Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH2:24]([C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1)[CH3:25]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.180 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 16%). MS (ISP) 421.1 [(M+H)+]; mp 209° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:13][O:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: Oc1cccc(-c2ccsc2)c1
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCOc1cccc(-c2ccsc2)c1)OC
Temperature: 90 °C
Reaction time: 6 h

Procedure:
1.3 g of 3-(3-thienyl)phenol, 1.09 ml of 3-bromopropanal dimethylacetal and 1.1 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and the mixture was heated at 90° C. with stirring for 6 hours. Ethyl acetate and Water were added, and the organic layer separated was worked up in a customary manner, then the product was purified by silica gel column chromatography [hexane/ethyl acetate=30/1→20/1] to give 1.0 g of 3-[3-(3-thienyl)phenoxy]propanal dimethylacetal as a colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=2)[CH:18]=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17]([C:18]4[O:19][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)[CH:20]=[C:21]([Br:23])[CH:22]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)cc(-c2c3ccccc3cc3ccccc23)c1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cc(-c2nc3ccccc3o2)cc(-c2c3ccccc3cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (27.7 mmol) of 3-(anthracen-9-yl)-5-bromobenzaldehyde and 3.6 g (33.2 mmol) of 2-aminophenol were dissolved in 100 ml of acetic acid, and then agitated at room temperature for 30 minutes. Next, 14.7 g (33.2 mmol) of lead (IV) acetate was added thereto. The resulting mixture was agitated at 50° C. for 1 hour. Then, water was poured therein. The resulting product was treated with ethyl acetate to perform extraction, and then the solvent was removed under a reduced pressure. The extract was separated through a column and dried, obtaining 4.5 g (Y=33%) of a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH:8]=[CH2:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)([O-:32])=[O:31].CCOC(/N=N/C(OCC)=O)=O>C(OCC)(=O)C.CCCCCC.CCOCC.C1COCC1>[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([O:10][CH:5]([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:4][CH2:3][CH:2]=[CH2:1])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCCC(O)CCC=C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A 300 ml-capacity three neck flask containing a stirring bar and connected to a condenser was sufficiently dried. Then, a nitrogen atmosphere was established in the flask, and 1,8-nonadiene-5-ol (8) (3.72 g, 2.66 mmol), PPh3 (6.98 g, 2.66 mmol), and 4-nitrophenol (4.43 g, 3.19 mmol) were introduced into the flask. Dried THF (50 ml) was further added to the mixture, the mixture thus obtained was stirred at room temperature, DEAD (12.2 ml, 3.19 mmol) was then dropped into the flask, and the mixture thus obtained was stirred for 5 hours. When generation of ether was recognized by thin-layer chromatography (hexane:ethyl acetate=10:1), the solvent was distilled off under reduced pressure, the mixture was purified by flash chromatography on silica gel (hexane:ethyl acetate=10:1). Thus, 1-nitro-4-(1,8-nonadiene-5-yloxy)benzene (11) (4.731 g, 1.7 mmol, yield: 65%) was obtained as an intended compound. 1HNMR values of 1-nitro-4-(1,8-nonadiene-5-yloxy)benzene (11) are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1onc(N)c1Br
Product: Cc1onc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br

Procedure:
N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide was prepared, using the method in Example 1b, from 3-amino-4-bromo-5-methylisoxazole and 4-biphenylsulfonyl chloride in 5% yield. The crude product was purified by column chromatography. After recrystallization from ethyl acetate/hexanes, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide (m.p. 154-156° C.) was obtained in 51% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:11].P(Cl)(Cl)(Cl)=O>>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][N:4]=1
Reactant: Oc1ncc(I)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(I)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
A 50 ml 3-necked round bottom flask, equipped with a thermometer, a reflux condenser topped with a N2 inlet, a stopper and a magnetic stirrer, was charged with 3.50 g (0.0137 mole) of 3-chloro-5-iodo-2-pyridinol, from STEP 1 above, 3.00 g (0.0144 mole) of phosphorus pentachloride and 5-10 ml of phosphorus oxychloride. The reaction mixture was heated to reflux and the solid dissolved resulting in a golden brown solution. The reaction mixture was stirred under N2 at reflux for 4 hours and then cooled to room temperature. The reaction mixture was poured into crushed ice and allowed to stand for about 1 hour. A tan precipitate, which was shown to be product and unreacted starting material, formed and was isolated by filtration and washed with pentane. The aqueous layer was also washed with pentane. The combined organic layers were washed with deionized water and saturated NaCl, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 0.4 g of a dark oil that crystallized upon standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]([CH3:9])[CH:7]=[CH2:8])[CH3:2].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:27]([CH:28]=[N:29][OH:30])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]([CH:7]1[O:30][N:29]=[C:28]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:32][CH:31]=2)[CH2:8]1)[CH3:9])[CH3:2]
Reactant: C=CC(C)=CC(=O)OCC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: CCOC(=O)C=C(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 84 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3-methyl-penta-2,4-dienoic acid ethyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl acetate:hexane (gradient) to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-but-2-enoic acid ethyl ester (0.93 g, 84%) as a mixture of diasteromers. MS found: (M+H)+=431.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:31]([OH:32])=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][NH2:39]>>[OH:32][C:31]1[C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=[C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:39][CH3:38])=[O:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CN
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Agent: Cl
Product: CNC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (49), from (4′-([2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy)-1,1′-biphenyl-4-yl)acetic acid (216 mg, 0.431 mmol) obtained in Example (7) and methylamine hydrochloride (50 mg, 0.74 mmol), the title compound was obtained as a colorless crystal (160 mg, yield: 72%).
Reaction SMILES: Br[CH:2]([CH2:17][OH:18])[CH2:3][CH:4]([CH:6]1[C:14]2([CH3:15])[CH:9]([CH:10]([OH:16])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)[CH3:5].CC(C)([O-])C.[K+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[CH3:15][C:14]12[CH2:13][CH2:12][CH2:11][CH:10]([OH:16])[CH:9]1[CH2:8][CH2:7][CH:6]2[CH:4]([CH3:5])[CH2:3][CH:2]1[CH2:17][O:18]1
Reactant: CC(CC(Br)CO)C1CCC2C(O)CCCC12C
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(CC1CO1)C1CCC2C(O)CCCC12C
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4.6 g of [3aS-[3a alpha, 3(R*,R*), 7beta, 7a beta]]-3-(3-Bromo-4-hydroxy-1-methylbutyl)hexahydro-3a-methyl-1H-inden-7-ol in 145 mL of dry t-butanol under an argon atmosphere and at room temperature is added 2.1 g of potassium t-butoxide. After stirring 50 minutes the mixture was cooled in an ice bath and 10 mL of saturated aqueous sodium dihydrogen phosphate was added. The mixture was stirred 10 minutes then poured into 500 mL of ice water and extracted 3×200 mL of methylene chloride. The combined extracts were washed successively with water, brine then dried over anhydrous sodium sulfate. Filtration and evaporation of solvent in vacuo gave 3.5 g of crude product. Medium pressure liquid chromatography eluting with hexane/ethyl acetate (1:1) gave 2.9 g (84%) of [3aS[3a alpha,3(R*,S*),7beta, 7a beta]]-Hexahydro-3a-methyl-3-(1-methyl-2-oxiranylethyl)- 1H-inden-7-ol. The analytical sample was crystallized from hexane/ethyl acetate. MP 62.5°-63° C.; [α]D25 -31.26° (c 1.0300, CHCl3). Calculated for C15H24O2 : C, 76.23; H, 10.24. Found: C 75.95; H, 10.01.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([O:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[CH2:24]([OH:27])[C:25]#[CH:26].C(N(CC)CC)C>CN(C=O)C.O.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>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([O:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:26]#[C:25][CH2:24][OH:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCO
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(C#CCO)cc1)OC
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of (2S)-2-methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionic acid ethyl ester (0.861 g, 2.53 mmol), propargyl alcohol (0.88 mL, 15.18 mmol), triethylamine (1.41 mL, 10.12 mmol) and dichlorobis(triphenylphosphine)palladium (II) in 10 mL of dry DMF was heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with diethyl ether (3×30 mL). The combined organic layers were washed with 0.5 N HCl (2×20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The residue purified by column chromatography (silica gel, hexanes/ethyl acetate 2:1, Rf0.17) to give a yellow-brown oil (0.211 g, 32%). 1H-NMR (200.15 MHz, CDCl3): δ 7.35 (d, 2H, J=8.1), 7.18 (d, 2H, J=8.1), 4.48 (s, 2H), 4.17 (q, 2H, J=7.3), 3.93 (dd, 1H, J=7.3, 5.7), 3.34 (s, 3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.2), 1.8 (s, 1H), 1.22 (t, 3H, J=7.3).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10]C(C#N)=[CH:12][CH:13]=[C:8]2[N:7](C(OCC)=O)[C:6]=1[CH3:21].[C:27]([OH:30])(=[O:29])[CH3:28]>Cl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]2[C:9]=1[NH:10][C:28]([C:27]([OH:30])=[O:29])=[CH:12][CH:13]=2
Reactant: CC(=O)O
Reactant: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2nc(C#N)ccc21
Agent: Cl
Product: Cc1nc2ccc(C(=O)O)[nH]c-2c1Cc1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(2,4-dichlorobenzyl)-5-cyano-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate (180 mg) in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) was refluxed under heating. The mixture was allowed to react overnight, and concentrated hydrochloric add (1 ml) was added, which was followed by reflux under heating for 10 hr. The reaction mixture was cooled and adjusted to pH 7 with a 30% aqueous solution of sodium hydroxide. After stirring for 2 hr, crystals were collected by filtration to give the object compound (135 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][NH:4][C:5]1[C:6]([NH2:29])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[N:9][C:10]=1[NH2:11].C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:29][C:6]1[N:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)[N:9]=[C:10]2[C:5]=1[N:4]([CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:37](=[O:38])[NH:11]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)CNc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
447 mg (0.94 mmol) of the compound from example 64A were initially charged in dimethylformamide (5 ml), then 758 mg (4.68 mmol) of N,N-carbonyldiimidazole and 1.57 ml (11.23 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: methanol/water with 0.1% formic acid gradient). This gave 163 mg (39% of theory) of the title compound in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([OH:23])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH:36](O)([CH3:38])[CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([O:23][CH:36]([CH3:38])[CH3:37])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: CC(C)O
Product: CC(C)OC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoic acid and isopropanol according to the procedure described in Preparation 21; Mass Spectrum: m/e=537 (M+1, 35Cl), 539 (M+1, 37Cl).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1(C(O)=O)[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1
Reactant: O=C(O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Solvent: Cc1ccccc1
Product: O=C1[C@H](CCCCl)C[C@H]2CO[C@H](c3ccccc3)N12
Temperature: 120 °C
Yield: 94.5 %

Procedure:
The (3R,7aS)-6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylic acid (32.65 g, 0.101 mol) was slurried in 300 mL of anhydrous toluene. The temperature of the mixture was raised to 120° C. over a ˜1 h period, and maintained at 120° C. for 2 h. After this time LC/MS analysis showed formation of the desired amide. The mixture was cooled to ambient temperature and transferred to a separatory funnel. The mixture was washed with 100 mL of half-saturated NaHCO3 solution and brine. During this process some insoluble material formed at the interface. This material was discarded. The toluene solution was stirred with 5 g of activated carbon (Norit, neutral) for 1 h, then filtered through a pad of Celite and evaporated. The amber syrup was placed on the vacuum line overnight. This afforded 26.7 g (94% yield) of (3R,6R,7aS)-6-(3-chloropropyl)-3-phenyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: [Li]c1ccccc1
Reactant: Cc1ncoc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl -5-oxazolecarbaldehyde (600 m g) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred solution of phenyllithium (2.0M solution in cyclohexane and diethyl ether, 2.8 ml) in tetrahydrofuran (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 1 hour the mixture was allowed to warm to room temperature. After a further 1 hour saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The product was purified by flash chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:29][C:30]3[C:33](=O)[C:32](=[O:35])[C:31]=3[O:36]CC)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)[CH:2]([CH3:4])[CH3:3].[NH:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([C:5]1[N:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:29][C:30]3[C:31](=[O:36])[C:32](=[O:35])[C:33]=3[N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCCNCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(Oc2nc(CC(C)C)cc3ccncc23)cc1)Nc1c(OCC)c(=O)c1=O
Product: CCOC(=O)[C@H](Cc1ccc(Oc2nc(CC(C)C)cc3ccncc23)cc1)Nc1c(N2CCCCCC2)c(=O)c1=O

Procedure:
Prepared in a similar manner to the compound of Example 43 from the compound of Example 74 and azepane. δH (d6 DMSO) 9.56 (1H, s), 8.69 (1H, d, J 5.7 Hz), 7.79 (1H, d, J 9.2 Hz), 7.75 (1H, d, J 5.7 Hz), 7.31 (2H, d, J 8.5 Hz), 7.29 (1H, s), 7.20 (2H, d, J 8.5 Hz), 5.16 (1H, m), 4.13 (2H, q, J 7.0 Hz), 3.80-3.40 (4H, br m), 3.27 (1H, dd, J 13.9, 4.5 Hz), 3.06 (1H, dd, J 13.9, 10.7 Hz), 2.45 (2H, masked d), 1.88 (1H, septet, J 6.7 Hz), 1.68-1.50 (4H, m), 1.50-1.35(4H, m), 1.18(3H, t, J 7.1 Hz)and 0.77 (6H, d, J 6.7 Hz); m/z (ES+) 570 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C([O-])([O-])=O.[K+].[K+].[CH:11]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C.C(OCC)C>[Br:1][CH2:2][CH2:3][S:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCCBr
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: BrCCSC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.4 ml (225.0 mmol) of 1,2-dibromoethane and 4.1 g (30.0 mmol) of K2CO3 were added to a solution of 3.7 ml (30.0 mmol) of cyclohexanethiol in DMF (46 ml). After 2 hours of stirring at RT, the mixture was diluted with diethyl ether (200 ml) and washed with saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting 6.1 g of crude product (2-bromoethyl)(cyclohexyl)sulfane were used for the further reaction without being purified further.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Li])[CH2:22][CH2:23]C.CCCCCC.C(I)CC>C1COCC1.O>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH3:19])[C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCI
Solvent: O
Product: CCCCc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Temperature: -70 °C
Yield: 45 %

Procedure:
2-Anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 74; 2 g, 7.55 mmol) was dissolved in anhydrous THF (100 ml) at RT under a nitrogen atmosphere. The stirring solution was cooled using dry-ice/acetone bath to −70° C. A 1.6M solution of n-butyl lithium in hexane (6.3 ml, 10.08 mmol) was added drop-wise keeping temperature <−60° C. until the dark red colour remained. One more equivalent of n-butyl lithium in hexane (4.7 ml, 7.55 mmol), was then added dropwise keeping the temperature below −60° C. At this point the solution stirred at −70° C. for 10 minutes when propyl iodide (809 μl, 8.29 mmol) was added, the temperature was maintained at −70° C. for an additional 10 minutes then allowed to rise to RT. The reaction was allowed to stir for 1 hr at room temperature when water (100 ml) was added. The aqueous layer extracted with EtOAc (2×20 ml). Organics were combined, dried solvent evaporated in vacuo. The residue was purified by flash silica chromatography DCM:MeOH (95:5) to yield the title compound (1.03 g, 45%) as a pure white solid NMR: 0.90 (t, 3H), 1.39 (m, 2H), 1.66 (m, 2H), 2.70 (t, 2H), 3.94 (s, 3H), 6.95 (t, 1H), 7.08 (d, 1H), 7.28 (t, 2H, 7.65 (d, 2H), 7.59 (s, 1H), 8.35 (d, 1H), 9.42 (s, 1H); m/z 308.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[CH3:10][C:11](C)([O-])[CH3:12].[K+].C(Br)C=C.S([O-])(O)(=O)=O.[K+]>O1CCCC1.CN(C)C=O>[CH2:12]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7])[CH:11]=[CH2:10]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc[nH]1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of methyl 1H-pyrrole -2-caboxylate (4.48 g, 35.8 mmol) in tetrahydrofuran (100 ml) were added potassium t-butoxide (4.2 g, 37.4 mmol) and dimethylformamide (20 ml), and the mixture was stirred for 10 minutes at room temperature. To the mixture was added allyl bromide (5.4 g, 44.6 mmol), and the mixture was stirred for 4 hours at room temperature. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give the subject compound (5.46 g, 92%).