Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=[N:3]1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:11]1[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])[CH3:17]
Reactant: Cn1ncc2c1CCCC(=O)C2
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CCCc2c1cnn2C

Procedure:
A mixture of 27.6 g of 4,6,7,8-tetrahydro-1-methyl-5(1H)-cycloheptapyrazolone and 100 ml of N,N-dimethylformamide dimethyl acetal was heated at reflux for 1.5 hours. The solvent was then removed under reduced pressure and the residue was flash chromatographed (10% methanol in dichloromethane) to give 4-(dimethylaminomethylene)-4,6,7,8-tetrahydro-1-methyl-5(1H)-cycloheptapyrazolone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH2:21])[CH3:16]>>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:16]
Reactant: CCN(CC)CCCN
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c2c1CCCC2=O
Yield: 85.1 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and N1,N1-diethylpropane-1,3-diamine 0.27 g (2.1 mmol) was reacted to give 0.26 g (85%) of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[C:35]([CH3:37])[C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH3:38])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:39](OC(=O)C)(=[O:41])[CH3:40].[I-].[Mg+2].[I-]>C(OCC)C>[C:39]([O:34][C:27]1[CH:26]=[C:25]([S:22]([O:21][C:20]2[C:35]([CH3:37])=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH3:38])(=[O:24])=[O:23])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2c(C)cc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C)ccc1C(=O)O
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred suspension containing 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.350 g, 0.572 mmol), acetic anhydride (4.55 mL) and magnesium iodide (0.159 g, 0.572 mmol) in anhydrous ethyl ether (10.0 mL, 0.05M) was refluxed for 0.5 h. The reaction was cooled to ambient temperature, quenched with H2O (150 mL), extracted with ether and concentrated. The crude product was dissolved in THF:H2O (1:1, 10 mL) and refluxed for 1 h. The reaction was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with ether and EtOAc. The combined organic extracts were concentrated and purified on 2% H3PO4 /MeOH treated silica gel, eluting with a 20 & 25% EtOAc/pet. ether step gradient to give 0.298 g (76%) of the title compound as a white solid; 1H NMR (DMSO-d6) δ 1.58 (s, 3 H), 2.15 (s, 6 H), 2.30 (s, 3 H), 2.45 (s, 3 H), 7.20 (s, 2 H), 7.46-7.54 (m, 2 H), 7.67 (t, 1 H), 7.94 (d, 1 H), 8.05 (dd, 1 H), 8.20-8.25 (m, 2 H), 13.75-13.95 (br.s., 1 H). mass spectrum (-ESI), m/z 651/653 (M-H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([N:23]2[C:27](=[O:28])[C:26]([C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)(O)[NH:25][C:24]2=[O:39])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH2:21])=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([N:23]2[C:27](=[O:28])[CH:26]([C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)[NH:25][C:24]2=[O:39])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH2:21])=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccc(C(N)=O)cc2)N2C(=O)NC(O)(c3ccc4c(c3)OCO4)C2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccc(C(N)=O)cc2)N2C(=O)NC(c3ccc4c(c3)OCO4)C2=O)n1
Temperature: 65 °C
Yield: 29.8 %

Procedure:
To a solution of 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl4-hydroxy-2,5-dioxo-imidazolidin-1-yl)-3-(4-carbamoyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (80 mg, 0.14 mmol) in acetic acid (4.0 mL) was added zinc (183 mg, 2.8 mmol). The mixture was heated to 65° C. for 6 hours. The reaction was neutralized with saturated sodium bicarbonate at 0° C. and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed and the product was triturated with methanol/diethyl ether, filtered and dried to give 2-[(S)-2-(4-benzo[1,3]dioxol-5-yl-2,5-dioxo-imidazolidin-1-yl)-3-(4-carbamoyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (23 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:28][CH2:29][CH3:30])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[C:7](O)=[O:8].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1.Cl>O1CCCC1.O.CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH2:28][CH2:29][CH3:30])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)=[O:8]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(Cl)c(C(=O)NCCc2ccc(O)cc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a solution of 4.86 g of 4-chloro-2-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid in 115 mL of tetrahydrofuran at 25° C. is added 2.25 g of carbonyl diimidazole, and the resulting solution is stirred at 25° C. for 3 hours. To the solution is added 3.94 g of tyramine and 23 mL of 2-propanol, and the mixture was stirred at 25° C. for an additional 3 hours. The reaction mixture is poured into water, and the resulting emulsion is adjusted to pH 3 employing hydrochloric acid and then extracted with chloroform. The combined extracts are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (elution: 10% 2- propanol/chloroform) affords 3.15 g of the product as an amorphous solid. NMR (300 MHz, DMSO-d6) δ 8.07 (t, 1H, J=8 Hz), 7.69-7.50 (m, 4H), 7.07-6.99 (m, 6H), 6.65 (d, 2H, J=8 Hz), 5.42 (s, 2H), 3.36 (quart., 2H, J=7 Hz), 2.63 (t, 2H, J=7 Hz), 2.50 (t, 2H, J=7 Hz), 1.51 (sext., 2H, J=7 Hz), 0.82 (t, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][CH2:36][C:37]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:38]
Reactant: COCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), 3-methoxypropionic acid (0.15 ml, 1.6 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.255 g), melting point: 149° C.
Reaction SMILES: N1C=CC=CC=1C(Cl)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([N:40]=[C:41]=[S:42])=[O:39]>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([N:40]=[C:41]=[S:42])=[O:39].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccn1
Agent: O=C(N=C=S)c1ccccn1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccn4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Pyridinecarbonyl isothiocyanate was prepared using commercially available 2-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 90%).
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[C:8]2[CH:16]=[C:15]([CH3:17])[O:14][C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:7]1[C:8]2[CH:16]=[C:15]([CH3:17])[O:14][C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1
Reactant: Cc1cc2c(Cl)nc(N)nc2o1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(N)nc2oc(C)cc12
Reaction time: 24 h

Procedure:
To 100 ml of anhydrous methanol was added 0.9 g sodium methoxide plus 1.7 g of 4-chloro-6-methylfuro[2,3-d]pyrimidin-2-amine and the mixture was heated to boiling for 24 hours. The methanol was then removed under reduced pressure and the product was triturated with water and filtered to afford a yield of 1.5 g, m.p. 173°-175°. An NMR (60 MHz) spectrum in trifluoroacetic acid solution exhibited absorptions at 2.5, 4.4 and 6.5 ppm in a 3:3:1 ratio indicating the title compound.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH:12]2[CH2:20][CH2:21][CH3:22])=[O:10])[CH:4]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2>CC(O)CCC>[CH2:20]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([C:5]1[N:6]=[CH:7][N:8]=[C:3]([NH:23][C:24]2[CH:25]=[C:26]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:28]2([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]2=[O:37])[CH2:27]3)[CH:4]=1)=[O:10])[CH2:21][CH3:22]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CCCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: CCCC(C)O
Product: CCCC1Cc2ccccc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
12.5 μL (50 μmol) 4M aqueous hydrochloric acid were added to 103 mg (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(2-propyl-2,3-dihydro-indol-1-yl)-methanone and 108 mg (0.36 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 2 mL 2-pentanol. The reaction mixture was refluxed for 2 h. The reaction mixture was evaporated down using the rotary evaporator and the residue was taken up in DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:15])=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH:9]1([CH2:8][C:7]2[CH:6]=[C:5]([CH3:15])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:3](=[O:21])[C:2]=2[NH:1][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(CC2CCCCC2)c(N)c1=O
Product: COC(=O)Cn1c(C)cc(CC2CCCCC2)c(NC(=O)OCc2ccccc2)c1=O
Yield: 57 %

Procedure:
1.12 g (3.83 mmol of methyl 3-amino-4-(cyclohexylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-1-acetate are reacted with phenylmethyl chloroformate under the conditions described in Example 3. 0.93 g of product is obtained after purification by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([C:22](=[O:38])[C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.I[C:40]1[CH:41]=[N:42][N:43]([CH3:50])[C:44]=1[C:45]1[N:46]=[N:47][NH:48][N:49]=1.[OH-].[Na+].CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.O1CCOCC1>[CH3:50][N:43]1[C:44]([C:45]2[N:49]=[N:48][NH:47][N:46]=2)=[C:40]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:8]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:38])=[CH:24][CH:25]=2)[CH:41]=[N:42]1
Reactant: Cn1ncc(I)c1-c1nn[nH]n1
Reactant: Cc1cccnc1N(C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2-c2nn[nH]n2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a round-bottom flask charged with a stir bar was added Preparation 24, tert-butyl (3R)-3-{(3-methylpyridin-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino}piperidine-1-carboxylate (1.53 g, 2.93 mmol) and Preparation 22, 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (674 mg, 2.44 mmol). To this was added dioxane (12.2 mL) and aqueous NaOH (4.07 mL, 3M solution, 12.2 mmol). The reaction mixture was heated to 70° C. under nitrogen atmosphere for 30 min. To a microwave vial was added the Pd(OAc)2 (34.3 mg, 0.153 mmol) and Catacxium A (123 mg, 0.342 mmol). The atmosphere was exchanged for nitrogen, and toluene was added. The catalyst was stirred at room temperature for 15 min, until a bright yellow slurry formed. At this point, the catalyst was added to the reaction mixture, and the temperature was adjusted to 100° C. The reaction mixture was stirred for 3 h at 100° C. After complete consumption of the starting material, the reaction was concentrated under reduced pressure. H2O (10 mL) was added. The reaction mixture was extracted with MTBE (3×25 mL). The aq. phase was cooled to 0° C., and 1M HCl was added dropwise to form a precipitate which was collected via suction filtration and dried in vacuo to obtain tert-butyl (3R)-3-(4-(1-methyl-5-(2H-tetrazol-5-yl)-1H-pyrazol-4-yl)-N-(3-methylpyridin-2-yl)benzamido)piperidine-1-carboxylate (1.2 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: CCOC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Product: CCOC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cccc32)c1

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and ethyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 6).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 2 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (50 mg) and triethylamine (30 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (11 μL) and stirred for 2 hours. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[O:15][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])=[O:5])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)c1sc2ccncc2c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2ccncc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 3-hydroxy-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.3 g, 5.82 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 ml) at 0° C. was added DIPEA (2.5 ml, 14.0 mmol) and nonafluorobutylsulfonyl fluoride (1.36 ml, 7.56 mmol). After 10 minutes the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase was isolated, dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 100:0 to 70:30) to afford the title compound as a colourless oil which crystallised on standing (420 mg, 14%). LCMS (method B): RT=4.46 min, M+H+=508.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Yield: 68.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (1.18 g, 3 mmol), 4-vinylpyridine (0.39 mL, 3.6 mmol), Pd(OAc)4 (62.5 mg), tris(o-tolyl)phosphine (312.5 mg), and triethylamine (6.25 mL) in acetonitrile (15 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 100:5-100:15 to afford the title compound (852 mg, 69% yield). MS (DCI/NH3) m/z 416 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.48 (s, 9H), 1.92 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.97 (m, 1H), 4.13 (m, 2H), 7.43 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 8.62 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C([Cl:30])C=C(C(OO)=[O:32])C=1.Cl>C(Cl)Cl.CCOCC>[ClH:30].[CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15]([CH3:16])=[O:32])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1csc(Nc2ncc(S(C)=O)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
3-(Benzyloxy)-N-(4-methylthiazol-2-yl)-5-(methylthio)pyridin-2-amine (prepared according to Example 7; 0.057 g, 0.166 mmol) was placed in CH2Cl2 (5 mL) and cooled to 0° C. MCPBA (0.0398 g, 0.166 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours, then quenched with sodium bisulfite and extracted with CH2Cl2. The organic layer was washed with saturated sodium bicarbonate, dried, filtered, and concentrated. The residue was purified by silica gel (40-80% EtOAc in hexanes) to give the free base. The free base was dissolved in CH2Cl2, and 2M HCl in ether was added. The solution was concentrated to give 3-(benzyloxy)-5-(methylsulfinyl)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.037 g, 56.3% yield). 1H NMR (DMSO-d6) δ 8.18 (d, 1H), 7.81 (d, 1H), 7.62 (m, 2H), 7.43 (m, 2H), 7.37 (m, 1H), 6.83 (s, 1H), 5.39 (d, 2H), 2.82 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z=360.0 (M+H-HCl).