Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:11]([CH3:22])[C:10]=1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:11]([CH3:22])[C:10]=1[CH2:23][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Solvent: CC#N
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CCl
Reaction time: 0.17 h

Procedure:
To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.31 g, 0.90 mmol) in acetonitrile (8 mL) was added thionyl chloride (0.33 mL, 4.5 mmol) at room temperature. A clear solution resulted. The reaction was completed in 10 min. The reaction mixture was evaporated to dryness to give crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as an oil. The crude oil obtained was taken up in ethanol (10 mL) to give a clear solution. To the solution was added sodium borohydride (380 mg, 10 mmol) in several portions. The reaction was completed within a few min. The reaction mixture was diluted with methanol. The resulting clear solution was evaporated to dryness to give a solid. The solid was repeatedly extracted with dichloromethane. The combined dichloromethane solutions were combined and evaporated to dryness. Purification of the residue by column chromatography on silica gel (methanol/dichloromethane, 5/100 to 8/100 v/v) afforded the title compound (0.20 g, 67% yield, HPLC Method 1 (Example 24), RT=14.4 min). 1H NMR (DMSO-d6+D2O) δ ppm: 7.36 (m, 5H), 6.53 (s, 1H), 5.50 (q, J=6.5 Hz, 1H), 5.00 (s, 2H), 3.56 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:29](=[O:30])[C:28]3[C:19](=[C:20]([O:31][CH2:32][CH2:33][CH3:34])[CH:21]=[C:22]4[C:27]=3[O:26][CH2:25][CH2:24][CH2:23]4)[NH:18][CH:17]=2)=[CH:12][CH:11]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C(OCC)(=O)C.O>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][N:18]1[C:19]2[C:28](=[C:27]3[C:22](=[CH:21][C:20]=2[O:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][O:26]3)[C:29](=[O:30])[C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=2)=[CH:17]1)[CH3:41]
Reactant: CCOC(=O)CBr
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)OCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)OCC)c13)OCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
Sodium hydride (60% oil base, 80 mg, 2.0 mmol) was added to a DMF solution (10 ml) of 3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-oxa-1-aza-phenanthren-4-one (600 mg, 1.64 mmol), the resulting mixture was then stirred at room temperature for 5 minutes. Ethyl bromoacetate (330 mg, 2.0 mmol) was added thereto and the resulting mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using medium pressure liquid chromatography (NH silica gel, n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure, giving a colorless oily substance ethyl[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetate (700 mg, yield: 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cnn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4bromo-1H-pyrazol-1-yl)pyridine (0.669 g, 3.0 mmol), 3-methoxyphenylboronic acid (0.453 g, 3.0 mmol) and potassium carbonate (0.828 g, 6.0 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and H2O (4 mL) were degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degassing continued a further 15 min. The resulting solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine. MP=89-90° C. 1H NMR (CD3Cl, 300 MHz) δ 8.84 (s, 1H), 8.45 (dd, 1H), 8.03 (s, 1H), 8.02 (d, 1H), 7.84 (dd, 1H), 7.34 (t, 1H), 7.23˜7.15 (m, 3H), 6.84 (dd, 1H) 3.87 (s, 3H). MS (ESI) 252.1 (M++H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[CH2:4][C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:25])[C:4](=[N:26][OH:27])[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
While a solution of 0.15 g of 7-(4-bromo-3-oxobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 2 ml of acetic acid was stirred at room temperature, 0.03 g of sodium nitrite was added dropwise over a period of five minutes. Then, the mixture was further stirred for 20 minutes, after which time it was concentrated to dryness under reduced pressure. The resultant vitreous solid was applied to a Merck silica gel plate No. 5715 and developed with ethyl acetate-acetic acid-water (8:1:1). The color reaction with a 0.5% solution of copper chloride gave a single yellow spot at Rf=0.327. Therefore, the product was assumed to be substantially the captioned compound and was subjected to the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9](=O)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[OH-].[NH4+:20].[Cl-].[NH4+:22].[C-:23]#N.[Na+]>>[NH2:20][C:9]([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:23]#[N:22]
Reactant: O=C(COC1CCCCO1)COC1CCCCO1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: N#CC(N)(COC1CCCCO1)COC1CCCCO1
Reaction time: 0.67 h

Procedure:
5.6 g of the product obtained in Stage 1 above is introduced into 8 ml of ammonium hydroxide, the mixture is taken to about -5° C. and 1.58 g of ammonium chloride and 1.23 g of sodium cyanide are added successively and the reaction medium is left to rise to ambient temperature for about 40 minutes then heated at 40° C.±5° C. under agitation overnight. It is returned to ambient temperature and extraction is carried out 3 times with chloroform, the organic phase is washed with salt water and dried. After purification on silica, eluting with cyclohexane-ethyl acetate: 3-7 with 0.5% of triethylamine, 4.41 g of expected product (pale yellow syrup) is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH3:28])[C:4]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25]CC)=O)[CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[CH3:29][C:30]1[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.[Cl-].C[Al+]C>>[CH2:1]([N:3]([CH3:28])[C:4]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23](=[O:25])[NH:36][C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[CH:35][N:34]=3)[CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: Cc1cnc(N)cn1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)CC)nc2)c2cc(C)oc2c1
Agent: C[Al+]C
Agent: [Cl-]
Product: CCN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3cnc(C)cn3)cc3oc(C)cc23)cn1
Yield: 60.3 %

Procedure:
The title compound (5) was prepared by a method analogous to that described in Example 1 using ethyl 4-(2-(ethyl(methyl)carbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-5a: 99 mg, 0.26 mmol), 5-methyl-2-aminopyrazine (84 mg, 0.77 mmol), dimethylaluminium chloride (1.29 mmol, 1M in hexane) and dimethylethere (4.5 mL) to afford N-ethyl-N-methyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide (5: 70 mg, 61%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12]O.S(Cl)([Cl:24])=O>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][Cl:24]
Reactant: Nc1ncnc2c1nc(NCc1cccnc1)n2CCO
Reactant: O=S(Cl)Cl
Product: Nc1ncnc2c1nc(NCc1cccnc1)n2CCCl
Temperature: 50 °C
Yield: 53 %

Procedure:
A mixture of 350 mg (1.22 mmol) 6-amino-9-(2-hydroxyethyl)-8-[(3-pyridinyl-methyl)amino]-9H-purine and 2 ml of thionylchloride was stirred at 50° C. After completion of the reaction (˜3h) the mixture was concentrated in vacuo and subsequently diluted with water and the pH was adjusted to pH 7 with ammonia. The precipitate was isolated, washed with water, ethyl acetate and diethylether to give 197 mg (53%) of the desired product. 1H-NMR (DMSO): 8.62 (s, 1H), 8.44 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.38 (t, 1H), 7.33 (m, 1H, NH), 6.32 (s, 2H, NH2), 4.60 (d, 2H), 4.34 (t, 2H), 3.92 (t, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18]1>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][C@H:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CN1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol, 60% in mineral oil) and (S)-1-methylpyrrolidin-3-ol (4.7 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10.9 g of the title compound. MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([C:25]2([F:29])[CH2:28][NH:27][CH2:26]2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2([F:29])[CH2:28][N:27]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:26]2)[CH2:24][CH2:23]1
Reactant: FC1(C2CC2)CNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(C2CC2)C1
Yield: 29.8 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 3-cyclopropyl-3-fluoroazetidine hydrochloride (CAN 936548-77-5, 12.8 mg, 84.4 μmol) to obtain the title compound (8 mg, 30%) as colorless liquid, MS (ESI): m/e=382.3 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([C:35](O)=[O:36])[CH:34]=1)[NH:31][CH:30]=[CH:29]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:35]([C:33]2[CH:34]=[C:26]([Cl:25])[CH:27]=[C:28]3[C:32]=2[NH:31][CH:30]=[CH:29]3)=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 62.4 %

Procedure:
167 mg (0.5 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine, 97 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 115 mg (0.6 mmol) of EDC.HCl were stirred over night at rt in 10 ml DCM. The product was purified by column chromatography (20 silica gel; DCM) to yield 160 mg (64%) product as a white solid. MS (EI) 512.2 (60), 514.2 (25) (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.[CH3:52][O:53][C:54](=[O:59])[CH2:55][CH:56]([NH2:58])[CH3:57]>C(Cl)Cl.O>[CH3:52][O:53][C:54](=[O:59])[CH2:55][CH:56]([NH:58][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:5]([C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH2:4][CH2:3][C:2]([CH3:1])([CH3:33])[CH3:32])=[CH:15][CH:14]=1)[CH3:57]
Reactant: COC(=O)CC(C)N
Reactant: CC(C)(C)CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: COc1nnnc(OC)c1Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CC(C)NC(=O)c1ccc(OC(CCC(C)(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-{4,4-Dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoic acid (95 mg, 0.21 mmol), chloro-dimethoxy-triazine (CDMT) (37 mg, 0.21 mmol), and 4-methylmorpholine (25 uL, 0.23 mmol) are combined in anhydrous DCM under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. 3-Amino-butyric acid methyl ester (26 mg, 0.23 mmol) and 4-methylmorpholine (50 uL, 0.47 mmol) is then added to the reaction mixture, and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with DCM and water and rinsed with 1N HCl. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The 3-(4-{4,4-dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoylamino)-butyric acid methyl ester is isolated after column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:18])[CH:5]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[CH3:24]C(O)=O>COC(OC)OC>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[C:6]([N:18]2[CH:24]=[N:22][N:21]=[N:20]2)[CH:7]=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:9]=1
Reactant: COC(=O)c1cc(N)cc(-c2ncccc2OC)c1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1cc(-c2ncccc2OC)cc(-n2cnnn2)c1
Reaction time: 0.08 h

Procedure:
A suspension of 3-amino-5-(3-methoxy-pyridin-2-yl)-benzoic acid methyl ester (530 mg, 1.96 mmol) in trimethoxymethane (1.5 mL) was stirred under nitrogen for 5 minutes. NaN3 (390 mg, 5.9 mmol) was added slowly, followed by HOAc (10 mL). The reaction mixture was stirred at room temperature for 72 hours, then was concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography through 80 g of silica using EtOAc/hexanes (20%-100%) to give 170 mg of 3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester, MS (M+H)=312.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[CH:35][N:34]=1>O>[C:39]([C:38]1[C:33]([CH2:32][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:40]
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: N#Cc1cccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Temperature: 70 °C
Reaction time: 19 h

Procedure:
202 g (0.68 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 litres of N-methyl-2-pyrrolidone are initially charged in the reactor and heated to 70° C. Subsequently, 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP) are added dropwise. The reactor contents are stirred at 70° C. for 19 hours. After the reaction has ended, 2.8 litres of water are added to the reaction mixture and it is cooled to 25° C. The product is filtered off, washed with 2 litres of water and dried at 70° C. in a drying cabinet under inertization.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@@H:29]3[CH2:32][C@H:31]([O:33][CH2:34]C(OCC)=O)[CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:41])[CH:10]=1)#[N:2].[CH3:42][Mg]Br.[O:45]1[CH2:49][CH2:48]CC1>O1CCCC1.[Cl-].[NH4+]>[F:41][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:40])[N:18]([C@H:29]2[CH2:30][C@@H:31]([O:33][CH2:34][C:49]([OH:45])([CH3:48])[CH3:42])[CH2:32]2)[C:19]2[N:20]([N:25]=[C:26]([CH3:28])[N:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2nc(C)nn12
Agent: [Cl-]
Agent: [NH4+]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl [(cis-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutyl)oxy]acetate (895 mg) in tetrahydrofuran (8 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (8 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (606 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12](CO)[O:11][C:10]1=[O:16].[OH-].[Na+].I(O)(=O)(=O)=[O:28].Cl>C1COCC1.O.CCOC(C)=O>[Cl:17][C:6]1[CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH:12]([OH:28])[O:11][C:10]1=[O:16]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Reaction time: 0.67 h
Yield: 75724.9 %

Procedure:
To (3R,5S)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxymethyl-dihydro-furan-2-one (375 g, 1.015 mmoles) dissolved in 5 vols of THF, add 750 mL of 2 N NaOH. After 40 min, add periodic acid (375 g, 1,644 mmoles), dissolved in 1,125 mL of water, over 17 min (Tmax 33° C.). Add EtOAc (3 L) followed by 800 mL of 5.0 N HCl and 600 mL of water. Agitate the layers and then separate. Wash the organic layer with 100 g of sodium thiosulfate in 1 L of water, then 1 L of water, and then 700 mL of saturated NaCl in water. Dry the organic layer over sodium sulfate and then solvent exchange into 4 volumes (1500 mL) of heptane. Collect the solid by filtration and dry under vacuum. Reslurry the resulting solid in 3 volumes (1 L) of acetonitrile at 55° C. Cool the mixture in an ice bath and collect the solid by filtration. Dry the solid under vacuum to afford 273 g (78% yield) of the title compound as a white solid. MS (m/z): 355 (M+1, 35Cl), 357 (M+1, 37Cl).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[NH:15]1[CH2:20][CH2:19][C:18]2([CH:25]3[CH2:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH2:23][O:22][CH2:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32]>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]3[CH2:16][CH2:17][C:18]4([CH:25]5[CH2:26][CH:27]=[CH:28][CH:29]=[C:24]5[CH2:23][O:22][CH2:21]4)[CH2:19][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: C1=CCC2C(=C1)COCC21CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C1=CCC2C(=C1)COCC21CCN(CCCOc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 1,5-dihydrospiro[4H-2-benzopyran-4,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield as a foam. FDMS m/e=376 (M+ of free base).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=3[N:17]=[N:18][N:19]=2)=[N:7][CH:8]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccc(C(F)(F)F)cn1
Product: NC(=O)c1cccc2c(NCc3ccc(C(F)(F)F)cn3)nnnc12

Procedure:
Compound 7 was prepared following general synthetic scheme 7 wherein (5-(trifluoromethyl)-pyridin-2-yl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [349 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.50 (t, 1H), 9.35 (s, 1H), 8.93 (s, 1H), 8.55 (d, 2H), 8.16 (dd, 1H), 8.05-8.01 (m, 2H), 7.65 (d, 1H), 5.07 (d, 2H).