Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CN(C)C=O>O>[Br:7][C:5]1[N:6]=[C:2]([N:11]2[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cs2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
A 100-mL round-bottom flask was charged with 2,4-dibromothiazole (1.00 g, 4.12 mmol), tert-butyl piperazine-1-carboxylate (0.918 g, 4.93 mmol), triethylamine (1.72 mL, 12.35 mmol) and N,N-dimethylformamide (20 mL). The resulting solution stirred for 18 h at 120° C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford tert-butyl 4-(4-bromothiazol-2-yl)piperazine-1-carboxylate (0.350 g, 23%) as brown oil. MS (ESI, pos. ion) m/z 348, 350 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccnc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccnc(Cl)c1CBr
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution 2,4-dichloro-3-methylpyridine (2.0 g, 12.3 mmol) in anhydrous carbon tetrachloride (50 mL) was added recrystallized 1-bromopyrrolidine-2,5-dione (2.25 g, 12.6 mmol) and benzoyl benzenecarboperoxoate (400 mg, 1.6 mmol). The mixture was stirred at reflux for 2 hours. After cooling to room temperature, the solid material was removed by filtration and washed with carbon tetrachloride (2×10 mL). The filtrate was recovered and evaporated. The solid product was dried in vacuo, affording 3-(bromomethyl)-2,4-dichloropyridine (2.9 g, 99% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@@H:42]([N:45]=[C:46]=[O:47])[CH2:43][CH3:44])C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].CCO[C:55]([CH3:57])=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C@H:34]([O:35][C:46](=[O:47])[NH:45][CH2:42][CH2:43][CH3:44])[C:57]2[CH:55]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reactant: CC[C@H](N=C=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCNC(=O)O[C@H](c1ccccc1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.404 mmol) in ether (12 mL) are successively added (S)-1-phenylpropyl isocyanate (130.4 mg, 0.809 mmol) and AlCl3 (54 mg, 0.404 mmol). The mixture is stirred at RT under nitrogen overnight. (S)-1-phenylpropyl isocyanate (150 μL) and AlCl3 (54 mg, 0.404 mmol) are again added and the mixture further stirred for 5 h. AcOEt is added and the reaction mixture quenched by the addition of an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one back extracted twice with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5) to give the title product TLC, Rf (CH2Cl2/MeOH 95:5)=0.35. MS (LC-MS): 656.2 [M+H]+; tR (HPLC, Nucleosil C18-HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, flow: 1 ml/min): 3.94 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=2)=[CH:13][C:12]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([N:28]=[N+:29]=[N-:30])[CH:20]=2)=[CH:13][C:12]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2cc(F)c(NC(=O)OCc3ccccc3)cc2F)ncn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Benzyl[4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (1.96 g) was dissolved in N,N-dimethylformamide (20 ml). Sodium azide (650 mg) was added thereto, followed by stirring at 60° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as white crystals (685 mg, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:40]3[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCS(=O)(=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), thiomorpholine-1,1-dioxide hydrochloride (73 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 8 mL of dichloromethane under stirring, and 4 mL of N,N-dimethylformamide was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(1,1-dioxo-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 6a (170 mg, yield 94%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][C:18]=3[O:33][CH3:34])[CH2:9]2)=[O:4].FC(F)(F)C(N1C2CCC1CC(C1C3C=CC(C4NN=NN=4)=CC=3OC3C1=CC=CC=3)C2)=[O:40]>>[CH3:34][O:33][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[O:20][C:21]1[CH:22]=[C:23]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][C:26]=1[CH:13]2[CH:8]1[CH2:7][CH:6]2[NH:5][CH:10]([CH2:11][CH2:12]2)[CH2:9]1.[C:3]([OH:40])([C:2]([F:36])([F:35])[F:1])=[O:4]
Reactant: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Reactant: COc1cccc2c1Oc1cc(-c3cccnc3)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(-c3cccnc3)ccc1C2C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 23, substituting 2,2,2-trifluoro-1-[3-(5-methoxy-3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone, 6k for 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j, the title compound 3-(5-methoxy-3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 7k was obtained as a TFA salt. MS m/z (MH+) 399.1.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[C:3]([OH:5])=[O:4].C[Si](C)(C)Cl.[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24](Cl)=[O:25])[C:20](=[O:27])[C:19]1=[O:28])[CH3:17].Cl.C(N(CC)CC)C>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([NH:1][CH:2]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[C:3]([OH:5])=[O:4])=[O:25])[C:20](=[O:27])[C:19]1=[O:28])[CH3:17]
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Reactant: NC(C(=O)O)c1ccco1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)O)c2ccco2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To an ice-cooled suspension of 2.55 g of DL-α-amino-2-furylacetic acid in 35 ml of methylene chloride was added 4.81 ml of trimethylchlorosilane. To the resulting mixture was added dropwise 5.04 ml of triethylamine over a period of 10 minutes at 5° to 10° C. The reaction was allowed to proceed at 15° to 20° C. for one hour. To the reaction mixture was added over a period of 15 minutes at 5° to 10° C. 7.01 g of a mixture of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride and triethylamine hydrochloride, said mixture containing 58.02% of the former. The reaction was allowed to proceed at 10° to 15° C. for one hour. After addition of 20 ml of water, the reaction mixture was stirred at room temperature for one hour, then at 5° to 7° C. for 30 minutes. The precipitated crystals were collected by filtration, washed with 5 ml of methylene chloride and 5 ml of water in this order, and then dried to obtain 4.75 g of DL-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-furylacetic acid, m.p. 179°-181° C. (decomp.), yield 85.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][CH:34]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C(Cl)(Cl)Cl>C(Cl)Cl>[I:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(I)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Temperature: 25 °C

Procedure:
To a mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (5.18 g, 19.0 mmol), prepared as described in Example 1d, and (4-iodo-phenyl)-carbamic acid 4-nitro-phenyl ester (8.00 g, 20.8 mmol), prepared as described in the preceding step, in DCM (20 mL) was added DIEA (3.44 mL, 20.8 mmol) with stirring at rt. After stirring at rt for 5 min, CHCl3 (20 mL) was added to thin the slurry, and after stirring for 4 h at rt, the greenish mixture was washed with 0.1 M NaOH (208 mL), and the resulting precipitate in the organic layer was filtered. The filter cake was dissolved in 92:8 DCM/MeOH (250 mL) and washed with water (1×50 mL) and 0.1 M NaOH (1×200 mL). The organic layer was then dried (Na2SO4), concentrated under reduced pressure, and the resulting greyish solid was triturated with hot toluene (1×20 mL) and filtered. The filter cake was washed with toluene (2×20 mL) to provide, after drying of the filter cake, the title compound as an off-white solid (7.84 g, 80%). Nmr reveals a single ˜15 mol % impurity. A sample was purified to homogeneity by flash chromatography. 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.58 (m, 2H), 7.35 (s, 1H), 7.25 (s, 1H), 7.17 (m, 2H), 6.49 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (m, 1H), 3.24-3.11 (m, 2H), 2.23-2.07 (m, 2H), 2.05-1.94 (m, 2H). LC/MS (ESI): calcd mass 518.1, found 519.2 (MH)+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:20](=[O:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]([CH3:26])[C:16](=[O:27])[CH2:15]2)[CH2:9][CH2:8]1)=[O:6]>O1CCOCC1.O>[CH3:26][N:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20](=[O:21])[N:14]([CH2:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)[CH2:15][C:16]1=[O:27]
Reactant: COC(=O)[C@H]1CC[C@H](CN2CC(=O)N(C)c3ccccc3C2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc21

Procedure:
LiOH (0.77 mmol, 0.02 g) was added to a solution of trans-4-(1-Methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-ylmethyl)-cyclohexane carboxylic acid methyl ester (0.64 mmol, 0.22 g) in 1:1 dioxane/water (16 mL) at 0° C. After 1 h at 0° C. the ice bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was washed with DCM (1×20 mL). To the aqueous layer HCl 2N was added until acid pH, then extract with DCM (3×15 mL). The organic layer was washed with brine dried over Na2SO4 anhydrous and the solvent was removed under reduced pressure to obtain the titled compound (0.18 g, yield 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[NH4+].[Cl-].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([NH2:31])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(N)=O)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a mixture of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 145 mg, 0.33 mmol), NH4Cl (160 mg, 3.0 mmol) and HATU (141 mg, 0.37 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 h and heated at 60° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (333:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (29 mg, 24%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.11-7.17 (2H), 7.36 (br s, 1H), 7.64 (d, J=9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.83-7.88 (2H), 8.05 (br s, 1H), 8.19-8.21 (2H), 8.30 (s, 1H). ESI-MS m/z 361.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1cccc(F)n1
Product: Cc1cccc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-6-methylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:35]=[C:34](F)[CH:33]=[C:32]([CH3:37])[C:29]=1[C:30]#[N:31]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:33]=[C:32]([CH3:37])[C:29]([C:30]#[N:31])=[C:28]([CH3:27])[CH:35]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(F)cc(C)c1C#N
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(C)c(C#N)c(C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-4-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[Si:19]([O:18][CH2:17][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][OH:13])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoic acid (2.5 g, 6.7 mmol) and TEA (1.9 mL, 13.4 mmol) in THF (50 mL) was added isobutyl chloroformate (1.1 mL, 8.04 mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 15 min and filtered. To the filtrate was added a suspension of NaBH4 (0.5 g, 13.4 mmol) in water (5 mL) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 30 min, quenched with saturated NH4Cl solution, and extracted with EtOAc (200 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxy-4,4-dimethylpentan-2-ylcarbamate (2.0 g, 83.1%). LRMS (M+H+-Boc) m/z 262.2.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:28][CH:29]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 9-{4-[4-(1,1-difluoroethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (300 mg) in THF (dry) (10 mL) and MeOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (77.7 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][NH:16][C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:20]1(CO)C=CC=C[CH:21]=1.BrC1C=CC(F)=NC=1.O[C@H]1CCNC1=O>>[CH2:5]([O:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:9][CH:8]=1)[C:4]1[CH:1]=[CH:3][CH:2]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1
Agent: Fc1ccc(Br)cn1
Agent: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)nc1

Procedure:
Following the sequence described for (R)-3-[6-(2-cyclopropyl-ethoxy)-pyridin-3-yloxy]-pyrrolidin-2-one, the title compound was prepared from phenyl-methanol, 5-bromo-2-fluoro-pyridine and (S)-3-hydroxy-pyrrolidin-2-one. MS ESI+: m/z=285 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CCC(=O)O)c1

Procedure:
Ten grams of m-methoxycinnamic acid in 100 ml. of ethanol is hydrogenated with 0.5 g. of pre-reduced 10% palladium-on-charcoal until the uptake of hydrogen ceases. The catalyst is removed by filtration and the filtrate evaporated to yield 3-(m-methoxyphenyl)propionic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][O:11]2)=[CH:6][C:5]=1[NH2:14])([O-])=[O:2].[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:14]=[C:16]([NH2:17])[N:15]=1)[CH2:8][CH2:9][CH2:10][O:11]3
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of nitroaniline 238 (2.05 g, 10.6 mmol) and cyanamide (1.78 g, 42.3 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (10 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×50 mL) and dried. The aqueous fraction was extracted with CHCl3 (3×50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give amine 239 (1.30 g, 56%) as a yellow powder: mp (MeOH/DCM) 280-283° C.; 1H NMR [(CD3)2SO] δ 7.32 (s, 1H, H-10), 7.31 (s, 1H, H-5), 6.96 (br s, 2H, NH2), 4.22 (dd, J=5.3, 5.2 Hz, 2H, H-8), 2.95 (br t, J=6.3 Hz, 2H, H-6), 1.92-1.98 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 159.1, 152.2, 143.4, 135.8, 128.7, 125.7, 102.6, 66.5, 25.0, 21.0. Anal. calcd for C10H10N4O2: C, 55.0; H, 4.6; N, 25.7. Found: C, 55.1; H, 4.6; N, 25.5%.