Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc2[nH]c(CO)nc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reaction time: 28 h
Yield: 67.2 %

Procedure:
To a solution of methyl 2-hydroxymethyl-1 H-benzimidazole-4-carboxylate (1.0 g) in N,N-dimethylformamide (10 ml) were added tert-butylchlorodiphenylsilane (1.87 g) and imidazole (495 mg) at ambient temperature and the mixture was stirred at the same temperature for 28 hours. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1) to give methyl 2-tert-butyldiphenylsiloxymethyl-1 H-benzimidazole-4-carboxylate (1.45 g) as an oil.
Reaction SMILES: [CH2:1]([N:9]1[C:14](=[O:15])[CH2:13][N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]([C:30]([O:32]C)=[O:31])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>C1COCC1>[CH2:1]([N:9]1[C:14](=[O:15])[CH2:13][N:12]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:11]([C:30]([OH:32])=[O:31])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(-n3cccc3)cc2)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCN1CC(C(=O)O)N(S(=O)(=O)c2ccc(-n3cccc3)cc2)CC1=O
Yield: 37.9 %

Procedure:
The compound of Example 57 (0.19 g, 0.4 mmol) was dissolved in 5 mL of THF, and 1 mL of 2N NaOH was added dropwise at 0° C. After reaction at room temperature for 3 hours, the reactant was concentrated under reduced pressure and acidified with a 2N HCl aqueous solution, extracted with ethyl acetate, and concentrated under reduced pressure. It was then recrystallized with hexane and ethyl acetate to obtain an ivory colored compound (0.07 g, yield 28%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[N:15]=[N:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:18](O)[C:13]=3[C:12]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:11]2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:33]>C(Cl)Cl>[Cl:33][C:18]1[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:16][N:15]=[C:14]2[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:11]=[C:12]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]=12
Reactant: CN1CCN(CCn2nc(N3CCCC3)c3c(O)c(-c4ccccc4)nnc32)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(CCn2nc(N3CCCC3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 60 °C

Procedure:
A suspension of 1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-3-pyrrolidin-1-yl-pyrazolo[3,4-c]pyridazin-4-ol (90 mg) in POCl3 (6 mL) and CH2Cl2 (3 mL) was heated to 60° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to provide Compound Iz (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14](=O)[CH3:15])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[CH:15])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)(C)NS(=O)(=O)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)NS(=O)(=O)Cc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a solution-of C-(4-Chloro-phenyl)-N-(1,1-dimethyl-2-oxo-propyl)-methanesulfonamide, 4.2 g (15.0 mmol) in 60 mL of dimethylformamide was added 1.3 g (31.5 mmol) of sodium hydride. The reaction mixture was heated at 90° C. for 24 H, then cooled to ambient temperature and concentrated to dryness. The residue was partitioned between ethyl acetate and water and was acidified to pH=3.0 with 1 N HCl. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was chromatographed over silica using chloroform as eluant to yield 3.27 g (80%) of the desired product, shown below, as a tan solid. 1H-NMR is consistent with structure; MS (ion spray) 270.3 (M−1); Anal. Calc'd for C12H14ClNO2S: C, 53.04; H, 5.19; N, 5.15. Found: C, 52.72; H, 5.18; N, 4.98. 5-(4-Chloro-phenyl)-3,3,4-trimethyl-2,3-dihydro-isothiazole 1,1-dioxide.
Reaction SMILES: C(CCC=N[NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH2:12][C@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)=[CH:10][CH:9]=1)#N>C(Cl)(Cl)Cl>[C:8]([CH2:9][C:10]1[C:9]2[C:8](=[CH:20][CH:19]=[C:11]([CH2:12][C@H:13]3[CH2:17][O:16][C:15](=[O:18])[NH:14]3)[CH:10]=2)[NH:7][CH:11]=1)#[N:7]
Reactant: N#CCCC=NNc1ccc(C[C@H]2COC(=O)N2)cc1
Solvent: ClC(Cl)Cl
Product: N#CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Yield: 153.6 %

Procedure:
A solution of the product from step (b) (2.5 g) and polyphosphate ester (20.0 g) in chloroform (40 ml) was refluxed for 20 minutes. Ice was added to the cooled mixture and the chloroform evaporated in vacuo. The remaining aqueous phase was extracted with ethyl acetate and the combined extracts evaporated in vacuo to give the desired product as a pale yellow oil (1.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:43]([C:40]3[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using the following starting materials: {4′-amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester and 4-chlorobenzenesulfonyl chloride.
Reaction SMILES: O[CH:2]([CH3:24])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(S(F)(F)[F:31])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:31][CH:2]([CH3:24])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1cc(N2CCN(C(=O)/C=C/C(C)O)CC2)c2ccccc2n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)/C=C/C(C)F)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-4-Hydroxy-1-[4-(2-methyl-4-quinolyl)piperazin-1-yl]pent-2-en-1-one (32.5 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (200 μl) and added to a solution of (diethylamino)sulphur trifluoride (DAST; 19 μl, 0.12 mmol) in 200 μl dichloromethane. The mixture was stirred for 30 minutes at room temperature, additional DAST was added (10 μl, 0.063 mmol) and stirring was continued for additional 30 minutes. Solid sodium carbonate (25 mg) was added, the mixture was filtered, the filtrate evaporated to dryness and the residue purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 4 mg (0.012 mmol, 12%).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>O1CCOCC1>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Reactant: COc1cccc(C(=O)Cl)c1OC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 79 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 30 minutes and then at 50° C. for 30 minutes. The reaction liquid is cooled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is allowed to stand overnight at room temperature whereby a part of the substance is crystallized. A small amount of ethanol is added to crystallize the substance wholly and the crystals are collected by filtration whereby 2.3 g (yield: 79.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained. M.P. 84.5°-86° C.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>ClCCl>[CH:17]1([CH2:16][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)[CH2:19][CH2:18]1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: BrCC1CC1
Solvent: ClCCl
Product: c1ccc2c(c1)CC[C@@H]1CN(CC3CC3)CC[C@@H]21
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 0.200 g (1.07 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in anhydrous dichloromethane (20 ml) was added 0.200 g (1.48 mmol) of (bromomethyl)cyclopropane and the reaction mixture was left to stand for 24 h. The solvent was removed in vacuo and the residue was chromatographed on flash silica, eluting with 10% methanol/dichloromethane to give 0.160 g (62%) of the title product as an oil. The hydrochloride salt was made using etheral hydrogen chloride. Upon evaporation of the solvent, washing with ether and recrystallisation from ethanol/ethyl acetate/petroleum ether, the title product hydrochloride was obtained as a white sold, m.p. 255°-257° C. NMR δ(D2O) 0.43 (2H, m), 0.78 (2H, m), 1.17 (1H, m), 1.58 (1H, m), 1.80-1.94 (2H, m), 2.67-2.77 (2H, m), 2.90-2.97 (3H, m), 3.09 (2H, d, J=7.4 Hz), 3.20 (1H, t of d, J=13.1 and 3.0 Hz), 3.74 (1H, m), 3.87 (1H, m), 7.22-7.31 (3H, m), 7.36-7.38 (1H, m). m/z (CI+, NH3) 242 (M+H)+, 182, 165.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]2=[O:20])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=3)[C:12](=[O:20])[O:13][C:14]([CH3:18])([CH3:19])[O:15][C:16]2=[O:17])=[CH:8][CH:9]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC2(Cc3ccc(Br)cc3)C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-benzoic acid methyl ester (3 g, 10.3 mmol) and K2CO3 (2.1 g, 15.4 mmol) in DMF (15 mL) was added 4-bromobenzyl bromide (3 g, 12.3 mmol). The solution was stirred at room temperature overnight. After partitioning between Et2O and water, the organic portion washed with brine, dried over Na2SO4 then concentrated to afford crude material which was crystallized from MeOH to afford 4-[5-(4-Bromobenzyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester as a white solid (4.12 g, 87%). 1H NMR (500 MHz, DMSO-d6): δ 7.91 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.02 (d, J=8 Hz, 2H), 3.81 (s, 3H), 3.45 (s, 2H), 3.38 (s, 2H), 0.71 (s, 3H), 0.65 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:36]=[C:37]([C:41](=[O:56])[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=1.[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[CH2:63]O>O1CCCC1>[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[CH2:63][O:34][C:35]1[CH:36]=[C:37]([C:41](=[O:56])[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Reactant: Cc1ccsc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1cccc(OCc2sccc2C)c1)c1ccccc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
A solution of triphenylphosphine (1.13 g) in tetrahydrofuran (30 mL) is treated with diisopropyl azodicarboxylate (0.84 mL) at 0-5° C. The suspension is then treated with methyl (RS)-5-(3-hydroxyphenyl)-5-oxo-4-(2-methylphenyl)pentanoate (671 mg) and 3-methyl-2-thienylmethanol (275 mg), and stirred at 5° C. for 15 minutes. The solution is evaporated and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (5:1 v/v), to give methyl (RS)-5-[3-(3-methyl-2-thienylmethoxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (350 mg), in the form of an oil. [NMR(CDCl3):- 2.0-2.5(4H,m), 2.25(3H,s),2.5(3H,s), 3.65(3H,s), 4.8(1H,m),5.1 (2H,q),6.85-7.5(10H)].
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[S:13]1[C:17]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2.Cl.[NH:32]1[C:36]([C:37]2[CH:38]=[C:39]3[C:49](=[CH:50][CH:51]=2)[O:48][C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][C:40]3=[O:52])=[N:35][N:34]=[N:33]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN1C(=O)CCC1>[S:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:45]3[CH2:46][CH2:47][C:42]4([CH2:41][C:40](=[O:52])[C:39]5[C:49](=[CH:50][CH:51]=[C:37]([C:36]6[NH:35][N:34]=[N:33][N:32]=6)[CH:38]=5)[O:48]4)[CH2:43][CH2:44]3)=[O:24])=[CH:25][CH:26]=2)=[CH:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2
Reactant: O=C(O)c1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1CC2(CCN(C(=O)c3ccc(-c4cc5ccccc5s4)cc3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
WSC hydrochloride (69.0 mg, 0.36 mmol) was added to a mixture of 4-(benzo[b]thiophen-2-yl)benzoic acid (76.3 mg, 0.300 mmol), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (96.5 mg, 0.300 mmol), HOBT (45.9 mg, 0.300 mmol), triethylamine (0.042 mL, 0.300 mmol) and NMP (1.5 mL), and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.44 (1H, d J=2.2 Hz), 8.25 (11, dd, J=8.5, 2.2 z), 8.00 (1H, d, J=8.3 Hz), 7.96 (1H, s), 7.89-7.83 (3H, m), 7.54 (2H, d, J=7.8 Hz), 7.44-7.33 (3H, m), 4.37-4.18 (1H, m), 3.65-3.18 (3H, m), 3.00 (2H, s), 2.13-1.75 (4H, m). MS [M−H]−=520.
Reaction SMILES: [I:1]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.O[CH:28]([C:58]1[O:59][CH:60]=[CH:61][N:62]=1)[CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:42][CH:43]4[CH2:48][CH2:47][CH:46]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:45][CH2:44]4)[C:32]=3[C:31]1=2>ClCCl>[I:1][CH:28]([C:58]1[O:59][CH:60]=[CH:61][N:62]=1)[CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:42][CH:43]4[CH2:48][CH2:47][CH:46]([N:49]([CH3:57])[C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:54])[CH3:55])[CH2:45][CH2:44]4)[C:32]=3[C:31]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(O)c2ncco2)CC4)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(I)c2ncco2)CC4)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.4 %

Procedure:
For the preparation of the starting material compound 47.1, see Example 47. A solution of iodine (244 mg), Ph3P (252 mg) and imidazole (143 mg, 2.10 mmol, 3.49 equiv) in dry dichloromethane (20 mL) was stirred at 0° C. for 30 min under nitrogen. Then a solution of tert-butyl N-(4-[[(3R)-3-[2-hydroxy-2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (310 mg, 0.60 mmol, 1.00 equiv) was added dropwise to the reaction mixture and the resulting solution was stirred for 2.5 h at room temperature. The reaction was then quenched with saturated aqueous NaHSO3 and extracted with 2×30 mL of dichloromethane. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate. After concentrated in vacuo, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(4-[[(3R)-3-[2-iodo-2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (230 mg, 61%) as a yellow solid. MS (ES): m/z 625 (M+H)+.
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:22][C:23]3[CH:24]=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:16][CH:15]=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3c(ncnc3Nc3cnc4ccccc4c3)C2)cc1
Temperature: 150 °C
Yield: 57.1 %

Procedure:
Sodium iodide (434 mg, 2.9 mmol) and hydriodic acid (0.4 mL, 47% aqueous solution) were added to a mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (500 mg, 1.93 mmol) and 3-aminoquinoline (418 mg, 2.9 mmol) in dioxane (4 mL) and the reaction solution was heated in a sealed tube via microwave at 150° C. for 20 min. The solvent was removed under reduced pressure. The residue was suspended in water, solid sodium carbonate was added to a pH>8, and the mixture was extracted with ethyl acetate. The organic layer was removed in vacuo and the residue was purified by column chromatography to yield the product as a beige solid (405 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][N:16]=[C:15](Cl)[C:14]=2[N+:20]([O-])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH3:3][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:20])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[4chloro-5-nitro-6-pyrimidyl]piperazine and triethylamine (0.3 ml) and palladium on carbon (5%, 0.13 g) in ethanol (100 ml) is charged with hydrogen gas (30 psi). After the theoretical amount of hydrogen gas is consumed, the catalyst is removed under reduced pressure. The filtrate is concentrated under reduced pressure to a foam which is diluted with an aqueous saturated solution of potassium carbonate and dichloromethane. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give to give the title compound, NMR (CDCl3) 1.49, 3.49, 3.29, 3.56, 7.98, and 8.39 δ.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:43]1([S:49]([N:52]2[C:56]3=[N:57][CH:58]=[C:59]([NH2:68])[C:60]([NH:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)=[C:55]3[CH:54]=[CH:53]2)(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:68][C:59]1[C:60]([NH:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)=[C:55]2[CH:54]=[CH:53][N:52]([S:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:51])=[O:50])[C:56]2=[N:57][CH:58]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)O
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
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: CC(=O)NCCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
3-Acetylaminopropionic acid (0.089 g, 0.675 mmol), HATU (0.256 g, 0.675 mmol), and diisopropylethylamine (0.141 ml, 0.840 mmol) were added sequentially to a solution of 1-benzenesulfonyl-N-4-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.250 g, 0.675 mmol) in CH2Cl2 (15 ml) at 25° C. The reaction mixture was stirred for 18 h at 25° C., then was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×125 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc (10 ml) to give a solid which was collected by filtration, washed with Et2O (10 ml), and air-dried to give 3-acetylamino-N-(1-benzenesulfonyl-4-cyclohexylamino-1H-pyrrolo[2,3-b]pyridin-5-yl)-propionamide as an off-white solid (0.183 g, 56%). LCMS (Method G, ESI): RT=0.82 min, m+H=484.3. This material was used in the next step below without additional purification or characterization.