Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][C:19]([CH2:24][N:25]5C(=O)C6C(=CC=CC=6)C5=O)([CH3:23])[C:18]=4[O:36][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(O)C.O.NN>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][C:19]([CH2:24][NH2:25])([CH3:23])[C:18]=4[O:36][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1(CN)NCCc2c1oc1cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 4 h

Procedure:
To a solution of 2-[7-(3-fluoro-phenylsulfanyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione (0.150 g, 0.317 mmol) in methanol (10.0 mL, 247 mmol) was added a solution of Oxone® (0.488 g, 0.794 mmol) in water (5.0 mL, 280 mmol) and the reaction mixture was stirred at room temperature overnight. After 3 h, the reaction was filtered, concentrated, and extracted with DCM/sat. aq. NaHCO3. The organic layer was dried, concentrated and purified by chromatography to afford 2-[7-(3-fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione as an off-white solid. A suspension of 2-[7-(3-fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione (0.015 g, 0.030 mmol) in ethanol (5.00 mL, 85.6 mmol) was refluxed with hydrazine monohydrate (0.040 mL, 0.80 mmol). After 4 h, the reaction was cooled, filtered, rinsed with MeOH, and the filtrate concentrated and dried under vacuum to afford a yellowish white solid. mp>250° C. dec.; MS m/z 375 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.5 (s, 3H), 2.7 (m, 2H), 3.15 (m, 1H), 3.36 (m, 1H), 4.0 (d, J=14 Hz, 1H), 4.15 (d, J=14 Hz, 1H), 7.2-8.0 (m, 7H)
Reaction SMILES: Cl[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:3]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:4][S:5][N:6]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1nsnc1-c1cccnc1
Solvent: CN(C)C=O
Product: c1cncc(-c2nsnc2N2CCOCC2)c1

Procedure:
A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) and morpholine (1.3 g, 15 mmol) in DMF (5 ml) was heated at 100° C. for 3 h. After evaporation water was added to the residue and extracted with ether. The combined and dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:1)). Yield: 0.68 g (91%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:22])(=[O:21])[NH:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:17]([O:16][C:14]([CH2:13][CH2:12][NH:11][S:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:23])=[O:2])(=[O:22])=[O:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1cccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 3-(2-tert-Butoxycarbonyl-ethylsulfamoyl)-benzoic acid methyl ester (step 1) (5.0 g, 14.56 mmol) and lithium iodide (2.53 g, 18.93 mmol) in pyridine (60 ml) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with DCM (60 ml) and poured into 1.5N HCl (60 ml). The aqueous phase was separated and extracted with DCM (6×60 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was purified using an Isolute® PE-AX 10 g cartridge (anion exchange column), eluting with MeOH (200 ml) and then a 1:1 mixture of MeOH/AcOH (200 ml) to afford the title compound as white crystals; 1H NMR (400 MHz, CDCl3) δ 8.63 (1H, s), 8.32 (1H, d), 8.14 (1H, d), 7.68 (1H, t), 5.63 (1H, t), 3.22 (2H, m), 2.51 (2H, t), 1.43 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:6]2[CH2:15][CH2:14][CH:13]([N:16]3C(=O)C4[C:18](=CC=CC=4)[C:17]3=O)[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=3[C:7]=2[C:27]=1[O:28][CH3:29]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[C:4]([OH:30])=[CH:5][C:6]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:27]=3)[CH3:18])[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=3[C:7]=2[C:27]=1[O:28][CH3:29]
Reactant: COc1c(OS(=O)(=O)c2ccc(C)cc2)cc2c(c1OC)C1=C(CCC1)C(N1C(=O)c3ccccc3C1=O)CC2
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(NC(C)c1ccccc1)CC2
Reaction time: 20 h

Procedure:
The product of Example 15 was dissolved in 700 ml of tetrahydrofuran and 2 g of palladium on activated charcoal were added. Hydrogenation (1.2 bar) was carried out for 20 hours and after filtering and evaporating the solvent, 6.9 g of the expected product were obtained which was identical to that of Stage A of Example 15.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:16][C:15]1=[O:26])[CH3:13].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:17]2[O:16][C:15](=[O:26])[N:14]([C@H:12]([CH3:13])[CH2:11][C:7]3[C:6]4[C:10](=[C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH2:18]2)[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](Cc1c[nH]c2c(N)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of (5R)-3-((1R)-2-(7-amino-1H-indol-3-yl)-1-methylethyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (28.4 mg, 0.0768 mmol) in tetrahydrofuran (1 mL) are added triethylamine (13.5 μL, 0.0969 mmol) and propionyl chloride (8 μL, 0.0921 mmol) under nitrogen atmosphere, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by preparative thin layer chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (34.3 mg, yield: 100%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[N:13][C:12]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[N:13][C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([F:38])=[C:32]([CH3:31])[CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(Br)c(C(=O)NCc2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(Nc3cc(C(=O)NC4CC4)ccc3C)sc2C(=O)NCc2ccccc2)ccc1F
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A microwave reaction flask was charged with 4-bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide (10 mg, 0.02 mmol, 1.0 eq), 3-methyl-4-fluorophenylboronic acid (32 mg, 0.21 mmol, 10 eq), tetrakistriphenylphosphine palladium (5 mg, 0.004 mmol, 0.2 eq), 200 μL of dioxane, and 200 μL of saturated aqueous K2CO3. The mixture was heated with stirring in the microwave at 120° C. for 10 minutes. The layers were separated and dioxane layer was concentrated and purified by preparative HPLC. Fractions containing product were concentrated to provide the title compound as a white solid (7.5 mg, 71%). HPLC (4 minutes gradient) tR 2.61 min; MS m/z 515.24 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 0.53 (m, 2H), 0.66 (m, 2H), 2.16 (s, 3H), 2.29 (s, 3H), 2.82 (m, 1H), 4.29 (d, J=4.3, 2H), 7.05 (t, J=8.9, 1H), 7.20-7.30 (m, 6H), 7.44-7.51 (m, 3H), 8.30-8.36 (m, 3H), 9.72 (s, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:13])[C:4]=1[O:14][CH3:15])#[N:2].[OH-].[K+].CO>>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:13])[C:4]=1[O:14][CH3:15])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C#N)ccc(C(=O)O)c1C
Temperature: 25 °C
Yield: 61.6 %

Procedure:
Methyl 4-cyano-2-methyl-3-(methyloxy)benzoate (150 mg, 0.73 mmol) in a solution of 35% aqueous potassium hydroxide:methanol (1:3, 4 mL) was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature, and the methanol was removed by rotary evaporation. Water (4 mL) was added to the mixture and the pH was adjusted to 2 using concentrated aqueous hydrochloric acid. The precipitate which formed was collected by filtration and was washed with water, then hexanes to afford 86 mg, 0.45 mmol (62%) of 4-cyano-2-methyl-3-(methyloxy)benzoic acid. 1H NMR (400 MHz, d6-DMSO): 7.72 (d, 1H), 7.60 (d, 1H), 3.90 (s, 3H), 2.40 (s, 3H). MS (EI) for C10H9NO3: 190 (M−H).
Reaction SMILES: Cl[NH:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 42F (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:13]
Reactant: NC(N)=O
Reactant: Cc1cccnc1Cl
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
To a mixture of 2-chloro-3-methylpyridine (15 g, 118 mmol) and urea hydrogen peroxide (44.07 g, 468.5 mmol) in DCM (300 mL) was added trifluoroacetic anhydride (98.55 g, 469.2 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 20 h. The mixture was then poured into water (150 mL), and the layers were separated. The organic layer was washed with saturated aqueous Na2S2O3 (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1) to afford the title compound (14.5 g, 86%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.76) (0.41 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.14 g, 37%). MS (ISP) 377.3 [(M+H)+]; mp 202° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[NH:14][CH:13]=[CH:12]3)=[CH:3][CH:2]=1.Br/[CH:19]=[CH:20]/[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.O.CC(=O)OCC>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14](/[CH:19]=[CH:20]/[C:21]2[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=2)[CH:13]=[CH:12]3)=[CH:3][CH:2]=1
Reactant: Br/C=C/c1ccc2ccccc2n1
Reactant: O=c1[nH]ccc2cccc(-c3ccncc3)c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2c(-c3ccncc3)cccc2ccn1/C=C/c1ccc2ccccc2n1
Temperature: 115 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
8-(Pyridin-4-yl)isoquinolin-1(2H)-one (40 mg, 0.180 mmol) and (E)-2-(2-bromovinyl)quinoline (50.6 mg, 0.216 mmol) were dissolved in 2 mL of DMF under argon. The reaction mixture was stirred for 10 h at 115° C. Then, water and EA were added. The organic phase was washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by chromatography (CombiFlash, normal phase, gradient elution, using 3-5% DCM in methanol) to yield the title compound as yellow solid (27 mg, 40.0%). LCMS: 376.1; Rt=1.497.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]2=1.N1C=CC=CC=1.[Cl-].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH:48]=[S:49])=[CH:43][CH:42]=1)(=[O:40])=[O:39].CO>ClCCl>[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([N:21]2[CH2:20][CH2:19][N:18]([C:17]3[C:6]4[C:5]5[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[NH:8][C:7]=4[N:14]=[CH:15][N:16]=3)[CH2:23][CH2:22]2)=[S:49])=[CH:43][CH:42]=1)(=[O:40])=[O:39]
Reactant: COc1cc2[nH]c3ncnc(N4CCNCC4)c3c2cc1OC
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2[nH]c3ncnc(N4CCN(C(=S)Nc5ccc(S(=O)(=O)Nc6ncccn6)cc5)CC4)c3c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 6,7-dimethoxy-4-piperazino-9H-pyrimido[4,5-b]indole (200 mg, 0.64 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography and eluted with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 50 mg (16%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]4([CH3:32])[CH2:31][O:30][CH2:29]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36].C(=O)([O-])[O-].[K+].[K+]>>[NH2:25][C:22]1[O:23][CH2:24][C@:20]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]4([CH3:32])[CH2:31][O:30][CH2:29]4)[CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][C:7]([C:41]2[CH:42]=[C:37]([CH:38]=[CH:39][CH:40]=2)[C:35]#[N:36])=[CH:12][CH:11]=3)[N:21]=1
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccc(C#N)c4)ccc2O3)COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A vial was charged with (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (92 mg, 0.186 mmol, prepared from the alcohol as described in Method CC6), 3-cyanophenylboronic acid (82 mg, 0.557 mmol), potassium carbonate (128 mg, 0.928 mmol), and Cl2Pd(dppf) (1.516 mg, 1.857 μmol). The vial was flushed with argon, then dioxane (928 μL) and water (0.5 mL) were added. The vial was sealed and placed in an 80° C. oil bath for 1.5 hours. An additional portion of catalyst (3 mg) was added and the mixture was returned to the 80° C. oil bath. Heating was continued for an additional 2 hours. The mixture was cooled to rt and was diluted with EtOAc (15 mL) and brine (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column, eluting with 0-50% of a 90:10:1 mix of CH2Cl2/MeOH/NH4OH in CH2Cl2 to give (S)-3-(2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)benzonitrile as a pale, tan solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:2][CH2:3][NH:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[O:6])=[CH:17][CH:16]=1
Reactant: O=C1CCCN1C(=O)NCCCl
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(SCCNC(=O)N2CCCC2=O)cc1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of 2.10 g (11.0 mmol) of 1-[2-chloroethylcarbamoyl]-2-oxopyrrolidine and 1.40 g (10 mmol) of 4-methoxybenzenethiol in 25 ml of DMF were added 2.47 g (16.5 mmol) of NaI and 3.02 g (22 mmol) of K2CO3, and the mixture was heated at 100° C. for 4.5 hr. The reaction solution was poured into ethyl acetate, washed with water, diluted hydrochloric acid, water, and saturated brine in order. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, whereby 2.78 g (94.6%) of the crystalline objective compound (I a-45) was obtained from the eluate with benzene/ethyl acetate (8/1-5/1 v/v). The needles melting at 64.0°-65.0° C. are obtained by recrystallizing from ether-n-hexane. The properties of the objective compound (I a-45) are shown in Table 7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([F:36])[CH:24]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([O:14][Si](C(C)(C)C)(C)C)[C@@H:10]([F:22])[CH2:9]2)=[CH:6][N:7]=1.Cl.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[C:3]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:36])[CH:24]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:22])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C3)cnc2N)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl 4-(3-amino-6-((1 S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (685.0 g, 1318.0 mmol) in EtOH (3.6 kg) was added aqueous HCl (36%, 400.5 g, 3954.2 mmol). The reaction mixture was heated to 30° C. and stirred for 4 hours. The reaction temperature was lowered to 5° C. and a solution of NaOH (342.7 g, 8567.5 mmol) in water (1.6 kg) was added. The reaction mixture was heated to 30° C. and stirred at this temperature for 18 hours. The pH of the reaction mixture was adjusted to 5 using 4 N aqueous HCl to form a solid precipitation. After distillation of EtOH under vacuum at 40-50° C., water (2.5 kg) was added to the residue and the temperature was cooled to 5° C. within 1 hour. The suspension was filtere, the solid was collected and dried under vacuum (<100 mbar) at 50-60° C. for 24 hours to give 4-(3-amino-6-((1 S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid as a brown powder (460 g, HPLC purity at 230 nm was 98.2%, quantitative yield). Mp 226-228° C. ESI-MS (m/z): 350.1282 ([M+H]+, 100). HPLC (method A), retention time 5.93 min. 1H NMR (400 MHz, DMSO-D6): 13.32 (br. s, 1H), 8.00 (t, J=8 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 6.24 (br. s, 2H), 5.16 (br. s, 1H), 4.44-4.49, 4.30-4.35 (m, 1H), 3.50-3.60 (m, 1H), 2.79-2.84 (m, 1H), 2.20-2.25 (m, 1H), 1.92-1.99 (m, 1H), 1.72-1.83 (m, 2H), 1.50-1.60 (m, 1H), 1.36-1.46 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:6]([NH2:21])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[N:9][C:10]=1[NH2:11].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:13]=2)=[N:7][C:6]=1[NH2:21]
Reactant: BrCC1CCCCC1
Reactant: COC(=O)Nc1c(N)nc(-c2n[nH]c3ncccc23)nc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
330 mg (1.1 mmol) of the compound of Example 1A and 212 mg (1.2 mmol) of bromomethylcyclohexane were initially charged in 5 ml of dimethylformamide, 389 mg (1.2 mmol) of cesium carbonate were added and the resulting mixture was stirred at RT overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire solution was separated by HPLC (Method 5). The appropriate fractions were freed from volatile components on a rotary evaporator, and the residue was dried under high vacuum. This gave 60 mg (19% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[OH:17])[N:3]=1>C(O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]2)=[C:9]([OH:17])[CH:10]=1
Reactant: Cc1cc(C)n(-c2ccc([N+](=O)[O-])cc2O)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(N)cc2O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.6 %

Procedure:
86 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-nitrophenol was dissolved in 1.7 ml of ethanol, and 43 mg of 10% palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for 45 minutes. After the insoluble matter was filtered off, the solvent was distilled off under reduced pressure to yield 30.4 mg of the title compound.