Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[OH:36][C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2noc3ccc(C(F)(F)F)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reaction time: 8 h

Procedure:
3-[2-(5-Trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 1.21 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 1 hour. The solvent was removed and then lyophilized overnight to give the title compound as colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:17]=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:17]=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[C:15]=2[OH:16])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(-c2scc(C=O)c2O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2scc(C=NNC(=S)Nc3ccc(C(=O)O)cc3)c2O)cc1
Yield: 23.2 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-formylthiophene (50 mg, 0.19 mmol) synthesized in Reference Synthetic Example 25 and 4-hydrazinocarbonothioylaminobenzoic acid (40 mg, 0.19 mmol) were stirred with dimethylformamide (1.9 mL) and concentrated hydrochloric acid (0.1 mL) at room temperature for 12 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform). Methanol/chloroform was added to the resulting crude product, and the precipitated yellow solid was recovered by filtration to give the desired product as a pale yellow solid (20 mg, yield 23%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[CH3:12][C:13]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc(O)cc1
Product: Cc1nnc(-c2ccc(O)cc2)o1
Yield: 99 %

Procedure:
A mixture of 9.6 parts of 4-hydroxybenzoic acid hydrazide and 44 parts of 1,1', 1"-[ethylidynetris(oxy)]trisethane is stirred and refluxed overnight. The precipitated product is filtered off and crystallized from 1-butanol, yielding 10.5 parts (99%) of 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol; mp. 238.8° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CCC1CCNCC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of tert-butyl (Z)-4-(2-{2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0652 g, 0.129 mmol) in methylene chloride (5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-7-[2-(piperidin-4-yl)ethyl]benzofuran-3(2H)-one (0.0402 g, 77%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CC(C)([O-])C.[K+].CN(P(N(C)C)(N(C)C)=O)C.O>O1CCCC1.C(OCC)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:6]2[CH2:2][CH2:3][CH2:4][S:5]2)[N:8]=1
Reactant: ClCCCSCc1cccnn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1cnnc(C2CCCS2)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of pyridazin-3-ylmethyl 3-chloropropyl sulphide (28.2 g) in anhydrous tetrahydrofuran (35 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below -20° C., to a solution of potassium tert.-butoxide (24 g) in a mixture of anhydrous hexamethylphosphorotriamide (35 cc) and anhydrous tetrahydrofuran (190 cc). The reaction mixture is subsequently stirred for 1 hour 30 minutes at -40° C. and is then run, at 0° C., into a mixture of distilled water (500 cc) and diethyl ether (500 cc). After decantation, the aqueous phase is extracted with diethyl ether (250 cc). The ether extracts are combined, washed three times with distilled water (1500 cc in total), dried over anhydrous sodium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. 2-(Pyridazin-3-yl)-tetrahydrothiophen (10.5 g) is thus obtained in the form of a brown oil.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1)=[CH2:2].S(OC)(O[CH3:16])(=O)=O>C1COCC1.CCOCC>[CH3:16][N:7]1[C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=[C:3]1[CH:1]=[CH2:2]
Reactant: C=Cc1nc(C#N)c(C#N)[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1nc(C#N)c(C#N)n1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
To a solution of 0.602 g (4.17 mmol) of 2-vinyl-4,5-dicyanoimidazole in distilled THF (15 mL) at 0° C. under nitrogen was added slowly while stirring 0.22 mL (2.32 mmol) of dimethyl sulfate and 0.60 mL (4.30 mmol) triethylaminine via syringe. The reaction solution was allowed to come to room temperature and was stirred for 15 hours. The reaction solution was concentrated down under a stream of nitrogen and dissolved in 10 mL CH2Cl2. This solution was washed twice with a 10% solution of NaOH and twice with a saturated solution of NaCl. CH2Cl2 was stripped off, leaving a brown oil. This oil was dissolved in approximately 1 mL of THF and precipitated out in hexane. The precipitate was vacuum filtered and dried to yield 0.345 g (52.4% yield) of a light brown, fluffy powder. This powder was dissolved in 100 mL of ether and vacuum filtered to remove undissolved particles. 20 mL of hexane was added to the ether solution, and the solution was cooled to 0° C. White, needle-shaped crystals were formed and vacuum filtered.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[F:41])(=[O:31])[NH2:30].C([O-])(=O)C.[K+]>C(#N)C.O>[C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:1]#[N:2])=[CH:6][CH:7]=2)=[CH:34][C:33]=1[F:41])(=[O:31])[NH2:30]
Reactant: NC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(N)=O)c(F)c3)cc2)CCOCC1
Temperature: 85 °C
Yield: 53 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 200 mg) and 4-carbamoyl-3-fluorophenylboronic acid (73 mg) in acetonitrile (8 mL) were treated with potassium acetate (79 mg) in water (4 mL). Nitrogen was bubbled through the mixture and then 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h under nitrogen. The reaction mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 100:0) to afford the sub-titled compound (108 mg).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([S:12][C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.O>[CH:7]1([S:12]([C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Sodium periodate (333 mg) was added to a solution of (5R)-3-[6-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (230 mg) in ethanol (12 ml) and water (4 ml). The mixture was stirred at room temperature under nitrogen for 3 h. and the ethanol evaporated in vacuo. The aqueous phase was diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% ethyl acetate-cyclohexane, to give the title compound (201 mg). LCMS RT=3.54 min.
Reaction SMILES: [CH2:1]([C:3](C)=O)[CH3:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:11]([NH2:6])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:2][CH2:1][CH3:3]
Reactant: CCC(C)=O
Reactant: c1ccncc1
Product: CCCCCCCCN
Yield: 489.6 %

Procedure:
A mixture of 20.4 g of the white solid obtained in Intermediate Preparation Example 8, 6.4 g of n-octylamine, 80 g of methyl ethyl ketone and 0.8 g of pyridine was heated at a temperature of 70° C. and reacted with stirring for 10 hours. After cooling, the reaction mixture was added in 800 mL of methanol with stirring over 15 minutes, and the mixture was further stirred for one hour. A deposited solid was collected by filtration and dried in vacuo to obtain 28 g of a pale whitish yellow solid. The resulting compound had a molecular weight measured by high-performance liquid chromatography of 15,000.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br.[I-].[Zn+2].[I-].ClC1C=CC=CC=1Cl>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 43.5 %

Procedure:
A mixture of 2-amino-4-bromopyridine (0.50 g, 2.89 mmol), copper (I) bromide (20.7 mg, 0.14 mmol), 1,10-phenanthroline monohydrate (28.9 mg, 0.14 mmol), zinc iodide (92.3 mg, 0.29 mmol), benzonitrile (298 mg, 0.29 mL, 2.89 mmol) and 1,2-dichlorobenzene (25 mL) was heated in a 100-mL 3-necked flask to 130° C. During 22 h a gentle flow of air was bubbled through the reaction mixture (69% conversion, HPLC method cf. example 1.3). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with EtOAc (30 mL) and the combined filtrates were concentrated on vacuum such that most EtOAc was evaporated off. The resulting solution of the crude product in 1,2-dichlorobenzene was then loaded on a silica gel column to yield after chromatography (hexane/EtOAC from 9:1 to 7:3) 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (345 mg, 41%) as an off-white solid with 97.6% purity (HPLC area-%, HPLC method cf. comparative example 1) containing as an non-separable impurity 1.4% of 7-iodo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine.
Reaction SMILES: Br[C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[N+:16]([O-:18])=[O:17])[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:19]1([CH3:34])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1OB(C1C=CC=CC=1)O.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:14][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:34])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Reactant: Cc1ccccc1OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-n2cc(C)nc2-c2ccccc2C)c1[N+](=O)[O-]
Temperature: 115 °C

Procedure:
Intermediate 1D, method D (0.6 g, 1.9 mmol) and O-tolyl phenyl boronic acid (0.56 g, 3.8 mmol) were dissolved in a solution containing 1,4-dioxane (16 mL) and water (4 mL). To this was then added potassium carbonate (0.56 g, 3.8 mmol). Argon was bubbled into the reaction for 3 min and (triphenylphosphine) palladium (0) (0.1 g, 5% mol) added. The reaction was sealed then heated to 115° C. for 16 hrs, poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 10:1 ethyl acetate/methylene chloride. A white solid (0.5 g) was recovered. MS (ES) m/z 324.1 [M+1]+
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.O.NN>CO.[Ni]>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)CCCN1CCCc2cc(N)ccc21
Temperature: 60 °C

Procedure:
To a stirred solution of N,N-dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (600 mg, 2.278 mmol) in methanol (12 ml) was added Raney nickel (60 mg, 2.278 mmol) followed by hydrazine hydrate (1.108 ml, 22.78 mmol). The resulting mixture was then stirred at 60° C. and monitored by TLC for consumption of the starting material. The reaction mixture was then filtered through celite and the filtrate was concentrated. The residue was then dissolved in dichloromethane, dried, filtered and concentrated to give a dark oil. 1H NMR (DMSO-d6) δ 6.37-6.34 (m, 1H), 6.30-6.26 (m, 1H), 6.22-6.20 (m, 1H), 4.17 (brs, 2H), 3.12-3.03 (m, 4H), 2.55 (t, J=6.45 Hz, 2H), 2.20 (t, J=6.9 Hz, 2H), 2.11 (s, 6H), 1.79 (quint, J=6 Hz, 2H), 1.56 (quint, J=7.12 Hz, 2H). ESI-MS (m/z, %) 234 (MH+, 100), 161 (60).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[OH:24])[CH:10]=1
Reactant: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.), stirred solution of 2-{3-chloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (0.4 g) in methanol (10 mL) was added sodium borohydride (32 mg). After 30 min, the reaction solution was concentrated in vacuo, partitioned between 1N hydrochloric acid and ethyl acetate, the organic phase dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (5% ethanol/dichloromethane) to afford the title compound of Step C as a colorless foam, 72 mg. MS Calc.:469.8; Found:467.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:17](=[O:19])[CH3:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available (S)-1-(3-bromophenyl)ethanamine (1.0 g, 5 mmol) was dissolved in THF (20 mL). Pyridine (0.5 mL) and acetic anhydride (0.51 g, 5 mmol) were added and the reaction mixture allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to provide A4a.1 (1.23 g) as a clear yellowish liquid. (M+H)+=242.15, 244.16.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C(Cl)(Cl)Cl>[C:6]([O:5][C:1](=[O:4])[NH:2][N:3]1[C:13](=[O:14])[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:15])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Yield: 80.2 %

Procedure:
To a mixture of tert-butyl carbazate (5.15 g, 38.97 mmol) and phthalic anhydride (5.77 g, 38.97 mmol) was added CHCl3 (70 mL). The reaction mixture was refluxed for 18 h. Removal of the solvent under reduced pressure yielded 8.20 g (80%) of the title compound as a white solid. MH+263.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(OCC)(=O)C.O.C(O)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
In a solution of 1.23 g of 5-(3,5-dichlorophenyl)-3-(3-methyl-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 10 ml of ethyl acetate, 5.0 ml of water, 5.0 ml of acetic acid and 0.66 g of reduced iron were added and stirred at 100° C. for 2 hours. After the completion of the reaction, the reaction mixture was filtered through Celite, 20 ml of water was added in the filtrate, extracted with ethyl acetate (20 ml×2). The organic phases together were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then with 10 ml of water, thereafter dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.05 g of crude aimed product as red-brown oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:17])([F:18])[F:16])[CH2:14][C@:9]([C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[F:1])([CH2:28][F:29])[N:10]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a microwave vial was dissolved N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (8d, 116 mg, 0.280 mmol) in MeOH (1120 μl) and added 1,8-diazabicyclo-[5.4.0]undec-7-ene (84 μl 0.560 mmol). The reaction mixture was stirred at 75° C. overnight. Cooled to room temperature. Concentrated down and used directly in the following step.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[O:11][N:10]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:7][C:6]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:22])([F:23])[F:21])[O:11][N:10]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1noc(-c2cnccc2C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
12.4 g of 3-(tert-butoxycarbonylmethyl)-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole are dissolved in 110 ml of dichloromethane and admixed with 57 ml of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 1.5 hours and subsequently concentrated under reduced pressure. The residue is repeatedly taken up in dichloromethane and reconcentrated to remove any remaining trifluoroacetic acid. The mixture is finally triturated with diethyl ether, giving 8.1 g of the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 87 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (80 mg, 0.24 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (87 mg, 87%) which was obtained as a white solid. MS: m/e=414.4 [M+H]+.