Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C(Cl)CCl.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC2[N:42]([OH:43])N=NC=2C=1.Cl.NO>CN(C=O)C.CCOC(C)=O.P(=O)(O)(O)O.C1COCC1>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:23][C:24](=[O:25])[NH:42][OH:43])([CH3:17])([CH3:16])[CH3:15]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccccc1
Agent: Cl
Agent: NO
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.3 %

Procedure:
DIPEA (32.7 mL, 188 mmol) and EDC (15.4 g, 80.5 mmol) were added to a solution of (R)-3-t-butoxycarbonylamino-4-phenylbutyric acid (15.0 g, 53.7 mmol), HOBt (7.3 g, 53.7 mmol), and hydroxylamine hydrochloride (7.5 g, 107 mmol) in DMF (150 mL). The mixture was stirred at room temperature for 1 day and then concentrated in vacuo to yield a pale yellow oil. The oil was distributed between 5% THF in EtOAc and 1M phosphoric acid. The organic layer was collected and washed with 1M NaOH. The alkaline aqueous layer was then acidified using 1M phosphoric acid and extracted with EtOAc. The organic layer was evaporated and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound as a white solid (1.0 g, 3.4 mmol). MS m/z: [M+H+] calcd for C15H22N2O4, 295.16. found 295.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][NH:19][C:20]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:15]>C1C=CC=CC=1.O1CCCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][NH:19][C:20]1[C:25]([NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:15]
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccccn1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccn1

Procedure:
Under a nitrogen atmosphere, triethylamine (0.30 mole) and a solution of freshly prepared acid chloride of 2-pyridine carboxylic acid (0.150 mole), obtained by heating at reflux 2-pyridine carboxic acid and excess thionyl chloride in benzene and then azeotropic distillation with benzene, in dry tetrahydrofuran (50 ml) were added simultaneously (dropwise) to a stirred and chilled (10°-20° C.) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester prepared by reducing N-(3-nitro-2-pyridinyl)glycine ethyl ester (0.106 mole) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred overnight at room temperature and was filtered. The filtrate was concentrated in vacuo and dissolved in ethyl acetate (250 ml). The solution was washed with saturated sodium bicarbonate solution (3×75 ml), water (2×75 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was crystallized from isopropyl ether-tetrahydrofuran giving 26.5 g (83%). A 3.0-g sample was twice recrystallized from isopropyl ether-tetrahydrofuran to give 2.4 g of a white needles, mp 98°-100° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.O>[Si:18]([O:17][C@@H:16]1[C:12](=[O:11])[CH2:13][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.51 mL) in CH2Cl2 (7.3 mL) was added a 4.0M CH2Cl2 solution of DMSO (0.86 mL) at −78° C. After 10 min, a solution of tert-butyl (3S,4S)-3-hydroxy-4-(tert-butyldimethylsilyl)oxypyrrolidine-1-carboxylate (920 mg) in CH2Cl2 (5.8 mL) was added, and the mixture was stirred for 2 hours at −45° C. Triethylamine (3.25 mL) was added, and after being stirred for 10 min at room temperature, water was added. The mixture was separated, and the aqueous layer was extracted with ether. The combined organic layer was washed with brine, and dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give tert-butyl (3S)-3-(tert-butyldimethylsilyl)oxy-4-oxopyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>>[C:41]12([NH:51][C:30]([CH:29]3[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]3[CH2:24][C:23]3[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=4[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=3)=[O:31])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NC45CC6CC(CC(C6)C4)C5)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 67.3 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.080 g, 0.134 mmol) was reacted with 1-adamantanamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.025 g, 0.179 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-1-ylamide (0.066 g, 68%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3766.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:16][C@H:15]3[C@@H:10]([O:11][P:12]([NH:18][C@@H:19]([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[O:13][CH2:14]3)[C@:9]2([OH:28])[CH3:27])[C:4](=[O:29])[N:3]=1.CCN(CC)CC.[CH2:37]([CH:40]([CH2:44][CH2:45][CH3:46])[C:41](Cl)=[O:42])[CH2:38][CH3:39]>C1COCC1.CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:28][C@:9]1([CH3:27])[C@@H:10]2[O:11][P:12]([NH:18][C@@H:19]([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[O:13][CH2:14][C@H:15]2[O:16][C@H:8]1[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH:40]([CH2:44][CH2:45][CH3:46])[CH2:37][CH2:38][CH3:39])=[N:3][C:4]1=[O:29]
Reactant: CCOC(=O)[C@H](CC)NP1(=O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@](C)(O)[C@@H]2O1
Reactant: CCCC(CCC)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)Nc1ccn([C@@H]2O[C@@H]3COP(=O)(N[C@@H](CC)C(=O)OCC)O[C@H]3[C@@]2(C)O)c(=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
Ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]amino}butanoate, prepared according the procedure described for Example 6, was diluted with a solution THF:DMF (5:2, 0.03 M). Et3N (4.0 eq.) and DMAP (0.2 eq.) were added then the mixture was cooled to 0° C. and 2-propylpentanoyl chloride (2.5 eq.) was added drop-wise. The mixture was immediately warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of 1N HCl (aq) to bring the pH to 6, and then the solvent was removed in vacuum. The crude was purified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O buffered with 0.1% TFA) to afford the title compound as white powder (36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH2:10][CH2:11][N:12]=1>O.OO.[Ni].C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: Fc1ccccc1C1=NCCO1
Agent: [Ni]
Agent: OO
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccccc1-c1ncco1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
A mixture of 2-fluoro-1-(4,5-dihydrooxazol-2-yl)benzene (4.5 g, 27.3 mmol), nickel peroxide hydrate (7 g) and benzene (40 mL) was heated 24 hours at reflux. The reaction mixture was allowed to cool to 25° C., then filtered and concentrated by rotary evaporation. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-fluoro-1-oxazol-2-ylbenzene (0.5 g, 3.07 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](OC)(OC)[CH3:12]>>[CH3:9][O:10][C:11](=[N:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: COC(C)(OC)OC
Reactant: Nc1cccc(O)n1
Product: COC(C)=Nc1cccc(O)n1

Procedure:
4.4 g (40 mmol) of 6-amino-2-hydroxypyridine are heated under reflux for 12 hurs in 30 ml of orthoacetic acid trimethyl ester The reaction mixture is then concentrated by evaporation Ether is added to the residue while stirring, the product crystallising out spontaneously. The product is filtered off with suction and dried under a high vacuum. N-(2-hydroxy-6-pyridyl)-acetimidic acid methyl ester having a melting point of 128°-129° is thus obtained.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si](C)(C)[N-][Si](C)(C)C.[Na+].[F:17][CH:18]([F:34])[C:19](=[O:33])[CH2:20][C:21]([CH3:32])([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])[CH3:22]>CS(C)=O.C1COCC1.CCCCCC>[F:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:21]([CH3:22])([CH3:32])[CH2:20][C:19]2([CH:18]([F:17])[F:34])[CH2:7][O:33]2)[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Reaction time: 0.25 h

Procedure:
To suspension of trimethylsulfoxonium iodide (0.22 g) in DMSO (0.5 mL) and THF (0.5 mL) stirred under nitrogen and cooled on ice was added sodium hexamethyldisilazide (1.0 mL, 1.0M in THF) dropwise over 5 minutes. After 15 minutes, a solution of 1,1,-difluoro-4-methyl-4-(2-methoxy-5-fluorophenyl)pentan-2-one (0.23 g) in THF (0.6 mL) was added dropwise and the mixture was allowed to come to room temperature over 2 hours. The mixture was diluted with hexane, washed with water, dried, filtered, and evaporated in vacuo to give 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane as an oil (0.25 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[N:15]([CH3:32])[C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1.C([O-])([O-])=O.[K+].[K+].I[CH:40]1[CH2:43][O:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:30][S:27]([C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[C:16]([N:15]([CH3:32])[C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:40]1[CH2:43][O:42][CH2:41]1)=[O:31])(=[O:29])=[O:28]
Reactant: Cc1cc(-c2ccccc2O)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Reactant: IC1COC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2OC2COC2)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-(2-hydroxyphenyl)-6-methylpyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (100 mg, 215 μmol) in DMF (2 mL) was added K2CO3 (59.5 mg, 431 μmol) and 3-iodooxetane (43.6 mg, 237 μmol). The reaction mixture was stirred for 2 hours at room temperature followed by stirring for 18 hours at 80° C. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (30 mg, 27%). MS (ESI): m/z=521.134 [M+H]+.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2C2CCc3cc(O)ccc3C2)cc1
Yield: 13.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N,N-diethylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.3 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:59]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])(=[O:64])[CH2:60][C:61]([O-])=[O:62].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCCl.CN(C1C=CN=CC=1)C>[C:66]([O:65][C:59](=[O:64])[CH2:60][C:61]([N:5]([CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:49])=[O:62])([CH3:69])([CH3:68])[CH3:67]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (27 mg, 0.040 mmol) in DCE (2 ml) was added Hunig's base (0.021 ml, 0.121 mmol), DMAP (1 mg, 8.19 μmol), Mono-tert-butyl malonate (0.012 ml, 0.080 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (19.38 mg, 0.060 mmol). The mixture was stirred at rt. After 5 h of stirring, the mixture was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-tert-butoxy-N-(2-(dimethylamino)ethyl)-3-oxopropanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (31.8 mg, 0.039 mmol, 97% yield). LCMS: m/e 813.4 (M−H)−, 3.46 min (method 6).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCNC2)n1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(Nc2nccc(-n3nnc4ccccc43)n2)C1
Temperature: 25 °C

Procedure:
To DCM (8 mL) was added (4-benzotriazol-1-yl-pyrimidin-2-yl)-piperidin-3-ylamine (0.15 g), methanesulfonyl chloride (35 μL) and TEA (0.285 mL), and the mixture stirred at RT. The product was purified by column chromatography on silica, using 100% DCM to 15% MeOH/DCM, then recrystallized from EtOAc to provide (4-benzotriazol-1-yl-pyrimidin-2-yl)-(1-methanesulfonyl-piperidin-3-yl)-amine. Mp=196.0-197.0° C., 1H nmr (300 MHz, DMSO-d6): δ ppm 1.40-1.76 (m, 2H), 1.78-2.14 (m, 2H), 2.72-2.86 (m, 2H), 2.89 (s, 3H), 3.49 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 7.41 (d, J=5.27 Hz, 1H), 7.58 (t, J=7.35 Hz, 1H), 7.73 (m, 1H), 8.22 (d, J=8.29 Hz, 1H), 8.55 (d, J=5.27 Hz, 1H), 8.88 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=O)C.C([O-])(=O)C.[NH4+]>CO.O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=1
Reactant: COC(=O)C1CC1c1ccc(OC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)C1CC1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
Methyl 2-[4-(acetyloxy)phenyl]cyclopropanecarboxylate (2.26 g, 9.65 mmol) was dissolved in a mixed solvent of methanol (80 mL) and water (20 mL), and ammonium acetate (5.95 g, 77.2 mmol) was added. The mixture was stirred at room temperature for 10 hr and further stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (1.78 g, yield 96%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C@@H:9]([CH3:40])[C:10]([NH:12][C@@H:13]([CH:37]([CH3:39])[CH3:38])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25][N:42]=[N+:43]=[N-:44])=[O:15])[CH:37]([CH3:39])[CH3:38])[CH3:40])[CH3:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN=[N+]=[N-]
Temperature: 90 °C
Yield: 89.6 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (Intermediate 2) (200 mg, 0.34 mmol) in DMF (4 mL) was added NaN3 (26.53 mg, 0.408 mmol) and the resulting mixture was heated at 90° C. for 3 h. The reaction was concentrated in vacuo and the obtained residue was dissolved in ethyl acetate (25 mL) and washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 12% EtOAc in hexanes) to give {(S)-1-[(S)-1-((S)-2-azidomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (140 mg), m/z=460 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][CH:9](Cl)[CH3:10])[CH:3]([CH3:5])[CH3:4].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][CH2:9][CH2:10][S:24]1
Reactant: CC(C)CNCCC(C)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCCCN1CC(C)C

Procedure:
4-Aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 3-hydroxybutylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chlorobutylamine HCl salt. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazepine.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:5][N:4]=1.[OH-:17].[Na+]>S(=O)(=O)(O)O>[CH3:1][S:2][C:3]1[C:7]([C:8]([NH2:9])=[O:17])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:5][N:4]=1
Reactant: CSc1nsc(Nc2ccncc2)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CSc1nsc(Nc2ccncc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 7 (1.0 g, 4.0 mmol) is dissolved in sulfuric acid (5 mL). The resulting solution is stirred at room temperature for 2 hours, heated to 50° C. for 3.5 hours, then at room temperature for 18 hours, then heated to 50° C. for 1 hour. The reaction was then cooled to room temperature and 1N NaOH (5 mL) was added. The resulting solids were filtered and washed with saturated aqueous sodium bicarbonate to provide 8 (1.15 g, 4.0 mmol). 1H NMR (d6 DMSO): 5 8.12 (2H, d, J=5.8 Hz), 6.78 (2H, d, J=5.8 Hz), 2.32 (3H, s); LRMS (M+): 267.0, (M−): 265.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[NH:18][CH2:19][CH2:20][CH2:21]Cl)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:23])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]3[CH2:21][CH2:20][CH2:19][N:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(Cl)c2)C(NCCCCl)=Nc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21
Reaction time: 64 h

Procedure:
3-(m-Chlorophenyl)-2-(3-chloropropylamino)-3H-indol-3-ol hydrochloride (0.742 g.) was dissolved in methanol (10 ml.) containing sodium methoxide (0.27 g.) and left at room temperature for 64 hours. The solution was evaporated to a foam which was triturated with water. The product was isolated as a white powder (546 mg.), m.p. 186°-187°C. Recrystallisation from acetonitrile raised the melting point to 190°-192°C.