Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.[I:20][C:21]1[CH:38]=[CH:37][C:24]2[N:25]3[CH2:31][N:29]([CH2:30][C:23]=2[CH:22]=1)[C:28]1[CH:32]=[CH:33][C:34](I)=[CH:35][C:27]=1[CH2:26]3.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:61]([OH:68])(=[O:67])/[CH:62]=[CH:63]/[C:64]([OH:66])=[O:65]>CN(C=O)C.CCOC(C)=O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:61]([OH:68])(=[O:67])/[CH:62]=[CH:63]/[C:64]([OH:66])=[O:65].[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:34]3[CH:33]=[CH:32][C:28]4[N:29]5[CH2:31][N:25]([CH2:26][C:27]=4[CH:35]=3)[C:24]3[CH:37]=[CH:38][C:21]([I:20])=[CH:22][C:23]=3[CH2:30]5)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: C[Sn](C)(C)c1ccc(OC2CN3CCC2CC3)cc1
Reactant: Ic1ccc2c(c1)CN1CN2Cc2cc(I)ccc21
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Ic1ccc2c(c1)CN1CN2Cc2cc(-c3ccc(OC4CN5CCC4CC5)cc3)ccc21
Yield: 56.1 %

Procedure:
The product of Example 28B (300 mg, 0.8 mmol) was coupled with the product of Example 28A (450 mg, 0.95 mmol) under the catalysis of Pd2(dba)3 (Aldrich, 30 mg, 0.033 mmol) and P(o-tolyl)3 (Aldrich, 30 mg, 0.1 mmol) in dry DMF (Aldrich, 4 mL) at 80° C. for 3 hours. It was then concentrated under reduced pressure and the free base of the title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O(NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) (60 mg, yield, 14%). The free base was treated with fumaric acid (Aldrich, 17 mg, 0.15 mmol) in EtOAc/MeOH (v.10:1, 5 mL) at ambient temperature for 10 hours to give the title compound (56 mg, 74%). 1H NMR (300 MHz, MeOH-D4) δ ppm 1.77-2.18 (m, 3H) 2.22-2.36 (m, 1H) 2.45-2.54 (m, 1H), 3.15-3.43 (m, 5H), 3.71-3.82 (m, J=14.9 Hz, 1H), 4.14-4.41 (m, 3H), 4.61-4.93 (m, 3H), 6.69 (s, 2H), 6.91-7.04 (m, 3H), 7.12-7.22 (m, J=8.8 Hz, 2H), 7.31-7.42 (m, 2H), 7.44-7.54 (m, 3H) ppm. MS (DCl/NH3) m/z 550 (M+H)+. Anal. Calculated for C28H28N3OI.1.15 C4H4O4: C, 57.33; H, 4.81; N, 6.15. Found: C, 57.13; H, 4.42; N, 6.22.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:12]2[N:11]=[C:10]([SH:13])[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>O.C(O)C>[F:18][CH:2]([F:1])[O:3][C:4]1[C:12]2[N:11]=[C:10]([S:13][CH2:21][C:22]3[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17]
Reactant: COc1cc2[nH]c(S)nc2c(OC(F)F)c1OC
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(CSc2nc3c(OC(F)F)c(OC)c(OC)cc3[nH]2)c1C
Yield: 87.7 %

Procedure:
1.0 g of 4-difluoromethoxy-5,6-dimethoxy-1H-benzimidazole-2-thiol, 0.75 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride, 0.3 g of sodium hydroxide, 2 ml of water and 10 ml of ethanol are stirred for 2.5 h at 60° C. The mixture is poured onto 100 ml of water and cooled in an ice bath. This gives 1.3 g (87%) of the title compound (m.p. 177°-179° C., from diisopropyl ether).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([OH:15])([CH3:14])[C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:15][C:5]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C(=O)O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 3.60 g (15.0 mmol) (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid ethyl ester, entity A, in 50 ml of tetrahydrofurane were added 0.65 g (16 mmol) of lithium hydroxide in 25 ml of water and the mixture was stirred for 18 hours at room temperature. After removal of the organic solvent by distillation the mixture was acidified to pH 1. Extraction with ethylacetate gave 2.70 g (85%) of the title compound as an oil, MS m/e (%): 214.3 (M−H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:24])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 53.6 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and isopropylamine (0.013 ml, 0.15 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (30 mg, 0.075 mmol, yield 54%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([C:9]([O:11]C)=[O:10])[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>>[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2ccc(O)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of methyl 6-hydroxybenzo[d]oxazole-2-carboxylate (0.19 g, 1 mmol) and 1N aqueous sodium hydroxide (2 mL) was stirred at room temperature overnight. The reaction mixture was then acidified with concentrated hydrochloric acid. The precipitate was filtered, washed with water, and dried under reduced pressure to afford 6-hydroxybenzo[d]oxazole-2-carboxylic acid as a white solid (0.16 g, 88%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.17 (s, 1H), 7.66 (m, 1H), 7.08 (m, 1H), 6.92 (m, 1H) ppm; MS (ESI): 180.1 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:16]=1.Cl[CH2:33]/[CH:34]=[CH:35]\[CH2:36]Cl>C1COCC1>[F:29][C:27]([F:30])([F:28])[C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:16]=[C:15]([C:14]3([C:13]([O:12][CH3:11])=[O:31])[CH2:36][CH:35]=[CH:34][CH2:33]3)[CH:20]=[CH:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: ClC/C=C\CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in THF, 3.8 ml, 3.8 mmol) was added slowly to a stirred solution of the ester from Example 3, Step 2, (509 mg, 1.7 mmol) in dry THF (8 ml) under N2 such that the internal temperature <−70° C. After 30 minutes cis-1,4-dichloro-2-butene (210 μl, 2.0 mmol) was added. The reaction was maintained at this temperature for 30 minutes, then transferred to an ice bath. After 90 minutes the reaction was removed from the cooling bath and stirred at room temperature for 30 minutes, then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 8% EtOAc/isohexane to give the title compound (278 mg, 47%) as an oil, which solidified on standing. 1H NMR (400 MHz, CDCl3) δ: 2.81 (2H, d, J 15.2), 3.44 (2H, d, J 15.3), 3.70 (3H, s), 5.79 (2H, s), 7.22 (2H, d, J 4.4), 7.66 (1H, s), 7.73 (2H, d, J 8.1), 8.08 (2H, d, J 8.1), 8.63-8.67 (2H, d, J 5.1); M/Z (ES+) 348 (MH+).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1
Reactant: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (46.9 mg, 0.0967 mmol, 1 eq), 1-piperidinepropanoic acid (40.5 mg, 0.255 mmol, 2.6 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (56.2 mg, 0.293 mmol, 3 eq), and 1-hydroxybenzotriazole (HOBt) (13.9 mg, 0.103 mmol, 1 eq) in anhydrous DMF (5 mL), DiPEA (85 μL, 0.48 mmol, 5 eq) was added under an atmosphere of N2 The reaction was stirred at rt for 18 h, after which all solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 5%→7N NH3/MeOH:DCM 2%→5%→8%→15%]. Fractions 25-39 were combined and concentrated in vacuo, yielding the desired amide, but which contained a considerable amount of 1-(3-dimethylaminopropyl)-3-ethylurea. The yellow solid was triturated in hot MeOH/sonication, giving the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=1.26 (s, br, 2H), 1.63 (m, 4H), 2.37-2.56 (m, 6H), 2.56-2.68 (m, 2H), 2.68-2.80 (m, 2H), 3.68 & 3.76 (t, J=5.6 Hz, rotamers, 2H), 4.22 & 4.25 (s, br, rotamers, 2H), 5.92 & 5.98 (s, rotamers, 1H), 6.18 & 6.22 (s, br, rotamers, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8, 1.6 Hz, 1H), 8.13 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 505.00/506.99 (27/10) [MH+]; m/z 407.96/409.98 (100/36) [MH+—C6H14N]. HPLC: tR=1.75 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16](=[N:22]O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[O:13][N:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: CCOC(=O)C(N)=NO
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cc(OC)ccc2OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
2-(2,5-dimethoxyphenyl)acetyl chloride (0.662 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.414 g (37%) of ethyl 5-(2,5-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:28])[N:13]([CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22](=[O:27])N(OC)C)[CH2:18][CH2:17]1)[CH3:14])([CH3:10])([CH3:9])[CH3:8].OS([O-])(=O)=O.[K+]>C1COCC1>[C:7]([O:11][C:12](=[O:28])[N:13]([CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH:22]=[O:27])[CH2:18][CH2:17]1)[CH3:14])([CH3:8])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CN(C)C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 12.25 g (313.11 mmol) LAH in 1.3 l THF was cooled (−50° C.) and treated during 30 min with a solution of 89.5 g (284.64 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 1.3 l THF. After 20 min at this temperature, the reaction was warmed up to 0° C., cooled (−78° C.) and hydrolyzed with a suspension of 90 g MgSO4.7H2O, 90 g silicagel in 292 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 90.4 (quantitative) of trans-(4-Formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester, MS: 255 (M).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([O:17][CH3:18])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([O:17][CH3:18])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5]1
Reactant: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(OC)nc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(CCO)c2c1ccc1cnc(OC)nc12
Yield: 43.7 %

Procedure:
To a suspension of ethyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 1.2 g (3.76 mmol) in toluene (20 ml), 500 mg (2.2 mmol) 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile were added. The mixture was submitted to microwave irradiation at 100° for 3 hours in a sealed vial. The volatiles were evaporated, the crude was dissolved with ethyl acetate and portioned with sat. NaHCO3, the organic layer concentrated to dryness. The residue was purified by chromatography (ethyl acetate/hexane 7/3) to afford the desired compound 520 mg (46%). HRMS (ESI) calcd for C15H16N4O4 [M+H]+ 317.3119 found 317.3126.
Reaction SMILES: [Cl-].[Cl:2]C(=[N+](C)C)Cl.C(Cl)(Cl)=O.[CH:12]1([NH:18][S:19](=[O:22])(=O)[OH:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCCl>[CH:12]1([NH:18][S:19]([Cl:2])(=[O:22])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: O=S(=O)(O)NC1CCCCC1
Agent: O=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 68 %

Procedure:
15 parts of dichloromethylenedimethylammonium chloride, suspended in 540 parts of 1,2-dichloroethane, are saturated with 40 parts of phosgene at 35° C, whilst stirring. 89.6 parts of cyclohexylsulfamic acid are now added and a further 550 parts of phosgene are then introduced in the course of 15 hours at 83° C, whilst stirring. After removing excess phosgene, and the solvent, under reduced pressure, 67.2 parts (68% of theory) of cyclohexylsulfamic acid chloride of boiling point 100°-114° C/0.01 mm Hg and melting point 43°-47° C are obtained by distillation of the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:18].[K+]>Cl.C1CCCCC1.ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[I:18]
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(I)c(Cl)c1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Part B. A solution of the aniline from Part A (17.97 g, 84.9 mmol) in concentrated hydrochloric acid (50 mL) was cooled to −5° C., and treated with a saturated aqueous solution of sodium nitrite (6.45 g, 93.5 mmol) After stirring for 30 min., the solution was diluted with 50 mL cyclohexane and 50 mL dichloromethane, and the resulting mixture was stirred vigorously while a saturated aqueous solution of potassium iodide (28.2 g, 170 mmol) was added dropwise. The resulting solution was allowed to stir for 12 h, then was partitioned between water and dichloromethane. The organic phase was washed with 1 N aqueous sodium bisulfite solution and brine. The three aqueous phases were back-extracted in sequence with dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by distillation to afford the product, 3-chloro-4-iodo-trifluoroanisole (21.38 g, 66.3 mmol, 78%). b.p. 60-70° C./l mm Hg (bulb-to-bulb). 1H NMR (300 MHz, CDCl3): Δ 7.87 (1H, d, J=8.8 Hz), 7.35 (1H, d, J=2.5 Hz), 6.87 (1H, J=ddd, J=8.8 Hz, 2.5H, 0.7 Hz). MS (H2O-GC/MS): m/e 324 (31), 323 (10), 322 (100).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:17])(=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC1OS(=O)N(C(=O)OC(C)(C)C)C1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
tert-Butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.7 g, 20.0 mmol) is dissolved in acetonitrile (50 mL) and H2O (30 mL) is added. The reaction mixture is cooled to 0° C. and sodium periodate (6.4 g, 30.0 mmol) is added. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na2HPO4 solution. Then the solution of RuCl3 (42 mg, 0.2 mmol) in H2O (0.5 mL) is added. The pH of the reaction mixture is kept between 6 and 9 by addition of Na2HPO4 solution. After stirring for 2 h, H2O (100 mL) is added and the pH is adjusted to 6 by addition of 2M HCl solution. The mixture is extracted with EtOAc and the organic layer is separated, washed with NaHCO3 and brine. The aqueous layers are back extracted once with EtOAc. Then all organic layers are combined, dried (MgSO4) and concentrated. Purification by flash column chromatography using a gradient elution of 5-80% ethyl acetate/hexanes affords the title compound (4.48 g, 89%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14].[Li+].[OH-].O>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[CH:15]([CH2:19][CH3:20])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)C(=O)Cl
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 7 h
Yield: 82.4 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in pyridine at 0° C. was treated dropwise with 2-ethylbutanoyl chloride (176 mg, 1.30 mmol). After 7 hours, 2M LiOH (5 mL) was added to the mixture and stirring was continued at room temperature for 30 minutes. Water (25 mL) was then added, and the solid formed was filtered, washed with water (3×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (235 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.06 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.53 (s, 1H), 2.30-2.24 (m, 1H), 1.62-1.52 (m, 2H), 1.47-1.41 (m, 2H), 0.90 (t, 6H); LCMS (APCI+) m/z 328, 330 (M+H)+, Retention time=3.20 minutes (Method 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].O1CCCC1.[OH-].[Li+]>O.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCOC(=O)C(C)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a stirred solution of ethyl 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoate (950 mg, 3.295 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added lithium hydroxide (236 mg, 9.885 mmol). The reaction mixture was refluxed for overnight, then cooled to room temperature, diluted with water (25 mL) and diethyl ether (25 mL). After phase separation the aqueous layer was acidified by HCl to a pH=3 and extracted with DCM (3×50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent of the filtrate was removed in vacuo to give 2-(3-fluoro-4-(methylsulfonylmethyl)-phenyl)propanoic acid (846 mg, 99%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:57]1[CH2:62][CH2:61][CH:60]([CH2:63][NH2:64])[CH2:59][CH2:58]1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]([NH:64][CH2:63][CH:60]3[CH2:61][CH2:62][O:57][CH2:58][CH2:59]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 17.4 %

Procedure:
A solution of the compound (11 mg, 0.02 mmol) obtained in step 2, HATU (76 mg, 0.20 mmol), DEIA (5.13 μL, 0.03 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (3.04 μL, 0.03 mmol) in DMF (2 mL) was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed to with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give the title compound (1.9 mg, 3.48 μmol, 14.2%) as a white powder.