Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[Cl:17][S:18](O)(=[O:20])=[O:19].O>S(Cl)(Cl)=O>[Cl:17][S:18]([C:15]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]2[O:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:5]=2[CH:14]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1Cc2cc(S(=O)(=O)Cl)c(Cl)c(Cl)c2O1
Yield: 101.6 %

Procedure:
To a solution (2.5 ml) of 1 g (3.83 mmol) of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (1) in 2.5 ml of thionyl chloride is dropwise added 1.25 g of chlorosulfonic acid under ice-cooling and the mixture allowed to react at room temperature for 2 hours. The reaction mixture is poured into iced water and extracted with 60 ml of ethyl acetate. The organic layer is dried and evaporated to give about 1.4 g of ethyl 5-chlorosulfonyl-6,7-dichloro-2,3-dihydrobenzofuran-carboxylate (2) as an oil.
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH2:2][C:1]([OH:4])=[O:3])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 4 h

Procedure:
t-Butyl acetate (159 mL, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at -78° C. followed by 4-bromobenzylbromide (200 g, 784 mmol). The bath temperature was kept at -15° C. for 4 hours whereupon the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water, and brine, drying with sodium sulfate to yield a pale oil. This was refluxed with trifluoroacetic acid (150 mL, 1960 mmol) for 1 hour. The trifluoroacetic acid was removed under vacuum and the residue was partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid at 0° C. and extracted with diethyl ether. This organic layer was washed with water and brine and was dried over sodium sulfate to obtain a white solid after removing solvent under vacuum, (167 g, 93%), 132-134° C. m.p.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].O1CCOCC1.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C([O-])([O-])=O.[K+].[K+]>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.O>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Yield: 21 %

Procedure:
To the solution of ethyl 5-(2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane (Preparation 4, 675 mg, 1.27 mmol) was added water (2.2 mL), 2-bromopyridine (302 mg, 1.91 mmol) and K2CO3 (352 mg, 2.546 mmol). The reaction was degassed for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) and heating at reflux for 2 hours. The reaction was cooled and concentrated in vacuo. The residue was purified using silica gel chromatography eluting with 20-50% EtOAc in heptanes to afford the title compound (128 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(CO)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine (Preparation is described in step 1 of Example 95).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CN(CCN1CCOCC1)C(=O)C1C=CC=[C:50]([C:51]([NH:53][C:54]2C=CC(N3CCCCC3)=C[C:55]=2[C:66]2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=[CH:68][N:67]=2)=[O:52])C=1.CC#N.N1CC[C@@H](NC(=O)C)C1>CN(C=O)C>[C:51]([NH:53][C@H:54]1[CH2:55][CH2:66][N:67]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:68]1)(=[O:52])[CH3:50]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)-pyridin-2-yl)phenyl)isophthalamide 4.8, except that CH3CN was substituted for DMF as the reaction solvent and (R)—N-(pyrrolidin-3-yl)acetamide was used as the amine component. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.99 (d, J=6.0 Hz, 1H), 8.70 (d, J=9.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J=6.0 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.88˜7.78 (m, 2H), 7.72˜7.54 (m, 6H), 4.72 (s, 1H), 4.51˜4.28 (m, 1H), 3.91˜3.52 (m, 8H), 2.30˜4.79 (m, 11H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1CCCC1=O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 39.5 %

Procedure:
Under a nitrogen atmnosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride (972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC indicated that the reaction was complete, the reaction solution was poured into distilled water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. A solid was isolated by filtration, rinsed with water and then dried in a vacuum oven. This material was stirred with chloroform (500 mL) and then filtered. The filtrate was loaded onto a silica gel column. The column was eluted with 1-5% methanol in chloroform. The purified material was dried in a vacuum oven to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a solid, m.p. 189.4-190.0° C. Analysis: Calculated for C24H27N5O.0.82 H2O: % C, 69.25; % H, 6.93; % N, 16.82. Found: % C, 69.50; % H, 7.15; % N, 17.02.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:37][CH3:38])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccccc3)n2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2ccc(C#N)cc2)nc1[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
The compound of Example 182 Part A (60 mg, 0.15 mmol) was dissolved in DMF (2.5 mL) and potassium carbonate (32 mg, 0.23 mmol) was added followed by ethyl iodide (0.015 mL, 0.19 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined extracts were washed with water and brine, then dried over Na2SO4, filtered and evaporated. The residue was chromatographed on silica gel to provide the product (48 mg, 76%). 1H NMR (400 MHz, DMSO-D6) δ 1.17 (t, J=7.25 Hz, 3H) 3.34-3.48 (m, 2H) 3.89-4.05 (m, 2H) 5.46 (d, J=7.03 Hz, 1H) 7.14 (d, J=7.03 Hz, 1H) 7.21 (t, J=7.47 Hz, 2H) 7.31 (d, J=7.47 Hz, 2H) 7.41 (t, J=7.25 Hz, 2H) 7.48 (d, J=7.03 Hz, 1H) 7.76-7.84 (m, 3H) 7.88 (s, 1H) 7.94 (d, J=8.79 Hz, 2H) 9.08 (d, J=8.35 Hz, 1H). m/z 421.2 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenylboronic acid (0.618 g, 5.065 mmol) is stirred in a mixture of DME (20 ml) and 2M Na2CO3 for 20 minutes. 3,5-dibromopyridine (1.0 g, 4.221 mmol) is added followed by PdCl2(Ph3P)2 (0.296 g, 0.4221 mmol) and the mixture is heated to 100° C. overnight. The DME layer is removed and is diluted with EtOAc, washing with 5M HCl (2×20 ml) then back extracted with EtOAc (70 ml). The acidic aqueous phase is basified with 6M NaOH (50 ml) and extracted with DCM (3×100 ml). The combined organic extracts are dried over MgSO4, filtered and evaporated to an oil which is stirred in iso-hexanes (15 ml) and the resulting solid is removed washing with a further 10 ml of iso-hexanes. Concentration of the organics in vacuo affords the title compound as a white solid MH+[235.74].
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=O)[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][C@H:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:15]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([CH:5]=3)=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=[CH:9][CH:10]=4)=[O:17])=[CH:33][CH:32]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOc1cccc2c1cc(C(=O)O)n2CC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2)C1
Product: CCOc1cccc2c1cc(C(=O)Nc1ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc1)n2CC

Procedure:
The above nitro compound was hydrogenated under conditions as described in previous intermediate to provide (S)-3-(4-amino-phenyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. The amide formation of N-ethyl-4-ethoxy-indole-2-carboxylic acid with (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester under the same conditions as described in earlier intermediates preparation provided (S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS for C28H35N3O5 calcd. (m/e) 493, observed 494 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6].C[C@@H]1NCCOC1.[OH:38][C:39]([CH3:44])([CH3:43])[C:40](O)=[O:41]>>[OH:38][C:39]([CH3:44])([CH3:43])[C:40]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6])=[CH:13][CH:12]=3)[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]=2[CH2:23]1)=[O:41]
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CNCC2
Agent: C[C@H]1COCCN1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CN(C(=O)C(C)(C)O)CC2

Procedure:
Compound hr was prepared generally following the procedures described in Examples 1, 27 and 30 and 147 except that (S)-1-(2-hydroxyethyl)-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea was used instead of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and 3S-3-methylmorpholine was used instead of morpholine in step 1 of Example 1. Additionally, 2-hydroxyisobutyric acid was used instead of oxazole-5-carboxylic acid in Example 147: LC/MS-m/z+499 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][O:16][C:17]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:49]([CH2:51][CH2:52][O:53][P:54](Cl)[N:55]([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])#[N:50].CN1C=CN=C1>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:13]([O:14][P:54]([O:53][CH2:52][CH2:51][C:49]#[N:50])[N:55]([CH:56]([CH3:57])[CH3:58])[CH:59]([CH3:60])[CH3:61])[C@@H:12]([CH2:15][O:16][C:17]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Agent: Cn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
To a cooled solution (0° C.) of 1,4-anhydro-2-O-benzyl-5-O-[bis(4-methoxyphenyl)(phenyl)methyl]D-ribitol (1.60 g, 3.04 mmol) and N,N-diisopropylethylamine (1.59 mL, 9.11 mmol) in DCM (20 mL), 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (1.44 g, 6.08 mmol) and 1-methylimidazole (0.12 mL, 1.519 mmol) were added. The reaction mixture was warmed to ambient temperature and stirred for 90 min. The reaction was then quenched with methanol (5 mL) and stirred for 5 min. The solvent was then removed in vacuo, and the residue was purified by flash chromatography using 20% ethyl acetate in hexane to obtain 0.94 g (1.293 mmol, 42.6%) of the pure product. LCMS: for C42H51N2O7P calculated 726.3. found 727.3 [M+H]+ and 749.4 [M+Na]+. 31P NMR (400 MHz, CD3CN) δ: 149.94, 149.70.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=1)[CH:36]=[O:37].O>CN(C)C=O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=2)[CH:36]=[O:37])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (500 mg, 1.44 mmol) in N,N-dimethylformamide (7.2 mL), potassium carbonate (300 mg, 2.17 mmol) was added. Under ice-cold conditions, the resultant mixture was added with 5-fluoro-2-nitrobenzaldehyde (220 mg, 1.30 mmol) and stirred at 60° C. for 1 hour. The reaction solution was cooled down to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzaldehyde (576 mg, yield 89%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2(C)C)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Temperature: 95 °C
Yield: 55.5 %

Procedure:
In a 10 mL sealed cap glass vial, 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (50 mg, 0.125 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (53.2 mg, 0.250 mmol) were dissolved in ACN (2 mL). N-ethyldiisopropylamine (0.033 mL, 0.188 mmol) was added, the cap was sealed, and the reaction mixture heated at 95° C. for 72 h. The reaction mixture was subsequently purified by preparative HPLC and basified to give the title compound as a light yellow solid (40 mg, 55%). [M+H] calc'd for C29H38ClFN4O5, 578.1. found, 577.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([O:30][CH3:31])=[N:23][C:24]([CH3:29])=[N:25][C:26]=1[O:27][CH3:28])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[N:23][C:22]=1[O:30][CH3:31]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1nc(C)nc(OC)c1N=C=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(OC)nc(C)nc2OC)c1NCCCO
Temperature: 70 °C
Reaction time: 72 h
Yield: 12 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.00 g, 7.73 mmol) and 5-isothiocyanato-4,6-dimethoxy-2-methylpyrimidine (4.89 g, 23.2 mmol) in tetrahydrofuran (25 mL) was stirred at 70° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 40-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(4,6-dimethoxy-2-methylpyrimidin-5-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (435 mg).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([CH3:20])[S:22][C:23]=4[CH:29]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc2ccc(C=O)cc2s1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 397.76 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](I)[CH3:35]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH2:34][CH3:35])[C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)N1CCc2nc(-c3ccncn3)cc(=O)n2CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(CC)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 1.8 %

Procedure:
To a solution of 10.00 g (41.27 mmol) of 4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in dry tetrahydrofuran (8 mL) under argon at −78° C. was added 2.00 mL (2.00 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 10 min and 1.28 mL of ethyl iodide (15.86 mmol) was added. The reaction was stirred at −78° C. for 1 h and then at 0° C. for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1% of methanol) to afford 0.100 g of a white solid (18%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.S(C1C=CC(C)=CC=1)(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:19][C:18]([F:21])([F:20])[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2cc(OCC(F)(F)F)ccc21
Temperature: 100 °C
Yield: 85.3 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (200 mg, 1.2 mmol) and 2,2,2-trifluoroethyl tosylate (345 mg, 1.4 mmol) in DMF (10 mL) was added potassium carbonate (339 mg, 2.5 mmol) at rt. The solution was heated at 100° C. overnight. The reaction was cooled, diluted with water (20 mL), and extracted with EtOAc (20 mL×3). Organics were dried (Na2SO4) and concentrated to give 250 mg (83%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 2.12-2.16 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.95 (2H, t, J=6.3 Hz), 4.34-4.46 (2H, m), 6.78 (1H, d, J=2.4 Hz), 6.87 (1H, dd, J=2.4, 8.7 Hz), 8.05 (1H, dd, J=8.7 Hz).