Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[C:15](OC(C)(C)C)=[O:16])=[CH:10][CH:9]=1.CCOC(C)=O>C1COCC1>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:23])([CH3:22])[CH2:15][OH:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1ccc(F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Lithium aluminum hydride (1.0M in THF) (Aldrich, St. Louis, Mo.; 12.98 mL, 12.98 mmol) was added to a solution of tert-butyl 2-(6-fluoropyridin-3-yl)-2-methylpropanoate (2.07 g, 8.65 mmol) in THF (34 mL) at 0° C. (gas evolution), and the resulting solution was stirred at 0° C. for 5 min. EtOAc (15 mL) was then added at 0° C. to quench excess lithium aluminum hydride, followed by 10% aqueous Na/K tartrate (150 mL). The resulting mixture was stirred at 25° C. for 10 min and then partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.22 (br. s., 1H), 7.78-7.84 (m, 1H), 6.89 (dd, J=8.6, 3.1 Hz, 1H), 3.63 (s, 2H), 1.36 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −72.21 (br. s., 1F). m/z (ESI, +ve) 170.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) and Hunig's base (0.31 mL, 1.8 mmol) is cooled in an ice bath and methanesulfonyl chloride (0.068 mL, 0.88 mmol) is added dropwise. The reaction is stirred cold for 45 minutes and washed with 0.1 N HCl (2×) and H2O. The organic phase is dried (Na2SO4), and concentrated to a white foam. The crude material is purified over silica (1.5% MeOH/dichloromethane) to afford 161 mg (48% yield) of the desired compound. 1H NMR (CDCl3) δ 7.17 (d, J=8.1 Hz, 1H), 7.07 (m, 2H), 7.00 (m, 2H), 6.85 (m, 3H), 4.45 (t, J=8.1 Hz, 1H), 3.96 (t, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.33 (t, J=8.4 Hz, 1H), 3.06 (s, 3H), 2.97 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 2.30 (s, 6H).). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S ¼H2O: C, 59.77; H, 6.57; N, 9.96. Found: C, 59.82; H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]1([CH2:16][CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1c(CCc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.87 g) and ethyl 2-(2-phenylethyl)-acetoacetate (1.62 g) in ethanol (30 ml) was treated with dry HCl as described in example 1a. Yield: 1.77 g (87%). Melting point 248-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][O:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][O:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)cc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.9 %

Procedure:
To the mixture of 6-chloro-5-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-1H-indole-3-carbaldehyde (50.0 mg, 0.15 mmol) in MeCN (2 mL) was added 2-methyl-2-butene (2.0 mL, 13.7 mmol), followed by sodium chlorite (138 mg, 1.53 mmol) and sodium phosphate monobasic hydrate (211.0 mg, 1.53 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 20 hours, and concentrated in vacuo. The residue was acidified with 1N aqueous citric acid (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (34-80% EtOAc/heptanes, with 0.2% formic acid modifier) to afford the title compound (18 mg, 34%) as a brown solid. MS (ES−) 342.3 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.98 (s, 1H), 7.66 (d, J=8.20 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J=8.20 Hz, 2H), 4.87-4.80 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:35][C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39](B(O)O)=[C:38]([O:48][CH3:49])[CH:37]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[C:39]3[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]([F:35])=[CH:37][C:38]=3[O:48][CH3:49])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
In a microwave tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (41.6 mg, 0.0679 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (18 mg, 0.085 mmol), DME (305 μL), EtOH (100 μL), and 1M aqueous Na2CO3 (140 μL, 0.140 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (4 mg, 3.4×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and irradiated in a microwave for 10 minutes at 150° C. and 200 W. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.24 (15% EtOAc/hexanes). LCMS=654.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.85 (s, 1H), 7.69 (s, 2H), 7.21-7.30 (m, 4H), 6.95-7.00 (m, 1H), 6.65-6.68 (m, 1H), 5.59 (d, J=8.0 Hz), 5.41 (d, J=8.0 Hz), 4.74-4.81 (m, 1H), 3.75-4.09 (m, 5H), 3.19 (m, 1H), 1.16-1.27 (m, 6H), 0.51 (d, J=6.7 Hz), 0.36 (d, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:15](=[O:17])[CH3:16]
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A stirred slurry of 842 mg (4.0 mmole) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmole) of 4-(N,N-dimethylamino)pyridine in 15 ml of N,N-dimethylformamide was cooled to ice-bath temperature, and then a solution of 449 mg (4.4 mmole) of acetic anhydride in 5 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 75 ml of water and 3 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was recovered by filtration. The solid was recrystallized from acetic acid to give 600 mg of fluffy, pale pink crystals, m.p. 237.5° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].C(OCC)(=O)C>CN(C)C=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[N:8][N:7]4[C:2]([N:32]([CH3:33])[CH3:31])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1cccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nn3c(N(C)C)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 70 %

Procedure:
To a solution of 4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (60 mg, 0.14 mmol) in N,N-dimethylformamide (10 mL) was added dimethylamine (7 mL 40% in water). The solution was heated in a steal bomb at 100° C. for 3 days. The bomb was cooled to room temperature and ethyl acetate was added to the reaction mixture. The organics were washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (95:5-dichloromethane: methanol) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyridin-7-amine (43 mg, 70%) as a yellow foam. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.95 (s, 1H), 7.35–7.30 (m, 2H), 7.24–7.21 (m, 2H), 6.97 (dd, 1H), 6.36 (d, 1H), 6.32 (d, 1H), 5.40 (broad s, 1H), 4.37 (m, 1H), 3.80 (s, 3H), 3.12 (s, 6H), 2.11–2.06 (m, 2H), 1.77–1.56 (m, 6H); MS m/z 429.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][NH:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:44]([CH2:45][C:46]([OH:48])=[O:47])[CH3:43])=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CNCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and tert.-butyl methylamino-acetate with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN1CCCC1=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5]2[N:6]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[S:3][C:4]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Yield: 80.8 %

Procedure:
To a solution of ethyl 2-bromo-4-(4-chlorobenzyl)thiazole-5-carboxylate (4.19 g, 11.6 mmol, prepared as described in Example 10) in N-methylpyrrolidinone (12.2 mL) was added potassium carbonate (3.21 g, 23.2 mmol) and morpholine (1.52 mL, 17.4 mmol) and the resulting mixture was heated to 130 degrees for 90 minutes. The reaction was cooled and the volatiles were removed by concentration at 65 degrees under oil pump vacuum. The residue was taken up in DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined DCM layers were dried over MgSO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (ethyl acetate/hexane=0/100→35/65) to give 3.44 g of the title compound as a white solid. (80% yield). LC/MS (FA) ES+ 367. 1H NMR (300 MHz, CDCl3) δ: 7.32-7.27 (m, 2H), 7.24-7.20 (m, 2H), 4.28 (s, 2H), 4.27 (q, 2H, J=7.2 Hz), 3.80-3.76 (m, 4H), 3.53-3.48 (m, 4H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[Br:18][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: Nc1cnc(C2CC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(C2CC2)nc1Br

Procedure:
A solution of 5-cyclopropylpyrazin-2-amine (79 mg, 0.584 mmol) in acetonitrile (10 mL) was cooled down to 0° C., and treated with gradual addition of NBS (140 mg, 1.46 mmol) over the course of 1 hour while closely monitoring reaction progress by LCMS. The reaction mixture was concentrated and the residue was triturated with EtOAc (2×5 mL) and the EtOAc supernatants were separated via centrifugation, combined and washed with 1N NaOH (3×1 mL) and the EtOAc layer was dried (over Na2SO4), concentrated and a crude brown reside was obtained. The crude product was further purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-30%) to afford 3-bromo-5-cyclopropylpyrazin-2-amine in colorless solid (38.2 mg, 38.5% yield). LCMS (m/z): 214.0/216.0 (MH+), 0.64 min.
Reaction SMILES: O.O.[Sn](Cl)[Cl:4].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.[ClH:35]>C(O)C>[ClH:4].[ClH:35].[CH2:6]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH3+:27])[CH2:17][CH2:18]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: [NH3+]c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
1 g tin (II) chloride-dihydrate was added to 290 mg (1-benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine in 18 mL ethanol. The reaction was refluxed for 15 min. DMF was added until the reaction was diluted. Then, 5 mL 10 M HCl in ethanol was added, the solvent was removed, 8 mL acetone was added and the mixture was stirred at RT. The precipitate was filtered to give 550 mg of the desired product. Rf: 0.35 (dichlormethane 9: methanol 1: ammonia 0.1), (M+H)+: 296
Reaction SMILES: [CH2:1]([NH:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[NH:12][C:13](=[O:21])[CH2:14][C:15](OC)([O:17][CH3:18])[CH3:16])=[O:7])[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[NH:12][C:13](=[O:21])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Oc1cccc(NC(=O)CC(C)(OC)OC)c1
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Oc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A mixture of 43 g of m-(n-butylcarbamoyloxy)-3,3-dimethoxy-butyranilide and 400 ml of toluene were stirred at 140°C. for 2 hours while removing the methanol formed and was then cooled and vacuum filtered to obtain 33 g of m-(n-butylcarbamoyloxy)-3-methoxy-crotonanilide (isomer E) melting at 166°C.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[C:23]([CH3:24])=[C:22]([CH2:25][OH:26])[N:21]=[CH:20]2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl>ClCCl.CCOCC>[ClH:4].[ClH:5].[C:1]([O:26][CH2:25][C:22]1[N:21]=[CH:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)([CH3:14])[CH3:13])[C:23]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(CO)ncn1CCCNC(C)(C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCc1ncn(CCCNC(C)(C)c2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (8.7 g) in dichloromethane (35.5 ml) was added dropwise with stirring to a solution of 1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-yl-methanol (3.55 g) in dichloromethane (88.8 ml) containing triethylamine (11.1 g) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. The mixture was diluted with dichloromethane, washed with 5M sodium hydroxide solution, dried and evaporated. The residue obtained was dissolved in ether and acidified with ethereal hydrogen chloride. The solid was collected by filtration and recrystallised from aqueous propan-1-ol to give 1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-ylmethyl acetate dihydrochloride, m.p. 188°-189° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([F:16])([F:14])[F:15])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:6][CH:7]=1
Reactant: N#CC[C@@H]1C[C@H](C(F)(F)F)CN1c1ccc(O)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC[C@@H]1CC(C(F)(F)F)CN1c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 110 °C
Yield: 87.8 %

Procedure:
2-((2S,4S)-1-(4-hydroxyphenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (49A, 0.020 g, 0.074 mmol) and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.029 g, 0.15 mmol) were dissolved in DMF (0.8 mL) and cesium carbonate (0.060 g, 0.19 mmol) was added. The mixture was heated to 110° C. for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography to provide (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (0.029 g, 0.065 mmol, 87% yield) as an inseparable mixture of diastereomers which was taken on to the next step. Example 59 (off white solid, 0.002 g, 5 μmol, 15% yield) was prepared from (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile following the procedure of 36C. LC-MS Anal. Calc'd for C20H16ClF6NO3 467.79. found [M+H] 468.0. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 7.78-7.86 (1 H, m), 7.51 (1 H, d, J=8.59 Hz), 7.01 (2 H, d, J=8.84 Hz), 6.89 (1 H, d, J=8.59 Hz), 6.75 (2 H, d, J=9.09 Hz), 4.21-4.33 (1 H, m), 3.62 (1 H, t, J=9.35 Hz), 3.48-3.56 (1 H, m), 3.12-3.28 (1 H, m), 2.85 (1 H, dd, J=15.92, 2.78 Hz), 2.65 (1 H, dt, J=13.64, 8.59 Hz), 2.28 (1 H, dd, J=15.92, 9.85 Hz), 2.02 (1 H, ddd, J=13.58, 7.89, 5.81 Hz). Analytical HPLC: RT=11.2 min, HI: 99.0%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[NH2:15]>CO>[CH3:9][O:8][C:6](=[O:7])[CH2:5][CH:4]1[CH2:3][NH:15][C:3]2[CH:4]=[C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH:13]=[CH:14][C:2]=2[O:1]1
Reactant: CC(C)(C)OC(=O)c1ccc(O)c(N)c1
Solvent: CO
Product: COC(=O)CC1CNc2cc(C(=O)OC(C)(C)C)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 244.9 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-aminobenzoate (3 g, 14.35 mmol) in methanol (20 mL) sodium hydrogen carbonate (1.5 g) was added and a solution of methyl-4-bromo crotonate (3 mL, 17 mmol) in methanol (5 mL) was added dropwise in 30 minutes and the resulting suspension was stirred 4 h at room temperature. The reaction mixture was concentrated in vacuo and taken up with ethyl acetate (250 mL) and water (300 mL). The organic phase was separated and the aqueous phase was extracted with more ethyl acetate (2×250 mL). The combined extracts were dried (Na2SO4) evaporated and the resulting oil dissolved in ethanol (25 mL), potassium carbonate (1 g) was added and the resulting suspension was stirred 4 h at room temperature. The reaction mixture was evaporated in vacuo and the resulting oil was diluted with dichloromethane (150 mL) and washed with water (3×100 mL), the organic solution was then extracted whit hydrochloric acid 1N (150 mL) and separated, the aqueous solution was neutralized with 1N sodium hydroxide and extracted with ethyl acetate (3×150 mL). The combined extract were dried (Na2SO4) evaporated to dryness in vacuo, the resulting crude was purified by flash chromatography on silica gel (n-hexane/ethyl acetate 3:1) to afford tert-butyl 2-(2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (5.4 g) as a white solid.