Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)(C)(C)C.[ClH:16].[CH3:17][O:18][NH2:19].Cl>CO.O1CCOCC1>[ClH:16].[CH3:17][O:18]/[N:19]=[C:9]1/[C@@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][CH2:10]/1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCC1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO/N=C1\CCCC[C@@H]1N
Yield: 127 %

Procedure:
To a solution of 2.13 g ((S)-2-oxo-cyclohexyl)-carbamic acid tert-butyl ester in 10 ml methanol was added 0.46 g O-methylhydroxylamine hydrochloride and the mixture was heated to reflux for 18 h. To the resulting yellow solution was added 2.0 ml of a 4M solution of hydrochloric acid in dioxane and the mixture was refluxed for 30 min. The reaction mixture was evaporated and dried under high vacuum. The semisolid residue was triturated under acetonitrile. The solid was collected by filtration and dried to constant weight under high vacuum to yield 1.25 g of the title compound as white crystals. MS (EI): 142 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18][C:29](=[O:30])[O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(F)c3)c2O1)OCc1ccccc1
Yield: 85.2 %

Procedure:
Treatment of (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (798 g, 6.382.86 mmol) with diisopropylethylamine (0.554 g, 4.29 mmol) followed by benzyl chloroformate (0.536 g, 3.14 mmol) generally according to the procedure described for Intermediate 12 provided 1.01 g (94%) of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. Rf=0.41 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C23H20FNO3: C, 73.2; H, 5.34; N, 3.71. Found: C, 72.96H, 5.38; N, 3.59. Chiral HPLC separation of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, isopropanol:hexane 2:8) provided two fractions. Fraction 1 (Rt=7.675 min, Chiralpak OD, isopropanol:hexane 2:8); Fraction 2 (Rt=9.182 min, Chiralpak OD, isopropanol:hexane 2:8).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C1COCC1>[OH:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: CCCCCCOc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(OC(=O)c2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
The 4-(hexyloxy)phenyl 4-(benzyloxy)benzoate obtained as described above (5.0 g, 12.4 mmol) and palladium on carbon (2.5 g in the wet state) were placed in a sealed container under a nitrogen atmosphere, and dehydrated THF was slowly added thereto. Then, 28 mL of 1,4-cyclohexadiene was carefully and slowly added thereto dropwise, while heating at 60° C. and stirring. After the addition, the mixture was further stirred for additional 3 hours at 60° C. After the mixture was cooled to room temperature, the mixture was filtered through Celite and the solvents were removed by distillation. Thereby, a white solid compound, 4-(hexyloxy)phenyl 4-hydroxybenzoate (3.8 g) was obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C6CCCCO6)[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>C(OCC)C>[CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCOC4CCCCO4)c3)cc1OCC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Yield: 95.9 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 45 (134 mg, 0.27 mmol) was dissolved in diethyl ether (5 mL) and treated with 1M HCl in diethyl ether (1 mL) then methanol (5 mL). After 30 min the reaction mixture was concentrated to dryness and the resultant residue triturated in diethyl ether to give 176 as a pale cream solid (105 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1 H); 8.23 (s, 1 H); 8.19 (d, J=8.23 Hz, 1 H); 8.03 (s, 1 H); 7.96 (s, 1 H); 7.39 (dd, J=8.24, 1.74 Hz, 1 H); 7.29 (d, J=1.68 Hz, 1 H); 5.46-5.36 (m, 1 H); 4.34 (t, 2 H); 4.17 (t, J=5.61 Hz, 2 H); 3.78 (t, J=5.58 Hz, 2 H); 3.13 (t, J=4.91 Hz, 2 H); 1.52 (d, J=6.57 Hz, 6 H). 1 Exchangeable proton not observed. LCMS: RT=10.68 min, M+H+=406
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:9]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[S:4]1(=[O:19])=[O:18].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:32](=[O:33])[CH2:31][C:30]([C:34]#[N:35])=[N:29]1.[F-].[K+].CN(C=O)C>O>[CH:15]([C:9]1[C:6]2[C:7](=[O:8])[N:3]([CH2:2][O:33][C:32]3[N:28]([C:22]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=4[Cl:20])[N:29]=[C:30]([C:34]#[N:35])[CH:31]=3)[S:4](=[O:19])(=[O:18])[C:5]=2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)([CH3:17])[CH3:16]
Reactant: N#CC1=NN(c2ccc(Cl)cc2Cl)C(=O)C1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1Cl)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (410 mg, 1.18 mmol), 2,4-dihydro-2-(2,4-dichlorophenyl)-5-cyano-3H-pyrazol-3-one (300 mg, 1.18 mmol), KF (68.44 mg, 1.18 mmol) and DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and was extracted with ether (3×50 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 310 mg of 4-isopropyl-6-methoxy-2-[1-(2, 4-dichlorophenyl)-3-cyanopyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2,4-Cl2 --Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 183°-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)cc(C)c2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone (Example 387) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 438.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1>C(OCC)C>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([OH:13])[CH3:5])=[C:10]([F:16])[CH:9]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CI
Agent: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a ice-cold solution of methyl magnesium iodide prepared from magnesium (1.7 g, 73.88 mmoles) and methyl iodide (4.58 ml, 73.88 mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles) in diethyl ether (10 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.40(t, J=8.2Hz, 1H), 7.30(dd, J=8.3,1.7Hz, 1H), 7.21(dd, J=9.9,1.9Hz, 1H), 5.17(q, J=6.4Hz, 1H), 1.49(d, J=6.5Hz, 3H).
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13].[N:16]#[C:17][NH2:18]>>[ClH:1].[CH2:6]([C:5]1[N:14]=[C:17]([NH2:18])[NH:16][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: C#CCCCCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-dec-9-ynoic acid methyl ester hydrochloride (1.50 g, 6.42 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.774 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (400 MHz, CD3OD) δ 6.09 (s, 1H), δ 2.19 (t, 2H), δ 1.95 (t, 1H), 1.93 (m, 2H), δ 1.39-1.11 (m, 8H) ppm; 13C NMR (75 MHz, CD3OD) δ 148.5, 131.0, 110.1, 83.9, 68.3, 28.6, 28.5, 28.4, 28.3, 25.7, 17.8 ppm; HRMS (ESI) calcd for C11H18N3 (M+) 192.1495. Found 192.1495.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>C1C=CC=CC=1>[CH3:1][N:2]([Si:15]([CH3:18])([CH3:17])[CH3:14])[CH2:3][CH2:4][N:5]([CH3:6])[Si:15]([CH3:18])([CH3:17])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: CNCCNC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(CCN(C)[Si](C)(C)C)[Si](C)(C)C
Reaction time: 3.5 h

Procedure:
A mixture of 176 parts by weight of N,N'-dimethylethylenediamine, 1000 parts by volume of benzene and 552 parts by volume of triethylamine were stirred at room temperature and at the same time 434 parts by weight of trimethylchlorosilane, diluted with 500 parts by volume of benzene, were added dropwise over the course of 3 hours. The mixture was stirred for a further 3.5 hours and left to stand overnight, and the precipitate present was filtered off and washed with benzene. The combined filtrates were concentrated in a rotary evaporator and the residue was distilled in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: O=C1CCOCC1
Product: O=c1nc(N2CCN(C3CCOCC3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 6.7 %

Procedure:
The synthesis was performed using 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9 and dihydro-2H-pyran-4(3H)-one (10 mg, 0.10 mmol) in a similar manner to Synthesis Example 72 to obtain the title compound (2.6 mg, yield: 6.6%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.C(#N)C>[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:24])[F:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(=O)N(Cc1cccc(C)c1)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of methyl N-[4′-(trifluoromethoxy)biphenyl-4-yl]oxamate (250 mg, 0.737 mmol), 3-methylbenzyl bromide (0.299 ml, 2.21 mmol), potassium carbonate (306 mg, 2.21 mmol), 18-crown-6 (20 mg, 0.074 mmol) and acetonitrile (10 ml) was stirred at 50° for 3 hors under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (320 mg, 98%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cccc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cccc(Cl)c1F)C2=O
Temperature: 100 °C

Procedure:
A degassed mixture of 2-bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate A) (0.392 mmol), 2-methoxyphenylboronic acid [5720-06-9] (0.549 mmol), (Ph3P)2PdCl2 (0.039 mmol) and K3PO4 (1.569 mmol) in DMF (4 mL) was heated at 100° C. for 8 h. After cooling to rt, the reaction mixture was concentrated. The residue was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3×). The combined organic phases were successively washed with water and brine, dried (Na2SO4) and concentrated. The residue was dissolved in MeOH and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional MeOH. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a light yellow solid. tR: 8.55 min (HPLC 2); ESI-MS: tR=1.43 min, [M+H]+523/525 (LC-MS 1); TLC: Rf=0.41 (98:2 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.56 (d, 0.5H), 7.50-7.56 (m, 1.5H), 7.45-7.49 (m, 1.5H), 7.30 (d, 1H), 7.27 (m, 1H), 7.19-7.25 (m, 2H), 7.14 (d, 1H), 7.05 (m, 1H), 6.92 (d, 0.5H), 6.51/6.67 (s, 1H), 6.25/6.27 (s, 1H), 3.93/3.97 (m, 1H), 3.77 (s, 3H), 1.87/2.36 (s, 3H), 1.27 (m, 3H), 0.48 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
A solution of 2-chloropyridine-4-carboxylic acid (10 g) in thionyl chloride (90 mL) was heated under reflux for 20 hours. The excess thionyl chloride was removed by distillation at atmospheric pressure and the oily residue was distilled to give 9.26 grams of 2-chloropyridine-4-carbonyl chloride having a boiling point of 144°-148° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OC[C:32]4([C:42]=3[CH:43]=C12)[C:40]1[C:35](=CC=CC=1)NC4=O.BrCC1CC1C>>[CH3:35][CH:40]1[CH2:32][CH:42]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1CC1CBr
Product: CC1CC1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-methylcyclopropane to replace 2-(bromonmethyl)-5-(trifluoromethyl)furan, the title compound was obtained (37%) as a white solid: MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: [NH2:1][OH:2].[N:3]1([C:9]#[N:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO.CCOCC>[OH:2][NH:1][C:9]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[NH:10]
Reactant: NO
Reactant: N#CN1CCOCC1
Solvent: CO
Solvent: CCOCC
Product: N=C(NO)N1CCOCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 139.3 %

Procedure:
A mixture of hydroxylamine (4.0 mL, 65 mmol) and morpholine-4-carbonitrile (5.00 g, 44.6 mmol) was heated at 80° C. for 24 h. After cooling to room temperature, the reaction mixture was diluted with MeOH and Et2O, then allowed to stand at room temperature for 2 days. The resultant precipitate was collected by filtration to give 9.02 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CCOCC2)cn1
Yield: 46 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (125 mg, 0.40 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=70:30 to 40:60, 73 mg, 46%) which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](Cl)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.CCN(CC)CC>C(Cl)Cl>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:26]
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1-c1ccccc1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1
Yield: 119.1 %

Procedure:
A mixture of (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (179 mg, 0.745 mmol), biphenyl-2-carbonyl chloride (210 mg, 0.97 mmol), Et3N (196 mg, 1.95 mmol) was stirred into DCM (7.0 mL) for 18 h at room temperature. Then reaction mixture was diluted with more DCM (25 mL) and washed successively with 1N aq. NaOH (5 mL) and water (2×15 mL). The organic phase was concentrated under reduced pressure. The crude residue was purified on HPLC (basic system) to yield pure title compound (373 mg, 99%). MS (ESI) mass calcd. for C27H24N4O, 420.52; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00-7.32 (m, 11H), 7.29-7.18 (m, 1H), 6.75 (dd, J=9.9, 4.2, 2H), 4.70-4.42 (m, 1H), 4.30-3.90 (m, 3H), 3.8-3.74 (m, 0.66H), 3.51-3.30 (m, 1.35H), 3.13-3.03 (m, 0.5H), 2.90-2.80 (m, 0.5H), 2.68-2.51 (m, 0.5H), 1.96-1.68 (m, 2H), 1.59-1.43 (m, 0.5H).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[C@@H:3]([NH:12]C(=O)OCC1C=CC=CC=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C@H:3]([CH:2]([CH3:23])[CH3:1])[C:4]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:11]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)[C@@H](N)C(=O)NCC(F)(F)F
Reaction time: 6 h
Yield: 65 %

Procedure:
A Parr shaker flask charged with (R)-benzyl (3-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)-butan-2-yl)carbamate (4.95 g, 14.9 mmol) in 100 mL of EtOAc and 25 mL of EtOH was treated with 175 mg of 10% Pd/C. The mixture was placed under 40 psi of hydrogen and shaken for 6 h. An additional 65 mg of 10% Pd/C was added to the reaction mixture which was then placed under 40 psi of hydrogen and shaken for 3.5 h. The reaction solution was then filtered through a pad of celite, concentrated in vacuo and purified by sublimation (75 to 85° C., 200-230 millibar) to afford the title compound as a white solid (1.92 g, 65%): mp 43-47° C.; 1H NMR (400 MHz, CDCl3) δ 8.04-7.74 (m, 1H), 3.92 (ddd, J=16.0, 9.3, 6.8 Hz, 1H), 3.84-3.60 (m, 1H), 3.23 (d, J=3.8 Hz, 1H), 2.23 (ddd, J=10.7, 7.0, 3.5 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.70.
Reaction SMILES: C=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:21].[Na+].O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.O>[O:21]=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of Compound 29a (1.6 g, 5.99 mmol) in a mixture of dioxane-water (32.9 mL and 11 mL respectively) under stirring at r.t. was added a 4% sol. of osmium tetroxide in water (0.762 μL, 0.125 mmol). After 2 h, was added portionwise milled sodium metaperiodate (2.56 g, 12 mmol) affording a suspension that tended to become clear gray from brownish. After 4 h H2O was added, extracting with EtOAc, washing with H2O, drying over Na2SO4, evaporating the solvent to dryness. The residual tawny semi-solid was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc 7:3) to give 0.96 g of the title compound as a grey solid. Yield: 59.5%
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Solvent: c1ccccc1
Product: Oc1ccc2c(c1CNc1ccccc1)CCCO2
Yield: 26 %

Procedure:
A mixture of 6-hydroxy-dihydrobenzopyran- 5-carboxaldehyde (206 mg, 1.16 mmol) and aniline (108 mg, 1.16 mmol) in benzene (6 mL) was heated to reflux for 30 minutes under nitrogen. After cooling the mixture was passed through a short column of silica gel and the eluate concentrated to an orange solid (119 mg). This material was taken up in methanol (10 mL) and hydrogenated at 40 psi using 10% Pd/C (12 mg) as catalyst. After filtration and concentration the crude product was purified by chromatography over silica gel (Hexane/ethyl acetate, 85/15, an eluant) to afford 6-hydroxy-5-phenylaminomethyl-3,4-dihydrobenzopyran (77 mg, 26%) m.p. 105°-107° C.