Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[CH:4][C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[F:9][CH:8]([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[C:3]([F:11])[CH:4]=1
Reactant: Fc1cc(C(F)F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 1-bromo-4-(difluoromethyl)-2-fluorobenzene (311 mg, 1.382 mmol) in THF (2.99 mL) was added butyllithium (1.6M solution in hexanes; 0.881 mL, 1.410 mmol) over ˜5 min at −78° C. The reaction mixture was stirred for 30 min at −78° C. then DMF (0.161 mL, 2.073 mmol) was added dropwise over ˜1 min. Stirring was continued for 20 min. The reaction mixture was quenched with aqueous 1M HCl solution/MeOH (2:1, 3 mL) and allowed to warm to room temperature. The mixture was diluted with 5 mL of water. The separated aqueous layer was with ether (5 mL). The combined organic layers were washed with 1M aqueous NaOH solution (10 mL) and saturated brine (10 mL), dried over MgSO4, filtered off and concentrated under reduced pressure. Repeated reaction with 420 mg of 1-bromo-4-(difluoromethyl)-2-fluorobenzene and combined crude materials for purification. The crude material was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate], providing 4-(difluoromethyl)-2-fluorobenzaldehyde (162.8 mg) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCCCCC.[CH3:38][CH:39]([OH:41])C.C(NCC)C>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:39](=[O:41])[CH3:38])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(C)O
Solvent: CCCCCC
Solvent: CCNCC
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
230 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7) was optically resolved, using an optical resolution column (CHIRALPAK AD 2 cmφ×25 cmL (by Daicel Chemical), mobile phase: hexane/2-propanol/diethylamine=20/80/0.1, flow rate: 10 ml/min), into an enantiomer A (retention time: 19.0 min) and an enantiomer B (retention time: 32.2 min) each as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([O:10][CH3:11])=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=[N:6][N:5]2[CH:15]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:9]1[C:4]2[N:5]([CH:15]=[C:2]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 92.5 °C
Yield: 80.4 %

Procedure:
Nitrogen was bubbled through a mixture of 6-bromo-4-methoxypyrrolo[1,2-b]pyridazine-3-carboxamide (77 mg, 0.285 mmol), phenyl boronic acid (104 mg, 0.855 mmol), tetrakis(triphenylphosphine)palladium (32.9 mg, 0.029 mmol) and 2M aq. potassium carbonate, (0.570 mL, 1.140 mmol) in DME (0.75 mL) for ˜1 minute. The reaction mixture was then heated to 90-95° C. for 1 hr. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried (MgSO4) and concentrated to afford a yellow solid that was chromatographed on a 12 g silica gel cartridge, eluting with a 0-100% EtOAc/hexanes gradient. The pure fractions were concentrated to a tan solid that was contaminated with a small amount of triphenylphosphine oxide. The material was triturated with ethyl ether to afford the title compound (62 mg, 0.229 mmol, 80% yield) as a tan solid. HPLC (condition M): retention time=2.36 min.; LCMS (ES+) m/z: 268.11 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 4.52 (s, 3 H), 5.73 (s, 1 H), 7.20 (d, J=1.8 Hz, 1 H), 7.27-7.35 (m, 2 H), 7.41-7.47 (m, 2 H), 7.63-7.68 (m, 2 H), 8.10 (d, J=1.8 Hz, 1 H), 8.69 (s, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[N:12])[CH:4]=[CH:3][N:2]=1>N.[Ni].CCO>[NH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]=[N:2][CH:3]=[CH:4]2
Reactant: N#Cc1cccc2ccncc12
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cccc2ccncc12
Reaction time: 22 h

Procedure:
To a solution of 0.1787 g (1.16 mmol) 25 in 10 mL NH3 saturated EtOH was added a 1 mL slurry of Raney nickel (50 wt. % in EtOH). After 22 h under H2 at atmospheric pressure, the reaction mixture was diluted with 25 mL EtOH and filtered over celite. The celite was washed with 200 mL EtOH, and the filtrate was concentrated in vacuo. Purification by flash chromatography (15×140 mm silica gel, linear gradient 5-8% (10% NH4HO:MeOH):CH2Cl2) afforded 26. 1H NMR (CDCl3, 400 MHz) δ 9.565 (s, 1H, ArH); 8.565 (d, 1H, J=5.66 Hz; ArH); 7.734 (d, 1H, J=8.13 Hz, ArH); 7.679-7.662 (m, 1H, ArH); 7.644 (d, 1H, J=8.14 Hz, ArH); 7.599 (d, 1H, J6.95 Hz, ArH); 4.460 (s, 2H, ArCH2); MS (Electrospray): m/z 159.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[C:20]([F:29])[CH:19]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([C:25]#[N:26])([CH3:28])[CH3:27])=[C:20]([F:29])[CH:19]=3)=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cnc2cccc(Cl)c21
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3cccc(Cl)c32)cc1F

Procedure:
2-(7-Chloro-1H-benzimidazol-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-fluorobenzyl]acetamide is synthesized according to example 14 with (7-chloro-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.712 mmol) prepared according to scheme 1, and 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (196 mg, 0.855 mmol) prepared according to scheme 8, Et3N (238 μL, 1.71 mmol) and HATU (325 mg, 0.855 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5%) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=14 mg as TFA salt, 0.035 mmol, 5%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67 (s, 6H), 4.30 (d, J=5.86 Hz, 2H), 5.24 (s, 2H), 7.10-7.22 (m, 3H), 7.23-7.28 (m, 1H), 7.38 (t, J=8.40 Hz, 1H), 7.62 (d, J=7.81 Hz, 1H), 8.31 (s, 1H), 8.81 (s, 1H). MS [M+H], calcd: 385.1, found: 385.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCCSc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O)C.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1C=O>C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][CH2:17][C:18]1=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=Cc1cccs1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN=C1CC=CS1)OCC
Yield: 100 %

Procedure:
A solution of 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. absolute ethanol is treated with 11.2 g. (0.1 mol) thien-2-aldehyde and the resulting mixture is heated under reflux and then evaporated to give 26 g. diethyl N-thien-2-ylidene-aminomethylphosphonate (yield: about 100%) in the form of a yellow oil giving a single spot in TLC (silica plate; eluant: ethyl acetate).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C(=O)(O)[O-]>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCOCC
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 35 g (0.251 mol) of 3-bromopropanol and 1 g of p-toluenesulphonic acid in 500 ml of diethylether, 32.5 ml (0.357 mol) of 3,4-dihydro-2H-pyran is added dropwise under cooling with ice water and the solution is stirred for 2 hours at room temperature. The mixture is neutralized with saturated aqueous bicarbonate. washed with brine and concentrated after drying, affording 56 g of 2-(3-bromopropyloxy)tetrahydropyran in practically quantitative yield as a viscous liquid, which may be used without further purification. (C8H15BrO2 ; F.W. 223.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
Cis-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.57 g, 8.87 mmol) was dissolved in MeOH (36.4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.335 mL, 8.87 mmol) in water (3.64 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.544 mL, 8.87 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (45.9 mL, 275.11 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.000 g, 60.7%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.82-1.93 (m, 1H), 2.13-2.27 (m, 2H), 2.30-2.39 (m, 1H), 3.06-3.16 (m, 1H), 3.42-3.53 (m, 1H), 3.66 (s, 3H), 4.04-4.12 (m, 1H), 5.06 (dd, 1H), 5.64 (d, 1H), 7.14-7.18 (m, 2H), 7.27 (t, 1H). MS m/z 371 (M+H)+
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[N:23][C:22](I)=[CH:21][N:20]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:22]2[CH:21]=[N:20][C:19]([Br:18])=[CH:24][N:23]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cnc(Br)cn2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 9 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid benzylamide (400 mg, 1.28 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (4 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2-bromo-5-iodo-pyrazine (292 mg, 1.0 mmol, 0.8 equiv), Pd(PPh3)4 (59 mg, 0.05 mmol, 4 mol %) in tetrahydrofuran (3 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 160° C. for 20 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-(5-bromo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (35 mg, 7%). 1H NMR (400 MHz, CD2Cl2) δ 9.12 (s, 1H), 8.63 (s, 1H), 7.28-7.36 (m, 5H), 6.22 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 2.72 (s, 3H); HRMS (M+H)+=389.01.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@@H:26]([CH3:25])[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5].[ClH:11].[CH3:12]O>>[ClH:11].[NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: NC(CC(=O)O)C(F)(F)F
Agent: Cl
Product: COC(=O)CC(N)C(F)(F)F

Procedure:
1.5 g of 3-amino-4,4,4-trifluorobutanoic acid (9.55 mmol, 1 equivalent) were initially charged in 18 ml of methanol which had been saturated with hydrogen chloride, and the mixture was stirred under reflux for 4 h. The reaction solution was then concentrated, evaporated repeatedly with dichloromethane and dried under reduced pressure. This gave 1.86 g (94% of theory) of the title compound.
Reaction SMILES: [P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].Br[CH2:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28]>>[P:1]([O:21][CH3:22])([O:19][CH3:20])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)n[nH]c2c1
Reactant: CCC(C)(C)C(=O)CBr
Product: CCC(C)(C)C(=O)Cn1nc(C(OP(=O)(OC)OC)=C(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared from 1-(6-methoxy-1H-indazol-3-yl)-2-methylprop-1-en-1-yl dimethyl phosphate from Method I Step B of Example 1 and 1-bromo-3,3-dimethylpentan-2-one from the above using a procedure similar to described in Method I Step C of Example 1. It was purified on RP-HPLC using 30-100% MeCN gradient without TFA to give colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) δ 7.70 (d, 9.0 Hz, 1H), 6.86 (dd, 2.1 & 8.9 Hz, 1H), 6.48 (d, 2.1 Hz, 1H), 5.29 (s, 2H), 3.86 (s, 3H), 3.56 (d, 11.3 Hz, 6H), 2.02 (d, 2.5 Hz, 3H), 1.82 (d, 3.5 Hz, 3H), 1.74 (q, 7.5 Hz, 2H), 1.28 (s, 6H), 0.94 (t, 7.6 Hz, 3H). NOE difference spectrum from irradiating 5.29 ppm singlet showed positive NOE at 6.48 ppm doublet and 1.28 ppm singlet. LC-MS: 3.48 min. (m/Z=313.2, 461.2, 439.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[OH:21].N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:54][CH2:55][NH:56]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:54][CH2:55][NH2:56]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCN
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
To 6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 15, 2.0 g, 6.6 mmol), 1,1′-azobis(N,N-dimethylformamide) (2.3 g, 13 mmol), triphenylphosphine (3.5 g, 13 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (2.1 g, 13 mmol) and DCM (40 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (30 mL) was added. The reaction mixture was allowed to stir at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel using 5% MeOH in DCM as the eluent to afford the title compound (2.53 g) MS m/z 347 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:9][C:6]2[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Oc1noc2cc(Cl)ccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)Oc2noc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol, 228.7 mg (1.41 mmol) of 4-methylpiperidine-1-carbonyl chloride and 164 μl (2.36 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 147 mg (42%), M+H+: 295.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17](Cl)=[O:18])=[CH:13][C:12]=1[O:22][CH3:23])(=[O:9])[CH3:8].Cl>N1C=CC=CC=1>[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])=[CH:13][C:12]=1[O:22][CH3:23])(=[O:9])[CH3:8]
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)N2CCCCC2)ccc1OC(C)=O

Procedure:
2 ml of piperidine was added to a solution of 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride in 100 ml of pyridine. The solution was reacted for hours at room temperature. After reaction, 200 ml of 2N hydrochloric acid was added to the reaction solution. The solution was extracted three times with 100 ml of ethyl acetate. The organic layer obtained was washed three times with 2N hydrochloric acid, twice with an aqueous sodium hydrogencarbonate solution and twice with an aqueous sodium chloride solution, and then was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, and the product obtained was recrystallized from methylene chloride/hexane, yielding 1.88 g of 1-(4-acetoxy-3-methoxycinnamoyl)piperidine (a compound of the present invention) as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>O1CCCC1>[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: O=C=NCCc1ccccn1
Reactant: CNc1cccc2ccccc12
Solvent: C1CCOC1
Product: CN(C(=O)NCCc1ccccn1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3.14 gm. (0.02 mole) of N-methyl-1-naphthylamine in 75 ml. of tetrahydrofuran there is added 2.96 gm. (0.02 mole) of 2-pyridylethylisocyanate with stirring. After 30 minutes of stirring at ambient temperature, the mixture is refluxed for 1 hour. The solvent is then removed in vacuo and the residue crystallized from alcohol-water (4:1 v/v) to furnish 3-methyl-3-(1-naphthyl)-1-(2-pyridylethyl)urea.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:13][CH3:14].CCN(CC)CC.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:14])[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: CNCc1c(C)c2ccccc2n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c(C)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred solution of 1,3-dimethyl-2-(methylaminomethyl)indole (1.5 g, 8 mmole), from Preparation 40, and Et3N (1.12 mL, 8 mmole) in CH2Cl2 (75 mL) at 0° C. was added acryloyl chloride (0.65 mL, 8 mmole) dropwise over 5 minutes. The reaction was stirred at 0° C. for 1 hr then was poured into ice water. The organic phase was separated, washed with brine, dried (MgSO4), and concentrated to dryness to give the title compound (1.7 g, 90%) as a yellow oil. This was used without further purification: TLC silica gel (50% EtOAc/hexanes) Rf=0.41.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([O:12][CH2:13][CH3:14])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:25]=[O:26]>>[C:1]([NH:4][C:5]1[S:6][C:7]([CH:25]=[O:26])=[C:8]([O:12][CH2:13][CH3:14])[C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1csc(NC(C)=O)c1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1c(C=O)sc(NC(C)=O)c1C#N
Reaction time: 4 h

Procedure:
210 parts of 2-acetylamino-3-cyano-4-ethoxythiophene (Example 7) are introduced into 1000 parts of dimethylformamide, and 200 parts of phosphoryl trichloride are added dropwise in the course of 4 hours. Stirring is continued for 4 hours at 60° C., after which the resulting crystal slurry is brought into solution by adding 600 parts of ice. This solution is stirred into 2000 parts of 12.5% strength sodium hydroxide solution, and acidified with hydrochloric acid after 6 hours. The precipitated product is filtered off under suction, washed with water and dried to give 201 parts of 2-acetylamino-3-cyano-4-ethoxy-5-formylthiophene. A sample recrystallized from dimethylformamide has a melting point of 276°-277° C. and possesses the following analytical values: