Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:25])([CH:22]([CH3:24])[CH3:23])[CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:31]O>>[CH3:31][O:20][C:19](=[O:21])[CH2:18][C:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([OH:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CO
Reactant: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C

Procedure:
A solution of 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid from Example RRRR (10.1 g, 29.5 mmol), MeOH (300 mL), and H2SO4 (0.2 mL) was refluxed for 3 days. The reaction was stripped to dryness and the product was partitioned between ethyl acetate and 5% NaHCO3. The solution was dried (MgSO4), and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[Li]C.C([Li])CCC.CN([CH:34]=[O:35])C.C(=O)(O)[O-].[Na+]>C1COCC1.CC(O)=O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[C:2]([CH:34]=[O:35])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (1.06 g, 2.66 mmol) is dissolved in THF (30 mL) and cooled to −78° C. MeLi (2.07 mL, 3.32 mmol) is added slowly, and stir for 10 minutes. n-Butyllithium (1.33 mL, 3.32 mmol) is added and the reaction mixture is stirred for 15 minutes. DMF (0.413 mL, 5.32 mmol) is added, and the reaction mixture is stirred for 30 minutes. The reaction mixture is warmed to room temperature and AcOH (2 mL) is added. The reaction mixture is stirred at room temperature for 1 hour, poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel (10-20% EtOAc in hexanes) to afford 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12]([O:16]NC1C=CC(C(O)=O)=CC=1C)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: Cc1cc(C(=O)O)ccc1NOC(C)(C)C
Product: CC(C)(C)ONc1ccc(C(=O)O)c(Cl)c1
Yield: 79 %

Procedure:
4-amino-2-chloro-benzoic acid was converted to product in 79% yield, using the procedure described for the synthesis of 4-tert-Butoxyamino-3-methyl-benzoic acid. 1H NMR (DMSO-d6): δ 1.49 (s, 9 H), 7.46 (d of d, 1 H), 7.71 (br s, 1 H), 7.80 (d, 1 H), 9.87 (s, 1 H) and 13.00 (br s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>CCN(CC)CC.CN(C1C=CN=CC=1)C.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccc(N)c(C#C[Si](C)(C)C)c2)CC1
Temperature: 70 °C
Yield: 55.7 %

Procedure:
To a degassed solution of methyl 1-(4-amino-3-bromophenyl)cyclopropane carboxylate (8 g, 0.03 mol) in Et3N (100 mL) was added ethynyl-trimethyl-silane (30 g, 0.3 mol), DMAP (5% mol) and Pd(PPh3)2Cl2 (5% mol) under N2. The mixture was refluxed at 70° C. overnight. The insoluble solid was filtered off and washed with EtOAc (100 mL×3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate=20:1) to give methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.8 g, 56%). 1H NMR (300 MHz, CDCl3) δ7.27 (s, 1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 3.60 (s, 3H), 1.55-1.51 (m, 2H), 1.12-1.09 (m, 2H), 0.24 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:22]=[C:23]=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:23]([NH:22][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=NCCc1ccccc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NCCc2ccccc2)c1O
Yield: 54.6 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (120 mg, 0.54 mmol) and phenethyl isocyanate (82 μL, 0.59 mmol) in 1.0 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), gave the desired product (109 mg, 55%). LC-MS (m/z) 369.8 (M+).
Reaction SMILES: [C:1]([C:4]([CH3:45])([CH3:44])[CH2:5][O:6][C:7]([N:9]1[CH2:13][C@@H:12]([N:14]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:42][CH3:43])=[O:8])(O)=[O:2].[Cl-].[NH4+].Cl.C1C=[N:53]C2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:4]([CH3:45])([CH3:44])[CH2:5][O:6][C:7]([N:9]1[CH2:13][C@@H:12]([N:14]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=2)[C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:42][CH3:43])=[O:8])(=[O:2])[NH2:53]
Reactant: On1nnc2cccnc21
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC(C)(C)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC(C)(C)C(N)=O
Reaction time: 18.5 h
Yield: 39.9 %

Procedure:
To a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 2-carboxy-2-methylpropyl ester (0.016 mmol; 10 mg), ammonium chloride (0.032 mmol; 1.7 mg), WSCD hydrochloride (0.032 mmol; 7.3 mg), HOAt (0.032 mmol; 4.4 mg) in DMF (0.4 ml) is added triethylamine (0.080 mol; 8.1 mg) at room temperature. The reaction mixture is stirred for 18.5 hours at the same temperature, and then quenched with water. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/MeOH) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 2-carbamoyl-2-methyl-propyl ester (4.1 mg, 40%); ESI-MS m/z: 642 [M+1]+, Retention time 2.04 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:36])[C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:32]([CH3:35])([CH3:34])[CH3:33])/[C:29]2=[O:36])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)C)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C(C)(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.36 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.30 (d, J=7.83 Hz, 1H) 6.57 (t, J=7.83 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H) 7.21 (d, J=8.08 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.57-7.64 (m, 2H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1nccn1C
Yield: 95.2 %

Procedure:
Using an analogous procedure to that described in Example 25, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (224 mg, 0.7 mmol), (prepared as described for the starting material in Example 24), and 2-chloromethyl-1-methylimidazole hydrochloride (140 mg, 0.8 mmol) were combined to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (150 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.[CH3:16][CH2:17]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CO
Product: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-amino-3-nitrobenzoate (D212) was prepared in an analogous manner to Description from commercially available 4-amino-3-nitrobenzoic acid using EtOH as solvent instead of MeOH.
Reaction SMILES: ClC1C=CC(C=O)=CC=1[N+]([O-])=O.C1(NC(C2CCNCC2)=O)CCCCC1.[CH:28]1([NH:34][C:35]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([N+:51]([O-])=O)[CH:45]=3)[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:35]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([NH2:51])[CH:45]=3)[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NC1CCCCC1)C1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: O=C(NC1CCCCC1)C1CCNCC1
Agent: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: Nc1cc(CN2CCC(C(=O)NC3CCCCC3)CC2)ccc1Cl

Procedure:
The title compound is prepared according to the reactions described above starting from 4-chloro-3-nitro-benzaldehyde and piperidine-4-carboxylic acid cyclohexylamide yielding after reductive amination 1-(4-Chloro-3-nitro-benzyl)-piperidine-4-carboxylic acid cyclohexylamide LC-MS A: tR=0.67 min; [M+H]+=380.03 and reduction with stannous chloride the title compound LC-MS A: tR=0.63 min; [M+H]+=350.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:9]2[CH2:27][NH:28][C@@H:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:48](=O)([O:54]C(C)(C)C)[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>ClCCl>[C:50]([O:49][C:48]([N:28]([CH2:27][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[O:15])[CH2:10]1)[C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccc(F)cc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 37 h
Yield: 47.8 %

Procedure:
To a solution of 888 mg of 4-(methoxycarbonyl)phenyl 4-(4-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidine-1-carboxylate in 9 mL of dichloromethane were added 0.7 mL of triethylamine and 868 mg of di-tert-butyl carbonate, followed by stirring at room temperature for 37 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 503 mg of 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as a pale yellow foamy substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][C:22]#[N:23]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:21][C:22]#[N:23]
Reactant: COc1cc(C(C)C)c(O)cc1Br
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(OCC#N)cc1Br
Temperature: 60 °C
Yield: 63.2 %

Procedure:
To a mixture of 5-bromo-2-isopropyl-4-methoxy-phenol from step 4 (0.831 g, 3.4 mmol) and K2CO3 (0.562 g, 4.1 mmol) in 17 mL dimethyl formamide (DMF) was added iodoacetonitrile (0.594 g, 3.6 mmol). The mixture was warmed to 60° C. for 30 minutes and then allowed to cool to room temperature. After cooling to room temperature the mixture was taken up in 50 mL of H2O and extracted with 1:1 toluene/ethyl acetate, washed with H2O and then with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. Purification via flash chromatography (1:1 hexane/CH2Cl2) afforded (5-bromo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (0.611 g, 63%) as a while solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:20])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1.Cl>CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C:4]([F:20])([F:3])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Reaction time: 2.5 h
Yield: 97.9 %

Procedure:
40 mL of a 2 mol/L sodium hydroxide aqueous solution was added dropwise over a period of 4 minutes under ice cooling to a 152 mL methanol solution of 15.2 g of the compound obtained in step 3-2, after which the reaction mixture was stirred for 2.5 hours at the same temperature. Upon completion of the reaction, the methanol was distilled off under reduced pressure, 100 mL of chloroform was added to the aqueous layer thus obtained, and then 90 mL of 1 mol/L hydrochloric acid was added dropwise over a period of 6 minutes under ice cooling. Once it was confirmed that the aqueous layer was acidic, liquid separation was performed, and the aqueous layer was extracted with chloroform (30 mL×2). The combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, then the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 14.1 g of residue (white solid). The residue thus obtained was crystallized from diisopropyl ether/n-hexane to obtain 12.6 g of the titled compound (colorless crystals).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:16])([F:15])[C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][C:27]([C:30]#[N:31])([NH:32][C:12]([C:9]2([C:8]([F:16])([F:15])[F:7])[CH2:11][CH2:10]2)=[O:13])[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Oxalyl chloride (0.20 ml, 2.3 mmol) and dimethylformamide (8 μl) were added to a solution of 1-trifluoromethyl-cyclopropanecarboxylic acid (308 mg, 2.00 mmol) in dichloromethane (2.1 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure. A solution of the resulting residue in dichloromethane (1.5 ml) was added dropwise to a solution of 4-amino-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (377 mg, 1.67 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) in dichloromethane (2.0 ml) over three minutes at 0° C., and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was then washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to give 4-cyano-4-[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid (519 mg, 86%).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:3][CH2:4][C:5]#[C:6][CH2:7]O.CCOCC.P(Br)(Br)[Br:20]>N1C=CC=CC=1>[Br:20][CH2:7][C:6]#[C:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C)=CCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC(C)=CCC#CCBr
Temperature: 25 °C

Procedure:
A mixture of 17 g. of 6-methylundec-2-yn-5-en-1-ol, 32.4 ml. of ether, and 2.07 ml. of pyridine was stirred under nitrogen in an ice-salt bath and 4.5 ml. of phosphorus tribromide was added. The ice-salt bath was then removed and the mixture was first allowed to warm to room temperature, then was heated under reflux for 2.5 hrs. The mixture was again cooled in an ice bath, and 15 ml. each of ether and water were added. The ether layer was separated, washed with aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated. The thus obtained residue was distilled, collecting 14 g. of a mixture comprising 1-bromo-6-methylundec-2-yn-5-ene at 85°-89°C./0.005 mm.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[Cl-].[Br-].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[CH2:1]1[O:5][C@@H:4]2[C@H:6]([O:9][N+:13]([O-:15])=[O:14])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:10].[CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10]
Reactant: O=[N+]([O-])O
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Br-]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O

Procedure:
Finally, German published patent application No. P 27 51 934 and the corresponding U.S. Pat. No. 4,065,488 describe a process wherein isosorbide in a first step is esterified by reaction with a lower alkanoic anhydride, chloride or bromide, in particular acetic acid anhydride, to yield a mixture of isosorbide, isosorbide-2-acrylate, isosorbide-5-acylate and isosorbide-2.5-diacylate. In a second step, isosorbide is extracted from this mixture in order to avoid formation of isosorbide-2.5-dinitrate in the following nitration reaction which is dangerous as explosive. In a third step, the mixture of isosorbide-2-acylate, isosorbide-5-acylate and isosorbide-2.5-diacylate is subjected to nitration with nitric acid and the resulting mixture of isosorbide-2-acylate-5-nitrate, isosorbide-5-acylate-2-nitrate and isosorbide-2.5-diacylate is subjected to partial saponification resulting in a mixture of isosorbide-2-nitrate, isosorbide-5-nitrate and isosorbide. Isosorbide-5-nitrate finally is separated from this mixture by recrystallization from appropriate solvents. Thus, this process also is characterized by a multitude of reaction steps and has the further disadvantage that isosorbide contained in the mixture obtained in the first reaction step, has to be extracted in order to avoid the formation of the explosive isosorbide-2.5-dinitrate in the subsequent nitration reaction.
Reaction SMILES: NC=C(C1C=CC=CC=1)C=O.C(OC)(=O)CC(OC)=O.C[O-].[Na+].[O:24]=[C:25]1[C:30]([C:31]([O:33]C)=[O:32])=[CH:29][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][NH:26]1.Cl>CO>[O:24]=[C:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][NH:26]1
Reactant: COC(=O)c1cc(-c2ccccc2)c[nH]c1=O
Agent: C[O-]
Agent: Cl
Agent: NC=C(C=O)c1ccccc1
Solvent: CO
Solvent: COC(=O)CC(=O)OC
Product: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 25.49 g. of 3-amino-2-phenyl-2-propenal and 27.32 g. of dimethyl malonate is reacted with 18.36 g. of sodium methoxide in one liter of methanol. The solution is stirred for 2 hours at room temperature and then is heated at reflux temperature for 3 hours. The resulting mixture is cooled and filtered to collect the precipitate. The solid is suspended in water and acidified with 10% aqueous hydrochloric acid to give a white solid. The solid is collected and washed with water followed by ethanol to yield 18.0 g. of methyl 1,2-dihydro-2-oxo-5-phenyl-3-pyridinecarboxylate. The ester is hydrolyzed by heating at reflux temperature for 2.5 hours in the presence of concentrated hydrochloric acid to give the product of the Example, m.p. 296° C. dec.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].CS[C:13](=[NH:15])[NH2:14].[CH:16]([NH2:19])([CH3:18])[CH3:17]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:16]([NH:19][C:8]([NH2:10])=[NH:9])([CH3:18])[CH3:17].[CH:16]([NH:19][C:13]([NH2:15])=[NH:14])([CH3:18])[CH3:17]
Reactant: CSC(=N)N
Reactant: CC(C)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)NC(=N)N
Yield: 82 %

Procedure:
Into a one liter reactor fitted with warming, cooling and stirring means were poured 108.5 g (0.39 mol) of bis (S-methylisothiourea) sulphate, 150 ml of water and 94 ml (or 68 g, i.e. 1.15 mol) of isopropylamine. The mixture was refluxed for two hours and then evaporated to dryness. The residue was taken up in ethanol from which there was obtained, after filtration, washing and drying, 96 g (yield 82%) of product.