Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1.C(N(CC)CC)C.[F-].[K+].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1)=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reaction time: 42 h
Yield: 383.9 %

Procedure:
Trimethylacetyl chloride (180.9 g, 1.500 mols) was added over 1 h to a mixture of 2-amino-6-bromo-pyridine (264.7 g, 1.530 mols), triethylamine (166.7 g, 1.650 mols) and toluene (1 L, KF=2 mg moisture/L) maintaining the temperature below 50° C. The mixture was aged at 25° C. for 42 h. A solution of 1M aqueous HCl (500 mL) was added and the biphasic mixture was filtered (after agitation for 5 min) through a pad of solka floc (10 g) which was washed with toluene (50 mL). The organic phase was separated from the filtrates and was washed with 1M aqueous HCl (2×500 mL), 2% aqueous NaCl (500 mL) and a mixture of saturated aqueous NaCl (250 mL) and saturated aqueous NaHCO3 (25 mL). The organic phase was dried over MgSO4 (10 g), filtered and evaporated to dryness to provide 380.7 g of crude title compound, which was diluted with toluene to give 1480.8 g of crude solution.
Reaction SMILES: [ClH:1].[CH3:2][C@@:3]12[CH2:11][NH:10][CH2:9][C@H:8]1[C:7]1[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([CH3:18])=[CH2:17])[C:6]=1[CH2:5][CH2:4]2>C(O)C.C(O)(=O)C.[Pd]>[ClH:1].[CH:16]([C:15]1[C:6]2[CH2:5][CH2:4][C@@:3]3([CH3:2])[C@@H:8]([CH2:9][NH:10][CH2:11]3)[C:7]=2[CH:12]=[CH:13][CH:14]=1)([CH3:18])[CH3:17]
Reactant: C=C(C)c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Reaction time: 18 h
Yield: 118.1 %

Procedure:
trans-3a-Methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (41 mg, 0.137 mmol) was dissolved in ethanol (2 ml) and acetic acid (0.5 ml). 5% Pd on C (0.298 mg) was added and the reaction mixture was stirred under an atmosphere of H2 (1 bar) for 18 h. The resulting suspension was filtered through celite and then passed through an SCX cartridge. The purified fractions were concentrated in vacuo and then dissolved in DCM (1 ml). 2 N HCl in Et2O (1 ml) was added and the solvent was removed in vacuo to afford trans-6-Isopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (43 mg), m/z: 230.3 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:16]=2[O:30]CC2C=CC=CC=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:29][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:16]([OH:30])[CH:17]=1)([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2(O)CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2(O)CCCNC2)c(O)c1
Yield: 70 %

Procedure:
A mixture of 8.5 g. (17.03 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-hydroxypiperidine, 2.0 g. of 10% palladium-on-carbon and 60 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and evaporated. The residue is recrystallized from ethyl acetate to yield 3.8 g. (70%) of the title compound. A second crop of the title compound 0.396 g. (7%) is obtained from the mother liquor.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(N(OC)C)=O)[CH:8]=[C:9]([CH:16]=1)[C:10](N(OC)C)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:23][Mg]Br.Cl.CC[O:29][CH2:30][CH3:31]>C1COCC1>[C:10]([C:9]1[CH:16]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[C:7]([C:30](=[O:29])[CH3:31])[CH:8]=1)(=[O:11])[CH3:23]
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: CON(C)C(=O)c1cc(C(=O)N(C)OC)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 4 l three-neck flask with a mechanical stirrer, a solution of 5-tert-butyl-N,N′-dimethoxy-N,N′-dimethylisophthalamide (O5.106; 254 g, 560 mmol) in THF (700 ml) was slowly added dropwise within 2 h to methylmagnesium bromide (3 M in Et20, 1.49 l, 4.48 mol). The solution was cooled during the addition, such that the temperature was kept between −10° C. and +5° C. On completion of addition, the cooling was removed and the reaction solution was stirred at RT for 16 h. The reaction solution was then added slowly to a cooled mixture of HCl (1 M, 500 ml) and ice. During this hydrolysis, the pH was kept between 3 and 6 by the addition of concentrated HCl. On completion of addition, MtB ether (1 l) was added. The phases were separated and the aqueous phase was extracted with MtB ether (1×500 ml). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The product was obtained as a colorless oil (123 g). LC-MS rt: 1.50 min [M+H]+: 219 (met. a)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4](N)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[C:3]=1[F:11]
Reactant: Br
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1c(Cl)cc(Br)c(F)c1Cl
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17])([O-:9])=[O:8].C=O.[C:21](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:21][CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])=[O:18])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: O=C(CCN1CCOCC1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of morpholine (2.27 g, 0.026 mol) in ethanol (10 ml) was treated with c-HCl (3 ml) for 10 mins, concentrated under reduced pressure to prepare morpholine HCl salt. To this mixture, 2′-nitroacetophenone (3.3 g, 0.02 mol), paraformaldehyde (0.8 g, 0.029 mol), c-HCl (0.1 ml) and anhydrous ethanol (10 ml) were added. The reaction mixture was stirred under reflux for 30 hrs. This reaction mixture was then cooled to room temperature, alkalized with 10% sodium carbonate solution, and the reaction mixture was extracted with dichloromethane(3×50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography with 5% ethanol in dichloromethane to give the desired product (1.5 g, 35%) as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+:6]([CH2:9][CH3:10])([O-])=[O:7].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>CCOCC>[CH3:10][C:9]1[C@H:3]2[CH2:2][O:1][CH2:5][C@H:4]2[O:7][N:6]=1
Reactant: CC[N+](=O)[O-]
Reactant: C1=CCOC1
Solvent: CCOCC
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NO[C@@H]2COC[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 2,5-dihydrofuran (5 g, 69.9 mmol) in ether (90 ml) was treated dropwise with a solution of nitroethane (5.46 g, 71.3 mmol) in ether (15 ml) at room temperature. Thereafter, triethylamine (70.7 mg, 699 μmol) was added followed by the dropwise addition of phenyl isocyanate (17.3 g, 143 mmol). The reaction mixture was stirred for 3 days at room temperature. For the workup, the white precipitate was filtered and washed with ether. The filtrate was evaporated and the crude product was purified by chromatography using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. After a second chromatography the (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (58% yield) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC([NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])=O)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([O-:48])=[O:47]>CN(C)C=O>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[C:36]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: O=C([O-])C(F)(F)F
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Solvent: CN(C)C=O
Product: NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: O=C(O)C(F)(F)F
Yield: 2 %

Procedure:
Using methods substantially equivalent to those described in Example 1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (321 mg, 1.29 mmol), N,N-dimethyl-formamide (0.2 mL) and 2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid (500 mg, 1.36 mmol) yielded, after deprotection of the coupled product using methods substantially equivalent to those described in Example 1-J, 20 mg (2%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccncc1

Procedure:
Following General Procedure C and using 4-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=152-154° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:11]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH3:12]
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromoethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].N1C=CN=C1.[CH3:16][Si:17](Cl)([CH3:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.O.CCOCC>[Br-:1].[CH3:16][Si:17]([CH3:24])([C:18]([CH3:20])([CH3:19])[CH:21]([CH3:23])[CH3:22])[O:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(C)(C)[Si](C)(C)OCCc1ccccc1
Product: [Br-]
Temperature: 0 °C

Procedure:
2-Bromophenethyl alcohol (43.80 g, 217.9 mmol) was dissolved in anhydrous CH2Cl2 (200 mL) and imidazole (16.32 g, 239.6 mmol) was added and stirred under argon 0° C. Dimethylthexylsilyl chloride (42.83 g, 239.6 mmol) was added dropwise and the reaction mixture was stirred for three days at room temperature. It was diluted with H2O (50 mL) and ether (100 mL) and partitioned. The aqueous layer was extracted with ether (2×100 mL). The combined organic layers were washed with 5% aqueous HCl (1 time), H2O (1 time), aqueous NaHCO3 (1 time), H2O (1 time), and brine, then dried (MgSO4) and concentrated in vacuo to obtain a yellow oil. The crude product was Kugelrohr distilled (55°-80° ) under oil pump vacuum to give the purified title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])C.[Li+].[OH-].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[F:47]>CO.C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:4]([C:6]2[C:7](=[O:22])[N:8]([CH2:20][CH3:21])[C:9](=[O:19])[N:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:11]=2)=[O:5])=[CH:42][C:41]=1[F:47]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c(=O)n(CC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)c(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cn(-c2ccc(F)cc2)c1=O

Procedure:
3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester was hydrolyzed with 1N LiOH in MeOH and THF at 65° C. The acid was coupled with 4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine using the method for example 1 to give 3-ethyl-1-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide mp 140-142° C.; LCMS m/z=575 (M+1); 1H NMR (DMSO) δ: 11.18 (s, 1H), 8.49 (d, 1H, J=2.5 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=3 Hz, J=13 Hz), 7.65-7.39 (m, 6H), 7.55 (s, 1H), 7.41 (s, 1H), 6.49 (d, 1H, J=5.0 Hz), 4.00 (q, 2H, J=7.4 Hz), 3.95 (s, 6H), 1.23 (t, 3H, J=7.3 Hz).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](O)[C:10]=2[N:11]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][C:9]1[C:10]2[N:11]=[C:3]([CH:2]([F:13])[F:1])[S:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2sc(C(F)F)nc12
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: FC(F)c1nc2c(Cl)ncnc2s1
Temperature: 80 °C

Procedure:
A mixture of 2-(difluoromethyl)thiazolo[5,4-d]pyrimidin-7-ol, N,N-dimethylaniline (0.800 mL, 6.31 mmol) and phosphorus oxychloride (6.00 mL, 65.5 mmol) in toluene (20 mL) was heated at 80° C. for 6 h. The reaction mixture was cooled of rt and the solvent removed invacuo. The residue was dissolved in DCM, evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with (EtOAc):hexanes (0:1→1:3) to give an off-white crystalline solid (252 mg, 18% over 2 steps). MS m/z=221.9, 223.9 [M+H]+. Calculated for C6H2F2N3S: 221.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]#N)[CH2:5][CH2:4]1.[OH-:9].[K+].[CH2:11]([OH:13])C>>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:13][CH3:11])=[O:9])[CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCC1(CO)CC1
Agent: [K+]
Product: COC(=O)CC1(CO)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (1 eq.) (prepared according to the procedure described in WO2005/105749 Example 2/Step 4) in ethanol (0.1 M) was added 8 N aqueous KOH solution (18 eq.). The reaction was heated to 100° C. and stirred for 18 h. After cooling to rt temperature, ethanol was removed in vacuo. The resulting aqueous solution was diluted with EtOAc and cooled in ice water bath. Concentrated HCl was added slowly with stirring over 15 min, keeping the temperature of the reaction below 10° C. After the reaction has reached pH<1, the aqueous layer was extracted by EtOAc. The combined organic extracts were dried over MgSO4 and filtered. The EtOAc solution was cooled down to 0° C., and a solution of diazomethane in ether was added until a faint yellow color persisted. The reaction was allowed to stir for an additional 10 min before concentrated in vacuo. The crude product was purified on flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as a liquid.
Reaction SMILES: C(O[C:4]1[CH:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18]C)=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.CO[CH:22](OC)[CH2:23][NH2:24].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][S:9][CH:8]2[C:4]3=[N:24][CH:23]=[CH:22][N:5]3[CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: COC(CN)OC
Reactant: CCOC1=NCCC1SCc1ccc(OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CSC2CCn3ccnc32)cc1

Procedure:
2-Ethoxy-3-p-ethoxybenzylthio-1-pyrroline (531mg) (synthesized according to the method disclosed in Japanese Patent Laid-Open No. 56987/1985), aminoacetaldehyde dimethylacetal (315mg) and acetic acid (180mg) were dissolved in 30 ml of ethanol and refluxed under heating for one hour. The reaction solution was evaporated to dryness in vacuo, the residue was distributed between benzene and 40 ml of water containing 4 ml of 1N sodium hydroxide aqueous solution, the benzene phase was washed with water and dried over MgSO4 and thereafter the solvent was distilled off in vacuo to obtain 700mg of colorless and transparent material. The oily material was dissolved in 30 ml of benzene, 1.14 g of p-toluenesulfonic acid (hydrate) was added thereto and refluxed under heating for one hour. The reaction solution was cooled, washed with 5% aqueous solution of sodium bicarbonate and water and dried, then the solvent was distilled off. The residue was purified by column chromatography using a column packed with 20 g of silica gel (eluent: Chloroform/methanol (19:1 v/v)) to obtain the objective compound as a colorless and transparent oil. The compound was crystallized during standing in a refrigerator (m.p.=65°~73° C.; yield: 0.53 g).
Reaction SMILES: O.NN.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]=2)[CH:5]=1>C(O)C>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:11]=2)[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccc(-c2cccnc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCn1ccc(-c2cccnc2)n1
Yield: 68.9 %

Procedure:
7 ml of hydrazine hydrate is added to a suspension containing 450 ml of ethanol and 22.33 g of the product of Stage A. The reaction medium is taken to reflux for 15 hours. The ethanol is evaporated off, the reaction mixture is agitated with 200 ml of ethyl acetate, washed with salt water, dried, filtered and concentrated. In this way 9.60 g of sought product is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>C(Cl)(Cl)Cl>[CH2:20]([N:23]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: COC(=O)Nc1ccccc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: C=CCN=Cc1ccccc1NC(=O)OC
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Methyl 2-formylphenylcarbamate (7, 1 g, 5.6 mmol) and magnesium sulfate (3 g) were added to a solution of allylamine (1.5 g, 26 mmol) in chloroform (10 mL) and mixture was stirred overnight. Then mixture was filtered and the residue was washed with chloroform (2×10 mL). The combined filtrates were washed with water (3×10 mL) brine (10 mL), dried with sodium sulfate, and concentrated on a rotary evaporator to afford 15 as yellow oil (1.2 g, 99%). IR (film) 1732, 1635 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.25 (s, 1 H), 8.43 (d, J=8.4 Hz, 1 H), 8.28 (s, 1 H), 7.40-7.34 (m, 1 H), 7.27 (dd, J=7.7, 1.4 Hz, 1 H), 7.02 (td, J=7.5, 0.9 Hz, 1 H), 6.05 (ddt, J=17.1, 10.5, 5.3 Hz, 1 H), 5.25 (ddd, J=17.2, 3.3, 1.6 Hz, 1 H), 5.20-5.13 (m, 1 H), 4.26-4.17 (m, 2 H), 3.76 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 164.94, 154.73, 140.38, 135.38, 133.25, 131.54, 121.49, 120.32, 118.05, 115.99, 62.88, 52.10; ESIMS m/z (rel intensity) 219 (MH+, 100); EIHRMS m/z M+ calcd. for C12H14N2O2, 218.1055; found, 218.1053.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.ClC1C=C([C:32]2[C:36]([CH2:37]OC3C=CC(C(O)=O)=CN=3)=[C:35](C)[O:34]N=2)C=CC=1.[NH2:49]C(C)(C)CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:49])=[O:21])=[C:17]([C:36]([CH3:37])([CH3:32])[CH2:35][OH:34])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(N)=O)c(C(C)(C)CO)n1
Yield: 53 %

Procedure:
As described for example 98b, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (56 mg, 0.16 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using 2-amino-2-methyl-1-propanol instead of 2,2,2-trifluoroethylamine, to the title compound (36 mg, 53%) which was obtained as a white solid. MS: m/e=417.3 [M+H]+.