Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C@@H:12]1[CH2:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[C:14]([CH3:24])[C@H:13]1[O:25]C(=O)C)=[O:11])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C@@H:12]1[CH2:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[C:14]([CH3:24])[C@H:13]1[OH:25])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
Anhydrous potassium carbonate (45.6 mg, 0.33 mmol) was added to a solution of 92 (100 mg, 0.33 mmol) in dry ethanol (2.8 ml) at 0° C. and the solution was stirred at room temperature for 12 hr. Ethanol was removed under reduced pressure and the residue was dissolved in methylene chloride and washed with saturated aqueous solution of ammonium chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica (25% EtOAc/hexane) to give compound 88 (81 mg, 94%, 99% ee) as a pale yellow oil: [α]20D=−8.1 (c=0.26, CHCl3); TLC Rf=0.27 (silica gel, 75% EtOAc/hexanes); 1H NMR (C6D6, 600 MHz) δ 8.69 (s, 1H), 6.89-6.83 (m, 2H), 4.57 (s, 1H), 3.38-3.34 (m, 2H), 2.40-2.38 (m, 2H), 2.16-2.11 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 174.602, 153.069, 149.938, 138.385, 136.681, 134.969, 131.441, 122.385, 84.064, 61.037, 51.692, 35.927, 18.483, 14.518, 13.070. HRMS calcd for C15H19NO3+Na+ 284.1263; found 284.1279 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1cccc(Br)c1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Part A: A suspension of 3-bromothiophenol (15.2 g, 81 mmol), bromoacetaldehyde dimethylacetal (9.5 mL, 81 mmol) and potassium carbonate (12.2 g, 88 mmol) in acetone (90 mL) was stirred at ambient temperature overnight. The solid was filtered and rinsed with ether. Evaporation of the filtrate afforded 23 g of 1-bromo-3-((2,2-dimethoxyethyl)thio)benzene which was carried forward without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNCCc1ccccn1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(CCc1ccccn1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N-methyl-2-(pyridine-2-yl)ethanamine (1.2 equiv) to give 169 (14.4 mg, M+1 432.1)
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].Cl[CH2:13][O:14][CH3:15]>CN(C)C=O>[CH3:13][O:14][CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: COCCl
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Salicylaldehyde (3 g) was slowly added to a N,N-dimethylformamide solution (50 mL) of sodium hydride (55%, 1.2 g) at 0° C. The mixture was stirred at the same temperature for 1 hour. Subsequently, chloromethylmethyl ether (2.9 g) was added thereto. After confirmation of the degree of reaction progress by TLC, the reaction was quenched with an aqueous solution of ammonium chloride. The organic layer was extracted with ethyl acetate and then was dried over anhydrous magnesium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain 3.9 g (yield: 96%) of 2-methoxymethoxybenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([S:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[C:5]#[N:6].Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:4]([S:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)([CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:34]2)[C:5]#[N:6])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCl)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 12.1 %

Procedure:
The procedure of Example 3 is repeated using 3.3 g of α-(2-chloroethyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 1.14 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 0.311 g of the desired product as a brown oil. MS(FAB):m/z 519 (M+H). Calcd for C30H34N2O4S 0.5H2O: C=68.28, H=6.99, N=5.31, S=6.80 Found C=68.56, H=6.55, N=5.21, S=5.73
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O-:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](=[CH2:21])[CH3:20].O>O1CCOCC1.S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][NH2:17])[C:13]([O:15][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(S)-(benzyloxycarbonyl)amino-3-aminopropionate (Fluka) (5.25 g, 22 mmol) in dioxane (75 mL) and conc. sulfuric acid (9 mL) was cooled to 0° C. and treated with 100 mL isobutylene in a Fisher Porter high pressure apparatus. The reaction was allowed to warm to room temperature and was stirred for 24 h. The reaction was vented, then poured into water (200 mL) to give an acidic solution that was extracted with ether (2×50 mL). The aqueous layer was carefully basified with conc. NaOH to pH 11-12 and extracted with 3×150 mL EtOAc. The EtOAc was removed in vacuo and the residue was azeotroped with toluene and dried under vacuum to give 4-1 as an oil. Rf (5% MeOH/CHCl3 saturated with NH3) 0.31. 1H NMR (400 MHz, CDCl3) δ7.3 (m, 5H), 5.6 (bs, 1H), 5.1 (s, 2H), 4.22 (bs, 1H), 3.05 (m, 2H), 1.45 (s, 9H), 1.4-1.2 (b, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.1 %

Procedure:
To a stirred solution of tert-butyl 3-aminobenzylcarbamate (Hah, Jung-Mi; Martasek, Pavel; Roman, Linda J.; Silverman, Richard B.; J. Med. Chem.; 2003, 46, 1661-1669) (287 mg, 1.29 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (0.27 mL, 2.0 mmol) and acetyl chloride (0.10 mL, 1.4 mmol) and the resulting solution was warmed up to room temperature slowly. After further stirring of 4 h, the reaction was quenched with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure. The residue oil was purified by column chromatography (60% EtOAc in hexanes) to provide tert-butyl 3-acetamidobenzylcarbamate (123.1 mg, 36%). N-(3-(aminomethyl)phenyl)acetamide was then generated by removal of the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: C(Br)(Br)[Br:2].[CH3:5][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>[Br:2][C:6]([CH3:5])([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrC(Br)Br
Reactant: COC(=O)C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C(C)(Br)C(=O)OC
Yield: 89.4 %

Procedure:
Bromoform (1.01 g, 0.4 mol), 1.46 g dimethyl methylmalonate, 200 mg tetra-n-butylammonium fluoride trihydrate (0.632 mmol), and 5 mL carbon tetrachloride were mixed at 24° C. for 2 h. The solution was found to contain 2.01 g (89% yield) of dimethyl α-bromo-α-methylmalonate.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:19]=[C:18]([NH:20][C:21](=[O:30])[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=1)=O)(C)(C)C.Cl.C(OCC)C>C(OCC)(=O)C>[ClH:28].[NH2:8][C:9]1[CH:19]=[C:18]([NH:20][C:21](=[O:30])[C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=1
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(NC(=O)OC(C)(C)C)cc2c1C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(N)cc2c1C
Yield: 183.7 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino)-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (1.56 g) in 4N-hydrogen chloride in ethyl acetate (10 ml) was stirred at ambient temperature for 1 hour and to the reaction mixture was added diethyl ether. The separated solid was collected, washed with diethyl ether and dried to give 5-amino-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan hydrochloride (1.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]1.C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C>>[CH2:30]([C@@H:25]1[NH:24][CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([O:7][C@@H:8]3[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]3)[CH:14]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: COc1ccc(Br)cc1O[C@@H]1CCN(C)C1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1O[C@@H]1CCN(C)C1

Procedure:
The title compound was prepared by the method outlined for Example 1 using (3R)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. LC/MS (Method B) 0.87 min, [M+1]+ 382.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[CH:49]=[C:48]([NH2:50])[CH:47]=[N:46]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:50][C:48]3[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 1-methyl-1H-pyrazol-4-amine (26 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H18ClN7O2, 364.13. found 364.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)(=O)C.O>[I:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(I)cc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cc(I)ccc2c(=O)[nH]1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-4-iodobenzamide (1.0 g, 3.61 mmol) in glacial acetic acid (10 mL) at rt was added diethyl oxalate (5 mL). The mixture was heated at 120° C. for 24 h. The mixture was cooled to rt and diluted with H2O until a precipitate formed. The precipitate was removed by filtration, washed with H2O, and dried under high vacuum for several hours to afford ethyl 7-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.0 g, 76%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, 3H), 4.48 (q, 2H), 7.90 (d, 1H), 7.95 (d, 1H), 8.20 (d, 1H), 8.28 (s, 1H), 12.78 (s, 1H); LC-MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH2:21])[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].[C:22]1([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:21][CH2:20][C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]3=[N:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=C(c4ccccc4)c4ccccc4)cnc32)cc1
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (2.00 g, 6.61 mmol, Example #5 Step C) in DCM (30 mL) was added diphenylmethanimine (1.16 mL, 6.61 mmol). After about 2 d, the reaction mixture was concd in vacuo to provide N-(diphenylmethylene)-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (2.75 g, 89%) as a foam and used without further purification. LC/MS (Table 1, Method a) Rt=3.02 min; MS m/z: 467 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C1COCC1>[CH3:14][N:15](/[CH:17]=[C:6]1/[CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:2]/1=[O:1])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1CCOC1
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 67.5 °C

Procedure:
A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (53.4 kg, 288 mol) in THF (133 kg) was treated with DMF-DMA (103 kg, 864 mol) in THF (472 kg) and heated at 65-70° C. under nitrogen for 20 h. The solution was cooled, evaporated under reduced pressure and solvent switched under distillation to cyclohexane. The resulting slurry was then filtered, cake washed with cyclohexane, and then water. The solids were then dried under vacuum at 35-40° C. to give tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([NH:18][C:19]([C@H:21]4[NH:25][CH2:24][CH2:23][S:22]4)=[O:20])[S:16][CH:17]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C=O)C>[CH2:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][S:22][C@H:21]1[C:19](=[O:20])[NH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[N:14]=1)=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3NCCS3)n2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3SCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C

Procedure:
A solution of (S)-thiazolidine-2-carboxylic acid [4-(4-cyclopropylcarbamoyl-phenyl)-thiazol-2-yl]-amide (50 mg, 0.13 mmol) in DMF (1 mL) was cooled to 0° C. DIEA (35 μL, 0.20 mmol) was added followed by benzyl chloroformate (30 μL, 0.21 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature over 2 hours. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 36.9 mg. MS: 509.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.55-0.74 (m, 4H), 2.80-2.91 (m, 1H), 3.10-3.27 (m, 2H), 3.65-3.75 (m, 1H), 3.90-4.04 (m, 1H), 4.94-5.17 (m, 2H), 5.51-5.55 (s, 1H), 7.06-7.41 (m, 5H), 7.79-7.98 (m, 5H), 8.41-8.48 (d, 1H), 12.50-12.60 (m, 1H).
Reaction SMILES: [C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:10]([O:9][CH:1]1[CH2:2][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH3:29])[O:17][C:10](=[O:9])[CH:11]1[CH2:12][CH3:13])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCCCCCCCCCCC1CC(OC(=O)c2ccccc2)C(CC)C(=O)O1
Yield: 100 %

Procedure:
138.5 g of benzoic anhydride and subsequently 2.5 ml of perchloric acid 70% were added to a suspension of 191.3 g of the δ-lactone from c) in 1250 ml of toluene. After stirring for 2.5 hours the reaction mixture in toluene was extracted with 1N sodium hydroxide solution in 20% sodium chloride solution and then with saturated sodium chloride solution. The organic phases were combined, dried and evaporated. 243.4 g (100.0%) of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-heptadecyl-δ-valerolactone, m.p. 64.5°-66°, resulted.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N+:4]([O-])[C:3]=1[C:10]#[N:11].C(=O)(O)[O-].[Na+].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:10]#[N:11])[N:4]=1)(=[O:19])[CH3:18]
Reactant: Cc1ccc(C)[n+]([O-])c1C#N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCc1ccc(C)c(C#N)n1
Temperature: 0 °C
Yield: 67 %

Procedure:
To acetic anhydride (20 ml) at 120° was added 3,6-dimethyl-2-pyridine-carbonitrile 1-oxide (5.28 g) and the solution heated at 120° for 5 minutes then under reflux for 2 hours. After cooling the solution was added to ice (ca. 150 g) and the mixture neutralized with sodium bicarbonate. It was extracted with ether (170 ml then 2×75 ml) and the combined extracts washed with brine (60 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by Biotage chromatography eluting with 2:1 hexane:ethyl acetate to afford the title compound (3.62 g, 67%) as a pale yellow oil
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])=[O:3].[NH2:15][NH2:16]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:15][NH2:16])=[O:9])(=[O:4])=[O:3]
Reactant: NN
Reactant: COC(=O)c1cccc(S(C)(=O)=O)c1
Solvent: CO
Product: CS(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 70 °C
Yield: 80 %

Procedure:
Methyl 3-(methylsulfonyl)benzoate (100 mg, 0.467 mmol) was added to hydrazine (22.44 mg, 0.700 mmol)) in methanol (10 mL) and refluxed for 12 h at 70° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the compound was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (80 mg, 80% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.07 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.62 (t, 1H, J=7.6 Hz), 3.04 (5, 3H). ESI-MS: 215.1 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[Cl:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1cccc(F)c1Cl
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(F)c3Cl)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-3-fluorophenyl)boronic acid gave 250. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.62 (s, 1H), 8.19-8.11 (m, 1H), 7.81 (s, 1H), 7.70-7.57 (m, 2H), 5.02-4.71 (m, 2H), 4.18-3.90 (m, 2H), 3.77 (s, 3H), 3.34-3.18 (m, 1H), 2.20-2.10 (m, 1H), 1.86-1.72 (m, 2H), 1.68-1.59 (m, 3H). LCMS (ES+) m/z 468 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11]C(=O)C2C=CC=CC=2)=[S:10])[CH:5]=[CH:4][CH:3]=1.CC(C)=O.[OH-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1cccc(Br)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: NC(=S)Nc1cccc(Br)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
4.933 g (14.67 mmol) N-{[(6-bromopyridin-2-yl)amino]carbonothioyl}benzamide was suspended in 40 mL methanol and additionally combined with 7 mL acetone. After addition of 1 N sodium hydroxide solution (40.0 mmol) the reaction mixture became completely clear with a light brown color. The mixture was heated for 40 min at 65° C. (oil bath temperature) and then stirred for 1 hr at room temperature. A solid crystallized out. The organic solvent was removed under vacuum, and after cooling on an ice bath the solid was filtered off and washed with water. The solid was dried over phosphorus pentoxide in a dessicator under high vacuum (4×10 mbar). The desired product N-(6-bromopyridin-2-yl)thiourea was obtained in the form of colorless needles in a yield of 3.158 g (13.61 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:15][CH2:14][CH2:13][O:12][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COCCO
Product: COCCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-methoxy-ethanol analogously to the preparation of Intermediate 98.1 as a colorless solid; ES-MS: M+=216.1; HPLC: AtRet=2.51 min.