Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:57])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:54]=[CH:53][C:34]([C:35]([O:37][CH2:38][CH2:39][O:40][P:41]([O:48]C(C)(C)C)([O:43]C(C)(C)C)=[O:42])=[O:36])=[CH:33][C:32]=2[O:55][CH3:56])=[O:29])[CH:5]=[CH:6][CH:7]=1.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>C(Cl)Cl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[Cl:1][C:2]1[C:3]([F:57])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:54]=[CH:53][C:34]([C:35]([O:37][CH2:38][CH2:39][O:40][P:41]([OH:48])([OH:43])=[O:42])=[O:36])=[CH:33][C:32]=2[O:55][CH3:56])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)OCCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)OCCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 12, 89.1 mg, 0.104 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (1 mL) and stirred for 45 min at 0° C. The reaction mixture was concentrated and the product was lyophilized to give chiral 2-(phosphonooxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate trifluoroacetate as a white solid (80.7 mg, 90% yield). MS (ES+) m/z calcd. for C33H35Cl2F2N3O8P: [(M+H)+]: 740. found: 740.
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-tridecanoyl tyramine was prepared by adding dropwise about 2.80 ml of tridecanoyl chloride to a cooled solution comprising about 1 g of tyramine and about 1.52 ml of triethylamine in THF. The reaction mixture was stirred at room temperature for 48 hours. The mixture was then poured into about 70 ml of a 10% HCl solution and the mixture extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 2 g of crude N-tridecanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). About 1 g of N-tridecanoyl tyranine was added to a stirred solution comprising about 152 mg of N-tridecanoyl tyramine, sodium hydroxide in 20 ml anhydrous DMF at 0° C. under nitrogen. The solution was stirred for 30 minutes; about 1 g of chlorosulfonamide was slowly added in one portion. The solution was then stirred at room temperature for 24 hours. After this time, the mixture was poured into a cold saturated sodium bicarbonate solution and the resulting solution was extracted with methylene chloride (3×50 ml). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 677 mg of product, which was then purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (20:1). The product produced is (p-o-sulfamoyl)-N-tridecanoyl tyramine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.O.Cl>C(O)CO>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1nc(N)nc(O)c1Br
Reactant: OCc1ccc(S)cc1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2 CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g. 1H NMR DMSO-d6: δ11.07 (brs, 1H); 7.18 (d, 2H); 6.99 (d, 2H); 6.87 (brs, 2H); 5.09 (s, 1H); 4.41 (s, 2H); 2.24 (s, 3H)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[C:3]=2[F:17])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, white solid (60 mg, 72%), MS (ISP) m/z=333.3 [(M+H)+], mp 332.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:33][C:34]1([CH3:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:19][C:20]([F:23])([F:22])[F:21])=[C:12]([NH:14][C:15](=[O:18])[CH2:16][N:37]3[CH2:38][CH2:39][C:34]([CH3:40])([CH3:33])[CH2:35][CH2:36]3)[CH:13]=2)[C:4](=[O:24])[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: CC1(C)CCNCC1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Product: CC1(C)CCN(CC(=O)Nc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc2OC(F)(F)F)CC1

Procedure:
The title compound was prepared as described for example 1e using 100 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenyl]-2-chloro-acetamide (raw material, as described above) and 15 mg 4,4-dimethylpiperidine. Yield: 2.5 mg
Reaction SMILES: CN1CCC(=[O:8])CC1.ClC1C=CC=CC=1C=O.[OH-].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[C:28]1[CH2:33][C:32](=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH2:31][N:30]([CH3:42])[C:29]1=O>C(O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[C:28]1[C:33](=[O:8])[C:32](=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH2:31][N:30]([CH3:42])[CH2:29]1
Reactant: CN1CCC(=O)CC1
Reactant: CN1CC(=Cc2ccccc2Cl)CC(=Cc2ccccc2Cl)C1=O
Agent: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CC(=Cc2ccccc2Cl)C(=O)C(=Cc2ccccc2Cl)C1
Reaction time: 0.03 h

Procedure:
A stirred solution of 11.3 g. (0.1 mole) of 1-methyl-4-piperidinone and 28 g. (0.2 mole) of o-chlorobenzaldehyde in 220 ml. of ethanol is treated with 11 g. (0.17 mole) of 85% KOH. The temperature rises to 34° and after approximately 2 minutes a solid begins to separate. After stirring for 30 minutes the yellow solid is filtered, washed with water, and air-dried to yield 31.6 g. of yellow, 3,5-bis[(2-chlorophenyl)methylene]-1-methyl-piperidinone; m.p. 148°-150°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A solution of 4-bromo-3-methylanisole (7, 92 g, 0.457 mol) in anhydrous THF (400 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 201 mL, 0.503 mol, 1.1 equiv) in hexane at −60–−65° C. under N2. The resulting reaction mixture was stired at −60–65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (94.56 g, 116 mL, 0.503 mol, 1.1 equiv) at −60–−65° C. The reaction mixture was stirred at −60–−65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (400 mL) at −60–−65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 200 mL). The combined organic extracts were then washed with H2O (200 mL), and saturated NaCl aqueous solution (200 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (400 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×100 mL), dried in vacuo at 40–45° C. for overnight. The crude product (8, 57.9 g, 75.86 g theoretical, 76.3%) was obtained as a white powder.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([N:24]([CH3:26])[CH3:25])[N:16]=1.[N:27]([C@@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C@@H:32](N2C=C(C)C(=O)NC2=O)[CH2:31]1)=[N+:28]=[N-:29]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:32]2[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([N:27]=[N+:28]=[N-:29])[CH2:31]2)=[C:17]([N:24]([CH3:26])[CH3:25])[N:16]=1
Reactant: CN(C)c1nc(N)nc2nc[nH]c12
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CN(C)c1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C
Yield: 41 %

Procedure:
To 500 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-dimethylaminopurine (0.0891 g, 0.5 mmol) and 3'-azido-3'-deoxythymidine (0.668 g, 2.5 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 24 mL solution of trans-N-deoxyribosylase (Example 2b) at an activity of 1400 units/mL was added. The reaction was heated at 50° C. Seven days later 0.0891 g, 0.5 mmol, of 2-amino-6-dimethylamino purine was added to the reaction. The reaction was terminated after fourteen days. The reaction was heated to 80° C. to precipitate the enzyme and then filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on 90 g of silica gel eluted with chloroform/methanol (97:3, v/v). Chromatography a second time on silica gel (230-400 mesh) eluted with chloroform/methanol (98:2, v/v) gave pure product. The product containing fractions were combined and the solvents removed in vacuo to give the product as a solid (41% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1.C(N(CC)CC)C>C(OCC)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH:26][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1
Reactant: Cn1cc(C2(CN)CCCC2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1cc(C2(CNC(=O)c3ccccc3)CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 9.8 g (0.07 mol) of benzoyl chloride dissolved in 70 cm3 of diethyl ether are added dropwise to a solution of 16 g (0.07 mol) of 1-(1-methyl-3-indolyl)-cyclopentylmethylamine and 7.08 g (0.07 mol) of triethylamine in 70 cm3 of diethyl ether so as to maintain a gentle reflux of the ether, and the mixture is then stirred for 2 hours at room temperature. The precipitate formed is thereafter drained, the ether solution is washed with water, dried over sodium sulphate and filtered and the ether is evaporated off from the filtrate. The residue thereby obtained is crystallised by washing with cold diisopropyl ether.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:38]3[CH:37]=[N:36][CH:35]=[C:34]([Br:33])[CH:39]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cncc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (0.134 g, 0.25 mmol), 3-bromo-pyridin-5-ylboronic acid (0.55 g, 0.27 mmol), Pd(PPh3)4 (0.014 g, 0.013 mmol), aq. 2M potassium carbonate solution (0.5 mL, 1.0 mmol) in degassed dioxane (2.0 mL) was heated in microwave at 80° C. for 30 minutes to give (S)-2-(2-(5-bromopyridin-3-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+: calc'd for C30H32BrClN2O3S: 617.1 (M+H+); found: 617.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25](=[S:27])[NH:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3].IC.[CH:31](N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25]([S:27][CH3:31])=[N:24][C:23]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1ccccc1
Solvent: CI
Solvent: CC#N
Product: CSC1=NC(=O)C(=Cc2ccc3ncc(S(C)(=O)=O)c(-c4ccccc4)c3c2)S1

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 61j), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one. LC-MS m/e 441 (MH+).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C:24]34[CH2:31][CH2:30][C:27]([NH:32]C(=O)OC(C)(C)C)([CH2:28][CH2:29]3)[CH2:26][CH2:25]4)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C:24]45[CH2:29][CH2:28][C:27]([NH2:32])([CH2:30][CH2:31]4)[CH2:26][CH2:25]5)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol), TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) was added SOCl2 (2.0 mL, 27.5 mmol). The reaction mixture was heated at about 80° C. for about 2 h then cooled to ambient temperature. The reaction mixture was washed with saturated aqueous NaHCO3 (3×50 mL). The aqueous portion was filtered to give 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+. The remaining filtrate was extracted with EtOAc (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reaction mixture was heated at about 50° C. for about 3 h. The precipitate formed was filtered, dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (3×20 mL). The layers were separated and the organic portion was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give additional 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (50%). MS: m/e=429(M+H+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[CH3:34][S:35]([N:15]1[CH2:16][C@@H:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][C@H:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To an ice-cooled solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (29 mg, 0.08 mmol) in THF (0.8 mL) with Et3N (60 μL, 0.4 mmol) was added methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (31 mg, 87%). MS (ESI): mass calcd. for C21H30FN3O4S, 439.19; m/z found, 440.5 [M+H]+. 1H NMR (CDCl3): 7.00-6.94 (m, 2H), 6.83-6.78 (m, 2H), 4.94-4.89 (m, 1H), 4.86 (ddd, J=8.8, 4.4, 4.4 Hz, 1H), 4.10-4.03 (m, 1H), 3.78-3.40 (m, 5H), 3.08 (d, J=4.0 Hz, 3H), 2.84 (dd, J=16.2, 7.8 Hz, 1H), 2.75-2.66 (m, 1H), 2.57-2.26 (m, 4H), 2.25-2.14 (m, 1H), 2.07-1.97 (m, 2H), 1.97-1.71 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[CH:8]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:55]([S:57][CH:18]1[CH2:17][CH2:16][N:15]([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:14]/[C:13]/1=[CH:12]\[C:11]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[N:9][CH:10]=1)(=[O:58])[CH3:56]
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (3.15 g) in toluene (50 ml) were added N,N-dimethylformamide dineopentyl acetal (3.5 ml) and thioacetic acid (0.89 ml) at room temperature. After being stirred at room temperature for 1 hour, the mixture was diluted with ethyl acetate, washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using ethyl acetate and hexane (1:4 to 1:0) as eluents gave crude (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (3.29 g) as a yellow amorphous solid.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(N(CC)CC)C>[C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([O:21][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]D25 -153.8° (c=1.0, methanol).