Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([OH:59])=O)[NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:60]([O:67][C:68](=[O:91])[NH:69][CH2:70][CH2:71][CH2:72][C@H:73]([NH2:90])[C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[O:81])=[O:75])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([NH:90][C@H:73]([C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)=[O:81])=[O:75])[CH2:72][CH2:71][CH2:70][NH:69][C:68]([O:67][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:91])=[O:59])[NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
350 mg (0.92 mmol) of HATU and 330 mg (2.56 mmol) of N,N-diisopropylethylamine are added to a solution of 320 mg (0.88 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine and 350 mg (0.73 mmol) of benzyl{(4S)-4-amino-5-[(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-5-oxopentyl}carbamate (Example 122A) in 5 ml of anhydrous DMF at 0° C. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is stirred with water, collected by filtration and dried under high vacuum.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9](=[O:26])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[N:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:35].[ClH:35].[ClH:35].[NH2:7][C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[N:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
[1-benzyl-2-oxo-2-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-yl)-ethyl-carbamic acid tert-butyl ester (0.046 mg) was dissolved in DCM (5 mL) and HCl/dioxane (0.5 mL) was added. The suspension was stirred at room temperature for 3 hours, after which it was concentrated to give (2R)-2-amino-3-phenyl-1-(4-pyrido[2,3-d]pyrimidin-4-yl-piperazin-1-yl)-propan-1-one trihydrochloride (0.031 g, 86%). Rt 1.55 min. MS (ESI+) [M+H]+363.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: BrCC1CCCCO1
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 12 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved in N,N-dimethylformamide (5 mL). 2-Bromomethyl-tetrahydro-pyran (0.34 g, 1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and the reaction mixture is stirred at 60° C. for 12 hours under N2. The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid residue is triturated with diethyl ether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellow filtrate (mixture of N1 and N3 regioisomers by NMR). The solids are collected and washed with diethyl ether to yield 0.12 g (37%) of the pure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+) m/z 496, 498 (M+, Br pattern) detected.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br.CCOCC>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccccc1Nc1ccccc1OC
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1Nc1ccccc1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A solution of 9.74 g (0.0359 mole) of ethyl 2-(2-methoxyphenylamino)benzoate in 50 ml of methylene dichloride was cooled to -78° C. and 114 ml of boron tribromide (1M in methylene dichloride) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at -78° C. for three hours, then at -40° C. for one hour and finally kept in a refrigerator at -4° C. overnight. Ether (50 ml) was added and the mixture poured into ice-water and ether. The ether solution was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to give 5.3 g of ethyl 2-(2-hydroxyphenylamino)benzoate, m.p. 105°-106° C.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 57 mg (57%) of the title compound as an off white solid.
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[N:16]=2)[CH:8]=[CH:9][C:10]=1[OH:11].Br[CH:30]([CH3:32])[CH3:31]>>[F:28][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)Br
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OCC(F)F)c2)n1
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(C)C)c(OCC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 317 and 2-bromopropane, white powdery 3-{2-[3-(2,2-difluoroethoxy)-4-isopropoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([CH2:29][C:30]#[N:31])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])C.[S:40]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41]1>>[C:34]([CH2:33][CH2:32][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)[CH:25]=[C:24]([CH2:29][C:30]#[N:31])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:39])([OH:36])=[O:35]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CC#N)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccsc1
Product: N#CCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1

Procedure:
The title compound was prepared according to general method described in step 4 by reaction of 4-[3-[6-(3-cyanomethyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester with thiophene-3-boronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM. Calculated for C31H36NO6S (M+H)1+ 550.22. found 550.20.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]\[C:13]([CH3:16])([CH3:15])[CH3:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[N:25][C:26]([O:28][Si](C)(C)C)=[CH2:27])[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[C:13]([CH:12]1[CH2:27][C:26](=[O:28])[NH:25][CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:6]21[C:5]1[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:7]2=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)/C=C1/C(=O)Nc2cc(Cl)ccc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 1c, E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one (0.23 g, 1 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.63 g, 2.5 mmol) prepared in example 1b, in toluene to give racemic (2′SR,3S,4′R)-4′-(tert-butyl)-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a mixture of two sets of diastereomers (Yield 0.21 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCc1cccnc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3cccnc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-aminomethylpyridine (0.010 mL, 0.098 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(pyridin-3-ylmethyl)amino methyl]indol-2-yl)isoindolinone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.Cl>O.C(O)C>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.8 %

Procedure:
5-amino-4,6-dichloropyrimidine (5.00 g, 29 mmol) and 4-chloroaniline (4.71 g, 36 mmol) were suspended in 80 ml H2O and 12 ml ethanol. Concentrated HCl (1.2 ml, 14.5 mmol) was added at room temperature followed by warming reaction to 82° C. After stirring for 19 hours the reaction was cooled to room temperature and stirred for 60 hours. The precipitate was collected on a sintered glass funnel and rinsed with water followed by hexanes. After drying under vacuum, I-(1A-1)a was obtained as an off-white solid (7.38 g, 98%): +ESI MS (M+1) 255.3; 1H NMR: (400 MHz, CD3OD): δ 7.87 (s, 1H), 7.66 (d, J=8.7 Hz, 2 H), 7.30 (d, J=8.7 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][C:30]([F:42])([F:41])[CH2:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([N:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]3[CH2:31][C:30]([F:29])([F:42])[F:41])[N:3]=2)[CH2:24][CH2:25]1
Reactant: FC(F)(F)Cc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(CC(F)(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1
Temperature: 155 °C
Yield: 53 %

Procedure:
A small vial was charged with 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.070 g, 0.17 mmol), 2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (0.042 g, 0.21 mmol), XPhos (0.012 g, 0.026 mmol) and Potassium phosphate (0.110 g, 0.519 mmol). Dry 1,4-dioxane (1.9 mL, 0.024 mol) was added. The whole was sparged with nitrogen for 3 min. Tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol) was added under nitrogen. The vial was sealed and heated at 155° C. (heating block temp) for 4 h. LC/MS indicates complete reaction. The solution was diluted with water and extracted with dichloromethane 3 times. The combined organics were washed with brine and dried over sodium sulfate. The material was purified by reverse phase HPLC to give 51.3 mg (53% yield) of 173 as a white solid. LCMS (MH+)=570.3. 1H NMR (400 MHz, DMSO) δ 8.25-8.15 (m, 2H), 7.91 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.42-7.31 (m, 2H), 4.65 (q, J=10.7 Hz, 2H), 4.90-4.25 (br m, 4H), 4.05 (s, 1H), 3.88-3.80 (m, 4H), 3.74 (s, 2H), 2.92 (d, J=11.1 Hz, 2H), 1.99 (t, J=11.1 Hz, 2H), 1.67 (d, J=11.2 Hz, 2H), 1.37-1.23 (m, 2H), 1.22-1.12 (m, 1H), 1.04 (s, 6H)
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].P(=O)(O)(O)O.[OH-].[Na+].NC(N)=S.[H][H]>[Pd].C1COCC1>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: [H][H]
Agent: [Pd]
Agent: NC(N)=S
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Yield: 91.2 %

Procedure:
A known amount of THF (26.7 g) is charged into a 0.5 L RBF, and 3.05 g of 14-hydroxycodeinone is added into it. With stirring 120 g of aqueous phosphoric acid (1M, 9.8%) is added. The mixture is stirred until the entire solid dissolved. While stirring 40% aqueous sodium hydroxide is added (12.5 g) dropwise over a 30-minute period until the pH of the solution reaches 6.20–6.30. An aqueous thiourea solution (0.001% w/w, 20.0 g) is then added to the reaction flask. This buffered solution is charged into a stainless hydrogenation vessel, followed by the addition of 0.150 g of 5% palladium on barium sulfate (dry basis). The vessel is sealed, pressurized to 15 psi with nitrogen, and then ventilated. This operation is repeated 3 times with nitrogen, and then with hydrogen. The reaction vessel is finally pressurized to 15 psi with hydrogen, and is stirred at this pressure until the reaction is completed (6 hours, residual 14-hydroxycodeinone<0.5 a/a % by HPLC). The hydrogenated solution is taken out from the stainless vessel. The catalyst is vacuum filtered off through a pad of Celite. The autoclave is rinsed with water (2×5 g) and the rinses are used to wash the catalyst cake on the filter. The filtrates are combined in a 0.5 L beaker with a magnetic stirrer. The solution is cooled in an ice-bath for 30 minutes and 15.5 g of ammonium hydroxide is added dropwise over a period of 30 minutes while cooling and brisk stirring continued. The addition of aqueous ammonia is mildly exothermic, so the rate of addition should be controlled such that the temperature does not exceed 30° C. A fine white precipitate formed during the basification process. The final pH of the suspension is 10–12. The precipitate is continuously cooled and stirred for 1 hour. It is then filtered, washed with water (3×10 g), and vacuum-dried for 3 h. A white solid of oxycodone (2.80 g, 91%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:50]([F:53])([F:52])[F:51])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([NH:16][CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH2:13]3)[NH:7][C:6]=2[CH:49]=1.[C:54]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[C:3]([C:50]([F:51])([F:52])[F:53])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:13][CH:14]([N:16]([CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:26])([CH3:27])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:54])[CH2:15]3)[NH:7][C:6]=2[CH:49]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.10 mmol) in methanol (2.5 mL) was treated with sodium cyanoborohydride (84 mg, 1.3 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% aqueous formaldehyde (0.12 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature till complete by LCMS. After 2 h, the reaction was complete and the reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 7 mL NaHCO3 and the aqueous phase was extracted with three 10 mL portions of CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated to yield a colorless stiff foam/glass. The crude material was purified by flash chromatography (20 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (62 mg, 80%) as a colorless glass: MS (ESI+) for C39H45ClF3N7O4 m/z 768.0 (M+H)+; MS (ESI−) for C39H45ClF3N7O4 m/z 766.3 (M−H)−; HPLC purity 92.1% (ret. time, 3.29 min).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH:6]=1
Reactant: Brc1c[nH]nc1-c1ccncc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cc(Br)c(-c3ccncc3)n2)nc1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
To 4-(4-bromo-1H-pyrazol-3-yl)-pyridine (200 mg; Example 4, Step 1) in 5 mL DMF was added slowly 0.043 g of a 60% suspension of sodium hydride in mineral oil. After 20 minutes 0.124 g 6-chloronicotinonitrile was added. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and resulting solid was collected by vacuum filtration to yield 0.26 g (89% yield) product as a tan solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 328.5 by positive ESI.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[C:28]1([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:9][CH2:8][CH2:7][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C1CCNCC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCCC4)CC3)c[nH]c12
Yield: 47.6 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (62 mg, 0.13 mmol) and piperidine (55.25 mg, 0.65 mmol) were allowed to react in the presence of K2CO3 (72 mg, 0.56 mmol) and NaI (Cat. 2.0 mg). The resulting residue purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (31.5 mg, 46%).