Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[CH2:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH2:17][NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19]
Reactant: Cn1c(=O)oc2ccc(-c3cncc(C=O)c3)cc21
Reactant: CCS(N)(=O)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NCc1cncc(-c2ccc3oc(=O)n(C)c3c2)c1
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of 5-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-3-carbaldehyde (51 mg, 0.2 mmol), ethanesulfonamide (33 mg, 0.3 mmol), Ti(OiPr)4 (118 uL, 114 mg, 0.4 mmol) in toluene (5 mL) was heated to reflux for overnight. After concentration, the residue was dissolved into CH2Cl2 (5 mL). NaBH(OAc)3 (127 mg, 0.6 mmol) was added at room temperature. The resulting mixture was stirred for 4 h at this temperature. Saturated NaHCO3 solution was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4. After filteration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 1-3.5%) and afforded the title product (50 mg), ESI-MS m/z: 348.0 [M+1]+, Retention time 1.01 min; 1HNMR (CDCl3, 400.342 MHz) δ 1.40 (t, J=7.4 Hz, 3H), 3.07 (q, J=7.4 Hz, 2H), 3.48 (s, 3H), 4.42 (d, J=6 Hz, 2H), 4.60 (t, J=6 Hz, 1H), 7.13 (s, 1H), 7.31 (s, 2H), 7.92 (s, 1H), 8.57 (d, J=14 Hz, 1H), 8.77 (d, J=1.4 Hz, 1H).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40]1[C:52]2[CH:51]([CH2:53][NH2:54])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:54][CH2:53][CH:51]1[C:52]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1c2ccccc2-c2ccccc21
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yi)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and 9H-fluoren-9-ylmethylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: COC(=O)C1C=CC(C)=C(Br)C=1.BrC1C=C(C#N)C=CC=1C.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:48])=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:47])[C:39]3[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=3[F:46])=[CH:33][CH:32]=2)[CH:30]=1)#[N:24].[N-:49]=[N+:50]=[N-:51].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:48])=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:47])[C:39]3[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=3[F:45])=[CH:35][CH:36]=2)[CH:30]=1)#[N:24].[F:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[C:38]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:29]2[CH:30]=[C:25]([C:23]3[NH:51][N:50]=[N:49][N:24]=3)[CH:26]=[CH:27][C:28]=2[CH3:48])=[CH:36][CH:35]=1)=[O:47]
Reactant: [N-]=[N+]=[N-]
Agent: COC(=O)c1ccc(C)c(Br)c1
Agent: Cc1ccc(C#N)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: Cc1ccc(C#N)cc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnn[nH]2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 120 °C
Yield: 159.9 %

Procedure:
N-(5′-cyano-2′-methyl-biphenyl-4-yl)-2,6-difluoro-benzamide (Compound A) was prepared by an analogous method as Compound 1 except that 3-bromo-4-methyl-benzoic acid methyl ester was replaced with 2-bromo-4-cyano-toluene. A mixture of Compound A (348 mg 1 mmol), sodium azide (78 mg 1.2 mmol), and ammonium chloride (65 mg, 1.2 mmol) in DMF (5 ml) was stirred and heated at 120° C. for 10 hr. After cooling the reaction mixture to room temperature, EtOAc (200 ml) was added, and the mixture was washed with water (60 ml×3). The EtOAc layer was concentrated and the residue was subjected to silica gel chromatography (Hexanes:EtOAc, EtOAc:MeOH) to give the product, 2,6-difluoro-N-[2′-methyl-5′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-benzamide (313 mg, yield 80%) as a off-white solid.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:22][C:20]3[N:21]=[C:14]4[C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=5)=[CH:18][CH:17]=[CH:16][N:15]4[N:19]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)cc1

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-{8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amine was prepared from 8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.237 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0877 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.051 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.7 Hz, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.49 (d, J=7.8 HZ, 2H), 7.01-6.95 (m, 3H), 6.69 (s, 1H), 3.30-3.15 (m, 5H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS=491 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:34])[CH3:33]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 199c (7.0 g, 20.2 mmol, 1.0 eq.), triethylamine (4.08 g, 40.4 mmol, 2.0 eq.), and THF (50 mL). To the mixture was added the solution of acetyl chloride (2.36 g, 30.3 mmol, 1.5 eq.) in THF (20 mL) dropwise. The reaction mixture was stirred at room temperature for one hour. After the reaction was completed, it was quenched with ice water and evaporated under reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was washed with 1:8 ethyl acetate/petroleum to afford 199d as a white solid (5.9 g, 76%). MS-ESI: [M+H]+ 388.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].O>O1CCCC1>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][Br:15]
Reactant: NCCCCCO
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCBr)NCCCCCO
Reaction time: 18 h
Yield: 78.8 %

Procedure:
Part A. A solution of 5-aminopentanol (30.0 g, 291 mmol) and triethylamine (50.0 mL, 359 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C., and a solution of 5-bromovaleryl chloride (30.0 mL, 226 mmol) in tetrahydrofuran (200 mL) was added dropwise. After slow warming and stirring for 18 hours, the mixture was poured into water (1 L), and the phases were separated. The aqueous layer was extracted with methylene chloride (2×600 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The oily product was purified by elution through a silica gel plug with ethyl acetate, and evaporation afforded the product, N-(5-hydroxypentyl)-5-bromopentanamide (47.3 g, 178 mmol, 79%).
Reaction SMILES: [NH2:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:4][CH:3]1[CH2:5][OH:6].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>ClCCl>[OH:6][CH2:5][CH:3]1[CH2:4][C:2]1([NH:1][C:26](=[O:27])[O:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Step b) To a solution of ((1RS,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)methanol (2.85 g, 13.7 mmol, Eq: 1.00) in dichloromethane (27.4 ml) was added at 5° C. diisopropylethylamine (2.65 g, 3.59 ml, 20.5 mmol, Eq: 1.5) and methyl chloroformate (1.42 g, 1.17 ml, 15.1 mmol, Eq: 1.1) dropwise via syringe. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a brown oil which was purified by silica gel flash chromatography with 0-100% EtOAc in heptane to give the title methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (3.52 g, 13.2 mmol, 96.6% yield) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (VII) (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77%)
Reaction SMILES: CN(C[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[Br:15][C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[N:25]([C:28]1[N:33]=[C:32]([C:34](OC)=[O:35])[CH:31]=[C:30]([CH3:38])[N:29]=1)[CH2:26][CH3:27].Cl.[OH-].[Na+]>C(OCC)C.CO.C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[CH:18][C:17]=1[N:25]([CH2:26][CH3:27])[C:28]1[N:33]=[C:32]([C:34]([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)=[O:35])[CH:31]=[C:30]([CH3:38])[N:29]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: CN(C)Cn1ccnc1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCN(c1nc(C)cc(C(=O)c2ncc[nH]2)n1)c1ccc(C(C)C)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 1-(dimethylaminomethyl)imidazole (0.63 g, 5 mmol) in anhydrous diethyl ether (50 mL) at −78° C. under a nitrogen atmosphere was added a solution of n-butyl lithium in hexanes (2.4 M, 2.1 mL, 5 mmol) dropwise and the pale yellow suspension was stirred at −78° C. for 1 h. Methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (1.47 g, 5 mmol) was added in one portion and the reaction mixture was warmed to room temperature over 23 h. A 1N HCl solution was added until pH=1 (test paper) and the reaction mixture was stirred for 4 h. A 3N NaOH solution was added until the solution became basic (pH=10; test paper). Three extractions with ethyl acetate, drying the combined organic layers over MgSO4, filtration and concentration in vacuo gave a brown oily solid. Column chromatography (chloroform:methanol::9:1) afforded the title product, a yellow glass (900 mg, 42% yield, Rf 0.43): mp 75-76° C.; NMR (CDCl3, 300 MHz): 12.2-12.1 (m, 1H), 7.7 (d, 1H, J=1), 7.45-7.35 (m, 2H), 7.3-7.2 (m, 2H), 6.55 (br s, 1H), 4.3 (sextet, 1H, J=7), 3.8 (sextet, 1H, J=7), 3.05 (septet, 1H, J=7), 2.65 (br s, 3H), 1.4 (d, 6H, J=7), 1.3 (t, 3H, J=7); CI-HRMS: Calcd: 428.1086 (M+H), Found: 428.1089; Anal (C20H24BrN5O) C, 56.08; H, 5.18; N, 16.35; Br, 18.66; Found: C, 56.20; H, 5.10; N, 15.88; Br, 18.73.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
2.0 g (0.01045 mol) of 1-benzyl-4-hydroxypiperidine were dissolved in 20 ml of dichlormethane and 5.1 ml (0.0366 mol) of triethylamine, cooled to 00 and treated with a solution of 1 ml (0.01255 mol) of methanesulfonyl chloride in 5 ml of dichloromethane. The mixture was stirred at 0° for 1/2 hr. Then, 10ml of 1N aqueous HCI were added, the mixture was stirred for 5 min. and the organic phase was washed with 1N aqueous HCI, with saturated bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. 0.97 g (35%) of 1-benzylpiperidin-4-yl methanesulfonate was obtained as yellow crystals. MS: me/e=270 (C13 H20NO3S+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)c2ccc(Cl)cc2)cc1

Procedure:
A THF solution (200 ml) containing t-butyl 4-bromobenzoate (19.9 g, 77.6 mmol), 4-chloroacetophenone (10 g, 64.7 mmol), Pd2dba3 (1.19 g, 1.29 mmol), BINAP (1.6 g, 2.58 mmol) and NaOtBu (8.7 g, 90.6 mmol) was refluxed under an argon atmosphere for approximately 5 hours. The solution was concentrated and then partitioned between EtOAc and water. The organic phase was washed with water, brine and dried over Na2SO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J=8.5 Hz, 2 H); 7.93 (d, J=8.7 Hz, 2 H); 7.43 (d, J=8.3 Hz, 2 H); 7.29 (d, J=8.2 Hz, 2 H); 4.30 (s, 2 H); 1.58 (s, 9 H). LC1 4.01 min. (M-tBu+H)=275
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>C(O)=O.Cl.C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)CCl
Yield: 85.9 %

Procedure:
57 g (0.256 mol) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene were warmed to 40° C. in a mixture of 250 ml of formic acid and 50 ml of concentrated hydrochloric acid for 1 hour. The mixture was then diluted with 400 ml of CH2Cl2 and ice, and was extracted 3 times by shaking with 2 N sodium hydroxide solution. After the methylene chloride phase had been dried over Na2SO4, the solvent was stripped off in a rotary evaporator. There remained 36 g (96%) of crude product. 32.2 g (0.22 mol, 86%) of 1-chloro-3,3-dimethyl-pent-4-en-2-one were obtained by distillation (b.p. 81°-84° C./24 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccc(Cl)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), 4-chloro-N′-isopropylbenzohydrazide (222.07 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) and dried so that ivory ((E)-tert-butyl 3-(3-(2-(4-chlorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (165.6 mg, 49%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[CH3:18].CC(=CC)C.O.O.P([O-])(O)(O)=[O:41].[Na+].Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]([OH:41])=[O:15])=[CH:12][C:11]=1[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C=O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CC=C(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.5 %

Procedure:
4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}-3-methylbenzaldehyde (50 mg, 0.11 mmol) synthesized in Example 51 was dissolved in a mixed solvent of t-butanol (5.0 mL) and water (2.0 mL), and 2-methyl-2-butene (0.15 mL, 1.42 mmol) and sodium dihydrogen phosphate dihydrate (80 mg, 0.51 mmol) were added, followed by slow addition of sodium chlorite (25 mg, 0.28 mmol) at 0° C. and stirring at 0° C. for 2 hours under nitrogen atmosphere. An aqueous sodium hydrogen sulfite solution (5 mL) was added at 0° C., and stirring was carried out at room temperature for 10 minutes. An aqueous sodium hydrogen sulfite solution (15 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (58 mg, yield ˜100%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:21](=[O:22])[CH2:20][NH:19][CH2:18][C:17]1=[O:23].[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:26]([S:30]([N:19]1[CH2:18][C:17](=[O:23])[N:16]([CH2:15][C:5]2[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:8]3[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=3[CH:6]=2)[C:21](=[O:22])[CH2:20]1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CNCC2=O)cc2cnc(C#N)nc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)N1CC(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 200 mg (0.59 mmoles) of 7-(2,2-dimethyl-propyl)-6-(2,6-dioxo-piperazin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 4 ml of pyridine, 184 mg (1.2 mmoles) of 1-butanesulfonylchloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 2 hours and the mixture is concentrated under reduced pressure. The obtained crude powder is dissolved in CH2Cl2, and the CH7Cl2 layer is washed with 1N aqueous HCl, brine, and then dried over MgSO4. The CH2Cl2 layer is concentrated under reduced pressure to give colorless powder, which is washed with ether to give 195 mg of desred 6-[4-(Butane-1-sulfonyl)-2,6-dioxo-piperazin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12]2)=[O:10])=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:13]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)N1CCC(c2ccc(Cl)cc2)=N1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To 3.2 g of N,3-bis-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide dissolved in 20 ml of tetrahydrofuran and cooled in an acetone bath maintained at -20° C., was added 1.5 ml of diisopropyl amine and 8.0 ml of a 2.7 molar solution of butyllithium in hexane. The resulting solution was stirred for 20 minutes and then cooled to -70° C. To this solution was added 0.5 ml of ethyl chloroformate. The reaction was allowed to stir for 10 minutes and then allowed to warm to room temperature over 10 minutes. The reaction was quenched with 1.0 ml of acetic acid and the reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 3.3 g of N,3-bis-(4-chlorophenyl)-4-carboethoxy-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR and IR data were consistent with the structure.