Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[ClH:38].C(OC(C)C)(C)C>O1CCOCC1>[ClH:38].[ClH:38].[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCNC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (300 mg) and 1,4-dioxane (3 mL) was added a 4 M solution (1.5 mL) of hydrogen chloride in 1,4-dioxane, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added diisopropyl ether (10 mL). The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (354 mg) as a pale yellow powder.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][C:26]=1[NH:37][C:38]([C:40]1[NH:41][CH:42]=[CH:43][N:44]=1)=[S:39].[OH-].[K+]>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[NH:44]1[CH:43]=[CH:42][N:41]=[C:40]1[C:38]1[S:39][C:27]2[C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[C:26]=2[N:37]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)c1ncc[nH]1
Agent: [Fe+6]
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [C-]#N
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3ncc[nH]3)nc12

Procedure:
According to scheme 1, to a suspension of a imidazole-2-carboxylic acid (X) was added CDI (1,1′-carbonyl-diimidazole) and stirred at ambient temperature for about 1 h. Then the mixture was refluxed and cooled to ambient temperature. 2-Methoxy-5-morpholin-4-yl-phenylamine (for R1=morpholinyl, IX) was added and the reaction mixture was heated to reflux for about 16 h. After workup 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (XI) was obtained, which was then treated with the Lawesson reagent. The reaction mixture was then heated to reflux for about 22 h. The obtained 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (II) was taken up in water and treated with KOH and potassium hexacyano ferrate to give 2-(1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (Ia for R1=morpholinyl).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=1>>[C:31]([NH:30][C:26]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[N:28][C:27]=1[CH3:29])(=[O:33])[CH3:32]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(=O)Nc1ccc(Cl)nc1C
Product: CC(=O)Nc1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)nc1C

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and N-(6-chloro-2-methylpyridin-3-yl)acetamide (89 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:24]=1
Reactant: O=C(O)c1ccccn1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of pyridine-2-carboxylic acid (1.26 g, 10 mmol) and 1,1′-carbonyldiimidazole (2.14 g, 13 mmol) in N,N-dimethylformamide (8 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 8 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyridine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.85 g, 57%) as a light yellow solid: LC/MS m/e calcd for C24H23N3O3 (M+H)+: 402.47, observed: 402.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([OH:28])[CH3:27])=[CH:21][C:20]=3[CH2:29][NH:30][CH3:31])[CH2:15][CH2:14]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.CS(C)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=3[CH2:29][NH:30][CH3:31])[CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CNCc1cc(CC(C)O)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CNCc1cc(CC(C)=O)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
285 mg (0,613 mMol) of trans-N-(4-chlorobenzene-sulphonyl)-N-methyl-4-[4-(2-hydroxypropyl)-methylaminomethylphenyl]cyclohexylamine are oxidised using the Pfitzner-Moffatt method (380 mg (1.94 mMol) of dicyclohexylcarbodiimide, 35 mg (0.3 mMol) of trifluoroaceticacid, 0.9 ml (12.8 mMol) of dimethylsulphoxide and 2 ml of benzene). 160 mg (56% of theory) of the title compound are obtained in the form of colourless crystals, melting point 98°-100° C. 1H-NMR spectrum (200 MHz, CDCl3); signals at ppm: 1.35 (m, 1H), 1.5-2.0 (m,9H), 2.15 (s,2H), 2.3 (s,2H), 2.4 (m, 1H) , 2.8 (s, 3H) , 3.15 (s,2H) , 3.55 (S, 2H) , 3.9 (m, 1H) , 7.1-7.7 (2q, 8H).
Reaction SMILES: C(OC1C=CC(C#C)=CC=1F)C1C=CC=CC=1.IC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1.C([O:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[C:54][C:55]2[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=2[CH:63]2[CH2:72][CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([O:73][CH3:74])[CH:69]=3)[CH2:64]2)=[CH:49][C:48]=1[F:75])C1C=CC=CC=1>>[F:75][C:48]1[CH:49]=[C:50]([CH2:53][CH2:54][C:55]2[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=2[CH:63]2[CH2:72][CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[C:68]([O:73][CH3:74])[CH:69]=3)[CH2:64]2)[CH:51]=[CH:52][C:47]=1[OH:46]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(C#Cc2ccc(OCc3ccccc3)c(F)c2)c1
Agent: C#Cc1ccc(OCc2ccccc2)c(F)c1
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(I)c1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)c(F)c1)C2
Yield: 85.3 %

Procedure:
Synthesized from 1-benzyloxy-4-ethynyl-2-fluorobenzene and 2-(2-iodo-4-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene according to an analogous synthetic method to Preparation Example 45, 2-[2-(4-benzyloxy-3-fluorophenylethynyl)-4-methoxyphenyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene (776 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (546 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 1-(2-chloroethyl)piperidine hydrochloride(421 mg, 2.29 mmol) and potassium carbonate(862 mg, 6.24 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow brown solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to give a yellow viscous oil (560 mg, 88.7%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06-8.05 (m, 1H), 7.24 (d, J=9.0 Hz, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.02-2.95 (m, 2H), 2.73-2.67 (m, 2H), 2.57-2.48 (m, 6H), 1.59-1.44 (m, 6H).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:12]=O.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC(CC)Oc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC(CC)Oc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 64.6 %

Procedure:
Piperidine (220 μL, 2.2 mmol) was added to a suspension of 3-methoxy-4-(pent-3-yloxy)benzaldehyde (0.50 g, 2.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.46 g, 2.1 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-methoxy-4-(pent-3-yloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.52 g, 66%) as a yellow crystalline solid; mp 82-85° C.; δH (400 MHz, DMSO-d6) 0.88 (t, J=7.2 Hz, 6H, CH3), 1.60 (p, J=7.2 Hz, 4H, CH2), 3.82 (s, 3H, OCH3), 4.25 (t, J=7.2 Hz, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.36 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 9.3, 25.5, 55.7, 80.1, 111.2, 114.5, 116.6, 119.8, 120.3, 122.5, 122.6, 127.1, 131.1, 134.0, 141.1, 141.6, 149.6, 149.9, 164.2, 169.5; HRMS (ESI) calculated for C22H25NO5 [M−H]− 382.1555. found 382.1649; vmax 749, 1139, 1259, 1505, 1584, 1650, 2934 cm−1.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][NH:16][C:17]([C:19]1[C:20]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:20]2[C:19]([C:17]([NH:16][CH2:15][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]4)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1cc2cc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)ccc2[nH]1

Procedure:
A solution of 5-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-1H-indole-2-carboxylic acid ethyl ester (0.043 grams, 0.099 mmole) in 1N sodium hydroxide (0.25 ml, 0.25 mmole) and ethanol (5 ml) was refluxed for 9 hours. The mixture was concentrated under reduced pressure to dryness and dissolved in water (2 ml). The mixture was acidified with 2 N hydrochloric acid giving a white solid which was isolated by filtration (0.032 g). M.P. 236-238; Anal. Calcd. for C22H16N3O4F: C, 65.18; H, 3.98; N, 10.37. Found: C, 65.12; H, 4.08; N, 10.20.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:18])([O-])=O>[Pd].CO>[NH2:2][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:18]
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1cc(Oc2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
10% Palladium on carbon, 50% water wet (1.43 g, 1.34 mmol) and 2-nitro-4-phenoxyphenol (3.10 g, 13.4 mmol) were combined under nitrogen and 30 mL MeOH was added. The mixture was exposed to H2 from a balloon and was stirred rapidly overnight. In the morning the reaction was flushed with nitrogen and filtered and concentrated in vacuo to give 2-amino-4-phenoxyphenol as a light brown solid. MS (ESI) m/z: Calculated: 201.1; Observed: 202.1 (M++1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:14]([CH:18]=1)[C:15](O)=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH2:50])[CH3:46]>O1CCCC1.O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:14]([CH:18]=1)[C:15]([NH:50][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(C(=O)O)c2)c(OCC(C)C)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
In 40 ml of tetrahydrofuran is dissolved 4.00 g of 5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoic acid, to which are added 0.95 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide. The mixture thus obtained is stirred at ambient temperature for one hour. To the reaction mixture are added 3.03 g of glycine ethyl ester hydrochloride and 4.2 ml of triethylamine successively, and the mixture thus obtained is stirred for one hour under reflux with heating. The reaction mixture is cooled to ambient temperature, chloroform and water are added, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 4.00 g of ethyl 2-{[5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoyl]amino}acetate as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[N+:15]([O-])([OH:17])=[O:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: O=C(O)CCC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])O
Product: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C

Procedure:
3-(3-Hydroxybenzoyl)propionic acid was added in portions to well stirred fuming nitric acid at -15° C. The resultant mixture was stirred a further 10 minutes in the cold then poured into ice-water. The crude product was triturated with methanol to give 3-(3-hydroxy-4-nitrobenzoyl)propionic acid, which after recrystallisation from water had m.p. 158° - 160.3° C (Found: C, 50.25; H, 3.75; N, 5.88; M+, 239 C10H9NO6 requires: C, 50.21; H, 3.79; N, 5.86%; M, 239)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cccc(C2CCCNC2)c1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
3-[3-(4-Trifluoromethoxy-benzenesulfonylamino)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (340 mg, 0.66 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. Aqueous NaHCO3 solution (10 ml) was added and extracted twice with ethyl acetate (25 ml). The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the pure product (250 mg, 95% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:26][CH2:27][C@H:28]([NH2:35])[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[CH:2]=[CH2:3].[C:37]([O:56][CH2:57][C:58](O)=[O:59])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[C:7]=1[CH2:25][S:26][CH2:27][C@@H:28]([C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[NH:35][C:58](=[O:59])[CH2:57][O:56][C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(C)no1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 1.07 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester and 0.96 g of trityloxy-acetic acid in 15 ml of acetonitrile, cooled to 0° C., were added 0.58 g of N-(dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 h, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 1.42 g of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-trityloxy-acetylamino]-ethylsulfanylmethyl]-benzoic acid allyl ester as a foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][O:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]2)=[C:5]([N+:22]([O-])=O)[CH:4]=[N:3]1>CO.[Pd]>[NH2:22][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:13][O:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(NC(=O)OC(C)(C)C)COC1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(N)c1C1CCC(NC(=O)OC(C)(C)C)COC1

Procedure:
A solution of tert-butyl N-[6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-yl]carbamate (53 mg, 0.16 mmol) in MeOH (25 mL) was passed through the H-Cube® (50 bar, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford tert-butyl N-[6-(4-amino-2-methyl-pyrazol-3-yl)oxepan-3-yl]carbamate as a brown oil. To a solution of this oil in DCM (5 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (72 mg, 0.20 mmol), PyBOP (133 g, 0.25 mmol) and DIPEA (0.17 mL, 0.94 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction was quenched with water and extracted with EA (3×). The organic layers were combined and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/heptane) gave tert-butyl N-[6-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]oxepan-3-yl]carbamate (100 mg, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]([C@@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH:25]=[CH2:26])C(=O)C1C=C(C)C=C(C)C=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si@]1(Cl)N(C)[C@@H](C)C(C2C=CC=CC=2)O1)C=C>>[CH2:1]([O:8][C:9]([NH:11][NH:12][C@@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH:25]=[CH2:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@@H](N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Agent: C=CC[Si@@]1(Cl)OC(c2ccccc2)[C@H](C)N1C
Product: C=CC[C@@H](NNC(=O)OCc1ccccc1)C(C)(C)C

Procedure:
Briefly, benzyl carbazate (compound A) was reacted with pivaldehyde to give (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester (compound B). Compound B was reacted with (S,S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (Compound C; see Leighton et al., J. Am. Chem. Soc. 125:9596 (2003) and WO 03/074534) to give (R)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid benzyl ester (compound D). Compound D was reacted with 3,5-dimethyl benzoyl chloride to give (R)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (compound B). Compound E was hydrogenated to give (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-hydrazide (compound F). Compound F was reacted with 2-ethyl-3-methoxybenzoyl chloride to give Compound 1. The crude material was triturated first with ether (2% ethanol) and then with 1:1 hexanes:ether in a fritted glass Büchner funnel. The product was then washed with deionized water with thorough mixing and allowed to dry in air. Compound 1 was isolated as a white powder.