Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:60](Br)[CH:61]=[CH2:62]>C1COCC1>[C:1]([O:5][C:6](=[O:49])[CH:7]([NH:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])[CH2:62][CH:61]=[CH2:60])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A solution of 346 mg (0.5 mmol) (2S,4R)-{[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-amino}-acetic acid tert-butyl ester in 10 ml THF at −78° C. was treated with 1.1 ml (1M in THF, 1.1 mmol) Lithium bis(trimethlsilyl)amide solution (LiHMDS). 0.127 ml (1.5 mmol) Allylbromide was added after 30 min and the reaction was warmed up to RT over night. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (4×), the organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silicagel (Hexane/EtOAc 2:1) and precipitation with Et2O/pentane gave 76 mg (21%) (2RS)-2-{(2S,4R)-[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-amino}-pent-4-enoic acid tert-butyl ester, MS: 733 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:35][CH2:36][NH:37][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:28])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCCN1CCCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 48 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example 1d was reacted with 2-pyrrolidin-1-yl-ethylamine (34.2 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (50.6 mg, 64.0%). HRMS (ES+) m/z Calcd for C29H36Cl2N4O+H [(M+H)+]: 527.2339. found: 5277338.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][OH:18]
Reactant: OC[C@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC[C@@H]2CO)c(F)c1
Temperature: 75 °C
Yield: 96.4 %

Procedure:
A suspension of 3,4-difluoronitrobenzene (1.57 g, 9.8 mmol), (R)-2-pyrrolidinemethanol (1.0 g, 9.8 mmol) and K2CO3 (1.36 g, 9.8 mmol) in 30 mL DMF was heated at 75° C. for 20 h, whereupon the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (19:1 CH2Cl2:MeOH) afforded 2.27 g (96%) of (R)-[l-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol, an orange solid. Data for (R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol: Rf 0.17 (7:3 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, 1H, J=9.1, 2.6), 7.89 (dd, 1H, J=14.4, 2.6), 6.68 (t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75 (m, 3H), 3.40-3.50 (m, 1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)[C:33]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:34])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (400 mg, 1.15 mmol), 2-tert-butoxycarbonylamino-3-(4-cyanophenyl)propionic acid (320 mg, 1.2 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 50 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 218 mg, 1.15 mmol), and DMF (5 mL) was shaken at room temperature for 8 hours. The reaction mixture was then poured into 20 mL of ethyl acetate, washed with 5 mL of 2N HCl solution, saturated NaHCO3 (20 mL), water (10 mL), and brine (10 mL). The organic layer was concentrated under vacuum and purified by column (silica gel, EtOAc/hexane 1/1) to afford the intermediate (1-(4-cyanobenzyl)-2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)amino]piperidin-1-yl}-2-oxo-ethyl)carbamic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH3:28])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].O[Li].O.Cl>O1CCCC1.O>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH3:28])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4cnn(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2cnn(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylate (70 mg, 0.18 mmol) in tetrahydrofuran (20 mL) was added LiOH.H2O (9.0 mg, 0.36 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (30 mL), adjusted the pH to 6 with hydrochloric acid (3N), and filtered to give 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylic acid as a light yellow solid (20.5 mg, 30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([NH2:35])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)[NH:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCCl

Procedure:
A 2.0 g (6.43 mmol) portion of 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) in 2-ethoxyethanol (20 mL) is heated to 60° C. To this is added 1.7 g (7.10 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine (U.S. Pat. No. 4,973,599) and 0.74 g (6.43 mmol) of pyridine hydrochloride, and the resulting mixture is refluxed for 2 hours. After cooling, the precipitated solid is filtered, washed with aqueous sodium bicarbonate and dried in vacuo to give 2.93 g of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile as a tan solid, mp 271-276° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2]>CO.C(O)(=O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:18])=[O:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
3-[6-(3-Fluoro-benzenesulfonyl)-naphthalen-1-yl]-acrylic acid ethyl ester (2.0 g) was dissolved in a mixture of methanol (20 mL), acetic acid (20 mL) and EtOAc (50 mL) in a Parr vessel. Palladium on activated carbon (1.0 g, 10% Pd) was added, and the vessel was purged with nitrogen. The reaction mixture was stirred at room temperature under 60 atm (4.14 Bar) hydrogen for 18 hours. The vessel was purged with nitrogen, and the reaction mixture was removed and filtered through Celite. The filtrate was evaporated under reduced pressure to give 2.0 g of 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].ClC(CCCCC)C(Cl)=C(C)C.C([O-])(=O)C.[Na+].[OH-:28].[Ca+2].[OH-:30]>C1C=CC=CC=1.C(N(CC)CC)C>[OH:28][CH2:1]/[C:2](=[CH:3]\[CH2:4][CH2:5][CH:6]([CH2:8][CH2:9][OH:30])[CH3:7])/[CH3:10]
Reactant: [OH-]
Reactant: C=CC(=C)CCC=C(C)C
Agent: CC(=O)[O-]
Agent: CCCCCC(Cl)C(Cl)=C(C)C
Agent: [Ca+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C/C(=C/CCC(C)CCO)CO

Procedure:
Prod.: (many methods) e.g. from Myrcene, via Myrcene dihydrochloride to Dichloro di-methyloctene. This is converted to Chloro di-hydrogeranyl acetate (andneryl acetate) with Sodium Acetate in Benzene in presence of Triethylamine. The acetates are saponified with Calcium hydroxide to yield Hydroxycitronellol, from which the aldehyde is prepared by oxidation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:4]=1[CH3:21].C[OH:23]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[O:23])[C:4]=1[CH3:21]
Reactant: CO
Reactant: COc1c(C)cnc(CSc2nc3ccccc3[nH]2)c1C
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reaction time: 1 h

Procedure:
53.5 g of 2-[[(4-methoxy-3,5-dimethyl-2 -pyridyl)methyl]thio]benzimidazole are dissolved in 1.2 l of methylene chloride and 100 ml of methanol and then cooled to -20°. 33.4 g of m-chloroperbenzoic acid, recrystallized from methylene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred for a further 60 minutes at -20° and then poured into a mixture of 250 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphinyl]benzimidazole of melting point 157°-159°.
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:21](O)[CH3:22])=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.C1COCC1.C1(OP([N:45]=[N+:46]=[N-:47])(=O)OC2C=CC=CC=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CCOC(C)=O.O>[N:45]([C@@H:21]([C:3]1[C:2]([F:1])=[CH:7][N:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]2)[CH3:22])=[N+:46]=[N-:47]
Reactant: C[C@H](O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](N=[N+]=[N-])c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
6-[5-Fluoro-4-((S)-1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (100 mg, 0.32 mmol), THF (1.4 mL) and phosphorazidic acid diphenyl ester (0.088 mL, 0.41 mmol) are combined and cooled to 0° C. DBU (0.061 mL, 0.41 mmol) is added dropwise. After 10 minutes, the reaction is warmed to room temperature for 18 hrs. The reaction mixture is diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to the crude product. Purification by flash column chromatography affords 90 mg of 6-[4-((R)-1-azido-ethyl)-5-fluoro-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O-].[Na+].CO.[NH2:16][S:17]([CH2:20][CH2:21][CH2:22]I)(=[O:19])=[O:18]>CO>[S:17]([CH2:20][CH2:21][CH2:22][S:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1)(=[O:19])(=[O:18])[NH2:16]
Reactant: NS(=O)(=O)CCCI
Reactant: Sc1ccc2nccn2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)CCCSc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
6-Mercaptoimidazo[1,2-b]pyridazine (1.5 g) and 28 W/W % sodium methoxide-methanol solution (2.1 g) were stirred in 30 ml of methanol at 50° C. for 3 hours. The mixture was cooled to room temperature, 3.0 g of 3-aminosulfonyl-1-iodopropane were added and stirred at room temperature for 1.5 hours. The mixture was distilled to remove the solvent and the residue was subjected to a silica gel chromatography, which was eluted with successive 2 V/V % methanol-chloroform, 2.5 V/V % methanol-chloroform and 3.2 V/V % methanol-chloroform. The fractions containing the object compound were collected and concentrated. The precipitate was collected by filtration, thereby yielding 1.6 g of 6-(3-sulfamoyl-propylthio)imidazo [1,2-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[OH:27]OS([O-])=O.[K+]>CO.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2
Reactant: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCSCC3)nncc2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCS(=O)CC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-3-[1-(thiomorpholin-4-yl)phthalazin-6-yl]benzamide (0.6 mmol) (Method A) in 10 mL methanol/H2O (8:2) was stirred at RT was treated with oxone® monopersulfate compound (1 mmol). The mixture was stirred at 0° C.-50° C. over 1h. The mixture was quenched with 20 mL sat. N2SO3, extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2 M ammonia methanol in dichloromethane to give the title compound. Found MS(ES+): 381(M+H)+.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(N)CCC1.[CH:36]([O:39][C:40]1[CH:41]=[C:42]([CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=1)C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O)([CH3:38])[CH3:37]>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:42]1[CH:61]=[C:62]([N:64]2[CH2:68][CH2:67][CH2:66][C:65]2=[O:69])[CH:63]=[C:40]([O:39][CH:36]([CH3:38])[CH3:37])[CH:41]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Agent: NC1CCC1
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from cyclobutylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)[C:34](=[CH:42][C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][C:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])([CH3:53])[CH3:52])[C:33]1=[O:59])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:59])[C:34]3([CH:42]([C:43]4[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=4[O:50][C:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])([CH3:53])[CH3:52])[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 29.2 %

Procedure:
To a toluene solution (50 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (77 mmol) was added E/Z 6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (8 g, 15.44 mmol). Then the reaction mixture were heated at 130° C. for 2. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (2.7 g).
Reaction SMILES: [C:1]([N:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:12]([N:17]=[C:18]=[S:19])(=[O:16])[O:13][CH2:14][CH3:15].II.C([O-])(O)=O.[Na+].CCOCC.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC.N1C=CC=CC=1.CO>[CH2:8]([C:7]1=[CH:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[S:19]/[C:18]/1=[N:17]\[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC=NC(C)(C)C
Reactant: CCOC(=O)N=C=S
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: c1ccncc1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)OCC
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of Example 1A (4.2 g, 27 mmol) in THF (100 mL) at room temperature under N2 was added O-ethyl carbonisothiocyanatidate (3.55 g, 27 mmol). The reaction mixture was stirred for 1 hour and iodine (6.8 g, 27 mmol), MeOH (100 mL) and pyridine (10 mL) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into saturated NaHCO3/Et2O and stirred for 30 minutes. Additional saturated NaHCO3 and Et2O were added and the organic layer was separated. The aqueous layer was extracted with Et2O (2×) and combined organics were dried (MgSO4) and concentrated in vacuo. Toluene and acetonitrile were added and evaporated to remove water and pyridine. The crude compound was purified by flash chromatography using 0-100% EtOAc in hexane as eluent to give 5.2 g of the title compound as yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 0.93 (t, J=7.3 Hz, 3H), 1.27-1.47 (m, 5H), 1.54-1.73 (m, 11H), 2.59-2.74 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 7.78 (s, 1H). MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][C:3]=1[F:27].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)CC(c1ccc(Cl)c(F)c1)c1c[nH]c2c(CSC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CSCc1cccc2c(C(CCO)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1.74 g (4.28 mmol) of the compound from Example 101A in 7 ml of tetrahydrofuran was added dropwise to 15.0 ml (15.05 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 20 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then water and acetonitrile were added, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.36 g (87% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13])=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]2=[O:13]
Reactant: COc1ccc(SC(C)(C)CC(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)CC(C)(C)S2
Yield: 78 %

Procedure:
To a solution of the acyl chloride (Compound 217, 21.5 g, 83.2 mmol) in 250 mL of CH2Cl2 at 0° C. was added dropwise a solution of SnCl4 (21.7 g, 83.2 mmol) in 30 mL of CH2Cl2. After 2 hours the reaction was quenched by slow addition of 150 mL H2O. The organic layer was washed with 1M aqueous HCl, 5% aqueous NaOH, H2O, and finally saturated aqueous NaCl before being dried over MgSO4. Concentration under reduced pressure and vacuum distillation of the residual oil (Bulb-to-bulb, 125-135° C., 5 mm/Hg) afforded 14.48 g (78%) of the title compound as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.62 (1H, d, J=2.9 Hz), 7.14 (1H, d, J=8.6 Hz), 7.03 (1H, dd, J=2.8, 8.3 Hz), 3.83 (3H, s), 2.87 (2H, s), 1.46 (6H, s).