Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][C:37]=1[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:47][S:44]([C:37]3[CH:38]=[C:39]([CH2:42][CH3:43])[CH:40]=[CH:41][C:36]=3[Cl:35])(=[O:46])=[O:45])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.38 mmol, prepared as described in Example 1 Step C) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL) was added 4-(dimethylamino)pyridine (138 mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol). The reaction mixture was stirred for 15 min, 2-chloro-5-ethylbenzenesulfonamide (74 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (100 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×50 mL), and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 84 mg of the title compound, a compound of the present invention, as a solid, m.p. 214-215° C. 1H NMR (CDCl3) δ 10.12 (br s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.53 (s, 1H), 7.40 (s, 2H), 2.77 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]#[N:20])[CH2:14]2)=[CH:9][CH:8]=1.Cl.[NH2:25][OH:26].C(N(CC)C(C)C)(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:25][OH:26])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#C[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carbonitrile (0.211 g, 0.001 mol) and hydroxylamine hydrochloride (0.047 g, 0.001 mol) were dissolved in ethanol (4 ml) and N,N-diisopropylethylamine (0.120 ml, 0.001 mol) was added. The reaction mixture was stirred under reflux for three hours. The reaction was cooled to room temperature, the solvent was evaporated and the residue extracted with dichloromethane and purified by column chromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to yield (0.220 g, 94% of theory) of a yellow oil. MS (m/e)=344.3(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([CH2:14][CH3:15])[CH:7]=1)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][CH3:15])[CH:7]=1)=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)ccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(C(=O)c2ccccc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
At -78° C., to a stirred solution of 4-(2-chlorobenzoyl)-2-ethylanisole (18 g, 65.5 mmol) in CH2Cl2 (295 mL) was added boron tribromide (12.4 mL, 0.131 mol). After the addition was complete, the reaction was allowed to warm to ambient temperature and stirred for 48 h. The reaction was slowly poured into crushed ice (200 g) and extracted with CH2Cl2. The organic extracts were washed with sat. aq. KH2PO4 (1×) and extracted with 2.5N NaOH. The aqueous extracts were washed with CH2Cl2 (1×), acidified with 2N HCl and extracted with CH2Cl2, dried (Na2SO4) and concentrated to give 14.48 g (85%) of the title compound. 1H NMR: consistent. mass spectrum (+ESI) m/z 261 (M+H). Anal. Calcd. for C15H13ClO2.0.2H2O: C, 68.16; H, 5.11; N, 0.00. Found: C, 68.18; H, 5.15; N, 0.00.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39](=[O:40])[CH2:38][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)CC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 ml). After stirring for 20 min, t-butylacetyl chloride (0.25 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed in vacuo and the residue was dissolved in dichloromethane (90 ml) and washed with 0.1N HCl (30 ml), water (30 ml), brine (30 ml) and then dried. Solvent was removed in vacuo and the solid residue was slurried in ethanol (10 ml) to give after filtration 0.55 g (77%) of the product: mp 145-147° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.39 (t, J=5.7 Hz, 1H), 7.87-7.69 (m, 3H), 5.19-5.12 (dd, J=5.3 and 12.4 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.92-2.83 (m, 1H), 2.63-2.51 (m, 2H), 2.08 (s, 2H), 2.08-2.04 (m, 1H), 0.97 (s, 9H); 13C NMR (DMSO-d6) δ 172.69, 171.35, 169.74, 167.51, 166.96, 139.61, 134.69, 133.41, 131.52, 127.11, 121.87, 48.86, 48.62, 37.53, 30.93, 30.52, 29.71, 22.00; Anal. Calcd. For C20H23N3O5+0.28 water: C, 61.52; H, 6.08; N, 10.76. Found: C, 61.23; H, 6.18; N, 10.57.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([C@@H:2]([CH3:5])[CH2:3][OH:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[C@H](N)CO
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)N1CCCC1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (566 mg, 7.54 mmol), 1,4-dibromobutane, and potassium carbonate (2.09 g, 15.1 mmol) in acetonitrile (70 mL) was heated at reflux overnight and allowed to cool to room temperature. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (75 mL) and washed (25 mL sat'd K2CO3). The aqueous phase was extracted with DCM (2×25 mL) and the combined organic extracts were dried over Na2SO4. The solvent was removed under reduced pressure and purified on a silica gel column to yield (S)-2-(pyrrolidin-1-yl)propan-1-ol (630 mg, 65%) as a clear oil. 1H NMR (CDCl3): δ 3.63 (m, 1H), 3.38 (m, 1H), 2.97 (br s, 1H), 2.69 (m, 1H), 2.60 (br s, 4H), 1.72 (br s, 4H), 1.06 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH3:24])[C:4](=[O:25])[C:3]=1[NH:26][C:27]([C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH:35]2[CH2:39][C:38](=[O:40])[N:37]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=3)[CH2:36]2)[CH:33]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CN(C=O)C.O>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][N:7]1[C:2]2[N:1]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([CH2:34][CH:35]4[CH2:39][C:38](=[O:40])[N:37]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=5)[CH2:36]4)[CH:33]=3)[NH:26][C:3]=2[C:4](=[O:25])[N:5]([CH2:22][CH2:23][CH3:24])[C:6]1=[O:21]
Reactant: CCCn1c(=O)c(NC(=O)c2cnn(CC3CC(=O)N(c4cccc(C(F)(F)F)c4)C3)c2)c(N)n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5cccc(C(F)(F)F)c5)C4)c3)nc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid {6-amino-1-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl}-amide (100 mg, 0.14 mmol) was taken in dry DMF (3 ml) under argon atmosphere, added P2O5 (61.4 mg, 0.43 mmol) and dipped the reaction flask in a oil bath at 100° C. and stirred the reaction mixture for 5 min. Then the reaction mixture was cooled to room temperature and diluted with water and filtered the solid (56 mg, 57%) as pure product.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.CN1C(=O)N(C)CCC1>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:10][C:6]1[CH:5]=[C:4]([I:3])[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOCCl
Reactant: Oc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COCCOCOc1cccc(I)c1
Temperature: 0 °C

Procedure:
To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in THF (10 mL), cooled to 0° C., is added 3-iodophenol (8.8 g, 40 mmol) and methoxyethoxymethyl chloride (5 mL, 44 mmol) in THF (50 mL). Then DMPU (10 mL) is added, the cooling bath is removed and the reaction is stirred for an hour. The reaction is diluted with ether, washed with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOP(=O)(Cc1cccc(C#N)n1)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Yield: 22.5 %

Procedure:
Diethyl (6-cyano-2-pyridyl)methylphosphonate (1.4 g, 5.8 mmol) and methyl thiosalicylate (1.9 g, 11.6 mmol) were dissolved in toluene (8 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 13 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (10:1, v/v) were collected, concentrated and recrystallized from diisopropyl ether-ethanol to give the titled compound (510 mg, 22%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH3:30][O:31][CH2:32][CH:33]([NH2:36])[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH2:32][O:31][CH3:30])[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Reactant: CCC(N)COC
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.50 g, 1.11 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.31 g, 2.22 mmol) were treated substantially as described in Part C of Example 19a to produce 0.40 g (89%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 403.8 [(M+H)+, 98].
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH2:9][N:10]2[CH2:25][CH2:24][C:13]3([O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14]3(O)[CH3:22])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]1([C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH2:9][N:10]2[CH2:25][CH2:24][C:13]3([O:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[CH2:22])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN1C(=O)OC2(CCN(CC=C(c3ccccc3)c3ccccc3)CC2)C1(C)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C1N(CCC)C(=O)OC12CCN(CC=C(c1ccccc1)c1ccccc1)CC2
Reaction time: 4.5 h
Yield: 85.7 %

Procedure:
12.6 g of 8-(3,3-diphenyl-2-propenyl)-4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]decane are refluxed in a mixture of 126 ml of acetic acid and 5.7 ml of acetic anhydride under nitrogen while stirring for 4 to 5 hours, then the solvent is distilled off under reduced pressure. The residue is made alkaline by adding 5% by weight aqueous sodium hydroxide solution and extracted with benzene. After washing the benzene phase with water to neutral and drying over anhydrous sodium sulfate, benzene is evaporated under reduced pressure and the remaining crude product is recrystallized from ethanol to give the title compound in 85.7% yield, m.p.: 126°-127° C.
Reaction SMILES: [CH3:1]N(C=O)C.[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([NH:22][CH:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:21])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[H-].[Na+].IC>C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([N:22]([CH:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH3:1])=[O:21])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(/C=C/c1ccc(-n2ccnc2)c(F)c1)NC1CCc2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)/C=C/c1ccc(-n2ccnc2)c(F)c1)C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DMF (1.0 mL) solution of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide (30.0 mg) obtained in Example 324, sodium hydride was added at 0° C. (10.0 mg), and the reaction solution was allowed to be warmed to room temperature. Iodomethane (54.0 μL) was added to the reaction solution, the reaction solution was agitated at room temperature for 3 hours, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent heptane-ethyl acetate=1:1), and 8.5 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:2]3[CH:10]=[C:9]([NH:11][C@H:12]4[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]4)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: NC(=O)c1cnc(Cl)cc1N[C@H]1CC[C@@H](O)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2ccc(Nc3cc(N[C@H]4CC[C@@H](O)CC4)c(C(N)=O)cn3)cc2)CC1
Reaction time: 18 h

Procedure:
A mixture of 6-chloro-4-((cis)-4-hydroxycyclohexylamino)nicotinamide (65 mg, 0.240 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (60 mg, 0.273 mmol), sodium phenoxide trihydrate (100 mg, 0.588 mmol), xantphos (30 mg, 0.051 mmol) and Pd2dba3 (20 mg, 0.021 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 120 C for 18 h. HOAc (1 mL) was added. The mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 453.5 (M+H); UV 202.9, 259.0 nm; t 0.380 min.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([F:43])([F:42])[C:39](O)=[O:40])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH2:44]([S:46]([NH2:49])(=[O:48])=[O:47])[CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([F:42])([F:43])[C:39]([NH:49][S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])=[O:40])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: CCS(N)(=O)=O
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C(=O)O)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)C(F)(F)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (43 mg, 0.22 mmol) is added to a stirred ice cold solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid [100 mg, 0.21 mmol, Example 81 (a)], ethanesulfonamide (24.5 mg, 0.22 mmol) and 4-dimethylaminopyridine (26.1 mg, 0.21 mmol) in dry DCM under nitrogen. The reaction mixture is stirred at room temperature overnight at 60° C. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography to afford ethanesulfonic acid [2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2,2-difluoro-acetyl]-amide [35 mg, Example 81(b)]. LCMS: RT=2.31 minutes; MS: 559, 561 (M+H); 1H NMR [300 MHz, CD3OD]: □8.18 (1H, b), 8.05 (1H, b), 7.75 (1H, d, J=4 Hz), 7.5 (1H, t, J=4 Hz), 7.42 (1H, s), 7.28 (2H, q, J=4 Hz), 6.55 (1H, s), 3.95 (3H, s), 3.7 (2H, b), 3.18 (2H, q, J=4 Hz), 3.08 (2H, t, J=3.5 Hz), 1.15 (3H, t, J=4 Hz). IC50=0.1 nM
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27](Br)=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC.[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[Pd](Cl)Cl.[Cu]I.CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([CH:30]=[CH2:31])=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(Br)ccn12
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Temperature: 45 °C
Yield: 61.3 %

Procedure:
A mixture of N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide (50 mg; 0.112 mmol), tributylvinyltin (43 mg; 0.13 mmol) and cesium fluoride (34 mg; 0.22 mmol) were mixed with DMF (1 mL) under nitrogen. Palladium (II) chloride (0.8 mg; 0.005 mmol), tri-tert-butylphosphine (18 mg; 0.009 mmol) and copper (I) iodide (1.7 mg; 0.009 mmol) were added and the mixture was purged with nitrogen and then heated in a sealed vessel at 45° C. for 16 hours. The mixture was added to water (30 mL) and extracted into ethyl acetate. The combined extracts were washed with water, dried (sodium sulfate) and filtered through a pad of silica. The solvent was removed under vacuum to provide a white solid which was triturated with ether to provide the desired product (27 mg) of sufficient purity to take to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[S:13][C:14]([C:18](O)=[O:19])=[C:15]([CH3:17])[N:16]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:14]2[S:13][C:12]([CH3:11])=[N:16][C:15]=2[CH3:17])=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Nc1cccc(CCO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cccc(CCO)c2)s1
Reaction time: 14 h
Yield: 73 %

Procedure:
2-(3-Aminophenyl)ethanol (1.202 g, 8.76 mmol) was added to a solution of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (1.652 g, 10.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.015 g, 10.51 mmol) and 1-hydroxybenzotriazole (1.420 g, 10.51 mmol) in dry DMF (20 mL). The mixture was stirred for 14 h then the DMF was removed under reduced pressure and the residue was partitioned between DCM and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel, eluting with ethyl acetate-cyclohexane (1:1 to 1:0) affording the title compound in 73% yield (1.772 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]([C:18](OC)=[O:19])=[C:16]([C:22](OC)=[O:23])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:19])[NH:31][NH:32][C:22](=[O:23])[C:16]=4[N:15]=[CH:14]3)=[CH:26][CH:27]=2)=[O:7])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OC
Reactant: NN
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(=O)[nH][nH]c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of 1-[4-(4-chlorobenzoyl)benzyl]-4,5-dimethoxycarbonylimidazole (3.31 g) in methanol (20 ml) was added hydrazine monohydrate (1.68 g) and the mixture was refluxed for 5 hours. The resulting crystals were harvested by filtration and suspended in water (100 ml) and, after addition of concentrated HCl (10 ml), the suspension was stirred at 80° C. for 30 minutes. The resulting crystals were collected by filtration and dried in vacuo to provide 2.67 g (yield 88%) of the title compound. 1H-NMR (DMSO) δ: 5.78(2H,s), 7.45-7.77(8H,m), 8.49(1H,s).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[C:10]([CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[CH:16]=2)[C:11]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)=[O:13])=[CH:19][CH:20]=1)#[N:25]
Reactant: NC1CCC(O)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(O)CC3)c2)cc1
Yield: 39.4 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.1 g (0.28 mmol) and 4-amino-cyclohexanol (0.046 g, 0.42 mmol) were used to afford 0.05 g of the required product. Percentage purity (LCMS): 92.3%, (M+1)=453.1+1.