Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[Na+].Cl[C:8]1[CH:9]=[C:10](C)[CH:11]=[C:12]([CH3:14])[CH:13]=1.[CH2:16](NC)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1>CCOCC.[Pd].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]>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:13]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:14]
Reactant: CCCCCCCNC
Reactant: Cc1cc(C)cc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccccc1C
Temperature: 105 °C
Yield: 126.1 %

Procedure:
This is an example of Pd/ligand 4-catalyzed aryl amination reaction for aryl amine synthesis. A reaction tube containing NaOtBu (120 mg, 1.25 mmol) was thoroughly evacuated and purged with argon. 5-Chloro-m-xylene (0.14 mL, 1.04 mmol), heptylmethylamine (0.21 mL, 1.25 mmol), a toluene solution of Pd(dba)2 (1.2 mL, 1.0 mg/mL, 2.1 μmol) and a toluene solution of ligand 4 (2.5 mL, 1.0 mg/mL, 6.2 ,μmol) and toluene (0.3 mL) were added to the reaction tube and the reaction was heated at 105° C. for 21.5 h. The reaction was taken up in ether (100 mL) and washed with H2O (30 mL) and brine (30 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluant to afford compound 2 (shown below in Table 1) as a yellowish oil (239 mg, 98%) after drying under vacuum. 1 H NMR (CDCl3): δ6.33 (br, 3H, ArH), 3.25 (t, J=7.6, 2H, —NCH2—), 2.89 (s, 3H, —N—CH3), 2.27 (s, 6H, Ar(CH3)2), 1.54 (br, 2H, —NCH2CH2—), 1.30 (br, 8H, —(CH2)4CH3), 0.89 (br t, J=6.6, 3 H, —CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[N:16]=[N:17][NH:18][N:8]=2)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)benzonitrile (400 mg, 1.851 mmol) in DMF (20 mL) was added sodium azide (361 mg, 5.55 mmol) at rt. The mixture was stirred at 120° C. overnight. LCMS showed the reaction was finished. The reaction was quenched by water. The mixture was extracted with EA (20 mL×3), washed with water, and concentrated to give 5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole (220 mg, 0.743 mmol, 40.1% yield): 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H). ES-LCMS m/z 260 (M+H).
Reaction SMILES: C(O)CCCCCCCO.FC1C(F)=C(OC)C(F)=C(F)C=1CBr.[F:25][C:26]1[C:42]([F:43])=[C:41]([O:44][CH3:45])[C:40]([F:46])=[C:39]([F:47])[C:27]=1[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38].FC1C(F)=C(OC)C(F)=C(F)C=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH2:89])[CH2:85][N:86]([CH3:88])[CH3:87])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH:89][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]1[C:26]([F:25])=[C:42]([F:43])[C:41]([O:44][CH3:45])=[C:40]([F:46])[C:39]=1[F:47])[CH2:85][N:86]([CH3:87])[CH3:88])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: COc1c(F)c(F)c(COCCCCCCCCO)c(F)c1F
Agent: COc1c(F)c(F)c(CBr)c(F)c1F
Agent: COc1c(F)c(F)c(COCCCCCCCC(=O)O)c(F)c1F
Agent: Cl
Product: COc1c(F)c(F)c(COCCCCCCCC(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)c(F)c1F

Procedure:
The title compound, m/e=479.4 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2,3,5,6-tetrafluoro-4-methoxy-benzyl bromide, leading to 8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2,3,5,6-tetrafluoro-4-methoxy-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:37])[NH:27][CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:27][CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:37])=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)NCC(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[(2-oxo-2-phenyl-ethylcarbamoyl)-methyl]-phenyl}-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-2-{4-[3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenyl}-N-(2-oxo-2-phenyl-ethyl)-acetamide trifluoroacetate as a white powder; MS: 493 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=3)[O:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[NH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=1)[NH2:22]>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:21]2[CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]3[CH2:6][O:7][C:8]4[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=[CH:12][C:13]=4[C:14]3=[N:22]2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CC1)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CC2)ccc1C#N

Procedure:
The title compound was prepared from methyl 3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate (Preparation 33), and 4-hydrazinyl-2-methylbenzonitrile hydrochloride (Preparation 2) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (65 to 85% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 23 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-methylphenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1H), 7.94 (d, J=7.8 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.11 (dd, J=8.6, 2.0 Hz, 1H), 4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.45 (dd, J=12.9, 10.5 Hz, 1H), 4.31 (t, J=10.0 Hz, 1H), 3.89 (ddd, J=13.0, 9.9, 5.7 Hz, 1H), 2.42 (s, 3H), 0.71-0.81 (m, 1H), 0.62-0.70 (m, 1H), 0.49-0.58 (m, 1H), 0.35-0.43 (m, 1H), 0.17-0.24 (m, 1H). ES-MS m/z 374 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34](O)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:53]1([CH2:58][CH2:59][NH2:60])[CH2:57][CH2:56][CH2:55][CH2:54]1>O1CCCC1>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34]([NH:60][CH2:59][CH2:58][N:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: NCCN1CCCC1
Reactant: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1nc(C(=O)NCCN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a suspension of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (3 g, 5.71 mmol) in tetrahydrofuran (THF) (25 mL) was added triethylamine (0.876 mL, 6.29 mmol), followed by isobutyl chloroformate (0.826 mL, 6.29 mmol). The reaction mixture was stirred at 0° C. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (0.979 g, 8.57 mmol) was added and the mixture was stirred at 0° C. for 30 min and warmed up to room temperature for 2 h. Solvent was removed and the residue was chromatographed to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydrocinnoline-3-carboxamide (1.2 g, 1.932 mmol, 33.8% yield). LCMS: (M+H)+: 621.2
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([N:12]([C:22]2[C:26]([Br:27])=[C:25]([CH3:28])[O:24][N:23]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[Br:27][C:26]1[C:22]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:11])=[O:10])=[N:23][O:24][C:25]=1[CH3:28]
Reactant: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Sodium hydroxide (1.3 g, 30.6 mmol) was added to a solution of N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzene-sulfon-amide (7 g, 15.3 mmol, prepared as described in (a)) in methanol (100 ml). The resulting solution was stirred at 25° C. for 30 h. Excess methanol was removed under reduced pressure. The residue was dissolved in water (50 ml) and acidified (pH 3-4) by the addition of concentrated HCl with cooling. The mixture was extracted with dichloromethane (2×100 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. Removal of the solvent gave N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide which was purified by crystallization from ethyl acetate/hexanes (4.5 g, 92% yield). The compound is identical to the one isolated in step (b).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:22]2[NH:23][C:24](=[O:34])[C:25]([OH:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)[CH2:21][CH2:20][C:15]2(OCC[O:16]2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:22]2[NH:23][C:24](=[O:34])[C:25]([OH:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C2(NC(=O)OCc3ccccc3)CCC3(CC2)OCCO3)[nH]c(=O)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C2(NC(=O)OCc3ccccc3)CCC(=O)CC2)[nH]c(=O)c1O
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A solution of ethyl 2-(8-(benzyloxycarbonylamino)-1,4-dioxaspiro[4.5]decan-8-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.8 g, 3.8 mmol) in THF (200 mL) was added 2N HCl (12 ml, 24 mmol) and the resulting mixture was heated for 2 h at 60° C. The reaction mixture was then cooled and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 fractions were dried (Na2SO4), filtered and concentrated to afford the title compound as a light yellow solid (1.5 g, 92% yield). 1H NMR (500 MHz, CDCl3) δ: 12.11 (s, 1H), 11.09 (s, 1H), 7.17-7.29 (m, 5H), 6.36 (s, 1H), 5.00 (s, 2H), 4.44 (q, 2H, J=7.02 Hz), 2.49-2.57 (m, 8H), 1.42 (q, 3H, J=7.05 Hz). LCMS (M+H)=430.38.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:37]2[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][CH2:31][N:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:35][CH:36]=2)=[N:4][C:3]=1[C:9](=[O:10])[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reactant: COCCCN(CCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C
Temperature: 21 °C

Procedure:
To a reactor was charged, 3-Amino-6-bromo-N-(pyridin-3-yl)pyrazine-2-carboxamide (1580 g), tert-butyl (3-methoxypropyl){3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate (2778 g) 1-butanol (23.7 L), potassium phosphate, tribasic, N-hydrate (2740 g) and water (1.58 L). The contents were stirred under nitrogen at ambient (21° C.). In a second reactor was made up a solution of 3-(di-tert-butylphosphonium)propane sulphonate (DTBPPS) (83.04 g); sodium tetrachloropalladate (45.52 g) and water (1.58 L). The catalyst/ligand solution was poured into the reaction; the reaction was inerted and heated up to 80° C. The reaction was stirred for 2 hours at 80° C. The batch was cooled to 60° C. and water (22.1 L) was added. The contents washed with water at 60° C. The organic layer and interface were filtered through perlite (500 g) made up with 1-Butanol (3.95 L). The organic liquors were recharged to the vessel and washed with water (11.1 L) at 60° C. The organic liquor was washed with 10% w/v aqueous sodium chloride (11.2 L) at 60° C. The organic liquors were heated up to 60° C. and distilled under vacuum to ˜10 relative volumes. The batch was cooled to 20° C. and left to stir for 16 hours under nitrogen. The contents were filtered and washed with 1-Butanol (4 L×2). The yellow free flowing solid was discharged and dried in vacuum oven at 40° C. overnight (tert-butyl (3-{4-[5-amino-6-(pyridin-3-ylcarbamoyl)pyrazin-2-yl]phenyl}propyl)(3-methoxypropyl)carbamate (2428 g)).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH2:17]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH3:29])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1OC
Solvent: c1ccncc1
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-(chlorosulfonyl)-2-methoxybenzoate (1 g, 3.78 mmol) in pyridine (3 mL) at 25° C. was added N-isobutyl-2,4-dimethylaniline (0.670 g, 3.78 mmol) and the reaction mixture stirred at 25° C. for 2 hours, then stood for 12 hours. The pyridine was evaporated in vacuo to give a yellow oil which was purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane). The appropriate fractions were combined and evaporated in vacuo to give the required product, 1.485 g, as a colourless oil. LCMS [LCMS2] Rt 1.37 min, m/z (ES+) 406 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:22]C([N-]C(C)C)C.IC>CO>[CH3:22][C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:18]2[C:13]([CH:12]=1)=[C:14]([CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=2
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: CO
Product: C=Cc1cccc2c1cc(C)n2S(=O)(=O)c1ccccc1
Yield: 30 %

Procedure:
1-(Phenylsulfonyl)-4-vinyl-1H-indole (190 mg, 0.7 mmol, Intermediate 45) was weight in to a pre dried reaction flask and purged with nitrogen gas for 1 h. Dry THF (50 mL) was added and the reaction flask was cooled to −78° C. before LDA (0.35 mL, 0.7 mmol, 2M) was added. The reaction was stirred for 15 minutes before iodomethane (95.2 mg, 0.7 mmol) was added. Allowed the reaction mixture to slowly reach RT ON. Added 1 mL MeOH and evaporated the reaction mixture on silica. Purified by flash chromatography using 20% DCM in hexanes. Got 61 mg of a white solid, 30% yield. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:25]=1[C:26]([F:29])([F:28])[F:27])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].C1(C2C=CC=CC=2)C=CC(CC(NC(C2C=NN(C3C=CC(F)=CC=3)C=2[C:59]([F:62])([F:61])[F:60])=O)C(O)=O)=CC=1>C1COCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([N:24]2[C:25]([C:26]([F:27])([F:29])[F:28])=[C:21]([C:19]([NH:18][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([C:59]([F:62])([F:61])[F:60])=[CH:16][CH:17]=4)=[CH:10][CH:11]=3)[C:3]([OH:2])=[O:37])=[O:20])[CH:22]=[N:23]2)=[CH:31][CH:32]=1
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: O=C(NC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 85 %

Procedure:
A solution of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.200 g, 0.731 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride (0.213 g, 0.731 mmol), HBTU (0.277 g, 0.731 mmol), and DIEA (0.450 mL, 2.566 mmol) as described in general procedure A. The crude compound was purified by flash column chromatography on silica gel using CHCl3 (+10% hexane) to give 0.150 g (41%) of 3-biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid methyl ester. A solution of this ester (0.085 g, 0.166 mmol) in THF (3.0 mL) was treated with LiOH (0.025 g) by general procedure I to afford (0.070 g, 85%) of the title compound 3-Biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid as a white solid. LCMS: 498 (M+1)+. 1H NMR (DMSO-d6) 8.94 [d, 1H], 8.08 [s, 1H], 7.58 [m, 6H], 7.42 [m, 7H], 4.63 [m, 1H], 3.22 [m, 1H], 3.04 [m, 1H].
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]3[C:6]=2[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH:3]=1.FC(F)(F)[C:32](O)=[O:33]>CCOC(C)=O.C[O-].[Na+].CO.C(Cl)Cl.[Cu]Br>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:4]1[CH:3]=[C:2]([O:33][CH3:32])[C:7]2[O:8][CH:9]3[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]3)[C:6]=2[CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCNCC21
Temperature: 85 °C
Reaction time: 4.5 h

Procedure:
In a 7 mL vial, copper (I) bromide (0.15 mmol, 22 mg) was diluted with 0.1 mL EtOAc and 0.6 mL of sodium methoxide in methanol (25 wt %). tert-Butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.5 mmol, 250 mg) was added to the thick slurry and heated to 85° C. on the orbit shaker. An additional 0.1 mL of EtOAc was added. After 4.5 hr, the solvent was removed in vacuo. The resulting material was diluted with water and extracted three times with EtOAc. The combined organics were washed with brine, dried over NaSO4, decanted and concentrated to give crude yellow-brown oil. This material was diluted with 4 mL CH2Cl2 and cooled to 0° C. with an ice bath. After 15 min, 4 ml trifluoroacetic acid was added and the reaction was stirred at rt. After 2 hr the solvent was removed in vacuo to give crude oil after a NaOH workup. The crude material was purified by column chromatography (0.5/3.5/96 NH4OH/CH3OH/CH2Cl2) to give 105 mg colorless oil (60%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH:37]=[CH:38][C:39]#[N:40]>CC(C)=O>[C:39](/[CH:38]=[CH:37]/[CH2:36][N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]3[N:16]([N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]=3[C:26]([NH2:28])=[O:27])[C:20]=2[CH2:21]1)#[N:40]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Reactant: N#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#C/C=C/CN1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (100 mg, 0.268 mmol) in 10 mL of acetone at RT was added K2CO3 (140 mg, 1.07 mmol). After stirring at RT for 2 hr, 4-bromobut-2-enenitrile (40 mg, 0.268 mmol) in 2 mL of acetone was added and stirred at RT overnight. The mixture was then partitioned between EA (50 mL) and water (100 mL). The aqueous phase was further extracted with 50 mL of EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated to get crude product which was further purified by pre-TLC (DCM/MeOH=15/1) to afford 7 mg (6%) of (E)-7-(3-cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.42-7.30 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.06 (d, J=7.6 Hz, 2H), 6.76 (dt, J=16.3, 4.6 Hz, 1H), 5.67 (d, J=16.3 Hz, 1H), 5.62 (s, 2H), 3.82 (s, 2H), 3.41 (d, J=4.6 Hz, 2H), 2.95-2.75 (m, 4H). MS (ESI) m/e [M+1]+ 439.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1.C(=O)([O-])[O-:19].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:17])=[O:19])[CH:11]=1
Reactant: N#Cc1cccc(-c2ccc(CO)cc2Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cccc(-c2ccc(CO)cc2Cl)c1
Reaction time: 18 h

Procedure:
2′-Chloro-4′-hydroxymethyl-biphenyl-3-carbonitrile (I-6c) was dissolved in 50 mL of dimethylsulfoxide and treated with potassium carbonate (2.8 g) followed by an aqueous hydrogen peroxide solution (10 mL of a 30% solution). After 18 hours, the reaction mixture was combined with 200 mL of water and extracted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (I-6d).
Reaction SMILES: [CH3:1][CH:2]([CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3](NC(OCC)=O)[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Ni]>[CH3:1][CH:2]([CH2:3][NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)NCC(C)C(NC(=O)OCC)NC(=O)OCC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)NCC(C)CNC(=O)OCC

Procedure:
10 g of the 2-methyl-1,1,3-tri(ethoxycarbonylamino)propane obtained in stage 1a) are dissolved in 90 ml of ethanol, 3 g of Raney nickel are added, and hydrogenation is carried out in a stirred autoclave at 165° C. and 50 bar of hydrogen for 10 hours. Conversion is complete, giving 2-methyl-1,3-di(ethoxycarbonylamino)propane with a selectivity of 95%.