Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)([CH3:3])[CH3:2].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A solution of crude 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid, 2-bromo-1,3-thiazole (0.206 g, 1.26 mmol) and potassium carbonate (0.174 g, 1.26 mmol) in benzene (10 mL), methanol (1 mL) and water (1 mL) was degassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.034 mmol) was added and the reaction mixture was degassed a further 15 min before stirring at 70° C. for 14 h. The reaction mixture was quenched with water (30 mL) then extracted with EtOAc (3×30 mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole as a brown oil. 1H NMR (CD3Cl, 300 MHz) δ 7.68 (d, 1H), 7.37-7.36 (m, 1H), 7.08 (d, 1H), 7.76-7.75 (m, 1H), 6.70 (dd, 1H), 1.46 (h, 3H) 1.09 (d, 18H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3c(C)cccc32)CC1
Yield: 73 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11.3) (0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083 g, 0.50 mmol), and K2CO3 (0.069 g, 0.50 mmol) in MeCN and shaken at 50°. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR (CD3OD) δ 7.15 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.4 Hz), 4.00 (t, J=7.2 Hz, CH2), 3.10 (d, J=12.1 Hz, 2H), 2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH3), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.31-1.24 (m, 9H), 0.90 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) δ 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.36.
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[C:9]2=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[C:11]([CH:13]=O)=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1.C([O-])(O)=O.[Na+].[CH3:29][CH2:30][O:31][C:32]([CH3:34])=[O:33]>C1COCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)[C:11](/[CH:13]=[CH:34]/[C:32]([O:31][CH2:30][CH3:29])=[O:33])=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of lithium hydride (68 mg, 4.0 mmol) in THF (5 mL) under N2 atmosphere was added triethyl phosphonoacetate (498 mg, 2.22 mmol). The mixture was stirred at rt for 30 min and to the reaction mixture was added a slurry of 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (433 mg, 1.53 mmol) in THF (15 ml). The mixture was heated at reflux for 2 h. After it was cooled to rt, aqueous NaHCO3 was slowly added followed by EtOAc. The organic layer was collected and the aqueous layer was back extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4) and evaporated to give a crude yellow solid that was purified by column chromatography (10:90 to 90:10 v/v EtOAc-hexanes) to afford the title compound (480 mg, 89%). 1H-NMR (CD3OD) δ 8.42 (d, J=8.0 Hz, 2H), 8.17 (s, 1H), 7.88 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.43 (d, J=16 Hz, 1H), 6.36 (d, J=16 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H); MS [M+H]+=354; LCMS RT=3.12 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:24]([O:15][CH2:14][C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH:18]=[CH:17][CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cc([N+](=O)[O-])ccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4.04 g 3-(2-fluoro-5-nitrophenyl)-benzyl alcohol, 2.23 g imidazole and 2.46 g t-butyldimethylsilylchloride in 100 ml N,N-dimethylformamide was stirred at room temperature for 30 minutes. The reaction mixture was then partitioned between water and ether. The combined organic extracts were washed three times with water, dried and evaporated yielding the product as a yellow oil (5.9 g, 99% yield) which was purified on silica gel to give a yellow solid of m.p. 44°-45° C. NMR (CDCl3, 250 MHz): 8.4 (dd, 1H), 8.34 (eight line multiplet, 1H), 7.5 (m, 4H), 7.3 (m, 1H), 4.83 (s, 2H), 0.95 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([F:17])[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C:30]1([C:33]([NH:1][C:2]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([F:17])[CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)([CH3:4])[CH3:3])=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(F)cccc1-c1ccc(C(C)(C)NC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
The above-mentioned amine (80 mg, 0.28 mmol), was dissolved in anhydrous DCM (4 mL). To this stirred solution was added 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (67 mg, 0.33 mmol), HOBt.H2O (8 mg, 0.08 mmol) and lastly EDCI (69 g, 0.36 mmol). This mixture was allowed to stir overnight. Solvent was then removed under reduced pressure and the residue was subjected to silica gel chromatography eluting with a 1-3% MeOH in DCM gradient to provide methyl 4′-{1-[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)amino]-1-methylethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (82 mg), giving LC/MS and proton NMR spectra consistent with theory.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:37][N:38]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3ncc4c(=O)[nH]c(=O)n(-c5cccc(C(F)(F)F)c5)c4c3n2)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (300 mg, 0.77 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (170 mg, 0.77 mmol), potassium carbonate (317 mg, 2.3 mmol) and tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, and concentrated. 400 mL water was added. The resulting mixture was filtered to obtain a crude product, which was dissolved in 20 mL 6M concentrated hydrochloric acid, and washed with dichloromethane (4×50 mL). The aqueous phase was added dropwise to an aqueous sodium carbonate solution, filtered, and washed with water. The resulting crude product was washed with methanol to produce 9-(2-aminopyrimidin-5-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (160 mg).
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37]C)=[O:36])[CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:26])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+].Cl>>[NH2:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]([NH:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)s1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)s1)C2
Yield: 76.8 %

Procedure:
A solution of 100 mg. of dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamate in 15 mL. of 1.0N aqueous sodium hydroxide is stirred at room temperature for 120 hours and the pH then adjusted to 7.0 through the careful addition of 5.0N hydrochloric acid. The solid which formed was collected by filtration and dried at 80° C. to yield 61.5 mg (76.8%) of N-[5-(2-{2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamic acid, m.p. 226°-240° C. (foaming and decomposition). NMR (DMSO-d6 300 MHz) delta: 9.80 (s, br, 1H), 8.45 (d, J=9 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 6.87 (d, J=3 Hz, 1H), 6.30 (s, 1H), 6.04 (s, 2H), 4.28 (m, 1H), 3.12 (m, 1H), 2.84 (m, 3H), 2.36 (m, 1H), 2.02 (m, 1H), 1.83 (m, 2H), 1.57 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 21 mg (0.18 mmol, 1.2 eq.) of phenyl isocyanate were reacted according to General Method 4. Yield: 58 mg (92% of theory)
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](B(O)O)=[CH:26][CH:25]=1.Br[C:38]1[C:39]2[C:44]([CH:45]=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:38]2[C:51]3[C:46]([CH:45]=[C:44]4[C:39]=2[CH:40]=[CH:41][CH:42]=[CH:43]4)=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12

Procedure:
3.6 g (11.7 mmol) of tri-o-tolylphosphine and then 437 mg (1.9 mmol) of palladium(II) acetate are added with vigorous stirring to a suspension of 93.0 g (500 mmol) of 4-methylnaphthalene-1-boronic acid, 100.0 g (389 mmol) of 9-bromoanthracene, 212.3 g (1 mol) of tripotassium phosphate in a mixture of 400 ml of dioxane, 600 ml of toluene and 1000 ml of water, and the mixture is refluxed for 16 h. After the reaction mixture has been cooled, the organic phase is separated off and washed three times with 500 ml of water. The organic phase is subsequently filtered through silica gel and evaporated to dryness. The oil which remains is taken up in 1000 ml of ethanol and dissolved under reflux. After cooling, the colourless solid is filtered off with suction, again washed by stirring with 1000 ml of ethanol and finally dried under reduced pressure. Yield: 103.0 g (83.1% of theory), about 96% according to 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.N(C(=O)C(NC1C=CC(N2CCC(CC(OC)=O)CC2)=NC=1)=O)N>>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][C:2]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:1])[CH2:3][CH2:4]2)=[N:9][CH:10]=1
Reactant: COC(=O)CC1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: COC(=O)CC1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Product: COC(=O)CC1(C)CCN(c2ccc(N)cn2)CC1

Procedure:
Prepared from methyl [4-methyl-1-(5-nitropyridin-2-yl)piperidin-4-yl]acetate following the method for Intermediate 77 stage ii). 1H NMR δ 1.01 (s, 3H), 1.41-1.45 (m, 2H), 1.52-1.58 (m, 2H), 2.30 (s, 2H), 3.12-3.19 (m, 2H), 3.34-3.38 (m, 2H), 3.58 (s, 3H), 4.52 (s, 2H), 6.62 (d, 1H), 6.89 (d, 1H), 7.58 (s, 1H); MS m/e MH+ 264.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: NC(CC1CCCCC1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
To a solution of α-cyclohexylmethyl-2-piperidinobenzylamine (1.13 g, 3.96 mmol) in acetonitrile (11 ml) are added, successively, 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid (1 g, 3.96 mmol), of triphenylphosphine (1.25 g, 4.76 mmol), triethylamine (1.11 ml, 7.92 mmol) and carbon tetrachloride (0.38 ml, 3.96 mmol) and the mixture is stirred for 15 hours at ambient temperature. It is then concentrated by evaporation in vacuo and partitioned between ethyl acetate and water. The organic extract is dried and filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=10/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]3([OH:32])[CH2:31][CH2:30][C:25]4(OCC[O:26]4)[CH2:24][CH2:23]3)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]3([OH:32])[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]3)=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(C3(O)CCC4(CC3)OCCO4)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C3(O)CCC(=O)CC3)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of 8-(1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 32) (658 mg, 1.50 mmol) in tetrahydrofuran (3.75 mL), 6 M hydrochloric acid (7.5 mL) was added at 0° C., and the obtained solution was stirred at room temperature for 5 hours. The reaction solution was neutralized by pouring it into ice-cooled 10% aqueous sodium hydroxide solution. The resulting solution was basified by addition of saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (523 mg, 1.33 mmol, 89%) as an amorphous product.
Reaction SMILES: ClCCl.[CH3:4][O:5][CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C.O>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH2:6][O:5][CH3:4])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCOS(C)(=O)=O

Procedure:
To a dichloromethane (50 mL) mixture of 3-methoxy-1-propanol (2.70 g, 30.0 mmol) and triethylamine (4.62 mL, 33.0 mmol), was added methanesulfonyl chloride (2.45 mL, 31.5 mmol) while stirring on ice, and the resulting mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1cccnc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1F
Yield: 78.8 %

Procedure:
A mixture of 2-fluoronicotinic acid (5.00 g, 35.4 mmol) and thionyl chloride (35 ml, 480 mmol) was refluxed for 48 hours. The thionyl chloride was distilled off at ambient pressure, the residue was distilled under high vacuum. The reaction affords 2-fluoronicotinoyl chloride (4.45 g, 78.7%) as white solid. MS: m/z=156.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:13]Br>C(Cl)(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][Br:13])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Yield: 65.9 %

Procedure:
In 200 ml of chloroform was dissolved 8.25 g of 4-nitroacetophenone, and 20 ml of a chloroform solution containing 8 g of bromine was added dropwise thereto under cooling. The resulting reaction mixture was concentrated, and the residue (concentrate) was recrystallized from chloroform/ether, collected by filtration, washed, and dried to obtain 8.03 g of p-nitrophenacyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[Cl:26][C:27]1[S:28][C:29]([CH2:32]Cl)=[CH:30][CH:31]=1>CN(C=O)C>[Cl:26][C:27]1[S:28][C:29]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:9]3[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)=[N:12]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(-c2n[nH]c3ccccc23)o1
Reactant: ClCc1ccc(Cl)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccc(Cl)s3)c3ccccc23)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
600 mg (2.3 mmol) of 3-(5-ethoxycarbonyl-2-furyl)indazole together with 265 mg (2.4 mmol) of potassium tert-butoxide were initially charged in 10 ml of DMF, 430 mg (2.6 mmol) of 2-chloro-5-(chloromethyl)thiophene in 1 ml of DMF were added dropwise and the mixture was stirred at RT for 2 h. Customary work-up gave 350 mg (41%) of the title compound. m.p.: 124-126° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Solvent: CO
Solvent: O
Product: COCC(=O)N(CCN1CCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methoxy-acetyl chloride (0.6 mL, 6.4 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) with stirring. The temperature was raised to 80° C. and stirring continued for 2 h. The reaction mixture was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.260 g (75.14%); 1H NMR (DMSO-d6): δ 0.71 (bs, 4H, 2CH2), 2.60 (bs, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.20 (s, 3H, OCH3), 3.70 (s, 3H, CH3), 3.80 (bs, 4H, 2CH2), 4.00 (s, 3H, OCH3), 5.40 (s, 2H, CH2), 7.65 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.19 (s, 1H, Ar). 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Reactant: CCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Yield: 89.2 %

Procedure:
2-(2,6-Difluoro-3-nitrophenyl)pyridine (1.00 g, 4.29 mmol), ethylamine (2.24 mL, 4.29 mmol) and then DIPEA (0.75 mL, 4.29 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 40 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to give the title compound as yellow oil (1.00 g, 90%). 1H NMR (CDCl3) δ: 8.73 (1H, ddd, J=6.6, 2.4, 1.3 Hz), 8.28 (1H, dd, J=12.6, 8.1 Hz), 7.80 (1H, td, J=10.3, 2.4 Hz), 7.45 (1H, dq, J=10.4, 1.6 Hz), 7.33 (1H, ddd, J=10.1, 6.5, 1.6 Hz), 6.51 (1H, dd, J=12.7, 10.9 Hz), 2.54-2.44 (2H, m), 1.03 (3H, t, J=9.6 Hz)