Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37]O)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCCl.ClCCCl.ClCCCl.C(Cl)Cl>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][Cl:20])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of triphenylphosphine (4.55 g, 17.4 mmol) and hexachloroethane (3.9 g, 16.5 mmol) in 1,2-dichloroethane (18 mL) prepared at 0° C. was added via cannula into a flask containing a solution of methyl N-(tert-butoxycarbonyl)-L-serinate (3.2 g, 14.6 mmol) in 1,2-dichloroethane DCE (40 mL), kept at 0° C. under N2 atmosphere. After the addition was completed, the reaction mixture was further stirred at room temperature for 2 h, diluted with DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated. Purification made through chromatographic column of silicagel eluted with 10% to 50% EtOAc in hexane for 30 min, to afford 2.13 g (61% yield) of title compound as white crystals. MS: m/z=260.0 (MNa+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:45])[C:9]([C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:32])=[O:31])([CH3:29])[CH3:28])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)=[CH:4][CH:3]=1.[CH3:46][Mg]I>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:45])([C:9]([C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:31])=[O:32])([CH3:28])[CH3:29])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)[CH3:46])=[CH:4][CH:3]=1
Reactant: CC(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)(C(=O)c1ccc(F)cc1)c1ccc(S(C)(=O)=O)cc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)(c1ccc(F)cc1)C(C)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 12 h

Procedure:
To a solution of Example 19 (93 mg, 0.144 mmol) in CH2Cl2 (4 mL) at −78° C. was added methyl magnesium iodide (3M, Et2O, 0.24 mL, 0.8 mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for 12 h, then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with dichloromethane/methanol, 99:1, 2×), then stirring vigorously the resulting residue in hexane/ethyl acetate/ether for 1 h and then filtration afforded the title compound as a white powder (mixture of diastereoisomers; 1:1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc([N+](=O)[O-])c1
Yield: 38.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-nitrophenylboronic acid (available from Aldrich Chemical Company, Inc.; 67 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-nitro-biphenyl-2-carboxylic acid (36 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.51 (m, 2H), 8.18-8.39 (m, 4H), 8.06-8.15 (m, 1H), 7.87 (d, J=7.0 Hz, 1H), 7.73-7.79 (m, 2H), 7.63-7.68 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].O.O1CCOCC1.[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:27][C:28]([NH:1][C@@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CC1CCCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 1 %

Procedure:
290 g (1.7 mol) of 2-amino-3-cyclohexylpropionic acid are dissolved in 375 ml of 4N NaOH. The solution is made up to 2 l with water and 500 ml of dioxane are added. 255 ml (1.7 mol) of benzyloxycarbonyl chloride are added dropwise at pH 10 under pH-state conditions. After 8 h, the solution is extracted twice using diethyl ether and acidified to pH 2 using 1N hydrochloric acid. The product is extracted 3 times using 200 ml of ethyl acetate each time. After washing the organic extract, drying over sodium sulphate and concentrating, 5 g of the title compound are obtained.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:38](=[O:49])N2CCCCC>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[O:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:38][OH:49])[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations using 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (56%): MS (ES+) m/z 488.3 (M+23).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.O>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
Anthranilonitrile (10.0 grams, 85.0 mmol) was dissolved in 350 mL of acetic acid. To this was added 2,5-dimethoxytetrahydrofuran (11.0 mL, 85.0 mmol). This was stirred at reflux for 2 hours after which time the reaction mixture was pored into water and the product extracted with dichloromethane. The organic layer washed with water, dried over sodium sulfate and chromatographed on a silica gel column using a mobile phase of 1:1 dichloromethane-hexane to afford the title compound as a white solid. NMR confirms structure.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:26][CH3:27])=[C:15]([C:17]3[CH:18]=[CH:19][C:20]4[C:21]([CH:25]=3)=[N:22][O:23]N=4)[CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.BrC1C=C(C=CC=1[O:45]C)CN1C2C=CC=CC=2N=C1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1C2C=CC(B(O)O)=CC=2OC1>CN(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.[Pd].C(OCC)(=O)C>[CH3:27][O:26][C:14]1[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:23])=[O:45])[CH:25]=2)=[CH:16][C:11]([CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(Cn2cnc3ccccc32)cc1Br
Reactant: COc1ccc(Cn2cnc3ccccc32)cc1-c1ccc2nonc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cnc3ccccc32)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Synthesis 5-(5-Benzoimidazol-1-ylmethyl-2-methoxy-phenyl)-benzo[1,2,5]oxadiazole (P-014). A suspension of 1-(3-Bromo-4-methoxy-benzyl)-1H-benzoimidazole (I-107, X═N) (250 mg, 0.778 mmol), 1 N aqueous cesium carbonate (2.4 mL), and triphenylphosphine (20.7 mg, 0.0788 mmol) in DMF (5 mL) was stirred. To the suspension was added benzo[1,3]dioxol-5-yl-boronic acid (155 mg, 0.946 mmol), the reaction purged with nitrogen, and bis(dibenzylideneacetone)palladium(0) (22.7 mg, 0.0394 mmol) was added under nitrogen. The reaction was stirred at 100° C. overnight. After cooling to room temperature, ethyl acetate (50 mL) was added. The organic suspension was washed with saturated aqueous ammonium chloride (2×50 mL), 1 N aqueous sodium hydroxide (3×50 mL), water (50 mL), and brine (50 mL), decolorized over activated carbon, dried over sodium sulfate, and removed under vacuum to give crude product. The product was purified by flash silica gel column chromatography eluting with 1% methanol in dichloromethane to give P-014 (102.1 mg, 36% yield) as an off white powder. 1H NMR (400 MHz, d6-DMSO) d: 8.446 (s, 1H), 8.054-8.020 (m, 2H), 7.715 (dd, J=9.60 Hz, 1.60 Hz, 1H), 7.651-7.649 (m, 2H), 7.605 (d, J=2.40 Hz, 1H), 7.440 (dd, J=8.60 Hz, 2.20 Hz, 1H), 7.244-7.147 (m, 3H), 5.485 (s, 2H), 3.787 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11](=[O:26])[NH:12]/[C:13](=[CH:17]\[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)/[C:14](=[O:16])[NH:15]/2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[C:10]2/[C:11](=[O:26])[NH:12]/[C:13](=[CH:17]\[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)/[C:14](=[O:16])[NH:15]/2)=[CH:27][CH:28]=1
Reactant: COc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccc(OC(C)=O)cc3)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccc(O)cc3)[nH]c2=O)cc1
Yield: 30 %

Procedure:
(3Z,6Z)-3-(4-Acetoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione was treated with aqueous sodium hydroxide in THF at room temperature for 8 hrs to give the title compound (1519) in 30% yield.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[N:11][CH:12]=1)=O.C(O)(=O)C.O.[NH2:23]N>CO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[N:11][CH:12]=2)=[N:23]1
Reactant: COC(=O)c1cncc(C(=O)C=CN(C)C)c1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cncc(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of methyl 5-(3-dimethylamino-1-oxo-2-propenyl)-3-pyridinecarboxylate (1.7 g), acetic acid (0.62 ml) and hydrazine monohydrate (0.53 ml) in methanol (34 ml) was stirred for 24 hours at ambient temperature, and the mixture was evaporated in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water, and the mixture was adjusted to pH 9 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 5-(pyrazol-3-yl)-3-pyridinecarboxylate (1.24 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([O-:24])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A solution of a mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (from example 320 step 1, 60 mg, 0.0002 mol), m-nitroaniline (40.9 mg, 0.000296 mol), and p-toluenesulfonic acid (29 mg, 0.00017 mol) in dry 1,4-dioxane (1 mL, 0.02 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (free base). LCMS (M+H) 406.2.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:37]([N:1]2[CH2:4][CH:3]([C:5]([N:7]3[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]3)=[O:6])[CH2:2]2)=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CNC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)C2)cn1
Yield: 36.4 %

Procedure:
To a stirred solution of tert-butyl 4-(azetidin-3-ylcarbonyl)-1,4-diazepane-1-carboxylate (1.02 g, 3.6 mmol) and DIPEA (1.41 g, 10.8 mmol) in DCM (20 mL) was added a solution of 6-methylpyridine-3-carbonyl chloride (420 mg, 4.32 mmol) in DCM (5 mL) at 0° C. After 3 hours the reaction was diluted with DCM (10 mL), washed with saturated aqueous NaHCO3 (10 mL), brine (5 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 100:0:0 to 95:4.5:0.5 gradient of DCM/MeOH/NH3) gave the title compound (527 mg, 36%) as an orange-brown oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:21]([Cl:22])=[CH:20][C:7]([C:8]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:18][CH3:19])=[O:9])=[C:6]([O:23][CH3:24])[CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:21]([Cl:22])=[CH:20][C:7]([C:8]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][C@H:13]2[O:18][CH3:19])=[O:9])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCNC[C@H]1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCC(=O)c2ccccc2)C[C@H]1OC
Yield: 60.8 %

Procedure:
cis-4-Amino-5-chloro-2-methoxy-N-((3-methoxypiperidin-4-yl)methyl)-benzamide dihydrochloride (0.88 g) as a starting compound, 6-bromo-1-phenyl-1-hexanone (0.67 g) and potassium carbonate (1.37 g) were reacted and purified in the same manner as in Example 172 to give 0.67 g of cis-4-amino-5-chloro-2-methoxy-N-((3-methoxy-1-(6-oxo-6-phenylhexyl)-piperidin-4-yl)methyl)benzamide, m.p. 99°-101° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[CH2:19])[CH2:16]CO)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:20]1([OH:23])C[CH2:21]1>>[C:11]([C:9]1[CH:8]=[C:7]([C:15]2([CH:20]([OH:23])[CH3:21])[CH2:19][CH2:16]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: C=C(CCO)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: OC1CC1
Product: CC(O)C1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Yield: 40 %

Procedure:
The above unsaturated alcohol 8 (70 mg, 0.34 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 29 mg of [1-(3,5-di-t-butyl phenyl)-cyclopropyl]-ethanol (9) as a pale yellow oil in 40% yield. 1H NMR (400 MHz, CDCl3) δ7.25 (d, J=1.8 Hz, 1H, aromatic), 7.15 (d, J=1.8 Hz, 2H, aromatic), 3.65 (q, J=12.5, 6.7 Hz, 2H, aliphatic CH2), 1.83 (t, J=6.9 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.18 (t, J=5.6 Hz, 1H, alcohol), 0.84 (dd, J=9.9, 4.5 Hz, 2H, aliphatic CH2), 0.71 (dd, J=10.0, 3.9 Hz, 2H, aliphatic CH2). The above cyclopropyl alcohol (29 mg, 0.13 mmol) was oxidized as described in Example 1 to give 29 mg of 1-(3,5-di-t-butyl phenyl)-cyclopropaneacetaldehyde (10) as a clear oil in 100% yield. 1H NMR (400 MHz, CDCl3) δ9.79 (t, J=2.6 Hz, 1H, aldehyde), 7.25 (s, 1H, aromatic), 7.12 (d, J=1.3 Hz, 2H, aromatic), 2.59 (d, J=2.5 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.04 (dd, J=10.7, 5.2 Hz, 2H, aliphatic CH2), 0.88 (dd, J=10.6, 5.5 Hz, 2H, aliphatic CH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].[I:14]N1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[C:10]=1[I:14])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Solvent: ClCCl
Product: CCCc1n[nH]c(C(=O)OCC)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (5.5 mmol) of 5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 15 ml of dichloromethane and 1.23 g (5.5 mmol) of N-iodosuccinimide was added. The resulting solution was stirred at room temperature for 16 h. The solution was washed with aqueous sodium thiosulfate solution. The organic phase was dried with sodium sulfate and filtered. The resulting solution was passed through a short silica gel column, washing with dichloromethane. The solvent was removed under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[CH:3]=3)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1cccc(CCCCn2ccnc2)c1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Product: c1ccc(COc2ccc(-c3nc(COc4cccc(CCCCn5ccnc5)c4)co3)cc2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(4-benzyloxyphenyl)-4-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 87-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Li]C(C)(C)C.[I:21]I>C1COCC1>[I:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: II
Reactant: COc1ccc(NC(=O)C(C)(C)C)cn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(I)c(NC(=O)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(6-methoxypyridin-3-yl)pivalamide (Compound 1, 7.4 g, 35.6 mmol) in anhydrous THF (200 ml) at −78° C. under argon was added t-BuLi (1.7 M in pentane, 52 ml, 89.0 mmol) slowly. After stirred at −78° C. for 1 h, a solution of I2 (22.6 g, 89.0 mmol) in anhydrous THF (100 ml) at −78° C. was cannulated into the reaction over 20 min and the reaction was stirred for 15 min at −78° C. The cooling bath was then removed and the reaction stirred for 30 min, quenched cautiously with ice, extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[C:25]([C:26]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH:38]5[CH2:40][CH2:39]5)[CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][C:13]=2[Cl:41])=[CH:6][C:5]=1[Cl:42].C1COCC1.[OH-].[Li+].Cl>O.CO>[Cl:42][C:5]1[CH:6]=[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[C:25]([C:26]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH:38]5[CH2:40][CH2:39]5)[CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][C:13]=2[Cl:41])[CH:8]=[CH:9][C:4]=1[C:3]([OH:43])=[O:2]
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl ester (150 mg, 0.24 mmol, 1.0 equiv; Example 167) in a 2:2:1 mixture of THF, methanol and water (2 mL) was added lithium hydroxide (11.4 mg, 0.47 mmol, 2.0 equiv; [CAS RN 1310-65-2]) and the reaction mixture stirred at rt over night. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol to give 110 mg (75%) of the title compound as a light brown solid. MS (ISN): 616.1 [M−H]−.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH2:10](N)[CH:11]=[CH2:12]>C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]([CH2:12][CH:11]=[CH2:10])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C=CCN
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Product: C=CCN([Si](C)(C)C)[Si](C)(C)C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A 500-ml flask equipped with a distillation column, stirrer, thermometer and dropping funnel was charged with 193.7 g (1.2 mol) of hexamethyldisilazane and 7.0 g (0.02 mol) of dodecylbenzenesulfonic acid. To the flask kept at 70° C., 114.2 g (2.0 mol) of allylamine was added over one hour from the dropping funnel. The contents were stirred for 3 hours under reflux. Subsequently, the allylamine was distilled off over 8 hours. From the reaction solution, a fraction of 89 to 90° C. at 40 mmHg was collected by vacuum distillation, yielding 192.0 g of N,N-bis(trimethylsilyl)allylamine.