Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:38])([F:37])[F:36])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][C:29](=O)[C:30]([F:33])([F:32])[F:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:39][OH:40].Cl.CC([O-])=O.[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:36])([F:37])[F:38])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28]/[C:29](=[N:39]\[OH:40])/[C:30]([F:33])([F:31])[F:32])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(NCC(=O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(NC/C(=N\O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 130 °C
Yield: 51 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-oxopropyl)-1-naphthamide (Preparation 11, 100 mg, 0.2 mmol) in EtOH (5 mL) was added hydroxylamine.HCl (30 mg, 0.4 mmol), water (1 mL), and KOAc (40 mg, 0.4 mmol). Reaction was heated to 130° C. for 40 minutes in a microwave. Water was added to the crude reaction and extracted with EtOAc (2×75 mL). The combined organics were dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (24 g Redi-Sep column) eluting from 100% EtOAc to 50:50 EtOAc:heptane to afford (E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(hydroxyimino)-propyl)-1-naphthamide (52 mg, 51%) as a solid. 1HNMR (CDCl3) δ ppm: 9.06 (1H), 8.81 (1H), 8.26 (1H), 7.71-7.57 (4H), 7.51 (1H), 6.48 (1H), 4.64 (2H) 4.28 (1H), 3.89 (1H); m/z (Cl) 596 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:18]=[C:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.O>[CH2:18]=[C:19]1[CH2:24][CH2:23][CH:22]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: C=C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C=C1CCC(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)CC1
Yield: 49.6 %

Procedure:
To a mixture of ethyl 4-(piperazinyl)benzoate (2.00 g) and 4-methylenecyclohexan-1-one (0.98 g) in a mixture of methanol (40 ml) and acetic acid (1.47 ml) was portionwise added sodium cyanoborohydride (644 mg) with stirring under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was added water (200 ml) and the mixture was adjusted to pH 8-9 with saturated aqueous sodium hydrogen carbonate. The resulting precipitates were collected and chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(4-methylenecyclohexyl)-1-piperazinyl]benzoate (1.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Br[CH2:47][C:48](=[O:51])[CH2:49][CH3:50]>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:47][C:48](=[O:51])[CH2:49][CH3:50])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: CCC(=O)CBr
Product: CCC(=O)Cn1c(NC2CCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine and 1-bromo-butan-2-one to give the title compound: Rf=0.30 (silica gel, 40% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[C:9]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)=[O:37])[CH:32]=1.[Cl-].[NH4+]>O1CCOCC1.O.C(OCC)(=O)C.[Zn]>[C:48]([O:47][C:45]([N:42]1[CH2:41][CH2:40][CH:39]([NH:38][C:36]([C:33]2[CH:32]=[C:31]([C:9]3[C:10]([O:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:11][C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][C:8]=3[O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[O:35][N:34]=2)=[O:37])[CH2:44][CH2:43]1)=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc(N)cc2)c1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a stirred solution of tert-butyl 4-{[(5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazol-3-yl)carbonyl]amino}piperidine-1-carboxylate (5.3 g, 7.4 mmol) in a mixture of dioxane (100 mL) and water (20 mL) were added portion wise zinc powder (1 g, 14.8 mmol, 2 eq.) and ammonium chloride (3.9 g, 74 mmol, 10 eq.) at 100° C. After stirring for 30 minutes, the reaction mixture was cooled and diluted with ethyl acetate. After washing with 1 M Na2CO3 solution, the organic phase was dried over Na2SO4 and the solvent removed. The crude product was filtered over a small pad of silica gel eluting with hexane/ethyl acetate 3/1 to provide the title compound (4.38 g, 86% yield).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[C:39](=[O:55])[CH:38]=[C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][N:33]=3)[CH:42]=[N:41]2)=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Yield: 59 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 8a) instead of preparation 1c.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C.[O-2].[Zn+2]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
A suspension of 0.5 g (1.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 0.25 g (2.1.10-3 mol) of 4-hydroxybenzonitrile and 170 mg (2.1.10-3 mol) of zinc oxide (ZnO) in 4 ml of anhydrous toluene and 4 ml of acetonitrile is stirred at 50° C., under an inert atmosphere, in the presence of a molecular sieve (1 nm), for 48 h. The reaction medium is subsequently filtered on Celite® in ethyl acetate and then washed with a 1N aqueous solution of hydrochloric acid, water, a 1N solution of sodium hydroxide and then a saturated solution of NaCl. The solution obtained is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue obtained is purified by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent to give 194 mg (yield: 35%) of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][O:25]C(C)(C)C)[CH:15]=3)=[O:11])=[C:4]([F:31])[C:3]=1[O:32][C:33]1[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[C:35]([Cl:41])[CH:34]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][OH:25])[CH:15]=3)=[O:11])=[C:4]([F:31])[C:3]=1[O:32][C:33]1[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[C:35]([Cl:41])[CH:34]=1
Reactant: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(NC(=O)CCO)cc4[nH]3)c2F)c1
Temperature: 105 °C
Yield: 20.3 %

Procedure:
N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-2-carboxamide (0.049 g, 0.082 mmol) was dissolved in 4N HCl in dioxane (3 mL). The mixture was heated in a 105° C. oil bath under a reflux condenser for 3 days. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.009 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1H), 9.82 (s, 1H), 8.69-9.06 (m, 1H), 7.91-7.99 (m, 1H), 7.78 (s, 1H), 7.42-7.56 (m, 4H), 7.35 (t, 1H), 7.08 (d, 2H), 4.30-4.70 (m, 2H), 3.54-3.82 (m, 2H), 2.39-2.46 (m, 2H). ES MS: m/z 541 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC(=O)C(C)(C)C

Procedure:
To a cis/trans mixture of 1-benzyl-3-methyl-piperidin-4-ol (50 g, 243 mmol, prepared as described in Can. J. Chem. (1972) 50, 803) in THF is added triethylamine (51 ml, 365 mmol) followed by 2,2-dimethyl-propionyl chloride (45 ml, 365 mmol). The reaction is exothermic and a precipitate is formed. The mixture is heated under reflux for 18 hours, cooled, filtered and washed with ether. The organic layers are washed with 1N-NaOH and brine, dried and evaporated. The crude is purified by chromatography on silicagel using hexane and EtOAc (5%) to give pure trans-isomer as a colourless oil.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[B:17](OCC)([O:21]CC)[O:18]CC>C1COCC1>[CH2:1]([B:17]([OH:21])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOB(OCC)OCC
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCB(O)O
Temperature: -20 °C
Yield: 93 %

Procedure:
To a stirred solution of tetradecylmagnesium chloride (50 ml, 1M in THF) was added at −20° C. to THF (50 ml) followed by triethyl borate (10.2 ml, 60 mmol). The reaction mixture was stirred briefly at −20° C., and warmed up slowly over 3 hours to room temperature. Most of the solvent was removed on rotary evaporator and the concentrated mixture was poured into water (300 ml) and pH of the mixture was adjusted to about pH 4 using 12N hydrochloric acid. After being stirred for 10 hours, precipitated tetradecylboronic acid was isolated by filtration, washed three times with water and dried with air overnight. The dried white solid was washed with cold hexane to remove a trace of tetradecane and dried with air to yield 11.3 g (93%) of n-tetradecylboronic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[S:13][C:12]([S:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:11][N:10]=1.[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:33][CH2:34][CH2:35]Cl)=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl-].[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:33][CH2:34][CH2:35][N:18]2[CH2:19][CH2:20][CH:15]([S:14][C:12]3[S:13][C:9]([CH3:8])=[N:10][N:11]=3)[CH2:16][CH2:17]2)=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCC(C(=O)N(CCCCl)c2cccc(Cl)c2)CC1
Reactant: Cc1nnc(SC2CCNCC2)s1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Sc3nnc(C)s3)CC2)c2cccc(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
4-(5-Methyl-1,3,4-thiadiazol-2-ylthio)piperidine trifluoroacetate (59 mg, 0.18 mmol) was dissolved in dry acetonitrile (1.5 mL). To the solution were added 1-acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide (50 mg, 0.14 mmol), potassium carbonate (77 mg, 0.56 mmol) and potassium iodide (23 mg, 0.14 mmol), and the mixture was stirred at 80° C. for 5 hours. The mixture was cooled to room temperature, and to the mixture was added saturated sodium chloride solution (3 mL). The mixture was extracted three times with ethyl acetate (2 mL). The extracts were combined and concentrated under reduced pressure. The concentrate; was purified by using HPLC to give the titled compound as a colorless oily substance (32.2 mg, 28%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62](O)=[O:63]>>[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:63]
Reactant: COCCOCC(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COCCOCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 4.1 %

Procedure:
The crude product obtain using Compound 18 (200 mg, 0.602 mmol), N-methylmorpholine (0.132 mL, 1.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and 2-methoxyethoxyacetic acid (0.0674 mL, 0.722 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=80/20) to obtain Compound 127 (0.011 g, 4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=[C:2]3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cnc2ccc(C)cc2c1Cl
Reactant: NNc1ccccc1
Product: Cc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3f and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 2.46 (3H, s), 7.16 (1H, t, J=7.41 Hz), 7.41 (2H, dd, J=8.51, 7.14 Hz), 7.46 (1H, dd, J=8.52, 1.92 Hz), 7.58 (1H, d, J=8.51 Hz), 8.00 (1H, br), 8.21 (2H, dd, J=7.69, 1.10 Hz), 8.66 (1H, s). m/z 276.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][C@@H:14]([CH3:36])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31](=[O:33])[CH3:32])=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:34][CH3:35])=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][C@H:14]([CH3:36])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31](=[O:33])[CH3:32])=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:34][CH3:35])=[CH:20][CH:21]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate (step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol (20 ml) was added 2N aqueous NaOH (5 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, extracted with diethyl ether (2×50 ml). The organic layer was washed with brine, dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (1:1) afforded 1.16 g (80%) of title compound as a colorless solid (79% e.e.). Recrystallization from hexane/diethyl ether afforded 717 mg of a colorless needle (99% e.e.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COCC(=O)CC(=O)OC
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COCC(=O)C(=Cc1ccc(F)c(F)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42970.2 %

Procedure:
To a solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47%). This product was a mixture of cis and trans isomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[N:24]=[N:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[OH:36]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:23]2[N:24]=[N:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[O:36][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Oc5ccccc5)nn4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.79 mmol), 2-fluoro-4-(6-phenoxy-pyridazin-3-yl)-phenol (Step 2, 0.50 g, 1.79 mmol) and DMAP (0.22 g, 1.79 mmol) in 6 mL of toluene (in microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (4.5 g, 29.97 mmol) in dichloromethane (50 ml) was added methanesulfonic acid (40 ml). This was followed by the addition of sodium azide (2.73 g, 42.0 mmol) in several batches with stirring over 2 hours at 0° C. The reaction mixture was then quenched with aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 10%-100% ethyl acetate in petroleum ether to afford 6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one as a white solid (2.5 g, 51%); (ES, m/z): [M+H]+ 166; 1H NMR (300 MHz, CDCl3): δ 8.11 (dd, J=6.0, 8.7 Hz, 1H), 7.07-7.00 (m, 1H), 6.94 (dd, J=2.4, 8.7 Hz, 1H), 6.57 (br s, 1H), 3.61 (t, J=6.6, 2H), 3.03 (t, J=6.6, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)=[CH:14][CH:13]=1
Reactant: CCC(C[C@H](N)CO)c1ccc(Cl)cc1
Reactant: N#CBr
Product: CCC(C[C@H]1COC(N)=N1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1b (S)-2-amino-4-(4-chloro-phenyl)-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 255.2 ([{37Cl}M+H]+), 253.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
In a 15 mL round-bottomed flask, 3-(tert-butoxycarbonylamino)pyrrolidine (0.50 g, 2.68 mmol) was dissolved in CH2Cl2 (5 mL). Triethylamine (0.45 mL, 3.22 mmol) was added and the reaction mixture was cooled to 0° C. Methanesulfonyl chloride (0.25 mL, 3.22 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was diluted with CH2Cl2 (20 mL) and quenched with 1.0 M aqueous HCl (5 mL). The aqueous layer was extracted with CH2Cl2 then the combined organics were dried over Na2SO4, filtered and concentrated to afford 0.90 g of (1-methanesulfonyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a light brown solid which was used without further purification.