Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].[CH3:43][N:44](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:45].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([N:44]([CH3:45])[CH3:43])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and dimethylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (11.5 mg, 35%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][C:58]=2[F:67])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:64])[F:65])[CH:60]=[CH:59][C:58]=2[F:67])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:68][CH:69]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 118 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After 3.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 90 mg light yellow viscous oil (53%). MS (EI) 530.2 (M)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C(O)CO>[F:11][C:8]1[CH:9]=[N:10][C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(CN)cc1
Reactant: NC(=O)c1cc(F)cnc1Cl
Solvent: OCCO
Product: COc1ccc(CNc2ncc(F)cc2C(N)=O)cc1
Yield: 50 %

Procedure:
A solution of 2-chloro-5-fluoro-nicotinamide (70 mg, 0.40 mmol) and 4-methoxybenzylamine (550 mg, 4.01 mmol) in ethyleneglycol (1 ml) was microwaved for 50 min at 140° C. A white solid was filtered off and the filtrate evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/heptane, 1/1) to obtain 5-fluoro-2-(4-methoxy-benzylamino)-nicotinamide (56 mg, 0.2 mmol; 51%) as white solid. MS (m/e): 276.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](=[NH:13])[O:12][CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 69 %

Procedure:
2,4-Dibenzyloxybenzoic acid was reacted with oxalyl chloride in toluene and DMF at 0-25° C. to give an acid chloride. The acid chloride was reacted with aqueous ammonia in methylene chloride to yield 87% (over 2 steps) of 2,4-dibenzyloxybenzamide. 2,4-Dibenzyloxybenzamide was reacted with triethyloxonium hexafluorophosphate in methylene chloride to yield 69% of ethyl 2,4-dibenzyloxybenzimidate. The ethyl 2,4-dibenzyloxybenzimidate was hydrogenated over a palladium/carbon catalyst with 1 atmosphere of hydrogen gas in ethanol, to yield 75% of ethyl 2,4-dihydroxybenzimidate. The overall yield for the reaction sequence was 34% for six steps.
Reaction SMILES: N[CH:2]1[CH2:7]C[CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.C(OC(=O)[NH:23]C1CCNCC1)(C)(C)C>>[NH2:23][CH:3]1[CH2:2][CH2:7][N:8]([C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(C(=O)N2CC[C@@H](N)C2)CC1

Procedure:
(4-Amino-piperidin-1-yl)-((R)-3-amino-pyrrolidin-1-yl)-methanone is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (4-amino-cyclohexyl)-carbamic acid tert-butyl ester with piperidin-4-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[CH3:13][S:14]([C:17]([CH3:25])([CH3:24])[CH2:18]OS(C)(=O)=O)(=[O:16])=[O:15]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])([CH3:25])[CH3:24])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(COS(C)(=O)=O)S(C)(=O)=O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)S(C)(=O)=O)cc(C)c1Br
Temperature: 160 °C
Yield: 28.6 %

Procedure:
4-Bromo-3,5-dimethylphenol (1.3 g, 6.51 mmol) and NaH (60% on mineral oil: 167 mg, 4.17 mmol) are stirred in 8 mL of N,N-dimethylformamide for 30 min in a microwave vial, methanesulfonic acid 2-methanesulfonyl-2-methyl-propyl ester (600 mg, 2.61 mmol) is added and the reaction mixture is heated in a microwave oven at 160° C. for 2 h. The solvent is removed under vacuum and the crude product is purified by flash chromatography (cyclohexane/ethyl acetate 99/01→90/10) to give the title compound (Yield: 250 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].N>N1C=CC=CC=1.CN(C=O)C>[NH2:30][C:31]1[C:32]([C:33]([NH2:35])=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=1[NH:40][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochlolide (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])[C:2]#[CH:3].Br[C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCN(CC)CC>C1COCC1.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.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][C:2]#[C:3][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#CCOCCCCCCCBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C#CCOCCCCCCCBr)c1
Yield: 46.1 %

Procedure:
7-Bromoheptyl prop-2-ynyl ether (55.1 g) in THF (250 ml) was added dropwise over ca 8 h to a stirred mixture of 3-bromobenzenesulfonamide (43.5 g), PdCl2(PPh3)2 (6.48 g), PPh3 (1.45 g), CuI (1.4 g) and Et3N (52 ml) in THF (250 ml) at 55±5° C. under nitrogen then the mixture heated for a further ca 15 hrs. The reaction was cooled, filtered through Celite and the solids washed with THF. The solution was concentrated and the product purified by chromatography on flash silica gel (600 g) eluting with petroleum ether:ethyl acetate (ratios ranging successively from 19:1 to 7:3) to give the title compound (33 g)—LC RT=5.85 min. NMR—300 MHz—δ (CDCl3)—7.95 (1H, t, J 1.5 Hz), 7.78 (1H, dt, J 8, 2 Hz), 7.55 (1H, dt, J 7.75, 2 Hz), 7.40 (1H, t, J 8 Hz), 5.0 (2H, br s), 4.3 (2H, s), 3.4 (2H, t, J 6.5 Hz), 3.35 (2H, t, J 7.25 Hz), 1.75 (2H, m), 1.55 (2H, m), 1.3 (4H, m).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]([OH:22])[CH2:20][OH:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:20][O:21][C:23]([CH3:28])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(O)CO)cnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CC1(C)OCC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 785.9 %

Procedure:
A solution of 1-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-ethane-1,2-diol (2.1 g, 6.61 mmol), p-toluene sulfonic acid (134 mg, 0.71 mmol) and 2,2-dimethoxy-propane (10 mL) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (2.0 g, 85%) as a white solid: LC/MS m/e calcd for C18H19N2SO4 [M+H]+ 359.42, observed 359.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 3H), 1.56 (s, 3H), 3.73 (dd, J=7.5 Hz, 8.3 Hz, 1H), 4.35 (dd, J=6.4 Hz, 8.3 Hz, 1H), 5.16 (dd, J=6.4 Hz, 7.5 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.42 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:7]([O:6][CH:5]([O:9][CH2:10][CH3:11])/[C:4](/[CH3:12])=[CH:3]/[CH2:2][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1)[CH3:8]
Reactant: CCOC(OCC)/C(C)=C/CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(OCC)/C(C)=C/COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 12.65 g of crude (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 6.4 ml of m-methoxyphenol, and 8.1 anhydrous potassium carbonate in 100 ml sieve dried dimethylformamide is stirred at room temperature under nitrogen for about 43 hours and the reaction mixture diluted to 500 ml with water and extracted with a 300 ml and two 100 ml portions of hexane. The combined hexane extracts are washed with two portions of brine and dried with sodium sulfate. Concentration of the hexane extracts yields 6.45 g (E)-1,1-diethoxy-(4-m-methoxyphenoxy)-2-methyl-2-butene.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[CH:4][CH:5]=[O:6].Cl.[C:8](=[O:11])([O-])[O-].[Na+].[Na+].[CH3:14]O>>[Cl:1][CH2:2][CH:3]=[CH:4][CH:5]([O:11][CH3:8])[O:6][CH3:14]
Reactant: O=CC=CCCl
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: COC(C=CCCl)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloro-1,1-dimethyoxy-2-butene (Reagent K) was prepared by reacting 7.46 g. of 4-chloro-2-butenal with 200 ml. of anhydrous methanol and a catalytic amount of hydrochloric acid. The reaction mixture was stirred at room temperature for 16 hours, neutralized with sodium carbonate, filtered, and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][C:14]1=[O:29])=[O:11].[H][H]>CO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:11])[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:29]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Reaction time: 4 h

Procedure:
To a solution of compound 31 in methanol (10 mL) 10% palladium on carbon was added. The reaction vessel was charged with hydrogen (40 p.s.i ) and agitated for 4 h. The catalyst was removed by filtration and the filtrate was concentrated and purified using column chromatography (1:15 MeOH:DCM) to yield compound 32 as a semi solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Cl.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.BrC1C=C(C)C([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=C(C)C=1>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([C:18]3[CH:9]=[C:10]([CH3:11])[C:3]([CH:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]([NH2:27])=[O:34])=[C:2]([CH3:5])[CH:1]=3)[CH2:16]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc2c(c1)CNCC2
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(F)cc3C2)cc(C)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (156 mg, 0.28 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (320 mg, 0.8 mmol) were added to dry toluene (60 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (1.9 g, 16.25 mmol), 7-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (1.28 g, 6.8 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 6.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (1.9 g, 76%).
Reaction SMILES: B(O)(O)O.O[CH:6]([CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH2:7][C:8](=[O:10])[CH3:9]>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:12][CH2:11][CH:6]=[CH:7][C:8](=[O:10])[CH3:9])=[CH:15][CH:16]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Yield: 99.1 %

Procedure:
0.85 Gram of boric acid was added to 80 ml of toluene, and the resulting mixture was refluxed for 3 hours with stirring and then cooled to 30° C. A solution of 6.00 g of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone in 20 ml of toluene was added thereto, and the resulting mixture was further refluxed for 8 hours with stirring. The refluxed mixture was washed three times with hot water and then dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 5.58 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis=38.7 : 1) (purity: 99.3%). The yield was 98.4%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[C:34](=[O:35])[C:33]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([C:43]6[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=6)=[CH:39][CH:38]=5)=[C:32]([CH2:51][CH2:52][CH3:53])[N:31]=[C:30]4[CH2:54][CH3:55])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>O>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[C:34](=[O:35])[C:33]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=6[C:49]6[NH:3][C:4](=[O:7])[O:5][N:50]=6)=[CH:39][CH:38]=5)=[C:32]([CH2:51][CH2:52][CH3:53])[N:31]=[C:30]4[CH2:54][CH3:55])=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCCc1nc(CC)n(-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of hydroxylammonium chloride (2.6 g), sodium hydrogen carbonate (3.2 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.46 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 38%).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C=O)C>[CH2:1]([C:3]1[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)ccnc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)ccnc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
2-Ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (1.00 g, 6.20 mmol) was dissolved in DMF (15 mL) and lithium hydroxide monohydrate (0.391 g, 9.31 mmol) was added at room temperature followed by stirring for 20 minutes. Then, 4-nitrobenzylbromide (1.34 g, 6.20 mmol) was slowly added to the mixture, and stirred at room temperature. After 30 minutes, water (20 mL) was added and precipitated crystals were collected by filtration, followed by washing with water. The crystals were dried under reduced pressure to obtain Compound P34 (0.819 g, 2.76 mmol, 45%).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12](Br)[CH:13]=[CH2:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:14][CH:13]=[CH2:12])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.5 %

Procedure:
To a solution of 5-nitro-2-thiophenecarboxylic acid (20 g, 0.11 mol) in DMF (140 ml) were added sequentially allyl bromide (40 ml, 0.46 mol) and triethylamine (64 ml, 0.46 mol) with cooling to maintain the temperature of the reaction mixture below 30° C. After addition of the reagents, the reaction mixture was stirred for 3 hours at ambient temperature and then diluted with ethyl acetate. The solid which precipitated was filtered off, the filtrate washed with water, washed with saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using a mixture of CH2Cl2 --petroleum ether (3:7) as eluent to give the title compound as a white solid (8.8 g, 38%).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[C:1]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 72.5 %

Procedure:
In a manner similar to that described in Example 3, decanoyl chloride (0.069 g, 0.00036 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.063 g of 4-[4-(decanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+348.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.CCCCCC.[B:23]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])OC(C)C.CC(O)(C(C)(O)C)C.C(O)(=O)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([B:23]2[O:28][C:29]([CH3:30])([CH3:31])[C:33]([CH3:34])([CH3:35])[O:32]2)=[CH:10][CH:9]=[N:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cnn(C2CCCCO2)c1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.), stirred solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (prepared as described in the literature: J. Med. Chem. 2004, 47, 2995-3008 and JOC 2008, 73, 4309-4312) (11.8 g, 78 mmol) in anhydrous THF (200 mL), 2.5 M n-BuLi in n-hexane (40 mL, 100 mmol) was slowly added, keeping T<−70° C. After addition the mixture was stirred at −78° C. for 1 h, then triisopropyl borate (23 mL, 100 mmol) was added dropwise, keeping T<−70° C. After addition the mixture was let to reach room temperature in about 2 h, then a solution of 2,3-dimethyl-2,3-butandiol (12.5 g, 105 mmol) in anhydrous THF (30 mL) was added, followed after 10 min by glacial acetic acid (6 mL, 100 mmol). The colorless jelly precipitate was filtered on a thick celite pad and washed thoroughly with diethyl ether. The filtrate was concentrated to yield a colorless oil that crystallized upon addition of n-heptane. The title compound was obtained as colorless crystalline powder (14.7 g, 53%).