Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])[C:11]([C:13]2([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)=[O:41].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][N:10]([CH2:9][C:4]3[CH:3]=[C:2]([C:46]4[CH:45]=[CH:44][CH:43]=[C:42]([CH:40]=[O:41])[CH:47]=4)[C:7]([CH3:8])=[CH:6][CH:5]=3)[C:11]([C:13]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]3)=[O:12])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(Br)c1)C(=O)C1(C(N)=O)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A mixture of N1-[(3-bromo-4-methylphenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (520 mg, 0.87 mmol), (3-formylphenyl)boronic acid (170 mg, 1.131 mmol), Na2CO3 (277 mg, 2.61 mmol) and PdCl2(dppf) (63.7 mg, 0.087 mmol) was diluted in a mixture of 1,4-dioxane (9 mL) and water (3 mL) in a 20 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 min and was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain a crude residue. It was then purified with a CombiFlash Companion eluting with 0 to 100% ethyl acetate in dichloromethane (product came out at 80% ethyl acetate). The product fractions were combined and concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (420 mg, 77%). LC-MS m/z 623 (M+H)+, 0.90 min (ret time).
Reaction SMILES: [K].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10]I>CN(C)C=O>[CH3:10][N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: CI
Reactant: O=c1ncc(F)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: Cn1cc(F)cnc1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
A mixture of the potassium salt of 5-fluoropyrimid-2-one (prepared as described in Undeheim, K. and Gacek, M. Acta. Chem. Scand. 23 (1969) 294 or Budesinsky, Z., Prikyl, J. and Svatek, E. Coll. Czech. Chem. Commun. 30 (1965) 3895) (0.01 mol) and methyl iodide (0.013 mol) in dimethylformamide (40 ml) was stirred at room temperature for 20 hours. The solvent was then removed under reduced pressure (1 mm Hg) and the said residue triturated with chloroform (4×50 ml). The chloroform solution containing the desired product was washed with aqueous 1 N NaOH (3 ml) and with water (3 ml). The dried (MgSO4) chloroform solution was then evaporated and the solid residue recrystallised from benzene; yield 40%, m.p.=177°-178° C. (Found: C, 47.21; H, 3.95; Calc. for C5H5FN2O: C, 46.88; H, 3.93)
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(N)[nH]n1
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To 5.88 g (25.77 mmol) of tert-butyl 5-nitro-1H-pyrazol-3-ylcarbamate diluted in 145 ml of methanol, are added under inert atmosphere 600 mg of palladium on charcoal (10%), then the reaction mixture is stirred under hydrogen atmosphere for 24 h. The solution is filtered on Celite and rinsed with ethyl acetate. The filtrate is concentrated to yield 4.93 g of tert-butyl 5-amino-1H-pyrazol-3-ylcarbamate in the form of a grey solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxy-5-trifluoromethylbenzoic acid (8.10 g), toluene (160 mL), N,N-dimethylformamide (5 droplets) and thionyl chloride (4.80 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and then used for the synthesis of (i).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:32])CO)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one (Example 102, Step D) (286 mg, 0.603 mmol) in THF (3 mL) and water (3 mL) was added sodium periodate (258 mg, 1.206 mmol) at room temperature. The slurry was stirred at room temperature for 1 h and then diluted with EtOAc and the layers were separated. The organic layer was washed with sat. Na2S2O3 and sat. aq. NaCl solution and dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22](C(OCC)=O)[CH2:21][C:19]=2[N:20]=1.ClC1N=[C:39](N2CCOCC2)[C:40]2CN(C(C)C)C[C:41]=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([CH:40]([CH3:41])[CH3:39])[CH2:21][C:19]=2[N:20]=1
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOCC3)c2C1

Procedure:
Method as (S)-Ethyl 2-(2-fluoro-4-(3-(2-hydroxyethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 167) using 4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 34)
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:27][N:28]=3)[N:25]=2)[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].Cl.[NH2:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(#N)C>[F:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:27][N:28]=3)[N:25]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
N,N-Diisopropylethylamine (160 μL, 0.90 mmol) was added to the mixture of 2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid (90.0 mg, 0.225 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (63 mg, 0.281 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (150 mg, 0.34 mmol) in N,N-dimethylformamide (2.0 mL) at 0° C. The mixture was stirred overnight at RT and was added to aqueous acetonitrile. The precipitates were filtered, dried to give the desired product (0.093 g, 72%). LCMS: (M+H)=569.5.
Reaction SMILES: [OH-].[Na+].Cl.[Br:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:23][CH2:22][S:21][C:20]([NH:24]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:19]3)[C:17]3[CH:16]=[C:15]([Cl:36])[N:14]=[CH:13][C:12]=3[O:11][C:8]2=[CH:9][CH:10]=1>CO.O>[Br:4][C:5]1[CH:6]=[C:7]2[C:18]3([CH2:23][CH2:22][S:21][C:20]([NH2:24])=[N:19]3)[C:17]3[CH:16]=[C:15]([Cl:36])[N:14]=[CH:13][C:12]=3[O:11][C:8]2=[CH:9][CH:10]=1
Reactant: O=C(NC1=NC2(CCS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1=NC2(CCS1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A 2 N NaOH solution (24.47 ml, 48.9 mmol) was added to a solution of N-(7-bromo-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazin]-2′-yl)-4-nitrobenzamide hydrochloride (9.5 g, 16.32 mmol) in MeOH (250 ml). The reaction mixture was heated to 65° C. for 3 hours. The reaction mixture was diluted with water (300 mL), stirred for 10 min, and then filtered. The solid was washed with water and dried under reduced pressure to afford 7-bromo-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazin]-2′-amine (3.9 g, 9.83 mmol, 60.3% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[C:28]([C:29]#[C:30][C:31]([C:34]2[CH:38]=[C:37]([CH:39]=O)[O:36][N:35]=2)([OH:33])[CH3:32])=[CH:27][C:15]2[C:16]3[N:17]([CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:18][CH2:19][O:20][C:14]=2[CH:13]=1.O.[CH3:42]C#N>C1(C)C=CC=CC=1.O1CCCC1>[F:11][C:12]1[C:28]([C:29]#[C:30][C:31]([OH:33])([C:34]2[CH:38]=[C:37]([CH:39]=[CH2:42])[O:36][N:35]=2)[CH3:32])=[CH:27][C:15]2[C:16]3[N:17]([CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:18][CH2:19][O:20][C:14]=2[CH:13]=1
Reactant: CC#N
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of KHMDS (0.9 mL, 3.20 equiv) in toluene (0.5M) was added dropwise to a stirred solution of Ph3PCH3I (180 mg, 3.02 equiv) in tetrahydrofuran (3 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 min. To this was added a solution of 9-fluoro-10-(3-(5-formylisoxazole-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (60 mg, 0.15 mmol, 1.00 equiv) in tetrahydrofuran (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 3 h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmol NH4HCO3 and CH3CN (25% CH3CN up to 40% in 10 min, up to 95% in 2 min, down to 25% in 2 min); Detector, UV 254/220 nm giving the titled compound (10%) as a light yellow solid.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:34]([O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][C:32]([C:43]([OH:45])=O)=[N:31]1.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>>[C:49]([CH2:48][C@H:47]([NH:46][C:43]([C:32]1[CH:33]=[C:34]([O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[N:31]=1)=[O:45])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])([OH:51])=[O:50]
Reactant: O=C(O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
0.675 mmol of TOTU and 1.35 mmol of EDIA were added to the filtrate containing 1-(2-fluoro-phenyl)-5-(pyrrolidine-1-carbonyloxy)-1H-pyrazole-3-carboxylic acid obtained in step 1. The mixture was stirred for 5 min at room temperature, and then 0.675 mmol of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid were added and the mixture was stirred overnight at RT. Then the solvent was evaporated and the residue subjected to preparative HPLC to give the title compound in a yield of 67%.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>C1CCCCC1>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (75.8 mg, 0.26 mmol), and copper (I) trifluoromethanesulfonate benzene complex (58.3 mg, 0.23 mmol) were added in an autoclave, and then 1-chloro-1-fluoroethylene (78.9 g, 0.98 mol) was charged under elevated pressure. After the mixed solution was cooled to 10° C., the a mixed solution containing 95% of ethyl diazoacetate (12.0 g, 100 mmol) and cyclohexane (50 g) was charged into the autoclave under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (170.0 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 6.45% (yield based on ethyl diazoacetate: 65.6%), and the ratio of cis-isomer/trans-isomer was 64.6/35.4. The optical purity of the cis-isomer was 99% e.e. (1S,2R), and the optical purity of the trans-isomer was 92% e.e. (1S,2S).
Reaction SMILES: O.Cl.C(OC([NH:10][C@@:11]1([C:35]([O:37]C(C)(C)C)=[O:36])[C@H:16]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([O:30]C(C)(C)C)=[O:29])=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1>[NH2:10][C@@:11]1([C:35]([OH:37])=[O:36])[C@H:16]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
Water (1.10 L) and 12.18M hydrogen chloride in water (789.88 mL, 9.62 mol) is added to a solution of di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (550.00 g, 962.07 mmol) in 1,4-dioxane (192.41 mL). The resulting slurry is stirred at 100° C. After 12 hours, the reaction is then cooled to 25° C., stirred for 12 hours, and then basified with NaOH (50% wt/wt) to pH=2.65. The resulting mixture is stirred at 10° C. for 30 minutes whereupon the precipitate is collected by filtration, washed with water (1 L) and methyl tert-butyl ether (1 L), and dried for 2 hours at 25° C., and then at 60° C. in a oven until constant weight to yield the title compound (300 g, 87% yield). MS (m/z): 360 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][OH:14]>C1(C)C=CC=CC=1.[Ag-]=O>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CO
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COCc1cc([N+](=O)[O-])ccc1F
Temperature: 60 °C

Procedure:
30 g (128 mmol) of the compound from Example 26A are dissolved in 1.3 l of anhydrous toluene, and 45 g (192 mmol) of silver(I) oxide and 24.6 g (769 mmol) of anhydrous methanol are added. The mixture is heated at 60° C. for 16 h. The mixture is then allowed to cool and filtered through silica gel. The product is eluted fractionally using a gradient of cyclohexane and cyclohexane/ethyl acetate 25:1. The product fractions are evaporated to dryness under reduced pressure and dried under reduced pressure. This gives 17 g (72% of theory) of the desired product.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:3][CH:2]([F:4])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(O)ccc1C
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC(F)F)ccc1C

Procedure:
Chloro(difluoro)methane is introduced with vigorous stirring for 90 minutes into a mixture of 50 g methyl 5-hydroxy-2-methylbenzoate (see below), 1.21 g tetrabutylammonium bromide, 52 g aqueous sodium hydroxide solution (50% by weight) and 500 ml dioxane. The reaction mixture is filtered and the filtrate is adjusted to pH 1-2 with 1n aqueous hydrochloric acid. The mixture is extracted with EA three times, the combined organics are dried over MgSO4, and the solvent is removed under reduced pressure. The resulting crude product is purified by filtration over a column (silica gel and PE) yielding methyl 5-(difluoromethoxy)-2-methylbenzoate, which is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (100 mg, 0.288 mmol) in CH2Cl2 (2 mL) was added pyridine (47 mL, 0.576 mmol, 2 equiv) followed by benzenesulfonyl chloride (44 μL, 0.345 mmol, 1.2 equiv). The reaction was allowed to stir overnight at RT. The reaction was diluted with CH2Cl2, washed with saturated aqueous NH4Cl and brine, dried over MgSO4 to give an oil. Purification by chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (114 mg, 0.234 mmol, 81%). The structure was confirmed by NMR and mass spectrometry. MS m/z 488 (M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[C:25](=[O:31])[NH:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH:27]1([NH:26][C:25]([C@@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18](=[O:19])[CH2:17][O:16][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=2)=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.4 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid ethyl ester in 20 ml of THF, 3.3 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 1 to precipitate the product, which was then collected by filtration. The residue was co-distilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 945 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3,3-dimethylbutanoyl chloride (0.050 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 701 [M+H]+.