Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH2:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH:39]1[C:30]2[CH2:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:4](=[O:5])[C:3]4[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=4[Cl:11])=[CH:44][CH:43]=3)=[O:27])[C:29]=2[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg of N,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. The reactants are refluxed in an oil bath at 110° C. for 18 hours. The xylene is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated, washed with 1N HCl, 1M NaHCO3, and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 370 mg of the desired product as a crystalline solid, m.p. 257°-259° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C)=[N+]([O-:16])C=C(C)N=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:34][CH3:35])=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:34][CH3:35])=[N+:28]([O-:16])[CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1
Reactant: CCc1cnc(CC)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Product: CCc1c[n+]([O-])c(CC)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Following the procedure of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine 1-oxide but substituting Preparation of 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine and making non-critical variations, the title compound was obtained (quantitative). It was used without preparation. 1H NMR (CDCl3) δ 1.12, 1.34, 2.55, 2.81, 2.89, 7.28, 7.40, 7.55, 8.11.
Reaction SMILES: [F:1][C:2]([F:21])([O:7][Si:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC)[O:9][CH2:10][CH3:11])[C:3]([F:6])([F:5])[F:4].S(Cl)([Cl:24])=O.Cl.[NH+]1C=CC=CC=1>>[F:1][C:2]([F:21])([O:7][Si:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([Cl:24])[O:9][CH2:10][CH3:11])[C:3]([F:6])([F:5])[F:4]
Reactant: O=S(Cl)Cl
Reactant: CCO[Si](OCC)(OC(F)(F)C(F)(F)F)c1ccccc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: CCO[Si](Cl)(OC(F)(F)C(F)(F)F)c1ccccc1
Reaction time: 18 h

Procedure:
152.0 g (0.460 mol) pentafluorophenyltriethoxysilane, 34 mL (0.460 mol, 54.724 g) thionylchloride and 6.910 g (0.0598 mol) pyridinium hydrochloride are refluxed and stirred for 18 h. Pyridinium hydrochloride is precipitated at −78° C. and the solution is filtrated. Pentafluorophenylchlorodiethoxysilane is isolated by vacuum distillation.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[OH:38][CH2:37][C@@H:30]1[C@@H:31]([OH:36])[C@H:32]([OH:35])[C@@H:33]([OH:34])[C@H:28]([C:21]2[CH:22]=[CH:23][C:24]([CH:25]([CH3:27])[CH3:26])=[C:19]([CH2:18][C:15]3[CH:16]=[C:17]4[C:12]([CH2:11][CH2:10][CH2:9][NH:8]4)=[CH:13][CH:14]=3)[CH:20]=2)[O:29]1
Reactant: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)NCCC2
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Step-VI: To a solution (2S,3R,4R,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.0 g, 1.0 mmol) in methanol (20 mL) was added 10% dry palladium on charcoal (200 mg) and conc. HCl (0.2 mL), and the mixture was stirred under hydrogen balloon pressure for 18 h. The reaction mixture was filtered through a celite bed which was washed with methanol and the filtrate was concentrated. The resulting residue was purified by preparative HPLC to furnish (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol (320 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([C:21]1[N:22]=[N:23][C:24](Cl)=[C:25]([C:40]([F:43])([F:42])[F:41])[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)[CH2:18][CH2:19][CH3:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:24]2[N:23]=[N:22][C:21]([CH2:17][CH2:18][CH2:19][CH3:20])=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)=[CH:29][CH:28]=3)[C:25]=2[C:40]([F:43])([F:42])[F:41])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 20.3 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.45 mmol, 0.29 g) in anhydrous DMF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (4.36 mmol, 0.175 g) and continued stirring for 10 min. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-5-trifluoromethyl-pyridazine (72.5 mmol, 25.0 g) in anhydrous DMF (1 mL). After 30 minutes, no starting material was remaining as indicated by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.17 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:53][CH2:52][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[C:48]([F:51])[C:49]=4[CH:50]=[C:42]3[C:41]=2[N:54]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.O.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]>[F:51][C:48]1[C:49]2[CH:50]=[C:42]3[C:41]4[N:54]=[C:37]([C:18]5[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]6[O:9][C:8]([C:5]7[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=7)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=6[CH:17]=5)[CH:38]=[CH:39][C:40]=4[O:53][CH2:52][N:43]3[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (56 mg, 0.199 mmol) and K3PO4.3H2O (159 mg, 0.597 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80° C. for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether/EtOAc=1:1.5) to provide the pure product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H-NMR (CDCl3, 400 MHz) δ: 7.99 (s, 1H), 7.93˜7.96 (m, 2H), 7.65 (s, 1H), 7.45˜7.50 (m, 2H), 7.17˜7.21 (m, 4H), 7.10 (d, J=8.0 Hz, 1H), 6.81˜6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]1([CH:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
A CH2Cl2 (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4 mmol) was added dropwise to a cooled (−5° C.) CH2Cl2 (200 mL) solution of (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol), triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g, 4.13 mmol), while maintaining the temperature between −5° C. and 0° C. The reaction was stirred at 0° C. for 9 hours, and then stored in a freezer (−25° C.) for 14 hours. It was allowed to thaw to ambient temperature and washed with water (200 mL), 1N HCl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide benzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidified upon standing (16.5 g). The chiral integrity of the product was not checked and that product was used for the next step without further purification. 1H NMR (DMSO-d6, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H), 7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H), 5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Cond. III); >90% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C22H20NaO5S: 419.09. found 419.04.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)c(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3,4-trifluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(CN)CCCC1>>[CH:5]1([CH2:1][NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2][CH2:23]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NCC1CCCC1
Product: Cc1nc(NCc2ccccn2)nc(NCC2CCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (cyclopentylmethyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.09 (m, 2H), 1.30-1.38 (m, 2H), 1.38-1.49 (m, 4H), 1.80-1.94 (m, 4H), 2.26 (s, 3H), 3.14 (bs, 2H), 4.70 (bs, 2H), 7.37-7.42 (m, 2H), 7.91 (t, J=7.52, 1H), 8.09-8.13 (m, 1H), 8.43 (s, 1H), 8.55-8.62 (m, 1H), 12.65 (bs, 1H); MS (ESI) m/z 312.8 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:7]1[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1.[Cl-].[Na+]>O>[N:1]1([CH:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClC1CCCc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(c1)CCCC2N1CCCC1
Reaction time: 0.12 h

Procedure:
Over a period of 7 minutes with stirring and while allowing it to heat up, 50 ml of pyrrolidine were added to a solution of 20 g of 8-chloro-5,6,7,8-tetrahydroquinoline in 50 ml of water. The temperature reached 57° C. at the end of the introduction and stirring was continued for 1 hour at this temperature. The temperature was then allowed to return to 20° C. and the reaction medium was saturated with sodium chloride and then was extracted with ether. The combined organic phases were dried and the solvents were eliminated under reduced pressure to obtain 20.22 g of 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline in the form of an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:2]=1.[CH3:20][N:21]=[C:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=1
Reactant: Oc1cccc(C2CCCN2Cc2cccnc2)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2cccnc2)c1
Reaction time: 13 h
Yield: 85 %

Procedure:
To a solution of 3-[1-(3-pyridinylmethyl)-2-pyrrolidinyl]phenol (0.92 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) followed by milled potassium carbonate (0.65 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 13 hrs, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate). The appropriate fractions were collected and concentrated to give 0.94 g (85%) of product.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH:11]12[O:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2.[OH-].[Na+]>O>[C:1]([N:13]1[CH2:12][CH:11]2[O:18][CH:15]([CH2:16][CH2:17]2)[CH2:14]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C1CC2CNCC1O2
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(=O)N1CC2CCC(C1)O2
Reaction time: 2 h

Procedure:
Heptanoyl chloride (14.86 grams, 0.1 mole) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride product of Example 3 (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water, at 10° C. After the addition of heptanoyl chloride, the reaction mixture was stirred for 2 hours and then left overnight at room temperature. The product was extracted from the reaction mixture with diethyl ether and treated with DARCO G60 (activated carbon) After the removal of the diethyl ether, the product 3-heptanoyl-8-oxa-3-azabicyclo (3.2.1)octane was obtained as a clear liquid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:17]1[C:21]([C:22](Cl)=[O:23])=[N:20][N:19]=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([N:17]1[C:21]([C:22]([NH:1][C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][N:9]=2)=[O:23])=[N:20][N:19]=[N:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: N#Cc1cccnc1N
Solvent: c1ccncc1
Product: N#Cc1cccnc1NC(=O)c1nnnn1Cc1ccccc1

Procedure:
2-Aminonicotinonitrile is reacted with 1-benzyl-1H-tetrazole-5-carbonyl chloride in stoichiometric amounts in the presence of an acid acceptor (pyridine). The product is washed with water, brine, and dried over CaCl2 to yield 1-benzyl-N-(3-cyano-2-pyridyl)-1H-tetrazole-5-carboxamide. The benzyl protecting group is then removed by hydrogenolysis with 10% Pd/C. The product is stirred in water and N NaOH is added to produce the title compound upon lyophilization.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C[O:20][C:21]1[CH:41]=CC2N=C(NC(=O)CC(=O)C3C=CC=CC=3)SC=2[CH:22]=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:22][C:21](=[O:20])[CH3:41])(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CCC(C)=O)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetone (II), MS (m/e) 358, 316, 301, 288, 261, 233, 221, 179 and 152; CMR (CDCl3) 207.5, 62.4, 41.4, 34.8, 19.4 and 16 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([Si:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([O:15][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:17][CH:18]=1
Reactant: O[Si](Cn1ccnc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](Cn1ccnc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g (0.0047 mol) of bis(4-fluorophenyl)hydroxy(1H-imidazol-1-ylmethyl)silane in 20 ml of tetrahydrofuran was added 0.8 ml (0.0063 mol) of chlorotrimethylsilane. A solution of 0.8 ml (0.0057 mol) of triethylamine in 5 ml of tetrahydrofuran is added dropwise, giving a thick white precipitate. The mixture is stirred overnight at room temperature, then filtered and concentrated to an oil. The residue is taken up in ether, filtered, and the filtrate is evaporated to afford the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:48][CH2:47][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>C(Cl)Cl>[F:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:29][CH2:30][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:47][CH2:48]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4F)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Reaction time: 2 h

Procedure:
TFA (10 mL) was cautiously added to a solution of tert-butyl 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate [Example 7, step c] (3.95 g) in DCM (40 mL). The resulting mixture was stirred for 2 h. The solvent was evaporated and the residue azeotroped twice with acetonitrile. The residue was dissolved in freshly distilled 2-methyltetrahydrofuran (100 mL) and washed 3 times with a mixture of brine and saturated sodium bicarbonate solution (10:1, 100 mL). The organic phase was dried over sodium sulphate, filtered and evaporated. The residue was azeotroped 3 times with isohexane to give the subtitled compound as a white foam. Yield 2.92 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:18]([C@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: CNC
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (10.00 mg, 0.019 mmol), dimethylamine (0.009 g, 0.2 mmol), TBTU (12.4 mg, 0.0388 mmol), and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.40-2.51 (m, 1H), 2.87 (d, J=6.1 Hz, 1H), 3.04 (s, 3H), 3.09 (s, 3H), 3.72 (br. s., 1H), 3.85 (dd, J=12.5, 6.4 Hz, 1H), 5.02 (t, J=8.7 Hz, 1H), 5.29 (br. s., 1H), 7.42-7.48 (m, 1H), 7.54 (td, J=7.7, 1.3 Hz, 1H), 7.96 (s, 1H), 8.02 (dd, J=15.2, 7.6 Hz, 2H), 8.14 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCO
Reactant: CCn1nccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnn1CC

Procedure:
To a solution of 1-ethyl-1H-pyrazole-5-carboxylic acid (950 mg) (for example, available from Fluorochem) in ethanol (50 ml) was added sulphuric acid (0.5 ml) and the mixture stirred at reflux under nitrogen for 70 h. The solvent was removed in vacuo and the residue partitioned between DCM (25 ml) and saturated sodium bicarbonate solution (25 ml) and separated using a hydrophobic frit. The aqueous layer was washed with DCM (2×20 ml) and the organic phases were combined. The solvent was removed in vacuo to give the title compound (1.09 g) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:16][C:11]1[S:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)cs1
Reactant: [Br-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(Br)s1
Temperature: 25 °C
Reaction time: 45 h
Yield: 84.1 %

Procedure:
To a solution of methyl 4-phenylthiophene-2-carboxylate (1.8 g) in DCM (18 mL) was added portionwise pyridinium tribromide (13.2 g) at 0° C. The reaction liquid was warmed to 25° C. and then stirred for 45 hours. The reaction mixture was cooled to 0° C., and a saturated aqueous Na2S2O3 solution (100 mL) was slowly added dropwise. The reaction mixture was extracted with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 90:10) to obtain methyl 5-bromo-4-phenylthiophene-2-carboxylate (2.06 g) as a colorless liquid.