Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>ClCCl>[N:27]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:11][CH:12]([NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:24])[CH2:13]2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 1.5 ml of dichloromethane, and 82 mg (0.55 mmol) of morpholine-4-carbonyl chloride and 58 μl (0.412 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 118 mg (90% of theory)
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CC1(C)CCCN1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CCCC1(C)C

Procedure:
By using 2,2-dimethylpyrrolidine (1.0 g) as a starting material, the title compound (1.25 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [C:1]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[N:19](CN(C)C)[CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[C:49]2=[CH:50][N:51]=[CH:52][C:53]([C:54]3[CH:59]=[C:58]([C:60](OC)=[O:61])[CH:57]=[CH:56][C:55]=3[C:64]#[N:65])=[C:48]2[CH:47]=[CH:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:38]([O:42][C:43]([N:45]1[C:49]2=[CH:50][N:51]=[CH:52][C:53]([C:54]3[CH:59]=[C:58]([C:60]([C:20]4[NH:19][C:17]5=[N:18][C:13]([N:10]6[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([C:26]7[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=7)[C:32]7[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=7)[CH2:8][CH2:9]6)=[CH:14][CH:15]=[C:16]5[N:21]=4)=[O:61])[CH:57]=[CH:56][C:55]=3[C:64]#[N:65])=[C:48]2[CH:47]=[CH:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(O[Si](c7ccccc7)(c7ccccc7)C(C)(C)C)CC6)nc5[nH]4)ccc3C#N)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of {5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-imidazo[4,5-b]pyridin-3-ylmethyl}-dimethyl-amine (574 mg, 1.12 mmol) and 4-(2-cyano-5-methoxycarbonyl-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (474 mg, 1.26 mmol, 1.1 eq) (Step 1 example 140) in THF (0.1M), cooled to −78° C., was slowly added 1M LDA (2 mol eq). After 1 hr, the reaction mixture was quenched with 50% acetic acid in water (0.25 vols.) at −78° C. The mixture was allowed to warm to room temperature and concentrated to remove most THF. The residue was diluted with EtOAc (20 mL) and basified with aqueous ammonium hydroxide (30%) until pH>8. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was then purified by trituration from Acetonitrile affording 4-(5-{5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine-2-carbonyl}-2-cyano-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester as a red solid (900 mg, 1.01 mmol, 90%). MS ESI m/z 802.7 (M+H)+.
Reaction SMILES: C([O:4][CH:5]1[C@@:17]2([CH2:18][CH2:19][CH3:20])[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]2)[C:11]2[C:6]1=[CH:7][C:8]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:9]([Cl:23])[C:10]=2[Cl:22])(=O)C.CO.[OH-].[Na+].Cl>O>[Cl:22][C:10]1[C:9]([Cl:23])=[C:8]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:7]=[C:6]2[C:11]=1[C:12]1[C@:17]([CH2:18][CH2:19][CH3:20])([CH:5]2[OH:4])[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=1
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl [(9-acetoxy-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate (4.27 g, 0.0094 mol), methanol (75 ml) and 1N sodium hydroxide (21 ml) was stirred at 25° C. for 4 hours, diluted with water (250 ml), acidified with HCl and extracted with ether and methylene chloride. The combined organic extracts were combined, washed with H2O, dried over MgSO4 and evaporated in vacuo to give [(5,6-dichloro-9-hydroxy-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid which melted at 206°-208° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH3:7]>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccco1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1CCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.4 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-furan-2-yl-ethyl)-amide (370 mg, 0.66 mmol) was dissolved in methanol (6 ml) and ethyl acetate (2 ml). The flask was flushed with argon then 20% palladium hydroxide on carbon (50% water, 100 mg, 0.71 mmol) was added. The reaction mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 48 h then filtered over Celite and rinsed with dichloromethane/ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 300 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(tetrahydro-furan-2-yl)-ethyl]-amide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(O[C:13]1(O[Si](C)(C)C)[CH2:15][CH2:14]1)C.[BH4-].[Na+]>CC(O)=O.CO.C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]2[CH2:15][CH2:14]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1cc(Br)ccc1NC1CC1
Temperature: 68 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloroaniline (C.A.S. 38762-41-3), (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) was added [(1-ethoxycyclopropyl)oxy]-trimethylsilane (1.199 ml, 5.57 mmol) dropwise at r.t. The reaction mixture was then refluxed at 67-69° C. for 3 h. under a N2 atmosphere. The mixture was then concentrated in vacuo to obtain a crude oil. Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer and a thermometer were added NaBH4 (0.366 g, 9.687 mmol) and anhydrous THF (10 mL). After cooling to 5° C., BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise and the mixture stirred under a N2 atmosphere at 5° C. for 1 h. The crude oil dissolved in THF (5 mL), was added dropwise at 5-10° C. over 20 min. After stirring at r.t. for 5 h, at reflux for 2 h. and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The Et2O layer was washed with water and dried (Na2SO4) followed by the removal of Et2O in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/AcOEt 99:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D34 (0.390 g, 32.6%).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(OC(=O)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1.O1CCCC1.[OH-].[Li+]>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1
Reactant: COC(=O)c1ccc2c(=O)[nH]ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH]ccc2c1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a mixture of methyl 1-oxo-1,2-dihydroisoquinoline-6-carboxylate (25 g, 0.133 mol), tetrahydrofuran (200 mL) and water (200 mL) was added lithium hydroxide (16.8 g, 0.40 mol) at room temperature, and the mixture was stirred for four hours. Thin layer chromatography (petroleum ether/ethyl acetate=1:1) indicated the reaction was complete. The reaction mixture was extracted with ethyl acetate (100 mL×3) to remove impurities. The aqueous layer was acidified with 4 N aqueous HCl to pH 5 and filtered. The solid was dried in vacuum to give 1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (11.3 g, 48%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 8.24 (d, 2H), 7.93 (d, 1H), 7.22 (d, 1H), 6.68 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.Br[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:36][CH2:35]3)=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)cc23)cc1Cl
Temperature: 60 °C
Yield: 10.9 %

Procedure:
N-(2-chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl)-N′-methylurea (125 mg) was added to dimethylformamide (1.5 ml), and then tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (141 mg) and potassium carbonate (93 mg) were added thereto and the mixture was heated at 60° C. for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain tert-butyl 4-(((4-(3-chloro-4-((methylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (21 mg) as light yellow crystals. These were dissolved in trifluoroacetic acid (1.0 ml), and the solution was stirred for 10 minutes at room temperature. Water (2 ml) was added, the mixture was neutralized with sodium bicarbonate, and the precipitated crystals were filtered out to obtain the title compound (16 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:37][N:38]([CH3:75])[C:39]1[CH:44]=[CH:43][C:42](/[N:45]=[N:46]/[C:47]2[CH:52]=[CH:51][C:50](/[N:53]=[N:54]/[C:55]3[C:66]4[C:67]5[C:58]([NH:59][CH:60]([C:68]6[CH:73]=[CH:72][C:71](O)=[CH:70][CH:69]=6)[NH:61][C:62]=5[CH:63]=[CH:64][CH:65]=4)=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[CH:41][CH:40]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:71]2[CH:70]=[CH:69][C:68]([CH:60]3[NH:59][C:58]4[C:67]5[C:66]([C:55](/[N:54]=[N:53]/[C:50]6[CH:51]=[CH:52][C:47](/[N:46]=[N:45]/[C:42]7[CH:41]=[CH:40][C:39]([N:38]([CH3:75])[CH3:37])=[CH:44][CH:43]=7)=[CH:48][CH:49]=6)=[CH:56][CH:57]=4)=[CH:65][CH:64]=[CH:63][C:62]=5[NH:61]3)=[CH:73][CH:72]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CN(C)c1ccc(/N=N/c2ccc(/N=N/c3ccc4c5c(cccc35)NC(c3ccc(O)cc3)N4)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C3Nc4cccc5c(/N=N/c6ccc(/N=N/c7ccc(N(C)C)cc7)cc6)ccc(c45)N3)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To an ice cooled solution of 1.47 g of 4-{[6-(acryloyloxy)hexyl]oxy}benzoic acid (5.00 mM) and 0.24 g of DMAP (2.00 mM) in 20 ml of dichloromethane, was added a solution of 1.03 g of DCC (5.00 mM) in 10 ml of dichloromethane dropwise. After complete addition (within 15 min) stirring was continued at 0° C. for further 90 min., then 2.57 g of 4-{6-[(E)-(4-{(E)-[4-(dimethylamino)phenyl]diazenyl}phenyl)-diazenyl]-2,3-dihydro-1H-perimidin-2-yl}-phenol (5.00 mM) were added to the reaction mixture which is further stirred for 3 h at room temperature. The obtained dark-brown mixture was filtered through a pad of 20 g of celite filter aid, the cake was washed with 60 ml of dichloromethane and the filtrate was concentrated to approximately ⅓, followed by precipitation with cyclohexane/hexane 50 ml/50 ml. The obtained brown precipitate was filtered off, washed with 10 ml of hexane and dried to give 3.80 g (4.80 mM, 96%) of 4-{6-[(E)-(4-{(E)-[4-(dimethylamino)phenyl]diazenyl}phenyl)diazenyl]-2,3-dihydro-1H-perimidin-2-yl}phenyl 4-{[6-(acryloyloxy)hexyl]oxy}benzoate dark-brown powder; λmax=547 nm, ε=53000 (THF). For total purification, the dye might be flash chromatographed on silica gel.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[C:8](Cl)[CH:7]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.[NH4+].[OH-].[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[C:8]([C:24]#[N:25])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)OCc1cc(Cl)nc(N(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(C#N)nc(N(C)C)c1
Temperature: 80 °C
Reaction time: 11 h

Procedure:
To a solution of 1.17 g (5.10 mmol) of (2-chloro-6-(dimethylamino)pyridin-4-yl)methyl acetate in 10 mL of DMF (degassed) was added 488 mg (4.16 mmol) of Zn(CN)2 and 519 mg (0.449 mmol) of Pd(PPh3)4. The mixture was stirred at 80° C. and more Pd(PPh3)4 was added in the following quantities at various intervals in a period of 10 h: 486 mg (50 min.), 708 mg (3 h), 657 mg (6 h). The temperature was increased to 100° C. and stirring was continued for about 11 h. Ethyl acetate and 50 mL of 10% NH4OH solution were added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine. The aqueous layer (brine) was extracted with EtOAc, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 284 mg of (2-cyano-6-(dimethylamino)pyridin-4-yl)methyl acetate as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+]>O1CCOCC1.[Zn]>[CH3:30][O:29][C:28]1[CH:2]=[CH:3][C:4]2[N:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[C:5]=2[CH:27]=1
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1COCCO1
Product: COc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2c1
Temperature: 80 °C
Yield: 55.1 %

Procedure:
To a mixture of (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.2 mmol) from Step 1 of Example 51 in 1,4-dioxane (1.4 mL) and aq 1 N NaOH (300 mL) was added zinc powder (134 mg, 2 mmol). The mixture was heated at 80° C. for 55 h. The mixture was cooled to rt, filtered, and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (45 mg, 56%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.64 (d, J=1.0 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.4, 8.2 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.80 (dd, J=2.3, 8.7 Hz, 1H), 5.41 (s, 2H), 4.76 (m, 1H), 3.76 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.14-1.29 (m, 4H). LCMS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C@H:35]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][CH:46]=1)[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:57][C:55]1[CH:54]=[CH:53][C:52]([F:58])=[C:51]([C:48]2[CH:47]=[CH:46][C:45]([CH2:44][C@@H:35]([NH:34][C:7]([C:4]3[O:3][C:2](=[O:1])[NH:6][CH:5]=3)=[O:9])[CH2:36][C@:37]([CH2:42][OH:43])([CH3:41])[C:38]([OH:40])=[O:39])=[CH:50][CH:49]=2)[CH:56]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1c[nH]c(=O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.4 %

Procedure:
2-Oxo-2,3-dihydrooxazole-5-carboxylic acid (7.1 mg, 55 μmol) and HATU (21 mg, 55 μmol) were combined in DMF (0.3 mL) and stirred at room temperature for 5 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF (0.5 mL) and DIPEA (29 μL, 164 μmol) were added, and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3 mg). MS m/z [M+H]+ calc'd for C23H22ClFN2O6, 477.12. found 477.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:69]([O:72][CH3:73])[O:70][CH3:71])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[N:63]([CH3:67])[CH:64]=[CH:65][N:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:71][O:70][CH:69]([O:72][CH3:73])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[N:58]([CH3:68])[S:59]([C:62]2[N:63]([CH3:67])[CH:64]=[CH:65][N:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1
Reactant: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1)SCc1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: CCOC(C)=O
Product: COC(OC)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccn4C)c3[nH]2)S1
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of triphenylphosphine oxide (2.41 g) in dichloromethane (15 mL) was slowly added trifluoromethanesulfonic anhydride (1.46 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxamide (4.4 g) and thioanisole (1.4 mL) in dichloromethane (20 mL) was added dropwise, and the mixture was stirred under ice-cooling for 1 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-4:6) to give the title compound (1.7 g, yield: 48%) as a pale-yellow oil. MS: 450 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5](Br)=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2ccc(Cl)cc2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound IH of Example 1 utilizing 1G and 4-chlorophenyl boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.31-7.23 (m, 6H), 7.19 (s, 1H), 6.89 (t, J=10.0 Hz, 2H), 6.65 (d, J=8.9 Hz, 1H), 6.52 (t, J=8.9 Hz, 1H), 6.26 (d, J=5.9 Hz, 2H), 5.27 (dd, J=16.5, 8.2 Hz, 1H), 3.61 (s, 2H), 3.00 (dd, J=13.6, 9.3 Hz, 1H), 2.85 (dd, J=13.7, 7.5 Hz, 1H). MS (m/z) 535.4 [M+H]+.