Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:38]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])([CH3:40])[CH3:39]>CCOC(C)=O.O>[Si:42]([O:26][C@@H:24]([CH3:25])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:27])[C:12]([NH:14][CH2:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A 500 mL round bottomed flask was charged with (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-N-(2-oxo-2-phenylethyl)butanamide (7.87 g, 20.4 mmol) and DMF (200 mL) then cooled to 0° C. Imidazole (6.94 g, 102 mmol) and tert-butylchlorodimethylsilane (9.22 g, 61.2 mmol) were added and the mixture was stirred and warmed to room temperature overnight. Water (200 mL) was added to the mixture followed by EtOAc (200 mL) and the phases partitioned. The organic phase was washed with water (2×100 mL), brine (100 mL), dried (Na2SO4) and concentrated to furnish the title compound as a white solid (8.2 g, 80%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.97 (d, J=8 Hz, 2H), 7.44-7.66 (m, 1H), 7.40 (d, J=8 Hz, 1H), 6.42 (d, J=8 Hz, 1H), 5.43 (d, J=6 Hz, 1H), 4.77 (dd, J=6, 8 Hz, 2H), 4.79 (dd, J=5, 15 Hz, 2H), 4.70 (d, J=5, 15 Hz, 1H), 4.52-4.58 (m, 1H), 3.85-4.89 (m, 1H), 2.39 (s, 3H), 1.24 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O1CCCC1.CO.[OH-].[Na+].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)c1cc(F)c(COc2cnc(OC(C)C)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-{[(5-chloro-6-isopropoxypyridin-3-yl)oxy]methyl}-2,5-difluorobenzoate (Preparation 14, 400 mg, 1.03 mmol) in a mixture tetrahydrofuran/methanol (1/1 10 mL) was added an aqueous solution of sodium hydroxide (2M, 2.6 mL, 5.15 mmol). The reaction was stirred at room temperature for 2 hours and diluted with ethyl acetate (20 mL). An aqueous solution of hydrochloric acid (2M, 10 mL) was added to pH 1. The organic phase was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colourless oil (240 mg, 94% over two steps). No further purification undertaken.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:59])([CH3:48])([CH3:46])[CH3:47]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.372 g, 1.1 mmol), HOBt (0.145 g, 1.1 mmol), EDCI (0.246 g, 1.32 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.275 g, 1.2 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclopentyl)-carbamic acid tert-butyl ester (592 mg, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[NH2:29]>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:29][C:28]4[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)NC(=O)C(C3CC3)O4)n2)cc(OC)c1OC

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 7.21 (m, 2H), 6.87 (s, 2H), 6.77 (d, 1H), 3.58 (s, 6H), 3.56 (S, 3H), 1.20 (m, 4H); LCMS: retention time 10.25 min; purity 96.5%; MS (m/e): 468 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[CH3:21][C:22]1[C:23]([CH:31](O)[CH3:32])=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1>C1C=CC=CC=1>[CH3:21][C:22]1[C:23]([CH:31]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:32])=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1
Reactant: Cc1cc2c(cc1C(C)O)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: Cc1cc2c(cc1C(C)SCC(=O)O)OCO2
Yield: 93 %

Procedure:
3.7 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid were added to 3.2 g of 1-(6-methyl-1,3-benzodioxol-5-yl)ethanol and the mixture was heated under reflux in 100 ml of benzene for 1 h. The reaction mixture was washed with water and then extracted with a 1 1N sodium hydroxide solution. The aqueous layer was washed with ethyl acetate, acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain a crystalline residue. After recrystallization from diisopropyl ether, 4.2 g of the intended compound was obtained in the form of white crystals.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][O:26][CH3:27])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[CH:13]=2)[CH:8]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)(=O)=O.[C-:41]#[N:42].[Na+]>CN(C=O)C>[C:41]([CH2:6][CH:7]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][O:26][CH3:27])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[CH:13]=2)[CH:8]1[C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)#[N:42]
Reactant: [C-]#N
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(COS(C)(=O)=O)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CC#N)C2c1ccc2c(c1)OCO2
Yield: 85.5 %

Procedure:
(1RS,2RS,3RS)-2-Methanesulfonyloxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.5 g, 2.96 mmol) was stirred in DMF (10 ml) under argon with NaCN (1.45 g, 29.6 mmol) at 60° C. for 20 h then cooled and partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (1.27 g, 86%).
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2CC3C[CH:8]([CH2:12][CH:4]1C3)[CH2:9]2)#[N:2].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1)#N.CS(N)(=O)=O.[N:56]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58][CH2:57]1>>[N:56]1([S:60]([NH:63][C:19](=[O:21])[C:18]2[CH:22]=[C:23]([CH:24]3[CH2:25][CH2:26]3)[C:15]([O:14][CH2:13][C:3]3([C:1]#[N:2])[CH2:4][CH2:12][CH2:8][CH2:9][CH2:10]3)=[CH:16][C:17]=2[F:27])(=[O:62])=[O:61])[CH2:59][CH2:58][CH2:57]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCCCC1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.061 g, 42%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.99 (d, J=12.6 Hz, 1H), 4.15 (s, 2H), 4.02 (t, J=7.6, 7.6 Hz, 4H), 2.18-2.08 (m, 2H), 2.03-1.97 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.39 (m, 4H), 1.20 (br s, 1H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −112.6 (s, 1F); MS (ES−) m/z 434.1 (M−1).
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[NH:8][C:25](=[O:27])[CH3:26])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1R,2R)-Cyclohexane-1,2-diamine (1.10 g, 9.68 mmol) was added into a Round bottom flask and was dissolved in Tetrahydrofuran (50 mL). The flask was cooled at 0° C., then 2,4,5-Trichloropyrimidine (1.60 g, 8.72 mmol) was added. A precipitate formed, and the reaction was stirred 10 min before Triethylamine (3.00 mL, 21.5 mmol) and Acetic anhydride (1.20 mL, 12.7 mmol) were added simultaneously via syringes. After 15 min, external cooling was removed, and the contents was stirred under an atmosphere of Nitrogen. After 45 min, the contents were partitioned between 100 mL DCM and 100 mL sat'd. sodium bicarbonate solution. The layers were separated, and the aqueous phase extracted once with 100 mL DCM. The organic fractions were washed once with 100 mL brine, dried (sodium sulfate) and then were concentrated onto 8 g Celite and chromatographed on an ISCO cartridge (120 g, 0-100% EA:Hex), with product beginning to elute at 75%. N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide was isolated as a white solid (1.08 g, 41%). m.p.=222-225° C.; LCMS (m/e) 303 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 6.30 (d, 1H, J=7 Hz), 5.69 (d, 1H, J=7.5 Hz), 3.83 (m, 2H), 2.25 (m, 1H), 2.04 (m, 1H), 1.90 (s, 3H), 1.80 (m, 2H), 1.33 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[C:11]([C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2)=[O:13]
Reactant: Clc1ccc(CCNCc2cc3ccccc3o2)cc1Cl
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1cc(Cl)cc2cc[nH]c12)N(CCc1ccc(Cl)c(Cl)c1)Cc1cc2ccccc2o1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of 72 mg (0.37 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 118 mg (0.37 mmol) of benzofuran-2-ylmethyl-[2-(3,4-dichloro-phenyl)-ethyl]-amine in DMF (5 ml) were added 131 mg (0.41 mmol) of TBTU and 126 μl (0.74 mmol) of N,N-diisopropylethyl amine and the mixture was stirred over night at RT. Then the reaction mixture was diluted with ethyl acetate and washed with water, brine, sat. NaHCO3 solution, 1N HCl and again with brine. The organic layer was then dried (MgSO4) and concentrated. The remaining residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 9:1) to yield the title compound as a yellow oil (145 mg, 79%). MS (ISP) 497.3 (M+H)+.
Reaction SMILES: Cl[P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1.[Si:8]([O:15][CH2:16][CH2:17][OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[Si:8]([O:15][CH2:16][CH2:17][O:18][P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1)([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=P1(Cl)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of freshly prepared 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.2 g, 0.1M) in dry dichloromethane (30 ml) was added, drop-wise, to a stirred mixture of 2-(tert-butyldimethylsilyloxy)ethanol (17.6 g, 0.1M), triethylamine (18.1 ml, 0.13M) in dry dichloromethane (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature and was stirred for a further 2 hours. The mixture was filtered and the filtrand washed with n-hexane. The filtrate was evaporated in vacuo, diluted with n-hexane (30 ml) filtered and the filtrate evaporated in vacuo to give a brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:29][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[C:19]([NH:16][C:17]([NH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:15][CH:14]=1)=[O:18])[CH:28]=[CH:27][CH:26]=2
Reactant: CC1CCN(c2ccc(CN)cc2)CC1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCC(C)CC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(4-methyl-1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.66 (s, 1H), 8.74 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 7.82 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 4.40 (d, 2H, J=6 Hz), 3.54 (m, 4H), 2.78 (s, 3H), 1.90-1.50 (m, 5H), 0.98 (d, 3H, J=6 Hz); MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N4O.2.6HCl: C, 59.64; H, 6.38; N, 11.59. Found: C, 59.31; H, 6.39; N, 11.19.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.O>CCOCC>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of 1,3-dibromo-5-methoxybenzene (15 g, 56.40 mmol) in anhydrous Et2O (200 mL) under nitrogen was cooled to −78° C. n-BuLi (38.80 mL of a 1.6 M solution in Et2O, 62.00 mmol) was added dropwise, and the solution was aged at −78° C. for 45 m. To the resulting heterogeneous mixture was added anhydrous DMF (4.78 mL, 62.00 mmol), and the solution was slowly warmed to RT. The mixture was poured into H2O (200 mL), and the aqueous phase was extracted with Et2O (3×125 mL). The combined organic fractions were washed with brine (100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent provided 11.70 g (96%) of 3-bromo-5-methoxybenzaldehyde (115).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16]/[C:17](/[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[CH:18]\[C@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)=[CH:18]\[C@H:19]1[C@H:21]([C:22]([O:15][CH2:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:13]=2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)OCc1cccc(Oc2ccccc2)n1
Yield: 91.8 %

Procedure:
4.02 g (0.02 mol) of (6-phenoxy-2-pyridinyl)-methanol and 6.07 g (0.02 mol) of (±)-trans-Z-3-(2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid-chloride were dissolved in 100 ml of anhydrous toluene, and 2 g of pyridine, dissolved in 10 ml of anhydrous toluene, were added dropwise to the solution at 20°-25° C., while stirring. The mixture was then stirred for a further 3 hours at 25° C. The reaction mixture was poured into 150 ml of water, and the organic phase was separated off and again washed with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off in a water jet vacuum. The last solvent residues were removed by incipient distillation for a short time at a bath temperature of 60° C./1 mm Hg. 8.6 g (92% of theory) of (6-phenoxy-2-pyridinyl)-methyl (±)-trans-Z-3-(2-chloro-2-(4-chlorophenyl)-vinyl)-2,2-dimethyl-1-cyclopropanecarboxylate were obtained as a yellow viscous oil. The structure was established by the 1H-NMR spectrum.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([OH:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=1.N1C=CC=CC=1>ClCCl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([O:39][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:30]=1
Reactant: C1=COCCC1
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCC[C@H](OC1CCCCO1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.23 ml (45 mmol) of 97% pure 3,4-dihydro-2H-pyran, followed by 762 mg (3.0 mmol) of pyridinium p-toluenesulfonate are added to a solution of 6.80 g (25.8 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 86 area % in 210 ml of dichloromethane in a 2-neck round-bottom flask with magnetic stirrer under nitrogen. The reaction mixture is stirred at room temperature for 24 h. HPLC analysis (system as in Example 5) shows besides pyridine (tret 4.8 min.) and 1.5 area % precursor (tret 9.8 min.), the product in the form of two diastereomers (ratio about 1:1, tret 14.1 and 14.4 min.). The reaction solution is concentrated to 70 ml in vacuo, diluted with 100 ml of diethyl ether and washed with 1×100 ml and 2×50 ml of water. The organic phase was concentrated in vacuo and the residue was dried under HV. 9.70 g of a pale yellowish oil which, according to HPLC, has a purity of 76 area % are obtained. Yield: 23.75 mmol, 92% of theory.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.CS(O[CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])(=O)=O>C(O)C>[N:1]([CH:11]([CH3:16])[CH2:12][CH2:13][C:14]#[N:15])=[N+:2]=[N-:3]
Reactant: CC(CCC#N)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CCC#N)N=[N+]=[N-]
Yield: 91.2 %

Procedure:
To a stirring solution of NaN3 (15 g) in boiling water (20 ml) was added a solution of crude 4-methanesulphonyloxypentanonitrile (37.7 g, ≈0.189 mol) in ethanol (240 ml) and the mixture refluxed for 1.5 h. After cooling the mixture was partitioned between H2O and CH2Cl2. The organic phase was dried and concentrated in vacuo to give 21.4 g of the title material as a light brown oil, (91.6): 1Hmr (CDCl3) δ: 4.05 (1H, q, J=13 Hz), 2.46 (2H, t, J=13 Hz), 1.8 (2H, t, J=13 Hz) and 1.35 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2242, 2100 cm-1.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:33]>>[Cl:33][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)CCc1c(Cl)nc(C)nc1C(F)(F)F

Procedure:
A mixture of ethyl 3-(2-methyl-6-trifluoromethyl-3H-pyrimidine-4-on-5-yl)propionate (0.61 g, 2.20 mmol), N,N-diethylaniline (0.33 g, 2.2 mmol), and POCl3 (8 mL) was heated under reflux for 2 h. The mixture was concentrated, poured onto ice, and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 0.65 g of product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([F:12])[CH:3]=1.[CH2:13]([Mg]Br)[CH3:14].[CH:17]1(C(C2C=CC(Cl)=CC=2)(O)C)C[CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])([CH2:13][CH3:14])[CH2:17][CH3:18])=[C:4]([F:12])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(Cl)cc1F
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 2.00 g (10.61 mmol) of methyl 4-chloro-2-fluorobenzoate and 31.8 ml (31.82 mmol) of a 1N solution of ethylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.27 g (55% of theory) of the title compound were obtained.