Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.O>C(#N)C.CC(N(C)C)=O>[C:11]([O:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(N)CC2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(NC(=O)Oc3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
Phenyl chloroformate (7.83 g, 50.0 mmol) was dissolved in acetonitrile (100 ml), and a solution of the 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester (13.82 g, 50.0 mmol) obtained in Example 1(1) in acetonitrile (50 ml) and DMA (50 ml) was added dropwise under ice-cooling. Triethylamine (7.0 ml, 50.0 mmol) was added thereto. After stirring at the same temperature for 2 hours, water was added thereto, and the precipitate was collected by filtration, thereby obtaining 4-(4-phenoxycarbonylaminopiperidin-1-yl)-benzoic acid tert-butyl ester (15.5 g, 78%) as a milky-white solid. The obtained 4-(4-phenoxycarbonylaminopiperidin-1-yl)-benzoic acid tert-butyl ester was used as is in the next reaction.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cc(F)ccc2F)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A solution of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.35 g, 0.70 mmol) in methanol (7.1 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (20 mg, 0.10 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (000 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2-5% methanol/dichloromethane) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.23 g, 71%) as a pale orange solid: HR-ES-MS m/z calculated for C22H26N4O5F2 [M+H]+ 465.1944, observed 465.1943; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.82 (m, 1H), 3.18-3.31 (m, 2H), 3.66-3.79 (m, 1H), 3.84 (dd, J=13.4, 7.5 Hz, 1H), 4.07 (dd, J=13.4, 3.6 Hz, 1H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.86 (dd, J=10.7, 4.7 Hz, 1H), 4.92 (d, J=5.4 Hz, 1H), 5.01 (s, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.15-7.32 (m, 1H), 7.43-7.60 (m, 3H), 10.76 (s, 1H).
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][C:13]#[CH:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCCCCCC>[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCO
Reactant: CCCCCCCS
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Product: CCCCCCCSC=CCCCCO
Yield: 29.7 %

Procedure:
To 1.332 gr (10 mmol) of n-heptyl mercaptan and 981 mg (10 mmol) of 5-hexyn-1-ol dissolved in 25 ml of heptane under an argon atmosphere was added a few crystals of dibenzoyl peroxide. The reaction was stirred magnetically and heated to reflux for 18 hours. It was then cooled and poured into 25 ml of 10% sodium bicarbonate and extracted with 3×25 ml of ethyl acetate. The organic phases were combined and dried over sodium sulfate, filtered, and evaporated to yield a yellow oil. The oil was chromatographed on eight silica gel type GF preparative plates, using hexane-ethyl acetate (4:1) as developing solvent. Following removal of the band corresponding to product from the plates, the product was extracted from the silica with methanol, 684 mg (30% yield) of pure 7-thia-tetradecan-5-ene-1-ol was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32]N)=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N(OCCC(C)C)=O.CN1CCOCC1.N[C@H:51]([CH2:56][OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54]>O1CCOCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:51]([CH2:56][OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -60 °C

Procedure:
To a solution of 0.91 g. (2 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidine hydrazide in 32 ml. of dimethylformamide was added 1.64 ml. of a 4.1N solution of hydrogen chloride in dioxane. The mixture was cooled to -60° C., and there was added 0.4 ml. of isopentyl nitrite. The temperature of the resulting mixture was then raised to -20° C. After confirming the disappearance of the hydrazide, the temperature of the mixture was lowered to -60° C., and then the mixture was neutralized by the addition of 0.8 g. of N-methylmorpholine. To the mixture was added 0.28 g. (2.4 mmole) of L-leucinol and the mixture was stirred at 4° C. for 23 hours; the solvent was then removed by distillation under reduced pressure, and water was added to the residue to form a colourless precipitate, which was separated by filtration and washed thoroughly with water and then with ethyl acetate. There was obtained 0.94 g. of the desired compound as a white powdery solid, melting at 181°-183° C.; [α]22 -19.4° (C=0.5, methanol).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][F:22]>CO>[F:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][OH:7]
Reactant: FCCCCCCCCCC/C=C\CCOC1CCCCO1
Solvent: CO
Product: OCC/C=C\CCCCCCCCCCF

Procedure:
Following the procedure described in Example 6 using 353.6 mg (1.26 mmol) of 14-fluoro-(Z)-3-tetradecen-1-yl tetrahydropyranyl ether and 350 mg Dowex in about 10 ml of methanol affords 14-fluoro-(Z)-3-tetradecen-1-ol. Purification by flash chromatography affords 14-fluoro-(Z)-3-tetradecen-1-ol (211.8 mg, 73%) as a clear colorless oil: Rf=0.27, hexane/ethyl acetate (7:3, v/v); IR (film) ν3200-3500 (OH), 3025 (alkane CH); and 1H-NMR (CDCl3) δ1.20-1.70 (m, 16H), 2.10 (m, 2H), 2.39 (br q, J=5 Hz, 2H), 3.65 (t, J=6 Hz, 2H), 4.41 (dt, J=48 Hz, 6 Hz, 2H), 5.45 (m, 2H).
Reaction SMILES: [Br:1]Br.C[O:4][C:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH:6]=1.COC(C)(C)C>C(Cl)Cl>[CH2:12]([O:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH:6]([Br:1])[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: COC1=CCC(OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C1CCC(OCc2ccccc2)CC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of bromine (0.56 ml, 10.90 mmol) in DCM (30 ml) was added dropwise to a solution of ((4-(methoxy)cyclohex-3-enyloxy)methyl)benzene (3.4 g, 15.57 mmol), which was prepared as described in the last step, in DCM (100 ml). The reaction mixture was stirred for 1 hour at room temperature. Tert-butyl methyl ether (150 ml) was added. The solution was washed with ice cooled water (200 ml), a saturated aqueous solution of sodium thiosulphate (100 ml), and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:2) as eluent, to give 1.40 g of a mixture of diastereoisomeres of 4-benzyloxy-2-bromocyclohexanone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:28]=1)CCC.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3[CH2:28][CH2:27][O:26][CH2:25][CH:24]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3=CCOCC3)cc2C1
Temperature: 100 °C
Yield: 74 %

Procedure:
To a stirred solution 6.32 mmol 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) in 20 ml DMF were added 12.6 mmol tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, 3.79 mmol triphenylarsine, 0.76 mmol bis(triphenylphosphine)palladium(II) chloride, 50.5 mmol lithium chloride and 0.63 mmol 2,6-di-t-butyl-p-cresol and the mixture was heated at 100° C. for 6 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid (74% yield). MS (m/e): 246.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.C(=O)([O-])[O-].O=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]2[NH:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
HCl salt of (3aS,7aS)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one (2 g, 7.72 mmol) was dissolved in MeOH (30 mL) and MP carbonate (12 g) was added. The mixture was stirred for one hour at rt and then filtered and concentrated in vacuo to provide a white solid. To a stirred solution of above freebase and tert-butyl 4-oxopiperidine-1-carboxylate (1.8 g, 9.04 mmol) in MeOH (40 mL) was added a solution of sodium cyanoborohydride (1 g, 14.49 mmol) and zinc chloride (0.73 g, 5.36 mmol) in MeOH (20 mL). The resulting solution was stirred at room temperature over night then concentrated in vacuo. A solution of 1N NaOH was added and aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with brine, dried and then concentrated in vacuo. The residue was purified using flash chromatography (linear gradient starting from 1-12% methanol in dichloromethane) to provide the desired compound as a white solid (2 g, 88%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.21-1.49 (m, 4H), 1.41 (s, 9H), 1.57-1.67 (m, 1H), 1.66-1.84 (m, 7H), 1.93 (d, J=11.13 Hz, 1H), 2.05-2.32 (m, 5H), 2.29-2.43 (m, 1H), 2.53-2.71 (m, 2H), 2.76-3.05 (m, 4H), 3.56-3.79 (m, 1H), 3.90-4.24 (m, 2H), 4.76 (s, 1H). MS (M+1): 407.3
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:34][CH2:33][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=[O:14])(C)(C)C.CCN(C(C)C)C(C)C.[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[CH3:44])[CH2:34][CH2:33][C:18]=2[N:19]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Reactant: Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Trifluoroacetic acid 4.0 ml (54 mmol) was added to a solution of 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 307 mg (0.789 mmol) in CH2Cl2 (8 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 380 μl and 2-methylbenzoic acid 118 mg (0.868 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 166 mg (0.868 mmol) and HOAt 16 mg (0.12 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 260 mg (0.64 mmol, 81% of theoretical) was obtained.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:22]=2[C:23](C[N-]OC)=[O:24])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([C:7]([NH:20][C:21]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:22]=2[CH:23]=[O:24])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[N-]CC(=O)c1c(F)cccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 2-triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 0.68 mmol) in THF (4 mL) at −78° C. was added lithium aluminum hydride (30 mg, 0.82 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (dry ice bath removed after addition of reagent) for 1 h. The reaction mixture was quenched with 20% KHSO4 and extracted with EtOAc (3×100 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 5% EtOAc-hexanes) provided 182 mg of the title compound (260 mg theoretical, 70% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]2.O>CN(C=O)C.C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH:22]=[N:2][OH:3])[CH:16]=[CH:15]2
Reactant: NO
Reactant: O=Cc1ccc2cc(Cl)ccc2n1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: ON=Cc1ccc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.33 g (4.8 mmol) of hydroxylamine hydrochloride and then 0.9 mL (4.6 mmol) of triethylamine are added to a solution of 0.83 g (4.34 mmol) of 6-chloroquinoline-2-carbaldehyde in 20 mL of DMF/ethanol (v/v 1:1). The reaction mixture is stirred for 16 hours at ambient temperature; then it is poured into water. The precipitated solid is filtered off and dried. Yield: 0.79 g (88% of theory); Rf value: 0.73 (silica gel; dichloromethane/methanol=9:1); C10H7ClN2O (206.63); mass spectrum: (M+H)+=407/209 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1I)[CH3:21].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)[CH3:21]
Reactant: CCc1c(I)cnn1-c1ccccc1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1c(C#Cc2cnn3cc(-c4cnn(C)c4)cc(OC)c23)cnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.080 mmol), 5-ethyl-4-iodo-1-phenyl-1H-pyrazole (24 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0079 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-ethyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1.C(N(CC)CC)C>CO>[CH3:15][C:11]1[N:10]=[C:9]([N:1]2[CH2:4][CH:3]([CH2:5][CH2:6][OH:7])[CH2:2]2)[CH:14]=[CH:13][CH:12]=1
Reactant: OCCC1CNC1
Reactant: Cc1cccc(F)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CC(CCO)C2)n1
Temperature: 150 °C

Procedure:
2-(Azetidin-3-yl)ethanol (4.91 mmol, 0.497 g), 2-fluoro-6-methylpyridine (9.83 mmol, 1.014 ml, 1.092 g), and triethylamine (14.74 mmol, 2.072 ml, 1.492 g) were dissolved in MeOH (2 ml). The solution was then heated (microwave) to 150° C. for 1 hour. Solvent was removed under reduced pressure. The resulting oil was redissolved in DCM and washed once with water. Solution was dried (Na2SO4), and solvent removed under reduced pressure to give a crude product. This was then purified by flash chromatography (10 g silica column, DCM to 2% MeOH in DCM gradient). Appropriate fractions were combined and solvent removed under reduced pressure to give final product. 1H NMR (CDCl3) δ: 7.32 (t, 1H), 6.43 (d, 1H), 6.08 (d, 1H), 4.13 (t, 2H), 3.69 (m, 4H), 2.84 (m, 1H), 2.39 (s, 3H), 1.92 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16](Cl)[N:15]=[CH:14][N:13]=1.ClC1C(C)=C(C2C=CC(C(F)(F)F)=CC=2)N=CN=1>>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(Cl)ncnc1-c1ccc(Cl)cc1

Procedure:
Prepared from 4-chlorophenylboronic acid and 4,6-dichloro-5-methylpyrimidine using the procedure described for Intermediate 62.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][OH:9])=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:11]>>[OH:9][N:8]=[C:7]([Cl:11])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: ON=Cc1ccncc1
Product: ON=C(Cl)c1ccncc1

Procedure:
4-Pyridinecarboxaldehyde oxime (30.6 g, 0.25 mol) was chlorinated in chloroform (350 ml) as described in Example 1 to produce N-hydroxy-4-pyridine-carboximidoyl chloride which was suspended in ether (500 ml) containing 2-chloroethanethiol (26.9 g, 0.25 mol). With ice bath cooling, triethylamine (5.l g, 0.5 mol) was added dropwise. After the addition, water was made, the suspended solid, crude 2-chloroethyl N-hydroxy-4-pyridinecarboximidothioate was collected on a filter and dried. This crude ester was added to a solution of sodium ethoxide (from 5.75 g sodium in 500 ml ethanol), and the reaction mixture stirred for 4 hours. Water was added and the product was extracted with ether to give 5,6-dihydro-3-(4-pyridinyl)-1,4,2-oxathiazine, mp 80°-82° C., (found: C, 53.16; H, 4.56; N, 15.07. C8H8N2OS requires C, 53.33; H, 4.48; N, 15.55).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[OH:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:22][CH:23]2[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.45 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (2 g, 11.55 mmol) and cesium carbonate (4 g, 12.28 mmol) in N,N-dimethylformamide (15 mL) was stirred under nitrogen overnight at room temperature. The resulting solution was quenched with 200 mL of water. The precipitate was collected by filtration, washed with 200 mL of water and dried in a vacuum oven to give 750 mg (60%) of tert-butyl 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate as a yellow solid: LC-MS: m/z=+461 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1)=O)C.O.C(OCC)(=O)C>C1COCC1>[OH:9][CH2:10][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccnc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(CO)c2c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
17 ml of a 1 M solution of LiAlH4 in THF are added dropwise to a solution of 4 g of 4-ethoxycarbonyl-6-methoxyquinoline in 100 ml of anhydrous THF, under an inert atmosphere of argon at a temperature in the region of 5° C. The reaction medium is maintained with stirring for 16 hours at a temperature in the region of 20° C. 50 ml of water and 50 ml of ethyl acetate are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The foam obtained is purified by flash chromatography (SiO2, EtOAc as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.86 g of 4-hydroxymethyl-6-methoxyquinoline is thus obtained, the characteristics of which product are as follows: