Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([NH:12][CH:13]3[C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:26]([OH:28])=[O:27])[C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[CH:30]([Al+]C(C)C)([CH3:32])[CH3:31].[CH3:37]C(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH:30]([O:28][CH:26]([CH3:21])[CH3:37])([CH3:32])[CH3:31].[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([NH:12][CH:13]3[C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:26][OH:27])[C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2NC(=O)c1ccnc2[nH]ccc12
Reactant: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: O=C(NC1c2ccccc2-c2c(CO)cccc21)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 100 ml three-necked flask under argon, reflux a suspension of 1 g of methyl ester of 9(R,S)-[(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)amino]-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 50 ml of anhydrous tetrahydrofuran, and then add, dropwise, 7.825 ml of a 20% solution of diisopropylaluminium hydride (DIBAL-H) in toluene. After stirring for 15 minutes at reflux, add a further 2.6 ml of the above solution of DIBAL-H and maintain the reflux for a further 15 minutes. After cooling to room temperature, the reaction medium is run, dropwise, into 25 ml of a saturated aqueous solution of ammonium chloride, and then extracted 3 times with 25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (97.5/2.5 by volume), and then formation of a paste with diisopropyl ether, in this way we obtain 200 mg of 9(R,S)-[(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)amino]-9H -fluorene-4-methanol, in the form of a beige solid, which is used, with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:33].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamide was hydrolyzed using 4 M HCl in dioxane (12 mL), and water (4 mL) at 100° C. to provide 4-chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide. The product was purified by HPLC. MS m/z: 465.4 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[C:8]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:7]1=[O:27])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:28])=[O:3])[C:7](=[O:27])[C:8]12[CH2:19][O:18][C:17]2[CH:20]=[C:21]3[C:25](=[CH:26][C:16]1=2)[CH2:24][CH2:23][O:22]3
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Yield: 98 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 98% yield as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.27-7.25 (m, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H); 13C NMR (75 MHz, CDCl3) 6177.8, 170.9, 162.1, 162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7, 92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4 (M−1).
Reaction SMILES: C1S[C:4]([C:6]23[C:14](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][N:8]([CH3:16])[CH:7]3CC)([O-:5])SC1.[CH2:20]([OH:22])[CH3:21]>[Ni]>[CH2:20]([O:22][C:4]([C:6]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH2:9][N:8]([CH3:16])[CH2:7]2)=[O:5])[CH3:21]
Reactant: CCO
Reactant: CCC1N(C)CC2CCCC1(C1([O-])SCCS1)C2=O
Agent: [Ni]
Product: CCOC(=O)C12CCCC(CN(C)C1)C2

Procedure:
2.42 g of ethyl(3-methyl-9-oxo-3-azabicyclo[3.3.1]non-1-yl)carboxylate ethylenedithioketal was dissolved in ethanol (200 ml). After adding 40 g of Raney nickel, the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with toluene/ethyl acetate) to thereby give 0.95 g of the title compound as a slightly yellow oily substance.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=C(C(O)=O)O[N:15]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:2]([C:1]([Cl:6])=[O:5])[O:3][N:15]=1
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Oxalyl chloride (0.07 mL, 0.74 mmol) was added dropwise to a stirred solution of 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (77 mg, 370 μmol) in THF (10 mL). The mixture was stirred at room temperature for 2 hours, then concentrated to yield the title compound (79 mg), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CC[N:26](CC)CC.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl.C(Cl)Cl.CO>[C:14]([O:13][C:11]([N:18]1[CH2:19][CH2:20][N:21]([C:3]2[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([NH2:26])=[O:7])[CH2:22][CH2:23]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c(O)cccc2C(N)=O)CC1

Procedure:
3-Hydroxybenzoic acid (0.483 g, 3.5 mmol), BOC piperazine (0.737 g, 3.96 mmol), Et3N (0.92 mL, 6.6 mmol), and CH2Cl2 (10 mL) were combined, cooled to 4° and solid Bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.889 g, 3.5 mmol) was added under Ar. The ice bath was removed and a clear solution was obtained on warming to 23°. After 1 h tlc(silica plates, 19:1 CH2Cl2 /CH3OH) indicated a completed reaction. The reaction was diluted with CH2Cl2 (100 mL), washed with 0.3 N HCl (20 mL), H2O (20 mL), satd aq NaHCO3 (20 mL) and satd aq NaCl (20 mL), dried (Na2SO4) filtered and concentrated to afford the title compound as a white foam. 1H NMR (CDCl3): d 7.20 (m, 1), 6.90 (s, 1), 6.86 (d, 1), 6.82 (d, 1) 3.69 (m, 2), 3.39 (m, 4), 1.46 (s, 9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48–2.63 (m, 2H), 2.74–3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20(d, 2H), 7.22–7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>CO>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: Nc1ccccc1F
Solvent: CO
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccccc3F)n2)cc1
Temperature: 180 °C
Yield: 77 %

Procedure:
A mixture of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine (0.37 g; 0.0013 mol; prepared as set forth in Example A-299), 7 mL of 2-fluoroaniline and 2 drops of methanol was heated at 180° C. in a sealed tube for 16 hours. Excess amine was removed by vacuum distillation and the residue was treated with ethyl acetate to give 0.35 g of N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine as a yellow solid (77%), mp: 239-240° C. Anal. Calc'd. for C19H13F2N5: C, 65.33; H, 3.75; N, 20.05. Found: C, 64.95; H, 3.80; N, 19.77.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Li].CO.C(Cl)(Cl)Cl>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:8])[C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC(c1cccnc1)c1cccs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (5.0 mL, 53 mmol) in THF at -78° C. was added 2-thienyllithium (1.0M in THF. 64 mL, 64 mmol) and the reaction mixture was stirred for 2 hours at -78° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (5%, then 10% methanol/CHCl3) gave 2-(3-pyridylhydroxymethyl)thiophene (6.30 g, 62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C([NH:47]C2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC(N)=O)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][C:31]([NH2:47])=[O:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: [N-]=[N+]=NCC(N)=O
Product: Cc1ccc(-c2cn(CC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.44 mmol) and compound 411. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 10:90 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 194.9, 167.1, 158.7 (dd), 155.7 (dd), 149.3, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0, 114.9, 112.0 (dd), 111.8, 105.0 (dd), 51.5, 19.4
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[CH:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[CH:12]=2)[O:26][CH2:25][CH2:24][O:3]1
Reactant: CC(=O)c1ccc2ccsc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc3ccsc3c2)OCCO1
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 6-acetyl benzo[b]thiophene (10.57 g, 60 mmole), p-toluenesulfonic acid (1.65 g) and ethylene glycol (33 ml) was heated to reflux in toluene (250 ml) for 2 hours with the continuous removal of H2O using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature. Then extracted with 20% saturated NaHCO3 (150 ml) and H2O (2×150 ml). After drying over Na2SO4, the solvent was evaporated in vacuo and the residue was crystallized from hexanes (50 ml) yielding 9.66 g (73%) of product.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[Si]([C:16]#[CH:17])(C)(C)C.N#N>C(Cl)Cl.CCN(CC)CC.CCCCCC.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.[Cu]I>[C:16]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2)#[CH:17]
Reactant: Cn1ccc2cc(I)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: C#Cc1ccc2c(ccn2C)c1
Temperature: 25 °C

Procedure:
5-iodo-1-methyl-1H-indole (1.5 g, 5.84 mmol) were dissolved in mixture of CH2Cl2 (10 ml) and NEt3 (5 ml) and the system was evacuated-back filled by N2 thrice. Pd(PPh3)2Cl2 (122 mg, 3% mol) and TMS-acetylene (0.858 g, 8.7 mmol) were added to it and again flushed N2 into the system. CuI (89 mg, 8% mol) was added and flushed N2 very quickly and reaction was stirred under positive pressure of N2 until reaction completed by TLC (ca. 3 hours). The reaction mixture was diluted with 10 ml of hexane and filtered through celite plug, purified by passing through small column and then suspended in MeOH (20 ml) containing 10 ml of THF. NaOH was added to reaction mixture and stirred at room temp until starting material consumed completely. The reaction mixture was concentrated to 10 ml and extracted with EtOAc from aqueous NH4Cl solution, which was purified by column chromatography; Yield (60%); 1H NMR (300 MHz, CDCl3) δ: 3.03 (s, 1H), 3.73 (s, 3H, NMe), 6.45 (d, J=3.0 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 7.33 (dd, J=9.0, 1.2 Hz, 1H), 7.80 (bs, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:37]([OH:39])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:33]6[CH2:34][CH2:35][C@H:36]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:37]6=[O:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
To a suspension of 47 (230 mg, 0.51 mmol, scheme 15) in DCM (5.1 mL) were added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (224 mg, 1.03 mmol) and acetic acid (59 μl, 1.03 mmol). After stirring for 20 min at room temperature, NaBH(OAc)3 (326 mg, 1.54 mmol) was added. The reaction mixture was stirred for 16 h, quenched by addition of 1N NaOH, and concentrated. The solid was collected by filtration and purified by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 107 (120 mg, 0.19 mmol, 37% yield). MS (m/z): 633.7 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[NH:39]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:39]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(O)C1CCNC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)C4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (2 mL), cooled to 0° C., and 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (110 mg, 0.663 mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction was stirred for 16 hours at RT, followed by 4 hours at 50° C. and 6 hours at 80° C. The reaction was cooled to RT, DBU (0.17 mL, 1.105 mmol) was added, and the reaction was stirred overnight at 40° C. The reaction was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a light-yellow powder (65 mg, 52.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.11 (d, J=6.7 Hz, 6H), 1.54-1.79 (m, 7H), 2.09-2.19 (m, 3H), 2.36 (br. s., 2H), 2.52 (br. s., 1H), 2.59 (br. s., 1H), 2.69-2.84 (m, 2H), 3.55 (br. s., 1H), 3.68 (br. s., 1H), 3.99-4.10 (m, 2H), 4.83 (br. s., 1H), 7.14-7.19 (m, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55-7.66 (m, 2H), 8.32 (dd, J=8.7, 6.0 Hz, 2H), 12.74 (br. s., 1H). MS, m/z (C32H42FN5O3): calcd, 563.3. found, 564.0 [M+H].
Reaction SMILES: C([Si](CCCC)(CCCC)O[C:7]1([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]1)CCC.C(O)(=O)C.O>C(O)C.[Zn]>[F:15][C:14]([F:16])([F:17])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CCCC[Si](CCCC)(CCCC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
A solution of 3.9 g (20 mmol) of 4-tri-n-butylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 10 mL of absolute ethanol was treated successively with 1.3 g (20 mmol) of zinc dust and 10 mL of a solution of 80% acetic acid - 20% water. The mixture was heated to reflux for one hour, allowed to cool to room temperature, and poured into 100 mL of water. The resulting aqueous mixture was extracted with three 50 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the ether layers afforded a residue which purified by short path distillation at 5.0 torr. At 60°-65° C., 0.80 g (47% yield) of 4-trifluoromethylphenol was collected.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:22].C[OH:24].[OH-].[Na+]>O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=2[F:10])=[C:14]([CH2:13][C:12]([OH:24])=[O:22])[CH:15]=1)[CH3:21]
Reactant: CCc1ccc2c(c1)CC(=O)N2c1c(F)c(F)cc(F)c1F
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol, is slurried in water containing a little methanol (10% v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture is stirred at 80–85° for 2–4 hours, then cooled to ambient temperature. The reaction solution is partially concentrated under reduced pressure (25–30 mm). After removal of 50 ml of the solvent, the mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml). The cooled mixture is acidified to pH 6.5–7.0 with aqueous HCl (12.1 N; 19.5 ml), keeping the temperature at 0–5°. The aqueous layer is discarded and the organic layer is washed with water (250 ml). The organic layer is concentrated under reduced pressure (20–100 mm) while exchanging the solvent to toluene. After the more volatile components have been removed, the batch volume is adjusted to 400–450 ml. This mixture is warmed to 70°, clarified, concentrated to one-half volume, and cooled to 0°. After stirring at this temperature for 2 hours, the product is collected and is washed with toluene/heptane (10:90; 100 ml). The resulting solid is dried under reduced pressure at 50–60° for 4–8 hours to give 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid of Example 3.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C@@H:34]([NH2:36])[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11](=[O:13])[NH:36][C@@H:34]([CH3:35])[CH2:33][NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:37])[F:38])=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Yield: 6.4 %

Procedure:
3-Benzylsulfanyl-2-(R)-[(morpholine-4-carbonyl)-amino]-propionic acid (182 mg, 0.56 mmol, 1.2 eq.), N1-(4-Trifluoromethoxy-phenyl)-(S)-propane-1,2-diamine from Scheme 1a (110 mg, 0.47 mmol, 1.0 eq.), and HATU (185 mg, 0.56 mmol, 1.2 eq.) were dissolved in CH2Cl2 (2 mL) at room temperature. DIPEA (245 μL, 1.41 mmol, 3.0 eq.) was added via syringe and the resulting mixture was monitored by LC/MS to completion. After the reaction was complete, the solvent was evaporated and directly purified by mass-directed HPLC and provided 22 mg (0.03 mmol, 5%) of a off-white solid (mono-TFA salt): HPLC-MS calcd. for C25H31F3N4O4S (M+H+) 541.2. found 541.3.