Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:36]([O:38]C(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.[C:64](O)(=O)[CH2:65][CH2:66][CH2:67]C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:36](=[O:38])[CH2:64][CH2:65][CH2:66][CH3:67])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)OC(O)C(=O)[C@@]1(OC(=O)CC)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
307 mg (0.35 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3), 36 μl (0.33 mmol) of valeric acid, 52 mg (0.35 mmol) of N-hydroxy-benzotriazole and 74 μl (0.66 mmol) of N-methylmorpholine are dissolved in 40 ml of dichloromethane, mixed with a solution of 84 mg (0.41 mmol) of dicyclohexylcarbodiimide in 10 ml of dichloromethane and stirred for 4 hours at room temperature. For working-up, the precipitated urea is filtered off, the filtrate is diluted with 40 ml of dichloromethane and washed with 40 ml each of 0.5N NaOH, 0.5N HCl and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation i.vac. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography on 200 g of silica gel 60 (dichloromethane→dichloromethane/methanol 95:5) yields 180 mg (64%) of N-(N-(N-(N -(valeroyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien -21-yl] ester and, after recrystallization, 157 mg (56%) in crystalline form from dichloromethane/diisopropyl ether/hexane.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of 4-(aminosulfonyl)benzoic acid (500 mg, 2.5 mmol) in MeOH (2 ml) at 0° C. is added thionylchloride (0.2 ml, 7.4 mmol). The reaction mixture is stirred at rt overnight. When TLC confirms the total consumption of the starting acid, the solvent and excess thionyl chloride are removed under reduced pressure to afford 400 mg (75%) of the title compound, which was used in the next step without any further purification. LC/MS: (ES+):215.9, (ES−):214.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:32][C:33]#[N:34]>C1COCC1>[C:33]([CH2:32][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:34]
Reactant: CCOC(=O)C(CC)CC
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CC)(CC)CC#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of ethyl 2-ethylbutyrate (21.60 g, 150 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamide prepared by treating diisopropylamine (16.67 g, 165 mmol) in dry THF (150 mL) with butyllithium in hexanes (2.5M, 66 mL, 165 mmol) at -78° C. for 1 h in a nitrogen atmosphere. The resulting mixture was stirred at -78° C. for 1 h, then a solution of bromoacetonitrile (21.60 g, 180 mmol) in THF (50 mL) was introduced slowly over a period of 30 minutes (the reaction mixture starts getting darker as the addition progresses). The resulting dark mixture was stirred overnight (ca. 16 h) and allowed to warm from -78° C. to room temperature. The reaction was quenched by addition of HCl (1N, 250 mL) at 0° C. The layers were separated, and the aqueous phase was further extracted with ether (3×100 mL). The combined organic extract was washed sequentially with 75 mL portions of saturated NaHCO3, water (several times), and brine, and dried over MgSO4. The solvent was removed in vacuo to give 27.77 g of dark colored liquid. After two vacuum distillations, the nitrile (12.35 g, 45%) was obtained as a colorless liquid: bp 84°-85° C. (1.3 mmHg). Analytical sample was prepared by column chromatography over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb distillation (pot temp. 80° C. (1 mmHg)).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[OH:16][CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[O:5][CH2:6][CH2:7][O:8][C:9]=2[CH:14]=1)[CH:1]=[CH2:2]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2c(c1)OCCO2

Procedure:
To a solution of vinylmagnesiumbromide in tetrahydrofurane (29 mL 1M) maintained at a temperature below 4° C. is added portionwise 2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (4.32 g). The mixture is further stirred at a temperature close to 0° C. for 1.75 h and hydrolized by adding an aqueous solution of ammonium chloride (36.5 mL 1M). The mixture is extracted with diethyl oxide. The organic layers are pooled, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography over silica gel, with heptane/ethyl acetate 1/1 as eluant, affords 1.12 g of 2,3-dihydro-6-(1-hydroxyallyl)benzo[1,4]dioxine as a yellow oil used without further purification.
Reaction SMILES: FC(F)(F)C([C:5](=[CH:11][N:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.FC(F)(F)C(=O)CC(OCC)=O.CN(C(OC)OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][N:12]([CH:11]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Agent: CCOC(=O)CC(=O)C(F)(F)F
Agent: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C=CN(C)C
Yield: 75 %

Procedure:
My result is especially surprising in view of the results reported by Beck et al., vide supra, who attempted to prepare (2) by reacting ethyl trifluoroacetoacetate with DMF dimethyl acetal in the presence of a catalytic quantity of p-toluenesulfonic acid. The reaction resulted in the formation of ethyl 3-(N,N-dimethylamino)-2-propenoate (4) in 75% yield. Presumably, the methanol by-product further reacted with the target compound (2) to give the unexpected product and methyl trifluoroacetate.
Reaction SMILES: [CH3:1][N:2]([C:11]([NH:13][CH3:14])=[S:12])[NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=O.C([O-])(O)=O.[Na+]>>[CH3:1][N:2]1[C:11](=[S:12])[N:13]([CH3:14])[C:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[N:3]1
Reactant: CNC(=S)N(C)NC(=O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1nc(-c2cccs2)n(C)c1=S

Procedure:
A stirred mixture of 2,4-dimethyl-1-(2-thienoyl)thiosemicarbazide (4.7g, 2.0×10-2 mole) and 1 molar aqueous NaHCO3 (200 ml, 2.00×10-2 mole) was heated to reflux for 6 hours. The reaction mixture was then placed in the refrigerator for several hours before the precipitate was collected by filtration. Crystallization from isopropanol afforded long colorless needles: 3.6 g (83%), mp 128°-129° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5.0 g, 20.6 mmol) and cyclohexanone (4.03 g, 41.2 mmol) in methanol (50 mL), acetic acid (0.247 g, 20.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.55 g, 24.6 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-bromo-3-(cyclohexylamino)-2-methylbenzoate (2.75 g, 41%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)=[O:17])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH3:31][N:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:27])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[C:16]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)=[O:17]
Reactant: CC1(C)OB(c2ccc(NC(=O)c3cc4ccccc4o3)cc2)OC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2ccccc2o1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a solution of benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (195 mg, 0.54 mmol, 1 eq) in 3.5 mL of DMF under nitrogen atmosphere was added NaH (60% in mineral oil, 23 mg, 0.58 mmol, 1.1 eq). After 30 min of reaction, iodomethane (0.05 mL, 0.8 mmol, 1.5 eq) was added and the reaction was allowed to go for 12 h. After work up and column chromatography, benzofuran-2-carboxylic acid methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (83 mg) was obtained in 41% yield. 1H NMR (400 MHz, Benzene-d6) δ ppm 1.3 (s, 12 H) 3.4 (s, 3 H) 6.9 (d, J=0.8 Hz, 1 H) 7.0 (m, 4 H) 7.2 (m, 2 H) 8.1 (d, J=8.3 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[CH3:23][C:24]1([CH3:40])[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1)=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:28]3[CH2:27][CH2:26][N:25]([C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=4)=[O:31])[C:24]([CH3:40])([CH3:23])[CH2:29]3)=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)N2CCNCC2(C)C)n1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)CC2(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 50 mg (0.22 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 80 mg (0.22 mmol) (2,2-dimethyl-piperazin-1-yl)-(6-methoxy-pyridin-2-yl)-methanone trifluoroacetate, 77 mg (0.24 mmol) TBTU and 0.10 mL (0.58 mmol) DIPEA in 1.5 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pd].C(O)C>[O:19]1[CH2:18][CH2:17][CH:16]([CH2:15][NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5][C:4]=2[NH2:1])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCC1CCOCC1
Yield: 99.6 %

Procedure:
A mixture of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (2.50 g), 10% palladium on carbon (0.25 g), and ethanol (40 mL) was placed under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to provide 2.23 g of N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine as a yellowish-orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:34][C@@H:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.CO>C(Cl)Cl>[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[C@@H:35]([NH:34][C:14]([C:12]1[S:13][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:10][CH:11]=1)=[O:16])[CH2:36]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Sc2ccc(Cl)cc2)s1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Sc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
TEA (1.5 mL, 10.9 mmol) was added to a suspension of the product of Step 33b (2.7 g, 10 mmol) in CH2Cl2 (100 mL). Diphenylchlorophosphate (2.08 mL, 10 mmol) was added and the resulting solution is stirred at room temperature for 30 minutes. To this solution is added a solution of (R)-3-aminoquinuclidine (1M in DMF, 9.1 mL, 9.1 mmol). The resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH, then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness and the resulting solid is triturated with ether and dried in vacuo to yield the desired product (2.4 g, 71%). Alternatively, these compounds can be converted to their hydrochloride salts and crystallized from MeOH/IPA. MS for C18H19ClN2OS2 (ESI) (M+H)+ m/z 379.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:28])[N:13]([CH:17]3[C:25]4[C:20](=[C:21]([O:26]C)[CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.B(Br)(Br)Br>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:28])[N:13]([CH:17]3[C:25]4[C:20](=[C:21]([OH:26])[CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1CCC2n1cccc(C(=O)Nc2ccc(Br)cc2)c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Nc1ccc(Br)cc1)c1cccn(C2CCc3c(O)cccc32)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of N-(4-bromophenyl)-1-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.4 g, 0.91 mmol) in Ch2Cl2 (2 mL) at 0 C was added BBr3 (1M in CH2Cl2, 9 mL). The reaction was stirred at 0° C. for 1 hr. It was poured into sat. aqueous NaHCO3 (50 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried and concentrated to a solid. The solid was washed with MeOH and CH2Cl2 to afford a white solid. It was further purified by prep. HPLC to afford N-(4-bromophenyl)-1-(4-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (120 mg, 31%). Retention time (min)=7.127, method [7], MS (ESI) 425.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.19 (s, 1H), 8.61 (dd, J=2.1 Hz, 7.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.15-7.30 (overlap with CDCl3, 2H), 6.81 (d, J=7.8 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.60 (dd, J=5.4 Hz, 7.2 Hz, 1H), 6.41 (t, J=7.0 Hz, 1H), 5.0 (br, 1H), 2.80-3.10 (m, 3H), 1.98-2.15 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Br)C.C(OCC)C.[C:18]([NH:21][CH2:22][C:23]([CH3:25])=[O:24])(=[O:20])[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]([OH:24])([CH3:25])[CH2:22][NH:21][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(=O)CNC(C)=O
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)NCC(C)(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A solution of 1-bromo-4-iodobenzene (1.843 g, 6.51 mmol) in THF (10 ml) was immersed in a dry ice-acetone bath. Ethylmagnesiumbromid (3M) in diethylether (2.90 ml, 8.69 mmol) was added very slowly by a syringe at −41° C. to −39° C. (exothermic reaction, grey precipitation!) and the reaction was kept at −40° C. for 1 hr. A solution of 1-acetamido-acetone (0.5 g, 4.34 mmol) in THF (4 ml) was added slowly below −60° C. The reaction was allowed to warm up to room temperature. The reaction mixture was quenched with aqueous saturated NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude material which was purified by preparative. HPLC (reversed phase). Fractions containing the product were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM) to obtain title compound as a yellowish solid (13% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][CH:3]=1.Cl.C(O[CH:23](OCC)[CH2:24][CH2:25][CH2:26][NH:27][CH3:28])C>O>[CH3:28][NH:27][CH2:26][CH2:25][C:24]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:23]=1
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: O
Product: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Temperature: 70 °C

Procedure:
The title compound was prepared by General Method 3. 1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine (250 mg) was suspended in water (2 mL) and 28% aqueous HCl (0.135 mL) was added. 4,4-diethoxy-N-methylbutan-1-amine (0.18 g) was added to the resulting solution and the reaction mixture was heated to 60-80° C. and an additional 28% HCl (0.135 mL) was added and the reaction mixture was heated for additional 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 7/3/1) to obtain the product.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][C:12]#[N:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.O.O.O.O.O.O.O.[Co](Cl)Cl>[C:3]1(=[O:2])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][NH:13]1
Reactant: COC(=O)C1(CC#N)CCCCC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCC12CCCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
A 0° C. mixture of 1-cyanomethyl-cyclohexanecarboxylic acid methyl ester (4.28 g, 23.6 mmol) and cobalt (II) chloride hexahydrate (2.81 g, 11.8 mmol) in THF (80 mL) and water (40 mL) is treated portion-wise with sodium borohydride (4.47 g, 0.118 mol) and is warmed to room temperature and stirred for 48 hours under N2. The reaction is treated with 28% ammonium hydroxide (3.1 mL) and filtered through hyflo. The solvent is removed from the filtrate in vacuo and the residue is diluted with minimal water and brine and is extracted three times with 3:1 chloroform:isopropanol. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is purified with a 0 to 10% methanol in CH2Cl2 gradient on silica gel to afford 1.95 g (54%) of the titled product. Rf=0.46 (9/1 CH2Cl2/methanol). MS (m/z): 154 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH:23]5[CH2:25][CH2:24]5)[N:18]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[CH:101]1([Zn+])[CH2:103][CH2:102]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:101]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH:23]6[CH2:25][CH2:24]6)[N:18]=5)[CH:15]=4)[N:10]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[N:9]=3)[CH:5]=[N:4][CH:3]=2)[CH2:103][CH2:102]1
Reactant: [Zn+]C1CC1
Reactant: Clc1cncc(-c2nn(C3CCCCO3)c3ccc(-c4cncc(C5CC5)n4)cc23)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: c1cc2c(cc1-c1cncc(C3CC3)n1)c(-c1cncc(C3CC3)n1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
A microwave tube was charged with 3-(6-chloropyrazin-2-yl)-5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Ex. 243e, 111 mg, 0.256 mmol), Pd(OAc)2 (3 mg, 0.013 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl, (X-Phos) (12 mg, 0.026 mmol) and the tube was sealed. The tube was evacuated under vacuum and backfilled with N2 (3×). THF (1.7 mL) was added and the mixture was cooled in an ice-water bath. Cyclopropylzinc bromide solution (0.5 M in THF, 0.62 mL, 0.31 mmol, Sigma-Aldrich) was added and the mixture was warmed to RT and stirred for 2 h. The mixture was filtered and the crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 24 mg of 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The column was eluted with 2-10% MeOH in CH2Cl2 to afford 50 mg of 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The two portions were combined to give 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (74 mg, 0.17 mmol, 66% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 439.2 (M+1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:27][C@@H:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:17])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:27][C@@H:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl (2S,3S)-1-(N-(4-(tert-butyldimethylsilyloxy)phenyl)-trans-2-(pyridin-2-yl)cyclopropanecarboxamido)-3-methylpentan-2-ylcarbamate (720 mg, 1.3 mmol) and tetrahydrofuran (25 mL) was treated with tetrabutylammonium fluoride (1 M THF solution, 2.5 mL, 2.5 mmol). The reaction was maintained at room temperature for 2 h, then concentrated under reduced pressure to afford an oil that was purified by column chromatography on silica gel (eluting with 40% ethyl acetate in hexanes) to afford a mixture of diastereomers that was purified by chiral chromatography [Column: ChiralPak AD-H 4.6×250 mm, 25% solvent B (60% Ethanol in hexane) in solvent A (hexane) isocratic, retention time: 6.08 min.] to afford tert-butyl (2S,3S)-1-((1R,2R)—N-(4-hydroxyphenyl)-2-(pyridin-2-yl)cyclopropanecarboxamido)-3-methylpentan-2-ylcarbamate as an oil: 1H NMR (300 MHz, CDCl3) δ 8.96 (br. s., 1H), 8.12 (d, J=4.8 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.79-6.95 (m, 3H), 6.54 (d, J=8.4 Hz, 2H), 5.13 (d, J=9.2 Hz, 1H), 4.28 (t, J=12.8 Hz, 1H), 3.49-3.66 (m, 1H), 2.87 (dd, J=13.6, 3.7 Hz, 1H), 2.47-2.61 (m, 1H), 1.84-1.98 (m, 1H), 1.38-1.47 (m, 1H), 1.32 (s, 9H), 1.23-1.28 (m, 1H), 0.85-1.01 (m, 1H), 0.73 (d, J=6.9 Hz, 3H), 0.68 (t, J=7.4 Hz, 3H); LRMS (ESI) m/e 454.2 [(M+H)+, calcd for C26H36N3O4 454.3].