Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:52]=[CH:51][C:16]2[NH:17][C:18]([C@@H:20]([NH:25][C:26](=[O:50])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][C@H:36]4[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34])=[C:29]([Cl:49])[CH:28]=3)[CH2:21][CH2:22][S:23][CH3:24])=[N:19][C:15]=2[CH:14]=1>ClCCl.C(O)(=O)C>[Cl:12][C:13]1[CH:52]=[CH:51][C:16]2[NH:17][C:18]([C@@H:20]([NH:25][C:26](=[O:50])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][C@H:36]4[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34])=[C:29]([Cl:49])[CH:28]=3)[CH2:21][CH2:22][S:23]([CH3:24])=[O:6])=[N:19][C:15]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
0.1 g (0.4 mmol) of 3-chloroperoxybenzoic acid is added at −10° C. to a solution of 0.3 g (0.4 mmol) of N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide in 10 mL of dichloromethane and 1 mL of glacial acetic acid and stirred for 30 minutes. Then the mixture is stirred for 4 hours at ambient temperature and washed with 5% sodium carbonate solution. The combined organic phases are dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel, eluting with dichloromethane/methanol (0%-10%). Yield: 0.1 g (59%); Rf value: 0.42 (silica gel; dichloromethane/methanol=9:1); C29H35Cl2N5O5S (636.60); mass spectrum: (M+H)+=636/638/640 (chlorine isotope) and (M−H)−=634/636/638 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (433 mg, 85%).
Reaction SMILES: [CH:1]1([Na:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.C[O:8][C:9](=O)[CH3:10]>O1CCCC1>[C:9]([C:1]1([Na:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:8])[CH3:10]
Reactant: COC(C)=O
Reactant: [Na]C1C=CC=C1
Solvent: C1CCOC1
Product: CC(=O)C1([Na])C=CC=C1

Procedure:
In accordance with the Rausch method, 10 ml of a tetrahydrofuran solution of cyclopentadienyl sodium (20 mmol/10 ml THF) and 4 ml of methylacetate were mixed in a nitrogen atmosphere, and refluxed for 20 minutes to obtain acetylcyclopentadienyl sodium. To the solution containing colorless crystals thereby obtained, 40 ml of benzene was added, and 10.6 g of tris-triphenylphosphine cobalt monochloride was further added whereby a red solution of bistriphenylphosphine-η5 -acetylcyclopentadienyl cobalt was immediately obtained. The solution was stirred at room temperature for about 1 hour. Then, an aqueous ammonium chloride solution was added to remove the excess acetylcyclopentadienyl sodium by transferring it to the aqueous phase. The organic phase was dried over sodium sulfate and then filtered. To the solution thereby obtained, 5 ml of 1,5-cyclooctadiene was added, and the mixture was refluxed for 1 hour on a hot water bath, and then concentrated under reduced pressure. The product was subjected to alumina column chromatography, whereupon an orange brown fraction eluted by a mixture of benzene/hexane (1:1) was isolated. The solvent was distilled off, and the product was recrystallized from benzene/hexane to obtain 0.32 g of brown crystals.
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49](=[O:50])[NH:48][C:46]2=O)[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:65])([F:64])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[O:66]([CH2:73][C:74]([NH:76][C:77]1[NH:78]C(=O)C2N=CN(C=2[N:129]=1)[C@@H]1O[C@H](COC(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H](O)[C@H]1OCOCC(C(F)(F)F)C(F)(F)F)=[O:75])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>>[C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[O:18][C@@H:17]([N:45]2[C:52]3[N:129]=[C:77]([NH:76][C:74](=[O:75])[CH2:73][O:66][C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[NH:78][C:49](=[O:50])[C:51]=3[N:48]=[CH:46]2)[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:63])([F:65])[F:64])[C:58]([F:59])([F:60])[F:61])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 51 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2g instead of the compound 2u. Yield was 51% (white foam).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:13]=3[CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:25][NH:26][O:27][CH3:28].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:18]1[C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:14][C:13]=2[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=1)=[O:20]
Reactant: CNOC
Reactant: COc1cc(C(=O)O)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N(C)OC)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 63.5 %

Procedure:
A solution of 44 (0.400 g, 1.27 mmole), N,O dimethylhydroxylamine hydrochloride (0.247 g, 2.53 mmole), DMAP (0.309 g, 2.53 mmole), and EDCI (0.364 g, 1.90 mmole), in 40 mL dimethylformamide was stirred at rt for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.290 g (63%) of amide 45 as a tan solid: Mp=100-102° C.; 1H NMR (DMSO-d6) δ 7.74 (dd, 1H, J=2.0 Hz), 7.66 (d, 1 H, J=8.6 Hz), 7.37 (s, 1 H), 7.31 (t, 1 H, J=8.7 Hz), 7.24 (d, 1 H, J=2.6 Hz), 6.93 (d, 1 H, J=2.6 Hz), 3.90 (s, 3 H), 3.82 (s, 3 H), 3.59 (br s, 3 H), 3.30 (s, 3H); MS 360 (M+H)+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])=[CH2:9]>CC(C)=O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Solvent: CC(C)=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
According to the present invention the following reactions are conducted simultaneously in a reaction system comprising step I of the process: reaction of phenol with acetone, reaction of phenol with p-isopropenylphenol resulting from thermal decomposition of process by-products and recycled to the reaction system, and isomerizational rearrangement of process by-products to obtain bisphenol A in the presence of a micro- and macroporous cation-exchange resin catalyst mixture. Step II of the process comprises cooling the post-reaction mixture together with water and acetone to obtain a precipitate of bisphenol-A/phenol in phenolic solution. Step III of the process comprises separation of the precipitate into crystalline bisphenol-A/phenol adduct and phenolic mother liquor I. The crystalline adduct is washed with the phenolic liquor and step IV follows, wherein the bisphenolA/phenol adduct obtained in step III is dissolved in the phenolic solution and the resulting mixture is cooled to obtain a bisphenol-A/phenol precipitate in phenolic solution. Step V comprises separation of the precipitate obtained in step IV into the crystalline bisphenol-A/phenol adduct and mother liquor II to be turned back to step III of the process. The bisphenol-A/phenol crystalline adduct is then washed with phenolic solution and step VI follows, wherein a high-purity bisphenol A is recovered by removal of phenol from the bisphenol-A/phenol adduct obtained in step V. Step VII of the process consists in distillation of the phenolic mother liquor I obtained in step III, and removal of acetone, water and part of phenol therefrom. Dewatered phenol liquor is turned back to step I of the process to the reaction zone and step VIII follows, consisting of thermal catalytic decomposition of part of the mother liquor I obtained in step(s) III and/or VII, resulting in a distillate comprising phenol, isopropenylphenol and process by-products. Step IX consists of catalytic rearrangement of the reactive components of the distillate obtained in step VIII, while leaving the p-isopropenylphenol contained therein substantially intact and the rearranged distillate is recycled to step I of the process.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[S:10][C:9]=12)=[O:4].[I-].[Na+].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>CC(C)=O.[Cl-].[Na+].O>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([C:3](=[O:4])[CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: C1CCNC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CCl)c4s3)[C@H](C)[C@H]12
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CN5CCCC5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-(7-chloroacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (161 mg) was dissolved in 5 ml of acetone to prepare a solution. Sodium iodide (67 mg) was added to the solution, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was dissolved in 5 ml of N,N-dimethylformamide to prepare a solution. Pyrrolidine (0.03 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was washed with diethyl ether to give 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: Ic1c[nH]c2ccncc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2cnccc21
Reaction time: 6 h
Yield: 105.9 %

Procedure:
To a suspension of 3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 47, 82 g, 340 mmol) and cesium carbonate (164 g, 504 mmol) in DMF (650 mL) was added 2-iodopropane (30.7 mL, 307 mmol) dropwise over 25 minutes at room temperature and the reaction was stirred for 6 hours. The reaction was poured into water (500 mL), stirred for 10 minutes and extracted into EtOAc (4×350 mL). The organic layers were combined, washed with brine, passed through a phase separation cartridge and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM followed by 50% EtOAc in DCM to afford the title compound as a pale brown gum (93 g, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]([C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(Cc2ccc(OCc3ccccc3)cc2)o1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)c1ncc(C)o1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 2-(4-(benzyloxy)benzyl)-5-methyloxazole (M5.2) (3.23 mmol) in THF (25 mL) at −78° C., was added dropwise LDA (4.5 mmol). The mixture was stirred for 18 minutes, followed by addition of ethyl bromoacetate (4.5 mmol). It was allowed to warm to room temperature for 3 hours, followed by addition of water, which was extracted with EtOAc. The extract was washed with brine and dried over Na2SO4 using standard work up conditions. Column chromatography (⅓ EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e: 366 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1)=[CH2:6])[CH3:2].C(N(CC)CC)C.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1)[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-acrylic acid ethyl ester (0.48 g, 1.57 mmol) and triethylamine (0.17 g, 1.64 mmol) was added to thioacetic acid (3 mL) at 0° C. under nitrogen. The mixture was stirred at room temperature for 4 h. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3 (aq) and dried. The crude product was purified by flash chromatography (2.5% MeOH in CH2Cl2) to give 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonylamino-pyridin-4-yl)-propionic acid ethyl ester (0.60 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]=[C:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:35])[C:29]=2[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH2:28][CH2:27][C:26]4=[CH2:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: C=C1CCc2c(O)cccc21
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: C=C1CCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 77 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-methylene-indan-4-ol (38 mg, 0.26 mmol) prepared as in example 30 to give the title compound (49 mg, 77%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2O)=[O:9])=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[CH3:17][C:13]1[C:12]2[O:9][C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:23]=4)[CH:6]=3)=[N:10][C:11]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cccc2nc(-c3cc(-c4cnn(C5CCN(C)CC5)c4)cnc3N)oc12
Temperature: 200 °C
Yield: 57.6 %

Procedure:
To a solution of 2-amino-N-(2-hydroxy-3-methyl-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (80 mg) in acetic acid (1.3 ml) was added TFA (1.3 ml). The clear mixture was sealed into a microwave tube. The reaction was heated to 200° C. in a 300 W microwave for 20 minutes. The solvents were evaporated. The residue purified by preparative HPLC using a Waters X-Terra reverse-phase column and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-(7-methyl-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (44.0 mg) NMR Spectrum: (DMSOd6) 1.94-2.10 (m, 6H), 2.22 (s, 3H), 2.62 (s, 3H), 2.84-2.92 (m, 2H), 4.09-4.17 (m, 1H), 7.27 (d, 1H), 7.32 (dd, 1H), 7.63 (bs, 2H), 7.64 (d, 1H), 7.93 (s, 1H), 8.30 (s, 1H), 8.44 (d, 1H), 8.52 (d, 1H); Mass spectrum: M+H+ 389.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[CH3:12]>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C@@H:13]1[CH2:11][CH3:12]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (S)-tert-butyl 3-ethylpiperazine-1-carboxylate gave (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate as an orange gum (110 mg, 65% over two steps). LCMS (ES+) m/z 310 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)([CH3:5])[CH2:3]O.S(Cl)(Cl)=O>C(OCC)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[O:15][CH2:3][C:2]([CH3:1])([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To the title compound of Example 2 (0.1 moles) was added dropwise, in the cold, thionyl chloride (0.4 moles) over 35 min. After stirring for one hour, the reaction was transferred to an addition funnel and added dropwise to rapidly stirring diethyl ether (700 ml). After stirring for 20 hours, the white solid was filtered under reduced pressure was washed well with diethyl ether. The dry solid was treated with 20% sodium hydroxide (75 ml). After stirring for 30 minutes the product was extracted into diethyl ether, and the aqueous layer was washed with ether. The combined ether extracts were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to an oil. The oil was distilled under vacuum to yield 20.0 g of the title compound as a colorless liquid, b.p. 69°-73° C./0.04 mm Hg.
Reaction SMILES: [CH3:1]S.[C:3]([NH:6][C:7](SC)([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:5])[CH3:4]>[Ni].CC(C)=O>[C:3]([NH:6][CH:7]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:8]([O:10][CH3:1])=[O:9])(=[O:5])[CH3:4]
Reactant: CS
Reactant: COC(CCC(NC(C)=O)(SC)C(=O)O)OC
Agent: [Ni]
Solvent: CC(C)=O
Product: COC(=O)C(CCC(OC)OC)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Four (4.0) cc of Raney nickel was suspended in 15 ml of acetone, and stirred for 2 hours at room temperature to be deactivated. To the system then 417 mg of 2-acetylamino-2-methylthio-5,5-dimethoxyvaleric acid methanethiol was added, followed by 18 hours' stirring at room temperature. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The residue was parted by a column chromatography (silica gel and ethyl acetate), to provide 310 mg of methyl 2-acetylamino-5,5-dimethoxyvalerate as a colorless oil. The yield was 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])=[CH:5][CH:4]=1
Reactant: COC(=O)CS
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CSC(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of 4,4'-dimethoxybenzhydrol (Aldrich) (300 mg, 1.23 mmol) and methyl thioglycolate (123 mg, 1.35 mmol) in 6 mL of 10% methanolic HCl is heated at reflux for 45 minutes. The reaction is cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. The product is concentrated in vacuo to give methyl [[bis-(4-methoxyphenyl)methyl]thio]acetate as a colorless oil in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:9]=1)=[O:4].[ClH:24]>CCOC(C)=O.CO>[ClH:24].[ClH:24].[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nn1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cn([C@H]2CC[C@@H](N)CC2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(cis-4-tert-butoxycarbonylamino-cyclohexyl)-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.53 g) in a mixture of 4.6 M HCl in EtOAc (25 ml) and MeOH (7.6 ml) was stirred 1 h at RT. The product precipitated and was collected by filtration. Yield: 1.36 g (58%). White powder. MS 225.0 (100, [M+H]+).