Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-phenylpropylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(3-phenylpropyl)amino-piperidine carboxylate. Yield: 110 mg. To a solution of tert-butyl 4-(3-phenylpropyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(3-Phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 61 mg; 13C-NMR (CD3OD, rotamers): δ 27.8, 29.4, 30.8, 32.3, 32.7, 33.3, 40.2, 40.5, 42.0, 44.5, 44.6, 44.9, 52.7, 54.56, 54.57, 54.9, 114.0, 114.1, 125.7, 126.1, 127.0, 127.4, 128.2, 128.3, 128.5, 129.47, 129.55, 141.2, 141.8, 158.9, 159.0, 172.5, 172.7.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)C.N1CCOCC1>CN(C)C=O.O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:14])=[CH:4][N:3]=1
Reactant: CCN1CCOCC1
Reactant: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (660 mg) in dimethylformamide (10 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.21 g), 1-hydroxybenzotriazole (0.86 g), N-ethylmorpholine (0.8 ml) and morpholine (0.55 ml). The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution and dried (MgSO4) then evaporated to afford the title compound as an off-white solid (783 mg). This was carried through without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(F)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(F)ccc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 26 (0.8 g, 1.78 mmol) was demethylated using pyridine hydrochloride (8.0 g, 69.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:12][CH2:11][CH2:10]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=2[O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 9a using 5-bromo-6-cyclobutoxy-3-pyridinecarboxylic acid and B-(4-chlorophenyl)-boronic acid (CAN 1679-18-1) as starting materials; MS (ESI): 302.2 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=[N:8][CH:9]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][NH:10][C:7]2[N:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:5][CH:6]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCN)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(CCNS(C)(=O)=O)cn1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 4 %

Procedure:
To a 20 dram vial was added tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate (140 mg, 0.34 mmol, 1.0 equiv), TEA (87 μL, 0.67 mmol, 2.0 equiv, THF (3 mL), and methanesulfonyl chloride (29 μL, 0.37 mmol, 1.1 equiv). The reaction was stirred for 2 h and then concentrated, followed by the addition of MeOH (1 mL) and 4N HCl/dioxane (3 mL). The reaction was stirred for 1 h, concentrated, and then purified by preparative TLC (5% MeOH/CH2Cl2) to give 5 mg of N-(2-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide (m/z [M+H]=366).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](NC)=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.FC1C=C(N2C[C@H](CNC(=S)C)OC2=O)C=CC=1N1CCOCC1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][CH:21]=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CNC(=S)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CC(=S)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](CNC=S)CN1c1ccc(N2CCOCC2)c(F)c1
Reaction time: 1.5 h
Yield: 28.5 %

Procedure:
A stirred mixture of 6 (0.38 g, 0.00118 mol) in dioxane (20 mL), under nitrogen was treated with 4 (0.51 g, 0.00126 mol), warmed to reflux during 30 min and kept at this temperature for 90 min. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH—CH2Cl2 and the slightly impure product was rechromatographed on silica gel with 25% EtOAc—CH2Cl2. The resulting product was crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of 7: mp 150-155° C. (dec); IR (DRIFT) 3322, 1752 cm−1; MS(ES) m/z 340 (M+H+), 362 (M+Na+); 1HNMR [300 MHz, (CD3)2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d,d, 1H), 3.94 (t, 2H), 4.12 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 9.33 (d, 1H), 10.59 (s, 1H). Anal. calcd for C15H18FN3O3S: C, 53.08; H, 5.35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19]C(=O)OC(C)(C)C)[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]>Cl.C(OCC)(=O)C>[NH2:19][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)[C:14]([N:15]([CH3:16])[CH3:17])=[O:18]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](N)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 112.2 %

Procedure:
tert-Butyl [(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethyl]-carbamate (227 mg, 0.630 mmol) was dissolved in a solution (10 mL) of 1 M hydrogen chloride/ethyl acetate, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (184 mg, 94%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][N:26]([Si](C(C)C)(C(C)C)C(C)C)[C:23]2=[N:24][CH:25]=1>C1COCC1>[F:19][C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][NH:26][C:23]2=[N:24][CH:25]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1cnc2[nH]ccc2c1
Reaction time: 0.25 h

Procedure:
Tetrabutylamonium fluoride, 1M in THF (2 mL), was added to a stirred solution of 5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 3.94 mmol) in THF (10 mL) at room temperature and stirred for 15 min. The solvent was evaporated and the crude product was purified by Biotage HPFC system (40-75% EtOAc/Hexane) to afford 5-fluoro-1H-pyrrolo[2,3-b]pyridine as a white solid (0.45 g, 84); Mass Spec.; MS 137 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.75(s, 1H), 8.17(t,1H), 7.81(dd,1H), 7.55(t,1H), 6.44(dd,1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]([OH:19])=O)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([S:41][C:42](=[O:45])[CH2:43][NH2:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C=O)C>[CH2:34]([S:41][C:42]([CH2:43][NH:44][C:17]([CH2:16][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1)=[O:19])=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCC(=O)SCc1ccccc1
Reactant: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(CC(=O)NCC(=O)SCc3ccccc3)cc(=O)oc2c1
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a solution of 10 (0.162 g, 0.62 mmol) in dry THF was added EDC (0.13 g, 0.68 mmol) and HOBt (0.104 g, 0.68 mmol). The reaction was stirred for 30 minutes under ice-cold conditions, followed by addition of 8 (0.135 g, 0.62 mmol) dissolved in minimal amount of DMF. The resulting solution was stirred further for 6 hours at RT. Upon removal of the solvent in vacuo, the resulting mixture was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a white solid, which was further purified by flash chromatography (silica gel, dichloromethane/ethanol=9:1) to afford 1 (0.15 g, 56%). 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=9.0 Hz, 1H), 7.27-7.23 (m, 7H), 6.38 (s, 1H), 4.1 (s, 2H), 3.73 (s, 2H), 2.91 (s, 2H), 2.32 (s, 3H). MS (ESI): m/z 448.0 [(M+Na)]+.
Reaction SMILES: Cl[CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH:2]([CH3:13])[CH2:3][CH2:4][C:5](=[O:6])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(Cl)CCC(=O)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C(C)CCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1F
Temperature: 50 °C
Yield: 69.8 %

Procedure:
To 100 mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50° C. and added 5.7 mol (414 mL) sulfoxide chloride. The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70%.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36]([N:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=3)[CH2:15][C@@H:16]2[CH3:20])=[O:37])[N:27]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: C[C@H]1CN(c2ccc(Cl)c(OCCF)c2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccc(Cl)c(OCCF)c2)CCN1C(=O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Temperature: 30 °C
Yield: 13.4 %

Procedure:
To a vial containing (S)-1-(3-(2-fluoroethoxy)-4-chlorophenyl)-3-methylpiperazine dihydrochloride (80 mg, 0.23 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (81 mg, 0.21 mmol), DMF (0.7 mL), and DIPEA (0.2 mL, 1.2 mmol). The reaction mixture was maintained at 30° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions were lyophilized to afford the indicated compound (14 mg, 13% yield): MS (ES) [M+H]+ expected 498.2, found 498.4; 1H NMR (CDCl3, 400 MHz) δ 9.95 (br s, 1H), 8.79 (dd, J=1.6, 8.2, 1H), 8.55 (dd, J=1.6, 4.4, 1H), 7.19-7.26 (m, 4H), 6.44-6.50 (m, 2H), 5.40 (br s, 2H), 4.77 (dt, J=4.2, 47.2, 2H), 4.26 (dt, J=4.2, 27.2, 2H), 2.78-4.42 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F-].[K+].Br[CH2:17]Br>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[O:12][CH2:17][O:13][C:10]=2[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCBr
Reactant: COC(=O)c1ccc(O)c(O)c1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1Cl)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a heavy walled vial containing methyl 2-chloro-3,4-dihydroxybenzoate (899.8 mg, 4.4 mmol, 1 equiv.) in 13 mL DMF was added KF (1.29 g, 22.2 mmol, 5 equiv.) and the mixture was stirred at room temperature for 30 min. Dibromomethane (0.375 mL, 5.3 mmol, 1.2 equiv.) was added and the mixture was heated to 120° C. for 4 h. The mixture was cooled down to room temperature, diluted with water, and extracted with ethyl ether. The combined ether layers were washed with 1M NaOH, water, brine, dried over anhydrous Na2SO4, filtered and solvent removed under vacuum. The crude product was absorbed onto silica and purified by flash column (silicagel, hexane:ethyl acetate 8 Å to give 395.8 mg (42%) of methyl 4-chlorobenzo[d][1,3]dioxole-5-carboxylate as a colorless crystalline solid. See Tetrahedron Lett. 38: 3361-3364 (1978); U.S. Patent Appl. Publication No. 20050009867.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=O)[CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.B.C1COCC1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH2:10][S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
(R)-4-(4-Morpholino-4-oxo-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide (INTERMEDIATE 73, 523.6 mg, 1.09 mmol) was dissolved under a nitrogen atmosphere in a solution of borane-THF complex (1M in THF; 2.4 ml, 2.4 mmol) and the resulting solution was stirred at room temperature overnight. The flask was opened to atmosphere and cautiously treated with MeOH (1.20 ml) followed by concentrated HCl (0.48 ml). The resulting mixture was heated at reflux for 3 hours and was then allowed to cool to room temperature. The pH of the mixture was adjusted to approximately 10 by the addition of aqueous solution of Na2CO3 (4 M) resulting in a precipitate. The mixture was dissolved in EtOAc (75 ml) and washed with water (40 ml), brine (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title product (406.6 mg, yield: 80%).
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[N:11]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])C1C=CC=CC=1.[Li+].[OH-]>O1CCCC1.O>[C:20]([N:11]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C@H:10]([C:9]([OH:39])=[O:8])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: COc1ccc(C[C@@H](C(=O)OCc2ccccc2)N(C(=O)CCCCCN)C(=O)OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H](C(=O)O)N(C(=O)CCCCCN)C(=O)OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 2.66 g (5 mmol) of the resultant compound of Example 170 in 60 mL of tetrahydrofuran was cooled to 0° C., treated with 0.63 g (15 mmol) of LiOH in 30 mL of H2O and allowed to stir for 2 h. After concentration of the solvent, the mixture was partitioned between H2O and ether, acidified, extracted with ethyl acetate, dried over MgSO4 and concentrated to give 1.55 g (70%) of the desired compound.
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10].C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+].Cl>CO>[C:11]1([CH:2]([NH2:23])[CH2:3][C:4]2[N+:5]([O-:10])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [BH3-]C#N
Reactant: O=C(Cc1cccc[n+]1[O-])c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: NC(Cc1cccc[n+]1[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
The ketone (10.72 g, 0.05 mol) prepared in step (a) above was combined with ammonium acetate (38.73 g, 0.5 mol), sodium cyanoborohydride (2.22 g, 0.035 mol) and absolute methanol (200 ml) and stirred at room temperature for 3 days. The mixture was acidified to pH 1 with concentrated HCl, then the methanol was evaporated. The residue was partitioned between water and chloroform and the aqueous layer was separated and basified with solid KOH. The precipitate was extracted into chloroform and the chloroform layer was dried (MgSO4). Concentration of the solvent afforded the amine as a syrup (3.3 g). The amine was converted to the hydrochloride by dissolving in ethyl acetate and adding a saturated solution of hydrogen chloride in isopropanol until acidic. The precipitated solid was filtered and recrystallized from ethanol/ether to give the title compound as a white solid (2.54 g), mp 202°-207° C. (dec).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].[OH:12][C@:13]1([CH3:20])[C@H:17]([CH3:18])[NH:16][C:15](=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[F:10][C:4]1[C:3]([CH3:11])=[C:2]([N:16]2[C:15](=[O:19])[CH2:14][C@@:13]([OH:12])([CH3:20])[C@@H:17]2[CH3:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1c(Br)ccc(C#N)c1F
Reactant: C[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(N2C(=O)C[C@](C)(O)[C@@H]2C)ccc(C#N)c1F

Procedure:
Using 4-bromo-2-fluoro-3-methylbenzonitrile (484 mg), (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg), tris(dibenzylideneacetone)dipalladium(0) (103 mg) and cesium carbonate (1.08 g), and in the same manner as in Example 62, the title compound was obtained as colorless crystals (yield: 376 mg, 63%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](F)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:17]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O>CN(C)C=O.O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@H:18]2[O:19][CH2:20][CH2:21][NH:16][CH2:17]2)=[CH:24][C:25]=1[C:30]([F:32])([F:33])[F:31]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(F)c(C(F)(F)F)c2)C1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 105 °C
Reaction time: 6 h

Procedure:
To a suspension of sodium hydride (43 mg, 1.08 mmol) in N,N-dimethyl formamide (3 mL) at 0° C. was added 2,2,2-trifluroethanol (108 mg, 1.08 mmol), and the resultant mixture stirred for 5 mins. N-Boc-(R)-2-(4-fluoro-3-trifluoromethylbenzyl)morpholine, example 2, intermediate (b) (98 mg, 0.27 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.5 mL) and the reaction mixture warmed to 105° C. and stirred at that temperature for 6 hrs. The reaction was cooled to room temperature and poured into water (20 ml). The suspension was extracted with ethyl acetate (20 mL×2). Combined organic extracts were washed with water (25 mL×2) and brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to yield the desired product as a colorless oil (87 mg) and used directly in the next reaction. The crude material was deprotected using TFA (20% v/v in dichloromethane, 2 mL) over 3 hrs, poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and dichloromethane: methanol (1:1, 2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine example 37 a colorless oil (59 mg).