Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH2:33][CH3:34])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][C:25]([CH2:33][CH3:34])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)oc1CC
Yield: 71.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (5 mL), ethyl 2-(4-aminophenyl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (99b) (0.2 g, 0.77 mmol) and pyridine (5 mL), to obtain 0.23 g of the title compound as a light pink solid (72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:21][O:20][N:19]([CH3:18])[C:12](=[O:14])[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 1-tert-butoxycarbonylisonipecotic acid (5 g, 21.8 mmol; Example 81, Step A), N,O-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide-hydrochloride (4.6 g, 24 mmol), 1-hydroxy-7-azabenzotriazole (0.3 g, 2.2 mmol), and anhydrous dimethylformamide (50 mL) was stirred at room temp. overnight. The resulting mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide N-Methoxy-N-methyl 1-tert-butoxycarbonylisonipecotamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 93 %

Procedure:
A solution of 4-(3-ethoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.28 g, 34.035 mmol) in ethanol (680 mL) was pumped through Pd/C cartridge using H-Cube apparatus (20° C., 10 bar, 2 mL/min.). The solvent was then evaporated under reduced pressure to give 4-(3-ethoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.55 g, 93%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=1.39-1.43 (t, 3H), 1.51 (s, 9H), 1.61-1.72 (dq, 1H), 1.78-1.90 (m, 1H), 2.66-2.74 (dt, 1H), 2.74-2.89 (m, 1H), 4.20-4.31 (m, 1H), 4.32-4.42 (q, 2H), 7.39-7.41 (m, 2H), 7.88-7.92 (m, 2H). MS: m/z=334 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[CH2:33][C@H:32]2[C@@H:22]([CH2:23][C:24]3[C:34]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]2=4)[NH:26][CH:25]=3)[N:21]([CH3:35])[CH2:20]1)(=O)=O.C>ClCCl.CN(C)C=O>[CH3:35][N:21]1[C@H:22]2[C@@H:32]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:34]=3[C:24]([CH2:23]2)=[CH:25][NH:26]4)[CH2:33][C@@H:19]([CH2:18][N:13]2[CH:12]=[CH:11][N:10]=[C:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2ccnc2-c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
1.0 g of 50% sodium hydride in an oil was added in small portions to a mixture of 10.5 g of 2-phenylimidazole and 60 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.5 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with acetone). The product thus obtained was treated with charcoal in dichloromethane, and recrystallized from dichloromethaneisopropyl acetate to obtain 1.0 g of the titled compound as colorless prisms having a melting point of 193°-195° C.
Reaction SMILES: FC1C=CC(C(F)(F)F)=CC=1[NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=[O:14].C(C1SC(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=CC=2)=O)=NC=1C1C=CC=CC=1)C.C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(O)=O)=CC=3)CC2)=CC=1)(C)(C)C.[CH3:101][O:102][C:103]1[C:108]2[N:109]=[C:110](N)[S:111][C:107]=2[CH:106]=[CH:105][CH:104]=1>>[CH3:101][O:102][C:103]1[C:108]2[N:109]=[C:110]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:14])[S:111][C:107]=2[CH:106]=[CH:105][CH:104]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)CC2)cc1
Agent: CC(C)(C)OC(=O)c1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Agent: CCc1sc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)nc1-c1ccccc1
Product: COc1cccc2sc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5)CC4)cc3)nc12

Procedure:
With the same method as described for the preparation of 4-{4-[4-(2-fluoro-5-trifluoromethyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-benzoic acid, 4-{4-[4-(5-ethyl-4-phenyl-thiazol-2-ylcarbamoyl)-phenyl]-piperazin-1-yl}-benzoic acid was prepared from 4-[4-(4-carboxyphenyl)-piperazin-1-yl]-benzoic acid tert-butyl ester and 4-methoxy-benzothiazol-2-ylamine. LCMS calc for C26H24N4O4S (m/e) 488, obsd 489 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31]([N:12]1[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 2,5-difluorobenzenesulfonyl chloride (319 mg), the title compound was obtained as a colorless oil (yield 160 mg, 33%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7]=O.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH:25]1[C:34]2[N:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1COCC1.Br.CC(O)=O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH:25]1[C:34]2[N:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=Cc1ncccn1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cnc(CNCCCCN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Using General Procedure B: To a solution of the crude aldehyde from above (332 mg) and N′-(1H-benzoimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (49 mg, 0.14 mmol) in THF (2 mL) was added NaBH(OAc)3 (89 mg, 0.42 mmol) and the mixture was stirred at room temperature for 1.5 h. The crude material was dissolved in saturated HBr/AcOH (2 mL) and stirred at room temperature for 5 minutes. The solution was made basic with 10 N NaOH(aq) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) afforded a yellow oil (44 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[N:30]=[N:29][CH:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])=[CH:10][CH2:9]1)=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[N:30]=[N:29][CH:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])=[CH:10][CH2:9]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ncnn4)OC3=O)cc2F)CC1
Agent: N
Solvent: CO
Product: O=C(CO)N1CC=C(c2ccc(N3C[C@H](Cn4ncnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
(5R)-3-(4-(1-(2-Acetoxyacetyl)-1,2,5,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one (365 mg, 0.82 mM) was treated with a saturated solution of ammonia in methanol (40 ml), warmed slightly to dissolve completely, then stirred at room temperature for 20 hours. The solvent was evaporated to give an orange oil which was triturated with diethyl ether to give the title compound as a pale yellow solid (211 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][CH:21]=[CH:22]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cncc(C#N)c2-c2ccc3[nH]ccc3c2)cc1OC
Yield: 60.1 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), indole-5-boronic acid (77 mg, 0.48 mmol), Pd(PPh3)4 (25 mg, 0.022 mmol) and aqueous saturated NaHCO3 (3 mL) in DME (4.0 mL) was heated at reflux for 5 h. The reaction mixture was partitioned between water and EtOAc. The combined organics were dried over Na2SO4 and concentrated to give a brown syrup, which was purified by preparative thin-layer chromatography eluting with 3% MeOH/CH2Cl2 to give 94 mg (61%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yl)nicotinonitrile 221 as an off-white solid. MS: 356.2 (M+H); melting range: 215-217° C.
Reaction SMILES: [Na].[SH:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.CC(O[CH2:13][C:14]1[CH2:23][S:22][C@@H:17]2[C@H:18]([NH2:21])[C:19](=[O:20])[N:16]2[C:15]=1[C:24]([OH:26])=[O:25])=O.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:21][CH:18]1[C:19](=[O:20])[N:16]2[C:15]([C:24]([OH:26])=[O:25])=[C:14]([CH2:13][S:2][C:3]3[N:7]([CH3:8])[N:6]=[N:5][N:4]=3)[CH2:23][S:22][C@H:17]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A 3.5 ml portion of acetonitrile was added to 0.570 g of dihydrate of 5-mercapto-1-methyl-1H-tetrazole sodium salt and 0.680 g of 7-ACA, and 1.64 g of diphosphoryl tetrachloride was added dropwise to the mixture under cooling over an external bath at -30° to -20° C., followed by adding 2.29 g of DCPA and rinsing with 0.5 ml of acetonitrile. The reaction solution was stirred at -5° to 0° C. for 5 minutes, warmed at 25° C., and stirred for 40 minutes to allow the reaction to proceed. The reaction solution was cooled and poured into ice-water, which was placed in a refrigerator overnight. The mixture was adjusted to pH 4.0 with 25% aqueous ammonia, and the resultant precipitate was recovered by filtration, washed with cold water and acetone successively and dried, thereby affording 0.732 g (89.3% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5 -yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR values of the product were in accordance with those of the authentic sample.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[O-:36][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCCCC(=O)CCCn1c(CCC)nc2c[n+]([O-])c3ccccc3c21

Procedure:
The general method described in Parts I and J of Example 28 was used to aminate 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g, 17.2 mmol) by reaction with m-CPBA (8.50 g) to provide 1-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one followed by reaction with p-toluenesulfonyl chloride (4.90 g, 25.8 mmol) and ammonium hydroxide solution (100 mL) to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one) as a white solid after recrystallization from aqueous methanol, mp 111-113° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.O1CCCC1.C([Li])CCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3[CH:29]=[C:30]4[C@:35]([CH:37]=[O:38])([CH2:36][C:27]=3[CH:26]=[N:25]2)[CH2:34][N:33]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:32][CH2:31]4)=[CH:20][CH:19]=1>O1CCCC1.C(O)C.C(O)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3[CH:29]=[C:30]4[C@:35]([CH:37]([C:2]5[O:1][CH:5]=[CH:4][N:3]=5)[OH:38])([CH2:36][C:27]=3[CH:26]=[N:25]2)[CH2:34][N:33]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:32][CH2:31]4)=[CH:20][CH:19]=1
Reactant: c1cocn1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ncco2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of oxazole (99 μL, 0.5 mmol) in dry tetrahydrofuran (2.5 mL) was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 1.65 mmol, 1.65 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −78° C. and butyl lithium (1.6 M solution in hexanes, 1.20 mL, 1.95 mmol) was added dropwise. The reaction mixture was stirred for 40 minutes at −78° C. A solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (250 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ethanol/acetic acid mixture (95:5, v/v; 50 mL) and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with water (20 mL), saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0-4% methanol in dichloromethane) to afford, as a mixture of diastereoisomers, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol as a white foam (136 mg). LCMS (Method A, ESI): RT 3.68 min, m+H=575.0.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Br)(Br)[Br:15]>CN(C=O)C.O>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of (b) (12 g, 70.5 mmol) in DMF (75 ml) was added dropwise phosphorous tribromide (8 ml, 84.6 mmol) over five minutes (slightly exothermic). The reaction was allowed to cool to room temperature and was then diluted with ice water (100 ml) and stirred 1 hour then diluted with additional water (300 ml). The product was filtered off, washed with water and air dried to provide 14.3 g of product (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccc(I)c(Br)c1
Product: Cc1ccc(Sc2ccc(Cl)cc2)c(Br)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 2-bromo-1-iodo-4-methyl-benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([OH:11])=[C:6]([F:12])[C:5]=1[F:13].C(=O)([O-])O.[Na+].Cl[CH2:21][C:22](Cl)=[O:23]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[F:13][C:5]1[C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:9][C:8]2[NH:10][C:22](=[O:23])[CH2:21][O:11][C:7]=2[C:6]=1[F:12]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(N)c(O)c(F)c1F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2c(c(F)c1F)OCC(=O)N2
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of 5-amino-2,3-difluoro-4-hydroxy-benzoic acid methyl ester (5.5 g, 27.1 mmol) and benzyl-triethylammonium chloride (6.2 g) in chloroform (300 mL) was warmed and sonicated until most of the solid was dissolved. The mixture was cooled in an ice bath and sodium hydrogen carbonate (10 g) was added, followed by chloroacetyl chloride (2.4 mL, 29 mmol). The combined mixture was stirred in cold for 1 hour and then under reflux for approximately 9 hours. It was then evaporated in vacuo and the resulting residue was treated with water and chloroform to give a solid. This solid was collected by filtration, washed with water, diethyl ether and dried in vacuo to give the title compound (3.7 g, 56%).
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:6]=1[F:20])=[O:4].Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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]>[F:21][CH:2]([F:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)=[CH:7][C:6]=1[F:20])=[O:4]
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(C(=O)C(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(F)cn2)cc1F)C(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-difluoro-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (21 g, 70 mmol), 2-bromo-5-fluoropyridine (12.32 g, 70 mmol), Na2CO3 (14.84 g, 140 mmol) in DMF (300 mL) and H2O (80 mL) was degassed and filled with nitrogen. Then Pd(dppf)Cl2 (2.56 g, 3.5 mmol) was added and the mixture was again degassed and filled with nitrogen. After stirring overnight at 90° C., the reaction mixture was poured into ice (80 g) and extracted with Et2O (500 mL×3). The combined extracts were dried (MgSO4), filtered and concentrated, and the residue was purified by column chromatography (PE/EA 20:1) to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:33])([F:32])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:33][C:14]([F:13])([F:32])[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]2[CH2:26][CH2:27][CH:28]([O:31][N:35]3[C:39](=[O:40])[C:38]4[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:36]3=[O:45])[CH2:29][CH2:30]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 1.0 ml, 2.2 mmol) was added to the mixture of 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ol (651 mg, 2.0 mmol), N-hydroxyphthalimide (359 mg, 2.2 mmol) and triphenylphosphine (577 mg, 2.2 mmol) in THF (8 ml) at 0° C. and stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica (EtOAc/Hexanes 10/90-50/50) to give 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (390 mg, 40%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: OCCOc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COCCOc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 2-phenoxyethan-1-ol (1.5 mL, 12.7 mmol) in dichloromethane (50 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.1 mL, 10.5 mmol). The reaction mixture is stirred at rt overnight. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue vacuum distilled to give 1.95 g of the product 440. 1H NMR (CDCl3) δ 7.40-7.25 (m, 2 H), 7.10-6.90 (m, 3 H), 4.30-4.15 (m, 5 H), 4.15-4.05 (m, 1 H), 4.05-3.90 (s, 2 H), 1.28 (t, 3 H)