Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]>[OH-].[Na+].O>[NH:12]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
Benzyloxycarbonyl chloride (abbreviated Z-Cl hereafter) (65 ml) and 114 ml of 4 N NaOH were simultaneously added under agitation with ice-cooling to a solution of 50 g of D-Leu in 191 ml of 2 N NaOH and stirred for a further one hour. After the reaction mixture was diluted with one liter of distilled water, it was rinsed three times with 300 ml each of ethyl acetate. The aqueous layer was adjusted to pH 2.0 with 4 N HCl under cooling with ice. The oily material formed was extracted with ethyl acetate. The ethyl acetate extract, after being washed with a saturated solution of sodium chloride, was dehydrated over anhydrous sodium sulfate and then evaporated under reduced pressure to give 44 g of colorless, transparent syrup.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=1.B([C:25]1[CH:36]=[CH:35][C:28]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])=[CH:27][CH:26]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:31][CH:30]([CH2:29][C:28]1[CH:35]=[CH:36][C:25]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=2)=[CH:26][CH:27]=1)[C:32]([OH:34])=[O:33]
Reactant: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(Oc2cc(-c3ccc(CC(N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
A microwave vial was charged with 4-chloro-2-amino-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1N) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 14.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-methylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24 Hz, 4H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, 1H), 6.75 (m, 1H), 4.30 (t, 1H), 3.21-3.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39](=O)[CH3:40]>O1CCCC1>[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](/[CH:9]=[C:39](\[C:33]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=2[F:31])/[CH3:40])[CH:8]=1
Reactant: Brc1cncc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)c1cc(F)ccc1F
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(=C/c1cncc(Br)c1)c1cc(F)ccc1F
Yield: 21.1 %

Procedure:
To a stirred solution of 3-bromo-5-((tri-phenylphosphino)methyl)pyridine bromide salt (200 mg, 0.337 mmol) in tetrahydrofuran (Volume: 4 mL) was added sodium hydride (90 mg, 0.843 mmol) at 0° C. A half hour later, 2′,5′-difluoroacetophenone (47.0 mL, 0.371 mmol) in tetrahydrofuran (Volume: 1 mL) was added to above solution. Ice bath was removed and heat it to reflux for overnight. Next morning, 10 mL water was added slowly then was extracted by ether (10 mL×3), combined all organic layers, dried over magnesium sulfate, concentrated and obtained a yellow oil which was purified by Preparative HPLC (Preparative HPLC Method 21) and obtained (Z)-3-bromo-5-(2-(2,5-difluorophenyl)prop-1-enyl)pyridine (22 mg, 0.071 mmol, 21.04%). 1H NMR (500 MHz, DMSO-d6) δ 8.45 (d, J=2.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.49 (t, J=2.0 Hz, 1H), 7.36-7.17 (m, 3H), 6.71 (s, 1H), 2.20 (d, J=1.2 Hz, 3H), Mass spec.: 312.1 (MH)+. and (E)-3-bromo-5-(2-(2,5-difluorophenyl)prop-1-enyl)pyridine (18 mg, 0.058 mmol, 17.21%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (dd, J=6.7, 1.8 Hz, 2H), 8.11 (t, J=1.8 Hz, 1H), 7.38 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 7.32 (td, J=9.7, 4.7 Hz, 1H), 7.28-7.21 (m, 1H), 6.72 (s, 1H), 2.23 (t, J=1.5 Hz, 3H), Mass spec.: 312.1 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:16]([C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:15]=[CH:14][CH:13]=1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
α-(1-t-Butoxyformamido)-m-toluic acid and β-alanine benzyl ester are coupled to give N-[α-(1-t-butoxyformamido)-m-toluoyl]-β-alanine benzyl ester, MS: 413 (4, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][C@@H:12]([NH:21][CH3:22])[C@H:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[N:21]([CH3:22])[C@H:12]([CH3:11])[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5]1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1Br
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@@H](c2ccccc2)OC(c2ccc(F)cc2Br)N1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution 2-bromo-4-fluorobenzaldehyde (15.2 g, 74.9 mmol) in toluene (80 ml) was added (1R,2R)-(−)-pseudoephedrine (13.6 g, 82 mmol) and the resulting mixture was refluxed removing water using a Dean-Stark trap for 16 h. The reaction was halted and cooled down to room temperature. The solution was washed with citric acid solution (1M, 100 ml), saturated sodium bicarbonate solution (50 ml), brine (50 ml) and dried (MgSO4). Then, it was filtered and the solvent was evaporated under vacuum to give title compound as yellow oil. (26.2, yield=97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([OH:11])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[N:18]=1.[NH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[NH:19]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:20]
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Temperature: 100 °C

Procedure:
To a flask was added 6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (8-2, 3.41 g, 13.23 mmol), anhydrous hydrazine (5.0 mL, 159 mmol), and finally 1.4 Dioxane (60 mL). The stirred reaction mixture was then heated to 100° C. in a hot oil bath under an atmosphere of nitrogen with an air cooled reflux condenser attached. Upon completion of the reaction the mixture was cooled to room temperature, suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-3 as an orange/tan foam. HRMS (M+H)+: observed=254.1041, calculated=254.1037.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C)ccc3N2)c1
Yield: 37.4 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and ethanesulfonyl chloride (108 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over Magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 75 mg of ethanesulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide yellow solid (Yield: 37%). MS (ESI+APCI) M+1=359.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:38])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Yield: 55 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol, prepared as per procedure described in U.S. Pat. No. 5,668,286) with Lawesson's reagent (1.1 mmol), in dioxane (10 ml) at a temperature 65° C. for 12 hours followed by silica gel column chromatographic purification in 55% yield. Mp; 141-143° C., Mass m/z 410.1 (ES+, 100%) for C19H24FN3O4S.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:27]([C:25]1[CH:26]=[C:21]([CH2:20][CH2:19][N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCCCCCCBr
Reactant: CC(C)(C)c1cc(CCNCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCN(CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 59.7 %

Procedure:
Stir a solution of 4.5 g (9.3 mmols) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]amine, 1.8 g (9.3 mmols) of 1-bromooctane, and 2.0 g (18.7 mmols) of sodium carbonate in 50 mL of acetonitrile for 17 hours at reflux temperature. Add another 0.3 g (1.6 mmols) of 1-bromooctane and stir at reflux for an additional 18 hours. After cooling, concentrate the reaction mixture, in vacuo, dissolve the resulting oil in 50 mL of toluene, and wash with water (2×50 mL). Dry the organic phase over magnesium sulfate and concentrate in vacuo. Flash column chromatography (120 g silica gel 60, 230-400 mesh, EM), using heptane followed by 1.5% isopropyl alcohol/heptane as the eluting solvents, gives 3.3 g (60.0%) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]octylamine as a slightly colored oil which GC area % analysis shows to be 99.0% pure.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:25][CH:26]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Yield: 96.3 %

Procedure:
(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (4.2 g) was deprotected following general procedure C. The hydrochloride salt was treated with 10% sodium carbonate and EtOAc. The aqueous layer was washed with EtOAc and the organic layers combined. The organic layers were dried over sodium sulfate and concentrated to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid methyl ester (3.4 g). LC-MS (m/z) 528. NMR (400 MHz, CDCl3): 7.51 (d, 1H), 7.44 (d, 1H), 7.29 (m, 2H), 7.23 (m, 1H), 7.68 (m, 2H), 6.69 (s, 1H), 6.68 (s, 1H), 5.64 (s, 1H), 4.97 (s, 2H), 4.03 (m, 2H), 3.79 (s, 3H), 3.73 (m, 1H), 3.40 (s, 3H), 3.09-2.90 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)=O)[CH2:3][CH2:2]1.O.NN.[OH-].[Na+]>C(O)COCCO.O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CCNCC1)c1ccnc2ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2c(CCC3CCNCC3)ccnc2c1
Temperature: 180 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
A mixture of 13 g of 2-(4-piperidyl)-1-(4-quinolyl)-ethanone, prepared as indicated in Example 1, and 10 ml of 98% hydrazine hydrate in 150 ml of diethylene glycol is heated at 180° C. for 2 hours. After cooling, 15 g of sodium hydroxide pellets are added and the mixture is kept at 180° C. for 18 hours. The reaction mixture is diluted with water, extracted with chloroform. The organic phase is washed with water, dried and evaporated under reduced pressure. 10 g of the desired product are obtained, which is converted into the hydrochloride by the action of hydrochloric acid in ethanol. 7.2 g of 4-[2-(4-piperidyl)-ethyl]-quinoline are obtained in the form of monohydrated dihydrochloride which melts at 210° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CS(C)=O.O>[CH3:13][O:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCOCC2)cc(O)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 5-fluoro-3-methoxy-2-nitro-phenol (2.0 g, 10.6 mmol) in dimethylsulfoxide (25 ml) is added morpholine (9.2 ml, 106 mmol) at room temperature. The resulting mixture is heated at 100° C. for 2 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (40 ml) and the aqueous layer is extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (30 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (45% ethyl acetate/hexane) to yield 3-methoxy-5-morpholin-4-yl-2-nitro-phenol (0.71 g, 2.78 mmol, 26%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.BrC1C=NC(C[CH:50]2[C:55](Br)=[CH:54][NH:53][C:52]([CH3:57])=[N:51]2)=NC=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:55]3[CH:54]=[N:53][C:52]([CH3:57])=[N:51][CH:50]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: CC1=NC(Cc2ncc(Br)cn2)C(Br)=CN1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
2 M aqueous Na2CO3 solution (1.67 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.80 g) and 5-bromo-2-(5-bromo-2-methyl-1,4-dihydro-pyrimidin-4-ylmethyl)-pyrimidine (0.40 g) in dimethylformamide (5 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (82 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 95:5->80:20) followed by HPLC (MeCN/H2O/NH4OH) to afford the title compound (340 mg) which was crystallized from 1:3 EtOAc/diisopropylether by scratching to yield a solid, mp 112-115° C. Yield: 0.25 g (34% of theory). Mass spectrum (ESI+): m/z=446 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[CH:18]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:7]=[C:2]([N:25]3[CH:26]=[C:22]([I:21])[N:23]=[CH:24]3)[N:3]=2)[CH2:20][CH2:19]1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C3CC3)c2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)nc(-n3cnc(I)c3)c2)cc1

Procedure:
The title compound was prepared 2-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.33) (1.0 g, 3 mmol) and commercially available 4-iodo-imidazole (0.782 g, 4 mmol) according to the general procedure IVa. Obtained as a yellow solid (1.44 g, 93%). MS (ISP) 456.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH:9]=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][CH:13]([Cl:18])[C:14]([F:17])([F:16])[F:15].O1CCCC1.CC(C)([O-])C.[Na+]>CN(C)C=O>[Cl:12][C:13]([Cl:18])([C:14]([F:17])([F:16])[F:15])[CH:9]([OH:10])[CH2:8][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)C(Cl)Cl
Reactant: COC(=O)CC(C)(C)CC=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)CC(O)C(Cl)(Cl)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To an agitated mixture of methyl 3,3-dimethyl-5-oxopentanoate (1.0 g), 1,1-dichloro-2,2,2-trifluoroethane (1.06 g) and dry tetrahydrofuran (10 cm3), maintained at -78° C., was added, over a period of 5 minutes, sodium t-butoxide (1.66 cm3 of a 42% w/w solution in dimethylformamide) after which the mixture continued to be agitated at -78° C. for a further 60 minutes. The reaction was quenched with saturated ammonium chloride at low temperature and the mixture allowed to warm to the ambient temperature. After addition of water (20 cm3) and separation of the organic phase, the aqueous phase was extracted with di-isopropyl ether (3×30 cm3) and the extracts combined with the organic phase, which was washed with brine (2×10 cm3) and dried over anhydrous magnesium sulphate. After removal of the volatile components by evaporation under reduced pressure the residual oil was purified by column chromatography (silica gel column eluted with a 9:1 mixture (by volume) of hexane and ethyl acetate) to give methyl 6,6-dichloro-3,3-dimethyl-5-hydroxy-7,7,7-trifluoroheptanoate as a colourless oil (yield 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=1)[NH2:7].[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:7][C:16](=[O:18])[CH3:17])[CH:8]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1Oc1ccccc1
Yield: 91.3 %

Procedure:
5-fluoro-2-phenoxyaniline 3 (5.14 g, 25 mmol) was dissolved in pyridine (15 mL) in a dry flask. At 0° C., acetyl chloride (2.3 mL, 33 mmol) was slowly added to the reaction, which was then refluxed for one hour, and subsequently, concentrated by vacuum. The residue was purified via column chromatography (silica gel) using CHCl3 as the eluent to give N-(5-fluoro-2-phenoxyphenyl)acetamide 4 as white solid (5.6 g, 90%): 1H-NMR (300 MHz, CDCl3) δ 8.29 (dd, J=10.5, 3.0 Hz, 1H), 7.74 (br s, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.5 Hz, 2H), 6.81 (2d, J=5.4, 5.1 Hz, 1H), 6.70 (2 dd, J1=J2=J3=J4=3 Hz, 1H), 2.17 (s, 3H). MS (GC) m/z 245(M., 100%)
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12]O)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:29])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:29][CH2:12][CH:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:26])[C:9]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1N(C2CCCCC2)CC(CO)C1(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Yield: 55 %

Procedure:
To 60.0 g. (0.17 mole) of 1-cyclohexyl-4-hydroxymethyl-3,3-diphenyl-2-pyrrolidinone in 400 ml. of chloroform was added 48.0 g. (0.40 mole) of thionylchloride with stirring. To this solution was added dropwise with ice bath cooling 40 g. (0.52 mole) of dry pyridine and the solution was refluxed for two hours. After concentrating in vacuo the residue was dissolved in chloroform and washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform solution was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was recrystallized from isopropyl ether and after drying weighed 34.5 g. (55% yield) and melted at 124°-126° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:38])(=[O:37])[N:26]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[C:30]([CH2:29][CH2:28][CH2:27][N:26]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:38])=[O:37])#[N:31]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCC#N)CCCC#N)C4(CC4)C3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#CCCCN(CCCC#N)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{4-[Bis-(3-cyano-propyl)-sulfamoyl]-4,7-diaza-spiro[2.5]oct-7-yl}-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 19) was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in MeOH (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.