Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:26][CH:27]([Cl:31])[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[CH:27]([Cl:31])[Cl:26])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: O=C(O)C(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1)C(Cl)Cl
Yield: 52 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.2 mmol, Example H) with dichloroacetic acid (2.1 mmol), dicyclohexylcarbodimide (2.1 mmol) in dichloromethane (10 ml) at a temperature 0-25° C. for 3 hours followed by silica gel column chromatographic purification in 52% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:40])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:43](Br)[CH:44]=[CH2:45]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:40])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([CH2:26][O:27][CH2:45][CH:44]=[CH2:43])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(CO)nn4)nn23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
To a stirred colorless solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate in DMF (2 mL) was added at once 60% NaH (10 mg, 0.250 mmol) at 0° C. After 5 min, allyl bromide (0.085 ml, 0.981 mmol) was added to the brown reaction mixture and stirred for 30 min at 0° C. and 1 h at rt. Then, quenched with EtOH and purified by prep-HPLC to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-((allyloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0334 g, 0.056 mmol, 57.2% yield) as brown paste. 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 6.45 (s, 1H), 5.98-6.08 (m, 1H), 5.83-5.97 (m, 2H), 5.73 (s, 2H), 5.40-5.53 (m, 1H), 5.30 (qd, J=1.6, 17.2 Hz, 1H), 5.17-5.24 (m, 2H), 4.64 (d, J=0.5 Hz, 2H), 4.13-4.28 (m, 2H), 4.06 (td, J=1.4, 5.7 Hz, 2H), 4.00-4.03 (m, 2H), 2.60 (s, 3H), 1.87-2.03 (m, 3H), 1.64-1.75 (m, 1H), 1.34 (s, 3H), 1.20-1.26 (m, 12H). LCMS (M+H)=596.6.
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].O[Li].O>C(O)=O.[Zn]>[OH:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28]
Reactant: Cc1cncc(Oc2cnc3c(c2C(O)CC(C)C)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: [Li]O
Agent: [Zn]
Solvent: O
Solvent: O=CO
Product: Cc1cncc(Oc2cnc3c(c2CCC(C)C)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.04 mmol) in HCOOH (2 mL) was added Zn dust (64 mg, 0.375 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated, dried to a residue then dissolved in THF (1 ml) and water (1 mL). Next LiOH.H2O (33.6 mg, 0.8 mmol) was added and the reaction was stirred at RT for 10 min then extracted with EA (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(5-methylpyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 mg, 7% yield) as clear oil. 1H NMR (CDCl3) δ: 8.29 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 6.99 (s, 1H), 4.26 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (d, J=18.8 Hz, 2H), 3.33-3.23 (m, 2H), 3.20 (s, 1H), 2.33 (s, 3H), 1.99-1.92 (m, 2H), 1.68 (dt, J=11.9, 6.0 Hz, 1H), 1.40 (dt, J=10.7, 6.8 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H). LCMS: MH+ 413 and TR=2.549 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[N:18])=[C:8]([Br:19])[C:7]=2[CH:20]=1.Cl[C:22]1[N:27]2[N:28]=[CH:29][CH:30]=[C:26]2[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=1.[Cl-].C(N(CC)CC)C>C(O)C>[Br:19][C:8]1[C:7]2[CH:20]=[C:3]([CH2:2][NH:1][C:22]3[N:27]4[N:28]=[CH:29][CH:30]=[C:26]4[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=3)[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Reactant: CCc1cc(Cl)n2nccc2n1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1

Procedure:
540 mg (1.65 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) and 300 mg (1.65 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) were heated with reflux in 4 ml dry ethanol for 13 h. In order to complete the conversion of the amine 200 mg of the chloride and 0.24 ml triethylamine in 4 ml dry ethanol were added, and the mixture was heated for additional 21 h. The solvent was removed in vacuo, and the title compound isolated from the residue by chromatography (hexane/acetone 95:5 to 75:25) to give colorless crystals after evaporation to dryness,
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C=O)=[CH:7][C:6]=1[O:14]C)(=O)C.O.[Li+].[OH-]>C1COCC1>[CH3:1][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:14]
Reactant: COc1cc(OC=O)ccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of 4-(formyloxy)-2-methoxyphenyl acetate (16 g, 76 mmol) in THF (50 mL)/H2O (50 mL) was added LiOH (7.7 g, 184.2 mmol). The reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure. The residue was extracted with EA (50 mL×3). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtrated and concentrated in vacuo to give black oil, which was purified by silica gel column (PE:EA=3:1) to afford 4.8 g of product (40%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46].C(=O)([O-])[O-].[K+].[K+]>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>[F:39][C:40]1[CH:41]=[C:42]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([S:20]([N:23]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:24]5[CH:29]=[CH:28][N:27]=[CH:26][N:25]=5)(=[O:22])=[O:21])=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]=3)=[CH:4][CH:3]=2)[CH:43]=[CH:44][C:45]=1[F:46]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)nc4OC)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)c(F)c1
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+]
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(-c5ccc(F)c(F)c5)nc4OC)nccc3c2)cc1

Procedure:
A microwave vial was charged with 1-(6-chloro-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate EEEEE; 0.052 g, 0.095 mmol), (3,4-difluorophenyl)boronic acid (0.022 g, 0.142 mmol), potassium carbonate (0.039 g, 0.285 mmol), and Pd(Ph3P)4 (10.96 mg, 9.49 μmol). The vial was flushed with Ar (g), then Dioxane (0.712 mL) and Water (0.237 mL) were added. The reaction was microwaved at 90° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-50% EtOAc:Heptane) to afford 1-(6-(3,4-difluorophenyl)-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. Triflic acid (0.050 mL, 0.563 mmol) was added and the reaction was stirred for one hour. The reaction was concentrated and the material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(6-(3,4-difluorophenyl)-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.78-8.71 (m, 2H), 8.59 (s, 1H), 8.33-8.28 (m, 1H), 8.28-8.23 (m, 2H), 8.13 (br. s., 1H), 8.02 (d, J=1.9 Hz, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.88 (d, J=7.9 Hz, 2H), 7.62 (td, J=8.6, 10.4 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 3.91 (s, 3H). m/z (ESI) 506.1 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[CH2:19]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1N)[CH:20]=[CH2:21]>N1C=CC=CC=1>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:20]([CH2:21][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH2:19]1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: C=CCOc1ccccc1N
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.1 g (30 mmol) of tert-butyl nitrite and 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) in 100 mL of pyridine at 65°-70° C. under a nitrogen atmosphere is added dropwise over 20 minutes a solution of 5.6 g (25 mmol) of 2-allyloxyaniline in 20 mL of pyridine. The evolution of gas is observed during the addition of the 2-allyloxyaniline. After the addition is complete, the reaction mixture is kept at 65°-70° C. for an additional forty minutes until gas evolution subsided. After cooling to ambient temperature, the reaction mixture is then concentrated. The residue obtained is purified by vacuum flash chromatography (heptane) to give 2.3 g of a viscous liquid in 63.7% yield. The structure is confirmed by 1Hnmr and elemental analyses.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13]>>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
In an analogous manner to that described in Example 20, 3-ethylsulphonyl-1,2,4-triazole was reacted with dipropylcarbamoyl chloride to give 1-dipropylcarbamoyl-3-ethylsulphonyl-1,2,4-triazole, m.p. 44° - 45°C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[O:38])=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)Cc1ccc(OCc3ccccc3)cc1)C2
Yield: 81.2 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.1 g) and 4-benzyloxyphenylacetyl chloride (1.3 g) according to an analogous synthetic method to Preparation Example 87, the title compound (1.6 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:27]1[CH:26]=[C:25]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:30]=[N:29][CH:28]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilysilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca, 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]2[N:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: OC1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a N,N-dimethylformamide (100 mL) solution of 2-chloro-5-cyanopyridine (36.2 g, 262 mmol) and 4-hydroxypiperidine (27.9 g, 275 mmol) was added potassium carbonate (40.1 g, 290 mmol). The reaction mixture was heated to 100° C. and stirred for 3 hours. It was cooled to room temperature, diluted with water (400 mL), and extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=2.3 Hz, 1H), 7.58 (dd, J=9.1, 2.4 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 4.10 (dt, J=13.6, 5.0 Hz, 2H), 4.01 (tt, J=8.3, 3.9 Hz, 1H), 3.37 (ddd, J=13.6, 9.2, 3.4 Hz, 2H), 2.61 (s, 1H), 1.99-1.92 (m, 2H), 1.62-1.53 (m, 2H); LC-MS: m/z 204.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[Cl:19].[F:24][C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([Cl:19])=[CH:17][C:16]2[N:20]=[C:27]([C:26]([F:31])([F:30])[C:25]([F:33])([F:32])[F:24])[NH:21][C:15]=2[CH:14]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(C(F)(F)F)c1

Procedure:
A solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, crude) in pentafluoropropanoic acid (20 ml) was stirred overnight at 80° C. in an oil bath and then quenched with ice-water (50 ml). The pH value of the solution was adjusted to 8 with sodium carbonate and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a off-white solid (76.1 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2].C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 97.2 %

Procedure:
Dry THF (20 ml) was added to 0.4 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.2 g of triethylamine and 0.27 g of ethyl bromoacetate. The resultant mixture was stirred at room temperature for 24 hours. After the completion of the reaction, THF was distilled off under reduced pressure, the residue was dissolved in chloroform, and the resultant solution was washed with water. The chloroform layer was dried over anhydrous Na2SO4 and then filtered. The chloroform was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1), 0.5 g of 8-cyano-11-(1-ethoxycarbonylmethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 97%).
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[O:18][C:19]([CH3:26])=[C:20]([CH3:25])[C:21]=1[C:22](Cl)=[O:23]>ClCCl>[CH:2]1([N:8]([C:22]([C:21]2[C:20]([CH3:25])=[C:19]([CH3:26])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Reactant: ONC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1oc(C)c(C(=O)N(O)C2CCCCC2)c1C

Procedure:
49 Parts of N-cyclohexylhydroxylamine hydrochloride is dissolved in 400 parts of dichloromethane; at room temperature a solution of 50.4 parts of sodium hydrogen carbonate in 500 parts of water and subsequently 51.6 parts of 2,4,5-trimethylfuran- 3-carboxylic chloride are added to the mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 75 parts of N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 300 parts of dichloromethane. To this solution there is added 36 parts of sodium hydroxide in 200 parts of water and 75.6 parts of dimethyl sulfate and the whole is stirred for 2 hours. The dichloromethane phase is then separated, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. Upon distillation of the residue there is obtained 52 parts of O-methyl-N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid having a boiling point at 0.3 mm Hg of 128° to 130° C and the refractive index nD25 : 1.5021. ##SPC11##
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCNCC4)c3F)s2)c1
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccn2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-2-yl)piperidin-4-yl)methyl)picolinamide (compound example 47) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 594. Ret. time: 1.41 min. (Condition I); analytical HPLC Ret. time: 5.73 min (Condition H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH2:22][CH3:23])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCOc1ccccc1N1CCN(C(=O)Nc2cc(CC)c(C)nc2OC)CC1
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([Zn]CC)C.[NH4+].[Cl-]>ClCCCl>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH:13]1[CH2:33][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[Zn]CC
Reactant: C=CCC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)CNC(=O)NC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CC(C)(C)NC(=O)NCC(C)(C)C(CC1CC1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylhex-5-enyl)urea (20 mg, 0.046 mmol) in anhydrous DCE (2 mL) at −10 C was added diethylzinc solution (0.46 mL, 0.46 mmol) and methyldiiodide (245 mg, 0.92 mmol) under nitrogen. Allowed reaction mixture to warm to RT and stirred overnight. The mixture was poured into sat NH4Cl, extracted with DCM (2×10 mL), dried (Na2SO4) and purified by HPLC to give 11 mg (50% yield) of 1-tert-butyl-3-(4-cyclopropyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylbutyl)urea. MS found: (M+H)+=451.