Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH2Cl2 (25 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol), triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and then partitioned between Et2O and water. The water layer was extracted with Et2O. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to yield [1-(methoxy-methyl-carbamoyl)-cyclopropyl]carbamic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: C(C1CCC(C)CC1[O:11][C:12]([CH:14]1[CH2:18][CH:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13])(C)C.[ClH:34]>C1(C)C=CC=CC=1>[ClH:34].[F:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][C@@H:17]1[CH2:16][NH:15][C@H:14]([C:12]([OH:13])=[O:11])[CH2:18]1
Reactant: CC1CCC(C(C)C)C(OC(=O)C2CC(Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1C[C@H](Cc2cccc(F)c2)CN1
Temperature: 25 °C
Yield: 81 %

Procedure:
4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl)ester (Preparation 35, 0.91 g, 1.96 mmol) was dissolved in toluene (2 ml). 6N hydrochloric acid (50 ml) was added and stirred at reflux for 18 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×20 ml). The aqueous layer was concentrated by evaporated under reduced pressure to give the title compound (417 mg, 81%) as a white solid. 1H-NMR showed a 7:1 ratio of cis:trans diastereoisomers so the product was recrystallised from isopropyl alcohol to give the title compound (170 mg, 65%) in a ratio of 14:1 cis:trans as determined by NMR.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34][OH:35])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH3:60][C:50]1[CH:55]=[CH:54][C:53]([S:56]([O:35][CH2:34][C@@H:20]([C@@H:19]2[C@:36]3([CH3:42])[C@H:16]([C@H:15]4[C@H:39]([CH2:38][CH2:37]3)[C@:40]3([CH3:41])[C:12]([CH2:11][C@@H:10]([O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:58])=[O:57])=[CH:52][CH:51]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.19 g. (0.00027 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, 1 ml. of pyridine and 0.104 g. (0.00054 mole) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield oily [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18]C(OCC(Cl)(Cl)Cl)=O)[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O>O1CCCC1.[Zn]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CNC(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.8 %

Procedure:
The above 2-amino-7-((2,2,2-trichloro-ethoxycarbonylamino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.0 g, 8.0 mmol) was dissolved in a mixture of tetrahydrofuran (15 ml) and a aqueous phosphate buffer (pH 3; 5 ml) followed by addition of zinc (16 g, 0.244 mol). The reaction mixture was stirred for 6 h at room temperature at which time the solvent was removed in vacuo. To the residue was added diethyl ether (20 ml) and water (40 ml). Sodium carbonate was added to the aqueous phase until pH=8 and the aqueous phase was extracted with dichloromethane (3×). The combined organic phases were, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (90 g) using a mixture of dichloromethane/ethanol/25% ammonia in water 100:10:0.7 as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 1.52 g (61%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH:12]=O)[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[C:8]([CH2:10][CH2:11][CH:12]=[CH:20][CH2:21][CH3:22])[CH:9]=1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(CCC=O)c(OC)c(OC)c1
Agent: [Br-]
Product: CCC=CCCc1cc(C(=O)OC)cc(OC)c1OC

Procedure:
3-Hex-3-enyl-4,5-dimethoxybenzoic acid methyl ester was prepared from 3,4-dimethoxy-5-(3-oxopropyl)benzoic acid methyl ester and propyltriphenylphosphonium bromide by following Method J. The crude product was purified by flash column chromatography on silica gel using 20% EtOAc in hexanes as an eluent to furnish 3-hex-3-enyl-4,5-dimethoxybenzoic acid methyl ester in 63% yield.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>CS(C)=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([O:9][CH:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)=[N:12][CH:13]=1
Reactant: OC1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1ccc(OC2CCNCC2)nc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Sodium hydride (56 mg, 2.3 mmol) was added to a solution of piperidin-4-ol (214 mg, 2.11 mmol) in DMSO (8 mL). After stirring for 30 minutes, 2,5-dibromopyridine was added. After stirring for 24 hours, sodium hydride (56 mg, 2.3 mmol) was added. After stirring for another 24 hours the reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol, ammonium hydroxide to afford 5-bromo-2-(piperidin-4-yloxy)-pyridine (316 mg, 58%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12]/[C:13](/[CH3:27])=[CH:14]/[C:15]1[C:20]2[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:19]=2[CH:18]=[CH:17][CH:16]=1.O>CO>[CH3:27]/[C:13](=[CH:14]\[C:15]1[C:20]2[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:19]=2[CH:18]=[CH:17][CH:16]=1)/[CH2:12][CH2:11][CH2:10][C:9]([OH:28])=[O:8]
Reactant: COC(=O)CCC/C(C)=C/c1cccc2c1NCCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C/C(=C\c1cccc2c1NCCNC2=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (43.32 mmol, 5.987 g) was added to a solution of Example 161 (7.22 mmol, 2.066 g) in 200 mL MeOH (gently heated with a heat gun to get it in solution) and 100 mL H2O. The reaction mixture was stirred at rt for 24 h. The MeOH was removed in vacuo and the residue was taken up in H2O and extracted with EtOAc. The aqueous layer was made acidic (pH 0-1) using 2N HCl when the product precipitates out of solution as a white solid. The solid was filtered, washed with H2O and dried (1.878 g; 96%). The product was used without further purification: mp=257-259° C.; 1H NMR (DMSO-d6) δ 1.83-1.93 (m, 2H), 2.33 (t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 3.52-3.56 (m, 2H), 4.22 (br s, 2H), 6.34 (s, 1H), 7.07 (t, 1H, J=6.0 Hz), 7.65 (d, 1H, J=6.0 Hz), 7.75 (d, 1H, J=6.0 Hz), 8.23 (t, 1H, J=6.0 Hz), 11.98 (br s, 1H); HRMS calcd. for C15H16N2O3 (M+) 272.1161, found (M+) 272.1151.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH:19][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=3)=[O:30])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)NCc2nc(C(=O)NCCc3cccc(Cl)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.4 %

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide (50 mg, 0.17 mmol) was dissolved in DMF (1 mL). 4-Ethyl phenylisocyanate (0.05 mL, 0.34 mmol) was added and the reaction mixture stirred at ambient temperature for 20 hours. The crude product was concentrated in vacuo. The product was purified by column chromatography (silica, 5% MeOH in DCM) to give a white solid (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD): 8.07 (s, 1H), 7.26 (m, 4H), 7.19 (m, 2H), 7.11 (m, 2H), 4.66 (s, 2H), 3.60 (t, 2H), 2.90 (t, 2H), 2.58 (q, 2H), 1.20 (t, 3H); MS (ESI-LCMS) for C22H24C1N4O2S: 443 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10]3)=[CH:5][CH:4]=1.CS([C:25]1[N:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][N:26]=1)(=O)=O>CN(C=O)C>[C:33]1([CH2:32][O:31][C:29]2[CH:28]=[CH:27][N:26]=[C:25]([O:18][CH2:17][CH2:16][CH2:15][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[N:30]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Reactant: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCOc2nccc(OCc4ccccc4)n2)C3)cc1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-propanol (P11, 144 mg) in dry DMF (1.8 mL) NaH (60% in mineral oil, 24 mg) was added at 0° C. The mixture was stirred at this temperature for 10 min, then at room temperature for 15 min. A solution of 2-(methylsulfonyl)-4-[(phenylmethyl)oxy]pyrimidine (135 mg) in dry DMF (1.1 mL) was then added. The reaction mixture was stirred at room temperature for 5 hours, then hydrolysed with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (5 g) eluting with dichloromethane/methanol from 100/0 to 98/2 to give the title compound as a colourless oil (171 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:35]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)[C@@H]2C1

Procedure:
A solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (29 mg, 0.059 mmol), DMAP (1 mg) and acetic anhydride (0.028 mL, 0.30 mmol) in 2 mL of pyridine was stirred at rt for 4 hr. Volatiles were removed and the crude was purified by reverse phase HPLC to afford the title compound. MS: (MH)+534.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:14]=2)[CH2:9]1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C

Procedure:
((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(4-ethyl-pyrazol-1-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (first step a) (9.75 g, 14 mmol) is dissolved in methanol (2 ml). (4M) HCl in 1,4-dioxane (15 ml) is added and the reaction mixture is stirred at room temperature over night. The compound is purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% HCl). The compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 594.31 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:17]=[C:16]([CH:15]=[CH:14][N:13]=2)[C:18]#[N:19])[CH2:4][CH2:3]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2cc(C#N)ccn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-Methylpiperidin-4-ol (0.457 g, 3.97 mmol) was dissolved in 5 mL of DMSO under argon and NaH (0.173 g, 3.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h and 30 min at 60° C. The mixture was allowed to cool and 2-chloro-4 pyridinecarbonitrile (0.500 g, 3.97 mmol) was added. The mixture was stirred for 2 h at ambient temperature and subsequently poured into 100 mL of water, extracted three times with EtOAc. The combined organic layer washed with water, dried over Na2SO4 and evaporated. The crude product was purified by preparative HPLC (Kromasil C8 50×250 mm, CH3CN/0, 2% HOAc 5/95-50/50). The product was freeze dried from water. Yield: 0.250 g (32%). 1H NMR (500 MHz, CD3OD) δ8.32 (d, 1H), 7.19 (dd, 1H), 7.12 (bs, 1H), 5.14 (m, 1H), 2.75 (m, 2H), 2.38 (m, 2H), 2.32 (s, 3H), 2.06 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][C@H:50]([OH:62])[CH2:51][N:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1>C(Cl)Cl>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH2:61][N:52]1[CH2:51][C@@H:50]([OH:62])[CH2:49][NH:48][C:18]([C:17]1[CH:21]=[CH:22][N:23]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1)=[O:19]
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)O)ccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinic acid (150 g, 0.47 mol) in DCM (1500 mL) was added HATU (178 g, 0.47 mol) and TEA (47 g, 0.47 mol) at 20° C., then the mixture was stirred at the temperature for 2 h. (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 g, 0.55 mol) was added to the solution, and the mixture was stirred at 20° C. for another 16 h, at which time TLC showed the completion of the reaction. The mixture washed with water (200 mL) and the combined organic phases were dried and concentrated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the title compound as yellowish oil. Four batches were run in parallel and produced a combined product weight of 510 g, yield: 53.2%. LCMS (m/z): 510.2 [M+H]+.
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:22]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Reactant: COc1ccc(N)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=O)CC2)cc1OC
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-piperidinium iodide (9270 mg), 3,4-dimethoxy aniline (3900 mg) and anhydrous potassium carbonate (437 mg) in ethanol (90 ml)/water (45 ml) were heated to reflux for 6 hours. Additional potassium carbonate (200 mg) was added and the reaction was heated to 100° C. over night. Water (50 ml) was added to the reaction mixture, which was extracted three times with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to leave the crude product as a dark oil. The residue was purified by column chromatography (ethyl acetate/hexanes=1:1) to yield the product as a yellow solid (3700 mg). MS (ESI): 236.1 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:24])[CH2:13][C:14]1[C:15]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[C:1]1([CH2:7][CH2:8][NH:9][C:21]([CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][C:12]([O:11][CH3:10])=[O:24])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cc1ccccc1CC(=O)O
Product: COC(=O)Cc1ccccc1CC(=O)NCCc1ccccc1

Procedure:
This was prepared from benzeneethanamine and 1,2-benzenediacetic acid monomethyl ester by the method described in Example 6 (a), MS; m/e 311
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:48])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:8].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:48][C:5]([CH3:4])([CH3:47])[C@H:6]([NH:18][C:19]([C@H:21]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:35]([F:46])[CH:34]=1)[C@H:22]([O:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:7]([NH:9][C@@H:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]
Reactant: CCO[C@H](C(=O)OC)[C@@H](CCCc1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCO[C@H](C(=O)O)[C@@H](CCCc1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 18.1 %

Procedure:
Lithium hydroxide hydrate (116 mg, 2.83 mmol) was added to a solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoate (368 mg, 0.566 mmol) in methanol:water=10:1 (5 mL) and the mixture was stirred at room temperature for 2 h. The solution was neutralised with 5% aqueous citric acid and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 5% aqueous citric acid (20 mL), washed with saturated aqueous sodium chloride (20 mL), dried MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane:methanol=20:1 to 10:1) gave the title compound (62 mg, 18%) as a colourless glass, and some mixed fractions. These were combined and repurified by flash chromatography (eluting with ethyl acetate:hexane:acetic acid=33:66:1 to 50:50:1) to give the title compound (37 mg, 11%), as a white solid.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2[C:16](=[N:17][NH:18][C:19]=2[NH2:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CC(O)=O>[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2=[C:19]3[N:18]([N:17]=[C:16]2[CH2:15]1)[CH:3]=[C:2]([Br:1])[CH:5]=[N:22]3)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1Cc2nn3cc(Br)cnc3c2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.5 %

Procedure:
A mixture of bromomalonaldehyde (2.02 g; 13.38 mmol; 1 eq.) and 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (3 g; 13.38 mmol; 1 eq.) in AcOH (21 mL) was stirred at room temperature for 40 minutes. The insoluble material was removed by filtration and the solution diluted with water (60 mL). The precipitate was filtered off, washed with water (3×) and dried. Recrystallization from iPrOH afforded the title compound (2.02 g, 45%) as beige solid. 1H NMR (DMSO-d6) δ 9.60 (d, J=2.2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 4.62-4.55 (m, 4H), 1.47 (s, 9H). HPLC (max plot) 99.8%; Rt 3.54 min. UPLC/MS: (MS+) 339.3 and 341.3 ([M+H]+).