Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][OH:33]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: COc1cccc(CO)c1
Product: COc1cccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-methoxybenzyl alcohol (111 mg; 0.789 mmol), example 70 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.BrBr.[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[N:20][CH:19]=1.[Br-]>O1CCOCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]2[S:26][C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=3)=[C:2]([CH3:14])[N:27]=2)[CH:21]=[N:20][CH:19]=1
Reactant: NC(=S)Nc1cncc(Cl)n1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Agent: BrBr
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.2 %

Procedure:
4-(2-Oxo-propyl)-benzenesulfonamide (prepared as described in European patent specification EP 91749 A2) (0.63 g, 2.9 mmol) is dissolved in dry dioxan (70 ml) at 0° C. and bromine (0.121 ml, 2.4 mmol) is added dropwise. The mixture is stirred for 45 minutes at room temperature then the solvent is removed in vacuo. 6-Chloro-pyrazin-2-yl-thiourea (0.35 g, 1.87 mmol) is added to a solution of the above bromide (0.546 g, 1.87 mmol) in ethanol and the solution is heated at 60° C. for 4 hours. The reaction mixture is allowed to cool and the solvent removed under vacuum to give the title compound (0.63 g). MH+ (ES+): 382.1, 384.2 (3:1)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH:11]1([C:15]2[N:23]3[C:18](C(=O)NC=N3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([C:15]2[N:23]3[C:18]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncnn2c(C3CCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrous pyridine (10 mL) was added phosphorus oxychloride (POCl3) (0.578 mL, 6.20 mmol) and stirred at rt for 15 min. This mixture was dropwise charged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3H imidazo[5,1-f][1,2,4]triazin-4-one (0.653 mg 2.07 mmol) in anhydrous pyridine (14 ml) and stirred for 1.5 h. The reaction mixture was cooled to 0° C. quenched with 2M NH3 in isopropanol (IPA) until basic then allowed to reach rt and stirred for an additional 2 h. The reaction mixture was filtered through a fritted Buchner funnel and washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography on silica gel [eluting with 30% EtOAc in DCM] resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m, 2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O.Cl>[CH3:18][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH:12]([CH3:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC1C(=O)CC(C(=O)O)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)C(C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.0 g of crude 5-methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 25 mL of N,N-dimethylformamide was added 1.2 g (8.7 mmol) of K2CO3, and 1.2 mL (19.3 mmol) of methyl iodide. The mixture was stirred at 80° C. for 20 min, cooled to ambient temperature, then diluted with 125 mL of 0.2M HCl(aq.). This was extracted with diethyl ether (3×20 mL), then the combined ether layers were extracted with water (1×20 mL), and brine (1×20 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 20% ethyl acetate/hexanes to give the 2,5-cis isomer. The 2,5-trans isomer eluted slightly faster than the desired cis isomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J=7.1 Hz, 3H) 1.40 (m, 9H) 2.59 (dd, J=19.2, 3.2 Hz, 1H) 3.12 (dd, J=18.3, 11.2 Hz, 1H) 3.66 (s, 3H) 3.92 (q, J=6.8 Hz, 1H) 4.63 (dd, J=10.7, 3.6 Hz, 1H), NOE observed between H-2 and H-5, not observed in the corresponding trans isomer; MS (ESI) m/z=256 (M−H)+.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][C@H:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9]>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][C@H:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc([C@H](C)Oc2cccc(Br)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Oc1cccc(Br)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Lithium hydroxide (2 g, 83.3 mmol) was added to a solution of (S)-methyl 4-(1-(3-bromophenoxy)ethyl)benzoate (1.8 g, 5.4 mmol) in methanol (100 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. 3 mol/L hydrogen chloride (aq) was added to make pH 2-3, and the product was extracted with dichloromethane. The combined organic phase was washed with Sodium Chloride (aq) (20 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give (S)-4-(1-(3-bromophenoxy)ethyl)benzoic acid (1.7 g, 98%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:19][CH2:20][C:21]1[C:22]([CH3:44])=[N:23][O:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3([C:41]([OH:43])=[O:42])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:44][C:22]1[C:21]([CH2:20][S:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4([C:41]([OH:43])=[O:42])[CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)[O:24][N:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCc1ccccc1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CS(=O)Cc1ccccc1
Reaction time: 0.25 h

Procedure:
m-Chloroperbenzoic acid (0.024 g, 0.11 mmol) was added to a solution of 1-[4′-(4-benzylsulfanylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.050 g, 0.11 mmol) in CH2Cl2. After stirring for 15 minutes the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([CH2:12][C:13]#[N:14])=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:20]I>O1CCCC1>[C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([CH:12]([CH3:20])[C:13]#[N:14])=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[N:2]
Reactant: CC(C)c1cc(CC#N)c(C(C)C)cc1C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C#N)c(C(C)C)cc1C#N

Procedure:
A mixture of 4-cyano-2,5-diisopropylbenzeneacetonitrile (22.6 parts), 4.8 parts of a 50% sodium hydride suspension in mineral oil, and 14.2 parts of methyl iodide in 300 parts tetrahydrofuran is stirred and heated at 50° for two hours. The reaction mixture is cooled and the tetrahydrofuran stripped under reduced pressure. The solid is washed with pentane and water and dried to give 4-cyano-2,5-diisopropyl-α-methylbenzeneacetonitrile.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[O:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15]CC)=O.[Cl-].[NH4+]>O1CCCC1>[O:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1([OH:15])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCCO1
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CCCO2)CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A flask was charged with 13.6 g of magnesium and 300 ml of tetrahydrofuran, to which 60.3 g of 1,4-dibromobutane was added dropwise at 50° C. After the completion of dropwise addition, the solution was stirred at 60° C. for one hour. To the solution below 40° C., 31.0 g of ethyl tetrahydrofurancarboxylate was added dropwise. The solution was stirred at room temperature for one hour, after which an aqueous solution of ammonium chloride was added for hydrolysis. Ordinary post-treatment yielded 30.2 g of 1-(2-tetrahydrofuranyl)cyclopentanol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=O)[CH3:19].C(=O)([O-])[O-]>C(Cl)Cl>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12]([C:18]([CH3:19])=[CH:2][C:1]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:10]2)=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1N
Reactant: CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 60 h

Procedure:
Acetophenone (0.66 mL, 5.69 mmol) was added to 1-(2-amino-4-chlorophenyl)ethanone (0.868 g, 5.69 mmol) and [Hbim]BF4 (1.50 g, 7.08 mmol) under Ar. The reaction mixture was heated at 100° C. for 57 h then cooled to rt and partitioned between EtOAc and H2O. The aq layer was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography on SiO2 (70 g, EtOAc in hexanes 0:100->1:40->1:30) afforded a lightly colored oil. The material was dissolved in DCM (100 mL) and stirred with PS-Ts-NHNH2 (2.07 g, 2.87 mmol/g, 5.94 mmol) for 2.5 d at rt and then with MP-carbonate (˜0.25 g, 2.74 mmol/g, 0.68 mmol) for 4 h. The resins were removed by filtration through Celite. The residue and Celite were rinsed with DCM multiple times. The filtrate was concentrated under reduced pressure to provide the title compound as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.18-8.12 (m, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.54-7.46 (m, 4H), 2.75 (s, 3H); MS (ES+): m/z 254.24 (35) [MH+]; HPLC: tR=3.82 min (OpenLynx, nonpolar—5 min).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[CH3:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([O:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[N:19]=1)=[O:17])[C:11](=[O:14])[NH:12][CH3:13]>>[F:2][C:3]1([F:7])[CH2:6][N:5]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C@@H:10]([C:9]([CH3:33])([CH3:32])[CH3:8])[C:11]([NH:12][CH3:13])=[O:14])=[O:17])=[N:19][C:20]=2[O:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH2:4]1
Reactant: FC1(F)CNC1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(C)(C)C
Agent: Cl
Product: CNC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
The title compound was synthesized by addition of 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) to 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide (Example 188) in analogy to the procedure described in Example 69 a, MS (EI): m/e=441.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)=[O:18])([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[F:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:17]([C:11]1([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:18])=[CH:27]2
Reactant: CCCC1(C(=O)c2cc3cc(F)ccc3[nH]2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CCCC1(C(=O)c2cc3cc(F)ccc3[nH]2)CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
4-(5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester 162 mg was dissolved in 1 M methanolic HCl and stirred at room temperature for 24 hours. The solvent was removed to afford an oil which was precipitated from diethyl ether to give (5-fluoro-1H-indol-2-yl)-(4-propyl-piperidin-4-yl)-methanone; hydrochloride 132 mg as a solid in 97% yield, MS=289 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:47].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[F:47])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(F)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a slurry of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (82 mg, 0.132 mmol, 1 equiv) in acetonitrile (2.6 mL) was added Selectfluor (56 mg, 0.159 mmol, 1.2 equiv). After stirring 18 h, reaction is an orange slurry. LCMS indicated ˜50% conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a yellow solid (22 mg, 26% yield). 1H NMR (500 MHz, CDCl3) δ 7.20-7.16 (m, 1H), 7.15-7.10 (m, 1H), 7.04-6.99 (m, 1H), 6.99-6.94 (m, 1H), 6.87-6.81 (m, 1H), 4.95 (s, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.35 (br. s., 2H), 4.19-4.11 (m, 2H), 2.80 (s, 3H), 2.78-2.73 (m, 2H), 2.27 (s, 3H), 2.18 (br. s., 2H), 1.81 (s, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) d−119.41 (s, 1F), −139.50 (s, 1F), −175.35 (s, 1F); LCMS (ESI, M+1): 639.5.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.O.Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([S:15]([O:14][C:4]2[N:3]=[C:2]([NH:1][C:27]([O:29][CH3:30])=[O:28])[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Reaction time: 0.17 h

Procedure:
150 g of methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide are suspended in 2 l of methylene chloride and 2 l of water while stirring. After cooling to 0°-5°, 50 ml of methyl chloroformate are added thereto. After stirring vigorously for about 10 minutes, the mixture is adjusted to a pH of 7-7.5 with about 150 g of sodium bicarbonate. The mixture is subsequently stirred at 0°-5° for a further 3 hours. The organic phase is separated and the aqueous phase is extracted with 1 l of methylene chloride. The combined organic phases are washed twice with 1 l of water each time, dried over sodium sulphate and evaporated in vacuo. There is obtained crude dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide which is used in the next step (a pure product of melting point 178°-180° can be obtained by digestion with ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclopentyloxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a yellow solid (40%). MS 315 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:20][CH2:21][CH2:22]Br)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:12]([O:20][CH2:21][CH2:22][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Yield: 92.4 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15.7 g.), 2-bromoethyl benzoate (27.5 g.), potassium carbonate (20.7 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) was treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.).
Reaction SMILES: [Br:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][C:3](=[O:5])[C:2]([Br:1])([F:8])[F:9])[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: CCOC(=O)C(F)(F)Br
Product: C=CCNC(=O)C(F)(F)Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Ethyl bromodifluoroacetate (100 g) was cooled to 0° C., and allylamine (39 mL) was added dropwise. The mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 105 g, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cc(-c2nc3cc(Br)ccn3n2)ccn1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 0.1 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.2 g, 4.09 mmol) and tert-butyl carbamate (576 mg, 4.91 mmol) as starting materials. The reaction affords [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (1.126 mg, 83.5%) as light brown powder. MS: m/z=330.0 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]([NH:21]/[N:22]=[C:10]1/[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12][CH2:11]/1)=[O:23])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N/N=C1\CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 38.1 %

Procedure:
1-Boc-3-piperidone (25 g; 125.47 mmol; 1.00 eq.) is dissolved in toluene (250 mL) to which tert-butyl-carbazate (16.58 g; 125.47 mmol; 1.00 eq.) is added and reaction mixture is heated to 60° C. for 4 hours. After this time reaction mixture is evaporated to dryness, taken up in ethyl acetate (100 mL) and heptane (100 mL), and the suspension is heated, then cooled down to rt and the suspension is filtered and dried to give 15 g (95%) of the title compound as a beige solid. MS (ESI−): 311.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].OS(O)(=O)=O.II.[I:19](O)(=O)(=O)=O>O.C(O)(=O)C>[I:19][C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)cc(C)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 88.2 %

Procedure:
To a mixture of 2,6-dimethylnitrobenzene (151 g, 1.0 mol), acetic acid (1200 ml), and conc. H2SO4 (60 ml) was added iodine (102 g, 0.4 mol) and periodic acid dehydrate (205 g, 0.9 mol). The resulting solution was heated at 90° C. for 4 days. After cooling to room temperature, the reaction mixture was diluted with water (2000 ml). The yellow crystals were filtered and washed with water to give 220 g of pure product (79%). 1H-NMR δ (DMSO-d6, 300 MHz): 7.95 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 2.27 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8](OCC)=[O:9])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][OH:9])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(OC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-isopropyloxybenzoate (12.0. g, 61.8 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (3.52 g, 92.7 mmol) by small portions under ice-cooling. The mixture was stirred at room temperature for 1 hr. and water (10 ml) was added under ice-cooling to allow decomposition. Insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the objective substance (10.0 g, 97%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@@H:7]2[C@H:3]1[CH2:4][C:5](=[O:8])[CH2:6]2.[C:10](OCC)(=[O:13])[CH2:11][CH3:12]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1([CH3:9])[CH:7]2[CH:3]1[CH2:4][C:5](=[O:8])[CH:6]2[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCOC(=O)CC
Reactant: CC1(C)[C@@H]2CC(=O)C[C@@H]21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCC(=O)C1C(=O)CC2C1C2(C)C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of (1S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (2.0 g, 16.1 mmol, step f above) in THF (20 mL) is treated with K. tert.-butylate (1.99 g, 17.7 mmol). The dark brown solution is stirred at rt for 30 min before ethyl propionate (18.5 mL, 161 mmol) is added. Stirring is continued at rt for 1 h. The mixture is diluted with 10% aq. citric acid and extracted with diethyl ether. The organic extract is washed with brine, dried over NaSO4 and the solvent is evaporated to leave rac-(1S,5R)-6,6-dimethyl-2-propionyl-bicyclo[3.1.0]hexan-3-one (2.35 g) as a brown oil. LC-MS: tR=0.99 min, [M+1]+=181.29, 1H NMR (CDCl3): δ 2.64 (dd, J=7.6, 20.0 Hz, 1H), 2.36-2.22 (m, 3H), 1.75 (d, J=7.6 Hz, 1H), 1.30-1.22 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 1.10 (s, 3H), 0.82 (s, 3H).