Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([NH2:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CCOC(C)=O.C1COCC1>[CH2:41]([NH:48][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:19])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: CCCCCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114 B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and heptylamine (50 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (25 mg, 0.052 mmol, 20% yield). 1H NMR (MeOH-d4, 300 MHz) δ ppm 0.87-0.95 (m, 3H), 1.34 (s, 12H), 1.37-1.43 (m, 7H), 1.43-1.51 (m, 6H), 1.58-1.71 (m, 2H), 2.13-2.27 (m, 1H), 2.18 (s, 1H), 3.32-3.37 (m, 2H), 3.40 (t, J=7.1 Hz, 2H), 3.87-3.97 (m, 2H), 4.19 (d, J=7.1 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.75 (dd, J=8.6, 1.9 Hz, 1H), 8.16 (s, 1H), 8.77 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 481 (M+H)+; Anal. Calculated for C30H44N2O3.0.2H2O: C, 74.40; H, 9.24; N, 5.78. Found: C, 74.43; H, 9.00; N, 5.81.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[CH:22]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:22]1([CH2:27][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)CC3CCCC3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cyclopentaneacetyl chloride (1.6 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours, poured into ice water and excess hydrochloric acid and extracted into ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is evaporated and the residue chromatographed on silica gel (130 g. 70-230 mesh) to give 2-sulfamoyl-5-benzothiazolyl cyclopentaneacetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CS(C)=O>C(Cl)(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1)[CH3:24]
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Reactant: CCNCC
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCOc1cccc2c1[n+]([O-])c1cccc(O)c1[n+]2[O-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide and 25ml of diethylamine were placed in a flask. To this was added 50ml of dimethylsulfoxide. The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was then diluted with 400ml CHCl3 and washed first with very dilute acetic acid and then with water until the water washes were neutral. The CHCl3 layer was extracted with 10 percent aqueous HCl. The combined HCl extracts were neutralized with sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was slurried with ether/pentane (1:1) and filtered to yield red crystals of 6-(3-diethylaminopropoxy)-1-phenazinol 5,10-dioxide, m.p. 78°-80° (dec.).
Reaction SMILES: C(O)(=O)CC.[NH4+:6].[OH-].[CH3:8][C:9]1[C:14](NC(=O)CC)=[C:13]([CH3:20])[N:12]=[C:11]([NH:21][C:22](=O)[CH2:23][CH3:24])[CH:10]=1>>[CH3:20][C:13]1[N:12]=[C:11]2[N:21]=[C:22]([CH2:23][CH3:24])[NH:6][C:10]2=[C:9]([CH3:8])[CH:14]=1
Reactant: CCC(=O)Nc1cc(C)c(NC(=O)CC)c(C)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCC(=O)O
Product: CCc1nc2nc(C)cc(C)c2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 8.44 g of a 55:45 mixture of 2-amino-3-nitro-4,6-dimethylpyridine and 2-amino-5-nitro-4,6-dimethylpyridine in MeOH (1.2 L) was added 10% Pd/C (2.4 g). The reaction vessel was evacuated then purged with H2 at 1 atm. and stirred vigorously for 18 h. Filtration through a celite pad, and concentration gave 6.65 g of a mixture of 2,3-diamino-4,6-dimethylpyridine and 2,5-diamino-4,6-dimethylpyridine as a dark solid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (8.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). This stirred mixture was heated to 90° C. for 3 h then to 100° C. for 1 hour. The inside walls of the flask were scraped with a spatula to assist dissolution of the solids. After the reaction was complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with NH4OH. The mixture was extracted (4×50 mL CH2Cl2), dried (K2CO3) and concentrated to give a mixture of the title compound and 4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO2, 5% MeOH/EtOAc) gave 1.66 g of the title compound as the slower eluting component.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].O>CO>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:13][CH3:12])[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(F)(F)F)ccn1
Yield: 85.1 %

Procedure:
A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 ml of methanol was stirred under reflux with heating for 4 hours. Water was added to terminate the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield: 85%) of 4-trifluoromethyl-2-methoxypyridine.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: OCC12COP(OC1)OC2
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCC12COP(OC1)OC2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 30.2 g (0.1 mol) of stearic acid chloride, followed by 10.1 g (0.1 mol) of triethylamine, are added dropwise at room temperature. After the slight evolution of heat has died away, the mixture is stirred for 10 hours under nitrogen at room temperature and the precipitated triethylamine hydrochloride is then filtered off. The filtrate is evaporated with exclusion of moisture, a yellowish oil remaining, which crystallises on being triturated with methanol. After filtering off under suction and drying, stearic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl-methyl ester (Stabiliser No. 9), melting point 49°C, is obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].CI.[CH2:17](Cl)Cl>CN(C=O)C>[CH3:17][O:3][C:4]1[CH:5]=[C:6]([C:11]([NH2:14])=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1N
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of NaH (washed three times with dry THF to remove oil, 0.145 g, 1.1 eq) in dry DMF (5 mL, CaH2 dried), 420 mg of methyl 3-hydroxy- 6-aminobenzoate (E) was added in 3 mL of DMF immediately followed by MeI (443 mg [0.195 m], 1.2 eq), and stirred at room temperature under argon for 16 hr, at which time TLC indicated the absence of E. 200 mL of CH2Cl2 was added and the mixture was extracted with brine (5×100 ml); the organic solvent was evaporated; the crude product was added to 200 mg of NaOH in 5 mL of water; and the reaction mixture was heated at 70° C. for 2 hr. The reaction mixture was neutralized to pH 7.0 with dilute HCl and extracted with CH2Cl2 (5×25 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to yield crude product, which was applied to silica gel (230-400 mesh and eluted with EtOAc/MeOH, 50:1) to yield product 39, 206 mg (yield 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](OC1C=CC=CC=1)=[N:7][CH:6]=[CH:5]2.C([O-])(=O)C.[NH4+:23].[OH-].[Na+]>>[NH2:23][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: Brc1ccc2c(Oc3ccccc3)nccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Nc1nccc2cc(Br)ccc12
Temperature: 150 °C
Yield: 71.8 %

Procedure:
A mixture of 12 g of 1c and 27 g of ammonium acetate was heated at 150° C. for 14 hours. After cooling to room temperature aqueous 3N NaOH was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine and aqueous 2N hydrochloric acid was added until pH2-3. The acid aqueous layer was separated, made basic (pH10) with aqueous 2N NaOH and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated to give 6.4 g of 1d. 1H-NMR 200 MHz (CDCl3) δ: 5.1 (2H, br s), 6.96 (1H, dd, J=6 Hz and J=1 Hz), 7.54-7.70 (2H, m), 7.88 (1H, d, J=2 Hz), 7.98 (1H, d, J=6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[C:18]1([S:24]([N:27]2[C:35]3[CH:34]=[C:33]([Sn](C)(C)C)[CH:32]=[C:31]([NH2:40])[C:30]=3[CH:29]=[N:28]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:40][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=2)[CH:34]=[C:35]2[C:30]=1[CH:29]=[N:28][N:27]2[S:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Solvent: CN(C)C=O
Product: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
In a separate microwave vial, 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (50 mg), N-(5-bromo-3-pyridinyl)benzenesulfonamide (39.5 mg) and chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (6.4 mg) were dissolved in DMF (1 ml) and the reaction was heated under microwave irradiation for 15 min at 120° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C(N(C(C)C)CC)(C)C>ClCCl>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: Nc1nccs1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
Cyclohexanecarbonyl chloride (4.38 g, 30 mmol) was added dropwise to a solution of 2-aminothiazole (3.00 g, 30 mmol) and di-isopropylethylamine (3.87 g, 30 mmol) in dichloromethane (50 ml) at 0° C. The mixture was warmed to room temperature, stirred for 18 h, washed with 1 N--HCl (2×50 ml) and 1 N--NaOH (2×50 ml), dried (MgSO4), and evaporated in vacuo to give the product (4.59 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1([C:30]([NH2:32])=[O:31])[CH2:5][N:4]([C:6]2[N:11]3[N:12]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:10]3[N:9]=[C:8]([CH3:29])[N:7]=2)[CH2:3]1.CO[C:35](OC)([CH3:37])[CH3:36]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:13]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:10]2[N:9]=[C:8]([CH3:29])[N:7]=[C:6]([N:4]3[CH2:3][C:2]4([C:30](=[O:31])[NH:32][C:35]([CH3:37])([CH3:36])[NH:1]4)[CH2:5]3)[N:11]2[N:12]=1
Reactant: Cc1nc(N2CC(N)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: COC(C)(C)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nc(N2CC3(C2)NC(C)(C)NC3=O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1

Procedure:
To a mixture of 3-amino-1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-azetidine-3-carboxylic acid amide (3A-6; 27 mg, 0.057 mmol) and 2,2-dimethoxypropane (0.75 ml, 6.1 mmol) in toluene (1.3 ml) was added acetic acid (5 drops). After stirring at reflux for 18 hours, the reaction was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12S column using 0-5% methanol in methylene chloride as eluant to afford after drying, in vacuo, 4A-1 (16 mg, 55%) as an off-white solid: +ESI MS (M+1) 508.1; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.56-7.42 (m, 4H), 7.34-7.30 (m, 4H), 4.92 (d, J=10.4 Hz, 1H), 4.73 (d, J=10.4 Hz, 1H), 4.43 (d, J=10.4 Hz, 1H), 4.19 (d, J=10.4 Hz, 1H), 2.40 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][C@H:24]([CH3:37])[C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.9 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (525 mg, 2.6 mmol), (2S,3R)-3-benzyloxy-2-tertbutoxycarbonylaminobutyric acid (880 mg, 2.9 mmol), HOAt (390 mg, 2.9 mmol), 4-methylmorpholine (0.60 mL, 5.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (560 mg, 2.9 mmol) in DCM (13 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(1S,2R)-2-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)propyl]carbamic acid tert-butyl ester (1.32 g). LCMS (Method B): RT 4.32 min [M+H]+ 494.3.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:36][CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([C:24]2[NH:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([C:16]4[C:12]([C:9]5[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:47])[CH3:1])=[CH:11][CH:10]=5)=[N:13][N:14]([CH2:36][CH2:37][NH:38][CH3:39])[CH:15]=4)=[C:18]3[CH:25]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:35]
Reactant: CN(C)Cc1cccc(-c2cc3c(-c4cn(CCN(C)C(=O)OC(C)(C)C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
To 1,1-dimethylethyl {2-[3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate (1.05 g, 1.65 mmol) was added 25% TFA in CH2Cl2 (25 mL).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: OCc1ccncc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cnccc1CCl
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95.1 %

Procedure:
To a mixture of 1.12 g of (3-fluoropyridin-4-yl)methanol and 5 ml of chloroform was added dropwise 1.26 g of thionyl chloride at room temperature, and the mixture was stirred at room temperature for 1.3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 1.22 g of 4-chloromethyl-3-fluoropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH2:43])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH:43][C:14](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (0.374 g, 1.617 mmol), 1-hydroxybenzotriazole hydrate (0.248 g, 1.617 mmol), and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 (0.318 g, 1.470 mmol) were combined in dichloromethane (3.0 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.286 mL, 1.617 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with of dichloromethane (2×2 mL), and the extracts were applied directly to a 25 g silica gel cartridge and purified with a gradient of 5-40% acetone/hexanes over 30 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61-8.64 (m, 1H), 7.96-7.99 (m, 1H), 7.42-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28 (d, J=7.3 Hz, 1H), 4.65-4.73 (m, 1H), 4.37-4.45 (m, 1H), 3.59 (d, J=13.1 Hz, 1H), 3.43 (d, J=13.1 Hz, 1H), 2.81-2.84 (m, 1H), 2.55-2.58 (m, 1H), 2.44-2.54 (m, 2H), 2.24-2.36 (m, 2H), 2.02-2.13 (m, 1H), 1.78-1.94 (m, 4H), 1.53-1.66 (m, 1H), 1.50 (s, 9H), 1.26-1.43 (m, 1H), 0.87 (d, J=5.5 Hz, 3H), 0.83-0.85 (m, 3H); MS (ES+) m/z 430 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O.C(Cl)(Cl)Cl>CO.[Pt]=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:14][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=[Pt]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
In 60 ml of methanol were dissolved 3.70 g of 2-aminodiphenyl ether and 3.70 g of 2,4-dimethoxybenzaldehyde, and then 70 mg of platinum oxide was added, followed by stirring at room temperature under a hydrogen stream overnight. To the reaction mixture was added 30 ml of chloroform for dissolving the precipitate, and the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 5.06 g of N-(2,4-dimethoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>C(OCC)(=O)C>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[C:8]=1[C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cccc1I

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-fluoro-6-iodobenzoic acid (1.03 g) in methanol (35 ml). After stirring at reflux for 5 days, with two further amounts of conc. sulphuric acid (1 ml) being added after 1 and 2 days, the solution was allowed to cool. The reaction mixture was diluted with ethyl acetate (200 ml) before being washed with water (2×80 ml), 8% aqueous sodium bicarbonate (2×100 ml), dried and concentrated in vacuo. Purification by chromatography eluting with System A (1:3) afforded the title compound (0.72 g) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)COc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 4-bromo-2-isobutoxybenzoic acid (14.0 g) in N,N-dimethylformamide (70 ml) were added dipotassium carbonate (14.2 g) and iodomethane (4.79 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate-hexane (1/1, 600 ml) and washed with water (500 ml). The water layer was extracted with ethyl acetate-hexane (1/1, 200 ml) and the extract was washed with water (200 ml). The combined organic layer was washed with brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave methyl 4-bromo-2-isobutoxybenzoate (12.0 g) as a pale yellow oil.