Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH2:5][CH:6]=C.CSC.CC1C=CC(S(O)(=O)=[O:26])=CC=1>CO.ClCCl.CC(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][C:4]([CH3:8])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH:6]=[O:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CCC(C)(COC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Solvent: CC(C)=O
Product: COCC(C)(CC=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 480.4 %

Procedure:
To a chilled (−78° C.) solution of (1-methoxymethyl-1-methylbut-3-enyl)benzene (1.67 g, 8.77 mmol) in methanol-dichloromethane was bubbled ozone gas until the solution turned blue. The excess ozone was then purged from the mixture with oxygen and then dimethyl sulfide (5 mL, 68 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The mixture was then concentrated in vacuo to remove the excess dimethyl sulfide and diluted with 20 mL of ammonium chloride and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford an oil which corresponded to the dimethyl acetal by 1H-NMR. The crude product was diluted with 40 mL of acetone and p-TsOH (300 mg, 1.57 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by 1H-NMR and indicated the presence of aldehyde and dimethyl acetal. The reaction was refluxed for 4 hours and monitored by TLC (ethyl acetate-hexanes (1:9)) and then cooled and diluted with saturated aqueous sodium bicarbonate solution and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with two 10 mL portions of saturated aqueous sodium bicarbonate solution, two 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1.45 g (85.9% yield) of 4-methoxy-3-methyl-3-phenylbutyraldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[C:43]([NH2:48])[CH:42]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:48][C:43]1[CH:42]=[C:41]([Cl:40])[CH:46]=[CH:45][C:44]=1[NH:47][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(Cl)ccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.9 %

Procedure:
6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-chloro-o-phenylenediamine (171 mg, 1.2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum. To the residue was added 5 ml of absolute ethanol. The solids were collected by vacuum filtration, washed with absolute ethanol and dried under vacuum to give the title compound (135 mg, 48% yield) as a brown solid. LC-MS (m/z) 282 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:23](O)=[O:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3]1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].C(N(CC)CC)C.C(Cl)CCl.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:26]([NH:29][C:23]([C:15]1[S:14][C:6]2[N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2](=[O:1])[CH:3]=[CH:4][C:5]=2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCNC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a stirred solution of the compound of Example 59 (174 mg, 0.5 mmol) in dry DCM (5 mL) was added allyl amine (29 mg, 0.5 mmol), triethylamine (101 mg, 1 mmol), and a catalytic amount of 4-dimethylaminopyridine followed by EDC (96 mg, 0.5 mmol). The reaction mixture was stirred at r.t. for 4 h and then poured into 2M HCl(aq) (20 mL). The product was extracted with DCM (2×20 mL) and the combined organic fractions dried (MgSO4), filtered and the solvent removed in vacuo. Purification by radial chromatography (silica, EtOAc) gave the title compound as a solid (70 mg). δH (CDCl3) 7.7–7.1 (11H, m), 4.48 (1H, d, J 10 Hz), 5.6–5.4 (1H, m), 5.28 (1H, bs), 4.84 (1H, dd, J 10, 1 Hz), 4.69 (1H, dd, J 10, 1 Hz), 3.8–3.6 (2H, m). LCMS (ES+) 387 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[N:24]([CH2:27][CH3:28])=[C:25]=[O:26]>ClCCl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:25](=[O:26])[NH:24][CH2:27][CH3:28])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Oc2cc(CC(=O)OC)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (the intermediate for example 4-1, 1st step, 20 mg, 0.063 mmol) and isocyanato-ethane (0.05 mL) and dichloromethane was stirred at room temperature for 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution with 0-30% ethyl acetate in petroleum ether) to afford [4-(1-ethylcarbamoyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (21.0 mg, 85%) as a viscous oil.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[N:16]([CH:17]4[CH2:33][N:21]5[C:22]6[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]5[CH2:19][CH2:18]4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:15]=[N:14][CH:13]=3)CCCC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34]C1C=CC(CC#C)=CC=1.FC1C=CC(CCl)=CC=1.C([Si](C)(C)C)#C.[N-]=[N+]=[N-]>>[F:34][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:12]2[N:16]([C@H:17]3[CH2:33][N:21]4[C:22]5[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]4[CH2:19][CH2:18]3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:15]=[N:14][CH:13]=2)=[CH:2][CH:3]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(c3ccccc3)CCCC1)CC2
Agent: C#C[Si](C)(C)C
Agent: Fc1ccc(CCl)cc1
Agent: [N-]=[N+]=[N-]
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](n1nncc1Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate from EXAMPLE 6 and 1-fluoro-4-prop-2-yn-1-ylbenzene prepared from 4-fluorobenzyl chloride and ethynyltrimethylsilane described in EXAMPLE 8 EXAMPLE 28.1 and 28.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively from EXAMPLE 6. MS (+ESI) m/z: 405.1.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 25 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.39 (dd, 1H, J=2.8, 6.8 Hz), 7.33–7.21 (m, 11H), 7.00 (t, 1H, J=5.6 Hz), 6.92 (t, 1H, J=9.2 Hz), 4.89 (s, 1H), 3.38 (dd, 2H, J=6.4, 12.0 Hz), 2.91–2.88 (m, 2H), 2.74 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.29 (t, 2H, J=7.6 Hz), 1.97 (dt, 2H, J=2.4, 11.6 Hz), 1.77–1.62 (m, 8H), 0.97 (t, 3H, J=7.2 Hz); ESMS m/e: 516.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]([N:7]1[CH2:11][C@@H:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])([C:17]#[N:18])[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[F:34])=[O:6].[Li+].[OH-]>C1COCC1.CO>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([C@@H:8]2[C@:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[C@H:10]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:11][N:7]2[C:5](=[O:6])[CH2:4][C:3]([OH:35])=[O:2])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)CC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
A mixture of methyl malonyl chloride (Aldrich, 127 mg, 0.93 mmol), DIPEA (Aldrich, 297.0 mg, 2.3 mmol) and rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (150 mg, 0.35 mmol) was stirred at rt overnight. The reaction mixture was concentrated and purified by RP-HPLC to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid methyl ester (136.2 mg, 73.5%). In a manner similar to the method described in Example 8, rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid methyl ester (120 mg, 0.23 mmol) was treated with 2 N LiOH (1.0 mL) in THF/MeOH (3 mL/1 mL) at rt for 3 hrs and purified by RP-HPLC to rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-3-oxo-propionic acid (21.2 mg, 18.2%). HRMS (ES+) m/z Calcd for C25H24Cl2F2N2O3+H [(M+H): 509.1205; Found: 509.1207.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15](I)[CH:16]=[CH2:17]>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:17][CH:16]=[CH2:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Reactant: C=CCI
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 55 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and allyl iodide (1.4 ml, 15.2 mmol) were treated overnight according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=10/1) the title compound (Rf=0.55, 2.0 g, 55% yield) was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([CH3:34])[CH2:31][C@H:30]([NH:35]C(=O)OC(C)(C)C)[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2.Cl>O1CCOCC1.CO>[NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([CH3:34])[CH2:31][C@H:30]([NH2:35])[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(C4CCN(C)CC4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the intermediate tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The resulting residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C27H36N7O [M+H]+: m/z=474.3. found: 474.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC3C=CC=CC=3)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.I[Si](C)(C)C.Cl>C(#N)C.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccccc3Cl)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Product: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
To a solution of (+)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamate (0.530 g, 1.34 mmol) in acetonitrile (25 mL) cooled to 0° C. was added iodotrimethylsilane (1.07 g, 5.38 mmol) and the reaction mixture was allowed to stir for 90 min. The reaction mixture was quenched by the addition of aqueous hydrogen chloride (25 mL, 2.0 N) and washed with diethyl ether (50 mL). The aqueous layer was neutralized with aqueous sodium hydroxide (50 mL, 2.5 N) and extracted with dichloromethane (2×100 mL). The combined organic fractions were washed with water (75 mL), saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. The oil was re-dissolved in isopropanol (2 mL) and hydrogen chloride (5.0 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.229 g (58%) of (−)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−11.06 (c 10.0 in dimethylsulfoxide); mp 186-188° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found C, 59.59; H, 5.13; N, 4.48.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][C:31](=[O:33])[CH3:32])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-c2nccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 60.4 %

Procedure:
To a stirred and cooled solution of 3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenylamine (example 326) (0.150 g, 0.369 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added acetyl chloride (0.030 mL, 0.406 mmol) and the mixture was stirred at 23° C. for 1 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by trituration with diethyl ether to give the title compound as a white solid (0.100 g, 60%). MS (ISP) 449.3 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8]P(OCC)(=O)OCC)[O:5][N:4]=1)[CH3:2].COC([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)C>>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:8]=[CH:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[OH:21])[O:5][N:4]=1)[CH3:2]
Reactant: CCOP(=O)(Cc1cc(CC)no1)OCC
Reactant: COC(C)Oc1ccccc1C=O
Product: CCc1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 6 g (0.02 mole) of diethyl (3-ethyl-isoxazol-5-yl)-methanephosphonate and 4.4 g (0.02 mole) of o-(1-methoxyethoxy)-benzaldehyde are reacted and the product is recrystallized from isopropanol. 1.7 g (32% of theory) of colorless crystals, of melting point 175°-176° C., are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:13](=[O:18])[N:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH:25]1[CH2:27][CH2:26]1)[CH2:11][CH2:10]2)(=O)=O.[CH3:30][N:31](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:17][C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH:25]3[CH2:27][CH2:26]3)[C:13]2=[O:18])=[CH:8][C:7]=1[C:30]#[N:31]
Reactant: O=C1c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)cc2CCN1c1cnccc1C1CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cc2c(cc1Cl)C(=O)N(c1cnccc1C1CC1)CC2
Yield: 24.3 %

Procedure:
7-Chloro-2-(4-cyclopropylpyridin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (I-91a: 170 mg, 0.381 mmol) in DMF (3 mL) was reacted with Pd2(dba)3 (6.97 mg, 0.007 mmol), dppf (16.9 mg, 0.003 mmol) and Zn(CN)2 (26.8 mg, 0.228 mmol) for 24 hours at 80° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) followed by preparative HPLC afforded 30 mg of the product (24.3% yield).
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[C:5]1(C(OCC)=O)[C:9]([O:11]CC)=[O:10].[OH-].[K+].C(O)C.Cl>O>[CH3:7][C:6]1([CH3:8])[CH:4]([CH:3]=[C:2]([Cl:19])[Cl:1])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O

Procedure:
The mixture of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethyl-1-ethoxycarbonylcyclopropanecarboxylate (1.5 g.) potassium hydroxide (2.0 g.) and ethanol (150 ml.) is refluxed for 2 hours, after which it is poured into water (500 ml.) and carefully acidified with concentrated hydrochloric acid. The white oily precipitate which is formed is collected by extraction with carbon tetrachloride, the extracts dried with anhydrous sodium sulphate, and the solvent evaporated under reduced pressure. The residual oil is heated under nitrogen to about 150°-160° C. for about 1.5 hours, and then cooled to form a crystalline mass. Recrystallisation from n-hexane yielded 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid, m.p. 87°-90° C., believed to be principally the trans-isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>O.COCCOC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a mixture of 2-amino-4-bromophenol (50 g, 266 mmol) and NaHCO3 (67.0 g, 798 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (45.1 g, 399 mmol) at 0° C. The mixture was stirred at 15° C. for 0.5 h and then stirred at 80° C. overnight. The mixture was cooled to ambient temperature and quenched with water (400 mL). The precipitate was collected by suction filtration, washed with water (200 mL) and petroleum ether (300 mL) in turn, and dried to give 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 97%) as a gray solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.07 (d, J=8.4 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.59 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)=[O:11].[CH3:25][CH2:26][O:27]C(C)=O.O>CN(C1C=CN=CC=1)C.C(OC(=O)C)(=O)C.CCOCC>[CH3:8][O:9][C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:26](=[O:27])[CH3:25])[CH:18]=1)=[O:11]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1nc(C)sc1-c1cccc(NC(C)=O)c1

Procedure:
Triethylamine (14.2 mmol) and DMAP (4.05 mmol) are added successively to a solution of 5-(3-amino-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (4.05 mmol) in acetic anhydride (25 mL). After stirring for 30 min EtOAc and water are added, the layers are separated and the aqueous layer is extracted once with EtOAc. The combined organic layers are washed with sat. aqueous NH4Cl solution, sat. aqueous NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo to give a crude product which is diluted with ether. The obtained suspension is filtered. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.81 min; [M+H]+=291.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:24]3[CH2:26][CH2:25]3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:24]3[CH2:25][CH2:26]3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl)oxy]-2-fluorobenzoate (Preparation 264, 54.0 g, 135.59 mmol) in dichloromethane (270 mL) was added trifluoroacetic acid (30.76 mL, 406.77 mmol). The resulting solution was heated at 45° C. for 24 hours and concentrated under reduced pressure at 45° C. tert Butyl methyl ether (100 mL) was added to the residue and the resulting slurry stirred at room temperature for 2.5 hours, filtered, washed with tert butyl methyl ether (20 mL) and dried to give the title compound as an off-white solid (45.0 g, 97%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:11][CH2:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[OH-].[Na+:29]>O>[CH:1]1([CH2:4][O:5][C:6]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:7][CH2:8][C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:12]([O-:14])=[O:13])[CH2:10][CH2:11]2)[CH2:3][CH2:2]1.[Na+:29]
Reactant: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
185 mg of 4-cyclopropylmethoxy-4-(4-fluorophenyl)-1-phenylcyclohexanecarboxylic acid were treated with 0.5 ml of a 1 M sodium hydroxide solution and 2 ml of water and cautiously heated to 100° C. The solution became clear. The sodium salt crystallized during cooling. It was filtered off with suction and dried. 155 mg of the title compound were obtained as silvery white flakes.