:16])[C:15]2[C:7]([C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=[CH:4]1>C1(C)C(C)=CC=CC=1>[C:7]12([C:11]3[C:12]([C:13]4[C:9]([CH:10]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:13][CH:14]=[CH:15]1)[C:8]1[C:14]([C:15]3[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:4]([C:3]([OH:1])=[O:16])[CH:5]=[CH:6]2
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(O)C1=C2C(=Cc3ccccc32)C2(C=CC=C3C2=Cc2ccccc23)C=C1

Procedure:
 In a 2 l flask, 100 g of fluorenone were dissolved in 1000 ml of dry xylene and admixed while stirring with 200 g of dry NaOH. The mixture was subsequently refluxed for 70 hours. After cooling, the mixture was filtered with suction and the residue was admixed with about 2 l of water. The aqueous suspension was filtered with suction and the precipitate was again slurried with toluene, filtered off with suction and dried. This intermediate was dissolved using about 5 ml of glacial acetic acid per 1 g by refluxing in a 500 ml two-necked flask fitted with reflux condenser and drying tube, 20 ml of concentrated HCl were added and the mixture was refluxed for 5 hours. The reaction mixture was evaporated to about half its volume and was subsequently poured into four times its volume of H2O. The precipitate formed was filtered off with suction, washed well with H2O and dried. To purify it further, it was dissolved at room temperature in an alkaline MeOH/water (10:1) mixture and shaken with toluene. The MeOH/water phase was separated off and, after acidification with hydrochloric acid, poured into water. The spirobifluorene-4-carboxylic acid which was precipitated was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1([CH2:57][CH2:58][OH:59])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:54]6[CH2:55][CH2:56][N:51]([CH2:57][CH2:58][OH:59])[CH2:52][CH2:53]6)=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: OCCN1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3)cn2)cc1
Yield: 103.6 %

Procedure:
Using 4-(4-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (70.4 mg, 0.104 mmol) obtained in Step A in Example 1-D-21 and 1-piperazineethanol (25.5 μl, 0.208 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (83.2 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-145) as a yellow powder (24.5 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON[C:18](=[O:24])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:15])[C:9]([CH3:14])([CH3:13])[C:10]([O:12][N:23]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)O
Reactant: NC(=O)CCC(=O)NO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoic acid (5 g), N-hydroxysuccinamide (2.65 g) in DCM (100 mL) was added triethylamine (6.42 mL) and EDC (4.41 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with sodium bicarbonate (100 mL), dried with magnesium sulfate, filtered and then concentrated to afford 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoate as a colourless oil (5.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[CH:14]=1.CN1CCOCC1.[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].O>CC1OCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([NH:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[O:19])[CH:14]=1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)O)S(C)(=O)=O
Solvent: CC1CCCO1
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@](CCn1cc(-c2nc3ccccc3o2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.420 g, 1.16 mmol) in 2-MeTHF (30 mL) was added N-methyl morpholine (0.165 g, 1.62 mmol, 1.4 eq), followed by CDMT (0.244 g, 1.39 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.162 g, 1.39 mmol, 1.2 eq) was added, and the reaction was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with 30%-100% ethyl acetate/heptane to yield (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (410 mg, 77% yield) as a colorless oil. LC-MS M−H 461.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1OC
Yield: 77 %

Procedure:
1-(3,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.30 g (77%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.5 [M+H]+. 1H NMR (MeOH-d4): 7.40 (m, 1H), 7.35 (d, J=2.0, 1H), 7.17 (m, 1H), 6.96 (m, 1H), 6.91 (d, J=7.6, 1H), 6.81 (d, J=8.5, 1H), 6.76 (m, 1H), 3.91 (m, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.40 (m, 3H), 2.40 (m, 6H), 2.28 (m, 1H), 2.11 (m, 1H), 1.91 (m, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 1.54 (m, 4H), 1.41 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CN2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.2 g (41 mmol) of 4-nitrobenzaldehyde and 3.8 g (40.6 mmol) of azetidine-hydrochloride are dissolved in 120 ml of ethanol. 2.6 g (41 mmol) of sodium cyanoborohydride are added at 0° C. The mixture is slowly heated to ambient temperature and then stirred for 18 hours. Then the solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and washed with water. The solvent is eliminated in vacuo and after chromatography of the residue on silica gel (ethyl acetate/methanol/NH4OH=95:5:0.5) a light brown oil is obtained.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:24][C:23]([CH2:25][C:26]([NH2:28])=[O:27])=[N:22][N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:24][C:23]([CH2:25][C:26](=[O:27])[NH2:28])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)Cc1nnc(S)s1
Product: NC(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Yield: 69.8 %

Procedure:
7-ACA and 5-mercapto-1,3,4-thiadiazol-2-ylacetamide were reacted as described in example 23a to give the title compound in 69.8% yield; δ(CF3CO2H) 3.93 (2H,s, C2 methylene), 4.63 (2H,s, --CH2CO--), 4.82 (2H,bs, --CH2S--), 5.47 (2H,s, β-lactam protons), 7.2-7.8 (2H,m, --CONH2).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:33][O:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O-:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[S:41](=[O:45])(=[O:44])([OH:43])[OH:42]>C(#N)C>[S:41]([OH:45])([O-:44])(=[O:43])=[O:42].[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:33][O:34][C:35]([C:38]([OH:40])=[O:39])([CH3:36])[CH3:37])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4n3CCCN4)CS[C@H]12)c1nsc(N)n1)C(=O)O
Solvent: CC#N
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccc4n3CCCN4)CS[C@H]12)c1nsc(N)n1)C(=O)O
Product: O=S(=O)([O-])O
Reaction time: 0.5 h

Procedure:
To a suspension of 7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer)(0.5 g) in acetonitrile (1 ml) was added 2M sulfuric acid (0.5 ml) at ambient temperature. The mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]-pyrimidinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) as crystals (380 mg).
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH3:13]O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:13])=[O:4]
Reactant: CO
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(F)(F)C(O)CC(C)C
Yield: 72 %

Procedure:
To a mixture of 28.11 g of Intermediate 1 (Example 1) and 280 g of methanol was added 0.6 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated under reflux for 8 hours. After cooling, the reaction mixture was concentrated to about 200 ml. The concentrate was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 21.8 g (yield 72%) of methyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Na]>ClCCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Place N-(6-aminopyridin-2-yl)-4-fluorobenzamide (P reparation 37) (2 g, 8.3 mmol)and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane (20 mL). Stir for 1 hr. then add sodium triacetoxyborohydrlde (4.38 g, 20.8 mmol). After stirring for 36 hr., quench with 1 N NaOH and dilute with CH2Cl2. Separate and extract the aqueous layer twice with CH2Cl2, combine organics, dry over MgSO4, and concentrate. Take up the residue in CH2Cl2, and place on two 10 g SCX colulmns. Wash the columns successively with CH2Cl2 and then with methanol. Elute the product with 2M NH3 in methanol. Concentrate and chromatograph on silica gel, eluting with a gradient of 0–10% (2M NH3 in methanol) in CH2Cl2) to give the title intermediate 3.11 g (90%): mass spectrum (ion spray): m/z 415.4 (M+1); mp 82.7° C.
Reaction SMILES: [N+]([O-])(O)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][N:16]([CH3:18])[CH2:15][C:14]3[S:19][CH:20]=[CH:21][C:13]2=3)=[CH:8][CH:7]=1.[NH3:22].F[C:24](F)(F)[C:25]([OH:27])=O>>[C:25]([NH:22][C:20]1[S:19][C:14]2[CH2:15][N:16]([CH3:18])[CH2:17][CH:12]([C:9]3[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=3)[C:13]=2[CH:21]=1)(=[O:27])[CH3:24]
Reactant: N
Reactant: O=C(O)C(F)(F)F
Reactant: CN1Cc2sccc2C(c2ccc(Br)cc2)C1
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1cc2c(s1)CN(C)CC2c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
25 ml of fuming nitric acid were added dropwise to 14.5 gm (0.047 mol) of 4-(p-bromo-phenyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in 100 ml of trifluoroacetic acid, while cooling, so that the temperature did not exceed 20° C. After all the nitric acid had been added, the mixture was stirred for a further 30 minutes. The reaction mixture was then poured over ice, concentrated ammonia was added until the mixture reacted alkaline, and the mixture was then extracted with methylene chloride. After the solvent had been evaporated, the residual 4-(p-bromo-phenyl)-6-methyl-2-nitro-4,5,6,7-tetrahydrothieno[2,3-c]pyridine was crystallized as its hydrochloride from alcoholic hydrochloric acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7](C(O)=O)=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCc1nc(-n2cccc2)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A suspension of 2-butyl-4-(1H-pyrrol-1yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid (Example 16, 50 mg) in toluene (10 mL) was heated at reflux for 1 hour. Evaporation gave a gummy solid that was redissolved in ether and evaporated again to give the title compound as a colorless powder. 1H-NMR (CDCl3) δ7.9 (d, 1H), 7.6 (m, 2H), 7.4 (d, 2H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (s, 2H), 6.5 (s, 1H), 6.1 (s, 2H), 5.0 (s, 2H), 2.4 (t, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH2:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>O1CCOCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:1][NH:11][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:15]=1[OH:20]
Reactant: COc1ccccc1O
Reactant: C=O
Reactant: NCCc1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(CNCCc2ccccc2)c1O
Temperature: 100 °C

Procedure:
To 10 ml. of dioxane are added 1.5 ml. of 37 % formalin and 2.42 g. of phenethylamine, followed by the addition of 3.2 g. of ortho-methoxyphenol dissolved in 3 ml. of dioxane. The mixture is heated at 100° C for 4 hours and distilled under reduced pressure to remove the solvent. The residue is purified by column chromatography on silica gel with a mixture of acetone and benzene (1:4) to obtain 2-methoxy-6-phenethylaminomethylphenol as an oil. Yield: 0.7 g.
Reaction SMILES: Br[C:2]1C=CC(OC)=C(C=1)C(Cl)=O.Br[C:14]1[CH:15]=[CH:16][C:17]([O:37][CH3:38])=[C:18]([CH:36]=1)[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]CC)=[O:32])=[CH:26][CH:25]=1)=[O:20].BrC1C=CC(OC)=C(C=1)C(NCCC1C=CC(CC(O)=O)=CC=1)=O>>[CH3:38][O:37][C:17]1[CH:16]=[CH:15][C:14]([CH3:2])=[CH:36][C:18]=1[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1)=[O:20]
Reactant: CCOC(=O)Cc1ccc(CCNC(=O)c2cc(Br)ccc2OC)cc1
Reactant: COc1ccc(Br)cc1C(=O)Cl
Agent: COc1ccc(Br)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Product: COc1ccc(C)cc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 5-bromo-2-methoxybenzoyl chloride, via ethyl 4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetate (oil), 4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p. 148°-150° C., after recrystallization from isopropanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.N1C=[CH:19][C:18](C(=O)CC(OCC)=O)=[CH:17][CH:16]=1.Cl.NC1[C:36]([N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])([CH3:37])[CH2:35][CH2:34]CN=1>>[CH3:37][C:36]1([N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[C:35]2[CH:19]([C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[CH:34]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1(N2C(=O)c3ccccc3C2=O)CCCN=C1N
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Product: CC1(N2C(=O)c3ccccc3C2=O)CCCC2C(=O)C=C(c3ccncn3)C=C21

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) the compound was obtained as a white powder.
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])N=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42](C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:11]=1[CH2:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([CH2:3][O:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=2)=[N:42][CH:41]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)n1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1cccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 2-(chloromethyl)-6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine (0.96 g), methyl 2-(3-hydroxyphenyl)acetate (0.50 g), anhydrous potassium carbonate (0.52 g) and N,N-dimethylformamide (15 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridylmethoxy]phenyl]acetate as a colorless oil (1.17 g, 87%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][C@H:29]([C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][C@@H:29]([OH:30])[C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Reactant: CNC[C@@H](O)c1cnccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)C[C@@H](O)c2cnccn2)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.7 %

Procedure:
A mixture of N-(4-fluorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (104 mg, 0.275 mmol), (1R)-2-(methylamino)-1-pyrazin-2-ylethanol (Preparation 80, 65 mg, 0.0.42 mmol) and diisopropylethylamine (72 μL, 0.0.41 mmol) in dry DMF (5.5 mL) was stirred at room temperature for 17 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo, providing a white solid. Attempted recrystallization from acetonitrile (20 mL, dissolved with warming and then cooled to room temperature) gave the title compound (31 mg) as a white solid upon concentrating the filtrate.