Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C:9]1[N:10]=[N:11][NH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:17][CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn[nH]n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nnc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2H-Tetrazol-5-ylmethyl)-carbamic acid tert-butyl ester (0.9 g, 4.5 mmol) is dissolved in dry DMF, NaH (60% dispersed in mineral oil) (0.18 g, 4.5 mmol) is added and the reaction mixture is stirred at room temperature for 5 minutes before ethyl iodide (0.35 ml, 4.5 mmol) is added. The reaction mixture is stirred overnight at room temperature and partitioned between EtOAc and water. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to afford an oil. Purification by flash chromatography on silica eluting with 2:1 iso-hexanes/EtOAc affords the title compound.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[NH:19]1.C([BH3-])#N.[Na+].O>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CC(O)C>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:14][C:12]1[CH:11]=[C:10]([CH3:16])[N:9]=[C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:13]=1
Reactant: CCCCCCSc1nc(C)cc(C=O)n1
Reactant: CC1CCCC(C)N1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CC(C)O
Solvent: O
Product: CCCCCCSc1nc(C)cc(CN2C(C)CCCC2C)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
2-Hexylsulfanyl-6-methyl-pyrimidine-4-carbaldehyde (0.2 g, 1 mmol) and 2,6-dimethylpiperidine (0.23 mL, 2 mmol) were dissolved in tetraisopropyl orthotitanate (0.5 mL) and stirred at 20° C. for 1 h. The solution was diluted with 2-propanol (5 mL) and treated with sodium cyanoborohydride (105 mg, 2 mmol) at 20° C. for 20 h. Water (1 mL) was added, and the resulting precipitate filtered off and evaporated. The product was extracted with AcOEt, sat. NH4Cl solution, dried and concentrated. The residue was purified by preparative HPLC chromatography on a YMC combiprep ODS-AQ column (75×20 mm iD, S-5 μM, 12 nm) with an acetonitrile-water gradient. One obtained 37 mg (36%) of a colorless liquid. MS: m/z=336 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:7]=[C:6]([Br:27])[C:5]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C(O)(=O)C>O1CCOCC1.[OH-].[Na+]>[Br:27][C:6]1[C:5]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:9]=[C:8]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:7]=1)[C:3]([OH:38])=[O:2]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)O)c1

Procedure:
A solution of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-benzyloxy)-benzoic acid methyl ester (5.7 g) in dioxane (135 ml) and 1N NaOH (15 ml) was stirred for 17 h. The mixture was acidified with conc. acetic acid and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in ethanol and then concentrated until a solid precipitated. The solid was collected by filtration and washed with petroleum ether.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1/[CH:13]=[C:14](/[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)\[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>ClCCCl.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]=[C:14]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH:15]([OH:20])[C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1Cl)n1cncn1
Yield: 63.8 %

Procedure:
166 Milligrams (1.02 mmole) of the present compound obtained in Example 1 was dissolved in a 1,2-dichloroethane/dimethylformamide (27 ml/0.5 ml) mixed solvent, and 5 ml of a 1,2-dichloroethane solution containing 975 mg (3.0 mmoles) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=94.8/5.2) was added dropwise thereto. After reaction at room temperature for 16.5 hours, 2% hydrochloric acid was added to separate the reaction solution into an aqueous and organic layers. After concentrating the organic layer, the residue was purified by column chromatography on silica gel to obtain 624 mg of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The ratio of the E-form alcohol to Z-form alcohol was 93.8 to 6.2, and the enantiomer ratio of the E-form alcohol was: (+)-isomer: (-)-isomer=18:82.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36](O)=[C:35]([F:40])[CH:34]=1)[CH3:26].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:35]([F:40])[CH:34]=1)[CH3:26]
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
Combine 1-(4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.257 g, 0.76 mmol) and 3-(3-Fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.150 g, 0.59 mmol) in toluene (3.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.223 g, 0.88 mmol) followed by tributyl-phosphane (0.22 mL, 0.88 mmol) under inert atmosphere. Stir at room temperature for 18 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-70% Ethyl acetate/hexanes gradient) to provide 0.305 g of title compound (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: COC(CN)OC
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)OC
Yield: 78.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2,2-dimethoxy-ethyl)-amide (700 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 2,2-dimethoxy-ethylamine (265 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.086 g, 0.30 mmol) in methylene chloride (4.0 mL) was added EDCI (0.75 g, 0.39 mmol) and HOBt (0.053 g, 0.39 mmol) at room temperature. After 30 min 2-aminopyridine (0.031 g, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provided 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-N-(pyridin-2-yl)acetamide (0.043 g, 39%) as a white solid, mp 168-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ccn2[C@@H]1C[C@@H](CO)[C@@H](O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of (1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (43.0 mg, 0.173 mmol) and imidazole (25.0 mg, 0.367 mmol) in dry DMF (2.00 mL) at 0° C. was added tert-butyldimethylsilyl chloride (29.0 mg, 0.192 mmol). The solution was stirred at rt for 2 h and concentrated in vacuo, the residue was dissolved in water and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (50.8 mg, 81%), which was taken on without further purification. LC/MS: Rt=1.38 min, ES+ 364 (FA standard).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24](Cl)=[O:25].Cl>>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:23]=1[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)=[O:25]
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(25.2 mg, 78%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 2,6 dichlorobenzoyl chloride (18.3 mg, 0.107 mmol), HRMS-FAB+ for C22H18N2OCl2F3, calculated MH+ (--HCl): 453.07483; found: 453.07779.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.CC1[N:40]=CC(C(O)=O)=NC=1>>[F:1][CH:2]([F:37])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[N:40][C:21]([CH3:22])=[CH:20][N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cn1
Reactant: Cc1cnc(C(=O)O)cn1
Product: Cc1cnc(-c2nc3cc(Oc4cccnc4OC(F)F)c(Oc4ccc(S(C)(=O)=O)nc4)cc3[nH]2)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 38 or in accordance with the method or by combining it with an ordinary method but using 4-(2-difluoromethoxy-pyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 215 and 5-methyl-pyrazine-2-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C.Cl>O.CN1CCCC1=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]2[NH:16][N:15]=[N:14][N:11]=2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C2OCCO2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1cc(C2OCCO2)ccc1-c1nnn[nH]1
Temperature: 150 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
A mixture of 4-(1,3-dioxolan-2-yl)benzonitrile (1.0 g), sodium azide (1.48 g), triethylamine hydrochloride (1.18 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred at 150° C. for 3 hrs. After cooling, 1 M hydrochloric acid and water were added to the reaction mixture to adjust to pH=3 to 4. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 5-[4-(1,3-dioxolan-2-yl)phenyl]-1H-tetrazole (0.300 g, yield 24%) as brown prism crystals. melting point: 197–199° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1>O1CCOCC1>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][N:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCCN5C)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 62c (140 mg, 0.37 mmol) in 1,4-dioxane (4.00 mL) was added DIPEA (129 μL, 0.74 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 150 mg, 0.37 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (73 mg, 31%). LCMS (Method 5): Rt 3.75 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.45 (1H, m), 1.60-1.83 (3H, m), 1.83-1.93 (2H, m), 1.93-2.07 (5H, m), 2.11 (1H, m), 2.20-2.33 (2H, m), 2.38 (3H, s), 3.05 (1H, dt, J 11.8, 2.8), 3.79 (1H, dd, J 10.9, 2.8), 4.91 (1H, dd, J 9.0, 5.7), 5.32 (1H, t, J 4.0), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.64 (1H, d, J 10.0), 8.43 (1H, d, J 1.7).
Reaction SMILES: Br[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(NC(C)C)(C)C.CCCCCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:37][Si:38]([CH3:40])([CH3:39])[C:41]#[C:42][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH:3]=1
Reactant: C=C1c2ccccc2C=C(Br)c2ccccc21
Reactant: C#C[Si](C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: C=C1c2ccccc2C=C(C#C[Si](C)(C)C)c2ccccc21
Yield: 47.9 %

Procedure:
To a stirred mixture of 4 (5.66 g, 20 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.7 g, 1 mmol), copper(II) acetate hydrate (0.18 g, 1 mmol) and triphenyl-phosphine (0.52 g, 2 mmol) in 40 mL of diisopropyl amine was added trimethylsilyl acetylene (2.16 g, 22 mmol) and heated to reflux. On refluxing for an hour the mixture turns dark and solidifies. The reaction mixture was diluted with 50 mL of hexane and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel with hexane/methylene chloride (9:1 by volume) as eluant to yield 2.88 g (50 percent) of trimethyl[2-(5-methylene-5H-dibenzo[a,d]cyclohepten-10-yl)ethynyl)silane, 5, as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[CH3:16][NH2:17]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of Intermediate 71B (150 mg, 0.61 mmol) in DCM (4 mL) was added methylamine (2.0 M solution in THF, 1.5 mL, 3.0 mmol) and TEA (0.424 mL, 3.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM, washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (flash chromatography, 12 g, EtOAC/hexane=0-100%) to give Intermediate 71C (45 mg, 31%) as a white solid. HPLC: Rt=1.112 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 8.90 (1H, s), 8.71 (1H, s), 8.46 (1H, s), 4.76 (1H, br. s.), 2.81 (3H, d, J=4.95 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[NH:32][C:33](=[O:35])[CH3:34])O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:31]([NH:32][C:33](=[O:35])[CH3:34])[CH:36]=[CH:37][CH:38]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 112. NMR (CDCl3): 2.27 (3H, s), 4.33 (3H, s), 7.34 (1H, br), 7.52-7.68 (5H, m), 7.84 (1H, d), 7.85 (1H, s), 8.10 (1H, s), 8.26 (1H, s), 8.96 (1H, s). MS: MH+ 383.12 (100%)
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].CN(C)C(N(C)C)=N.Cl.[N+:26]([CH3:29])([O-:28])=[O:27]>>[N+:26]([CH2:29][CH:3]([Si:2]([CH3:15])([CH3:1])[CH3:16])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])([O-:28])=[O:27]
Reactant: C[Si](C)(C)C=CC(=O)OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Product: C[Si](C)(C)C(CC(=O)OCc1ccccc1)C[N+](=O)[O-]
Reaction time: 15 h
Yield: 88 %

Procedure:
A solution of benzyl 3-(trimethylsilyl)acrylate (782 mg, 3.34 mmol) in nitromethane (3 ml)was added with N,N,N′,N′-tetramethylguanidine (105 μl, 0.838 mmol) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was added with aqueous hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (14:1)] to obtain benzyl 4-nitro-3-(trimethylsilyl)butanoate (863 mg, 88%) mentioned in the title as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=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.[C:67]([O:71][C:72](=[O:80])[CH2:73][CH2:74][C@@H:75]([C:77]([OH:79])=[O:78])[NH2:76])([CH3:70])([CH3:69])[CH3:68].Cl>CN(C=O)C.O>[C:67]([O:71][C:72](=[O:80])[CH2:73][CH2:74][CH:75]([NH:76][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[O:24])[CH:21]=[CH:22][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[C:77]([OH:79])=[O:78])([CH3:70])([CH3:68])[CH3:69]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150 mg, 0.33 mmol) in 10 ml of anhydrous DMF were added HATU (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl ester (102 mg, 0.50 mmol). The mixture was heated at 60° C. for 30 minutes, cooled to room temperature, and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid as white solid. Yield: 185 mg, 87%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([NH2:23])=[O:22]>>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([NH2:23])=[O:22])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: NC(=O)c1sccc1N
Product: NC(=O)c1sccc1NC(=O)Cc1cccc2ncccc12

Procedure:
The title compound was prepared from 2-(quinolin-5-yl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS(ESI) 312.1 [M+H], Retention time=0.351 min.