Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:12]=3)[CH2:7]2)[C:5](=[O:27])[NH:4][C:3]1=[O:28].Cl.N>CCOC(C)=O.CO>[NH2:18][CH2:17][C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@:6]1([C:5](=[O:27])[NH:4][C:3](=[O:28])[N:2]1[CH3:1])[CH2:14]2)=[O:26]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1C2
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN)cc1C2
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl (2-{[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]amino}-2-oxoethyl)carbamate from Step A (1.80 g, 4.63 mmol) in EtOAc (50 mL), at 0° C., was added anhydrous HCl (bubbled in through a pipet, for 5 minutes). After an additional 30 minutes of standing at 0° C., the solvent and excess HCl was removed in vacuo to yield a solid. This solid was then dissolved in the minimal amount of MeOH and treated with a methanolic 2 N ammonia solution (20 mL, 40 mmol). This mixture was stirred for 30 min at ambient temperature, before the bulk of the MeOH was removed in vacuo. The residue was applied to a silica gel column for purification, eluting with DCM:MeOH (10% conc. NH4OH)—95:5 to 85:15. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][NH:29][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccc(F)c(F)c1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)c(F)c4)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(3,4-difluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-(trans-4-[3-(3,4-difluorophenyl)-propylamino]cyclohexyl}-3H-benzoxazol-2-one (690 mg, 37%): 1H NMR (500 MHz, DMSO-d6): δ 7.33-7.24 (m, 2H), 7.12 (d, J=1 Hz, 1H), 7.06-7.02 (m, 1H), 6.98-6.93 (m, 2H), 3.51-3.10 (br s, 2H), 2.62 (dd, J=8, 8 Hz, 2H), 2.55 (dd, J=7, 7 Hz, 2H), 2.48-2.38 (m, 2H), 1.98-1.91 (m, 2H), 1.80-1.73 (m, 2H), 1.71-1.65 (m, 2H), 1.44 (dddd, J=10, 10, 10, 3 Hz, 2H), 1.13 (dddd, J=10, 10, 10, 3 Hz, 2H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[I-:45].[Na+]>ClCCl.O>[I-:45].[C:21]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[C:25]([S+:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]2=3)[CH:24]=1)([OH:23])=[O:22]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S1c2ccccc2-c2ccccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)O)cc1-[s+]1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Dibenzothiophene oxide (57 g, 285 mmol) and 4-methoxybenzoic acid (47.7 g, 314 mmol, 1.1 eq) were suspended in dichloromethane (400 mL) and cooled to 0° C. where Eaton's Reagent (285 mL) was added dropwise. The solution was taken off ice and stirred overnight at r.t. The reaction mixture was cooled back to 0° C. and quenched with the slow addition of water (800 mL), followed by ethyl acetate (500 mL). The precipitate was filtered off and the layers separated. The aqueous layer was extracted with ethyl acetate (2×500 mL) and the combined organic layers were washed with water (500 mL). Sodium iodide (341.6 g, 2.28 mol, 4 eq) in water (500 mL) was slowly poured onto the combined aqueous layers. Additional water was slowly added until precipitation of a viscous oil stopped. The crude oil was recrystallized from acetone afford the title compound (72.0 g, 55%) as a white solid. 1H NMR (300 MHz, (d-DMSO) δ: 12.0-13.0 (brs, 1H), 8.54 (d, J=7.8 Hz, 2H), 8.35 (d, J=8.1 Hz, 2H), 8.21 (dd, J=8.7, 2.1 Hz, 1H), 7.99 (t, J=7.8 Hz, 2H), 7.79 (t, J=7.8 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([OH:16])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)OC(C)(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.4 %

Procedure:
To a solution of tert-butyl 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoate (example 199a, 0.485 g, 1.09 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.73 g, 2.52 ml, 32.8 mmol) and the reaction mixture was stirred at room temperature for 14 hours. Volatiles were removed in vacuo and the residue was dissolved in toluene followed by evaporation to dryness. The procedure was repeated twice to yield the title compound (446 mg) as a crude solid which was used without any purification. MS (ESI, m/z): 387.5 (M−H+).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13]C)=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[OH:15])[CH:2]=[CH2:3].Br>C(O)(=O)C>[OH:13][C:12]1[C:4]2[CH2:1][CH:2]([CH3:3])[O:15][C:5]=2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=1
Reactant: C=CCc1c(O)cc(C(=O)O)cc1OC
Agent: Br
Solvent: CC(=O)O
Product: CC1Cc2c(O)cc(C(=O)O)cc2O1

Procedure:
A mixture of 30 grams of 4-allyl-3-hydroxy-5-methoxybenzoic acid, 150 cc of glacial acetic acid and 45 cc of 48%HBr is heated to the reflux temperature for 8 hours. After this time the reaction mixture is concentrated to dryness and the obtained residue, ground with water and filtered is crystallized from ethyl ether-petroleum ether. The product is obtained in a yield of 19.9 grams (71 percent of theoretical) and has a melting point of 181°-184° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[Cl:20][C:21]1[C:22]([F:43])=[C:23]([C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36]([O:38]CC)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[C:22]([F:43])=[C:23]2[C:24]([C:36]([OH:38])=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28](=[O:29])[C:27]2([CH3:41])[CH3:42])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(Cl)c(F)c2C(C)(C)C1=O
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
P2O5 (12.5 g, 88.1 mmol) was mixed with concentrated H2SO4 (11.2 mL, 81.3 mmol) at 0° C., and the resulting mixture was stirred for 30 minutes. Diethyl 2-(2-(3-chloro-2-fluorophenyl)-2-methylpropanoyl)malonate (1.00 g, 2.48 mmol) was added to the reaction, and the resulting mixture was stirred at 25° C. for 1 hour. The resulting mixture was quenched with ice, and, on melting, was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated, and dried in vacuo to give crude ethyl 7-chloro-8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.470 g). MS m/e=313 (M+H)+.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18]
Reactant: CC=CCC1Cc2c(Cl)cccc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2c(Cl)cccc2C1=O
Reaction time: 1.5 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 15.1 g of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone in 200 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide the mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 200 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 13.9 g (97%) of (RS)-2-(2-oxoethyl)-4-chloro-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [C:1]([C:6]1[C:7](=O)[C:8]2[S:14][CH:13]=[CH:12][C:9]=2[NH:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].N.P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:6]1[C:7]([Cl:19])=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2ccsc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CCCC(=O)c1cnc2ccsc2c1Cl

Procedure:
6-Butyrylthieno[3,2-b]pyridin-7(4H)-one (7.9 g, 0.0357 mol) and phosphorus oxychloride (30 ml) were heated under reflux for 1 hour. After allowing to cool the reaction mixture was poured onto ice basified with concentrated ammonia solution and extracted with dichloromethane (3×150 ml). The combined dichloromethane extracts were dried, filtered and evaporated to dryness to give 6-butyryl-7-chlorothieno[3,2-b]pyridine, 5.5 g. Recrystallization from hexane gave an analytically pure sample, m.p. 78°-80°.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([N:27]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:2]3[C:3]([CH3:19])=[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:32]=[CH:33]2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 100 °C
Yield: 7.2 %

Procedure:
To a stirred solution of 5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (159 mg, 0.14 mmol), in degassed DMF (3.0 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (184 mg, 0.55 mmol), K2CO3 (153 mg, 1.10 mmol), and H2O (0.5 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 15 mg (7%) of the desired product. 1H-NMR (DMSO-d6) 8.56 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.54 (s, 1H), 7.32-7.38 (m, 5H), 7.02 (d, 1H), 5.65 (s, 2H), 3.81 (s, 2H), 2.53-2.50 (m, 4H), 2.43-2.40 (m, 4H), 2.10 (s, 3H); LC-MS [M+H]+=454, RT=2.30 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:27]([C:26]1[C:22]([CH3:21])=[N:23][O:24][C:25]=1[CH3:30])=[O:28]
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1c(C)noc1C
Yield: 50 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3,5-dimethyIsoxazole-4-carbonyl chloride in 50% yield.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[Cl-:9].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:2][N+:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(N[n+]1ccccc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
1-Aminopyridinium chloride (104 parts) and p-chlorobenzoyl chloride (150 parts) were heated in xylene (750 parts) at 140° C. for 4 hours. The solid product was filtered off and recrystallised from n-butanol to give 1-(p-chlorobenzamido)pyridinium chloride (209 parts, 97% yield), melting point 241° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-in 300 ml of dimethylformamide were heated at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C(=O)C>[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (386 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a solution of 6′-phenoxy-3,3′-bipyridin-2-amine (302 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 4 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (323 mg) as an off-white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]=[C:7]([C@H:10]([CH2:19][CH:20]=C)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:8][CH:9]=1)=[O:4].I([O-])(=O)(=O)=[O:24].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]=[C:7]([C@H:10]([CH2:19][CH:20]=[O:24])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[O:8][CH:9]=1)=[O:4]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)N(C)C)co1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: CN(C)C(=O)c1coc([C@H](CC=O)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl (3R)-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}-5-hexenoate (Preparation 117) (1.0 g, 3.24 mmol) in acetone (20 ml) and water (20 ml) was treated with osmium tetroxide, 2.5% wt in tert-butanol (500 μl, 0.04 mmol) and stirred at room temperature for 5 minutes. Sodium periodate (2.13 g, 10.00 mmol) was added and the reaction mixture stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulphate solution (20% wt). The organic layer was washed with water (×2) and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (866 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:15]1([CH2:14][C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm) (CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:19]2[CH2:22][CH:21]([C@@H:23]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([C:35]#[N:36])[CH:29]=3)[C:24]([F:27])([CH3:26])[CH3:25])[CH2:20]2)[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][NH2:15])=[O:13])=[CH:4][CH:3]=1.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:11]([C:12]3[O:13][C:37](=[O:38])[NH:15][N:14]=3)[CH:10]=2)[N:19]2[CH2:22][CH:21]([C@@H:23]([C:28]3[CH:29]=[C:30]([CH:31]=[C:32]([F:34])[CH:33]=3)[C:35]#[N:36])[C:24]([F:27])([CH3:26])[CH3:25])[CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=O)NN)c2)C1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3n[nH]c(=O)o3)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3.0 g (5.85 mmol) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3-cyano-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzohydrazide in 100 mL of CH2Cl2 was added 3.73 mL (7.1 mmol) of phosgene solution (20% in toluene). The solution was stirred for 1.5 h at 0° C., The solution was concentrated ,and to the residue was added 6 mL of 2N NH3 in MeOH, and the mixture was concentrated again. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.26 (d, 3H, J1=22.1 Hz), 1.30 (d, 3H, J1=21.7 Hz), 2.39(t, 1H, J=8.0 Hz), 2.93-3.0(m, 2H), 3.12(t, 1H, J=7.3 Hz), 3.33(m, 1H), 3.69 (t, 1H, J=6.8 Hz), 4.35(s, 1H), 7.20 (d, 1H, J=9.7 Hz), 7.23 (d, 1H, J=7.3 Hz), 7.29-7.40(m, 7H), 7.48 (d, 1H, J=7.8 Hz), 7.68 (d, 1H, J=7.8 Hz), 7.97 (s, 1H); Mass Spectrum: m/e=535, (M+1, 35Cl), 537 (M+1, 37Cl).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].Cl.[OH-:24].[Na+]>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([OH:24])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: [OH-]
Reactant: COC(=O)C1(CCC(C)(C)C)C(=O)CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Yield: 56 %

Procedure:
A solution of Example 8C (0.28 g, 0.93 mmol) in 1 N NaOH (11.2 mL) was stirred at 45° C. for 2 days. The solution was neutralized to PH 3 with 1 N HCl, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound as a white solid (0.135 g, 56%).
Reaction SMILES: O.[F:2][C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][C:4]=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=[O:20].Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].FC1C=CC=CC=1B(O)O>>[OH2:20].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:53][CH2:54][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=2)[CH2:56][CH2:57]1)=[O:49]
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Agent: OB(O)c1ccccc1F
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5ccccc5F)cc34)CC2)o1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(2-Fluorophenyl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid hydrate 20 was prepared, according to the procedure described for compound 12, from compound 15 and (2-fluorophenyl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes. Yield: 20 mg, 7%.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1([CH3:17])[C@@H:9]([CH2:10][C:11](=O)[CH3:12])[C@H:8]1[C:14]([OH:16])=[O:15].Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20]>O>[CH3:6][C:7]1([CH3:17])[C@@H:9]([CH2:10][C:11](=[N:23][O:22][CH:19]([CH3:21])[CH3:20])[CH3:12])[C@H:8]1[C:14]([OH:16])=[O:15]
Reactant: CC(=O)C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: CC(C)ON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C[C@H]1[C@@H](C(=O)O)C1(C)C)=NOC(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1.85 g of sodium bicarbonate in 50 ml of water, were added 1.70 g of (1R,cis)-2,2-dimethyl-3-(2-oxopropyl)cyclopropanecarboxylic acid and 1.15 g of isopropoxyamine hydrochloride at room temperature. The reaction mixture was stirred at room temperature for 4.5 hours and filtered through celite. The filtrate was acidified with concentrated hydrochloric acid to a pH of 2, and extracted with methylene chloride. The organic extract was washed with a sodium chloride solution, dried over magnesium sulfate, stripped and concentrated under high vacuum to give the desired product as a slightly amber oil.