Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31]Cl)[CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][O:19][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:23]=1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Reactant: ClCCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
A suspension of 0.70 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 0.50 g of 4-(3-pyridinyl)butylchloride, 0.40 g of potassium iodide and 0.39 g of potassium carbonate in 12 ml of dimethylformamide was stirred over night at a bath temperature of 50° C. The reaction mixture was diluted with ethylacetate, washed with water, dried (potassium carbonate) and concentrated. The residue was chromatographed on 75 g of silica gel eluting with ethyl acetate to give 0.46 g of a yellow solid which was recrystallized from ethyl acetate-hexane to give 0.33 g (32%), mp 95°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][NH2:14])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([O:24][C:25](=[O:26])[NH:14][CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)[CH3:23]
Reactant: COc1cc(CCN)cc(F)c1OC
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc(F)c(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-fluoro-4,5-dimethoxy-phenyl)-ethylamine (576 mg) and triethylamine (0.8 ml) in dichloromethane (20 ml) was added dropwise at 0° C. ethylchloroformate (300 μl). The mixture was stirred for 1 h, poured into ice water, neutralized with NaHCO3 and extracted with dichloromethane. The organic layers were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was passed through a short silica column (heptane/ethyl acetate as eluent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)(=[O:22])=[O:21])=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[C:4](Cl)[N:3]=1.CS(C)=O.C[O-].[Na+].[C:40](O)(=[O:42])C>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)(=[O:22])=[O:21])=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[C:4]([O:42][CH3:40])[N:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(Cl)nc(Cl)c2)c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(Cl)n1
Temperature: 100 °C

Procedure:
To a crude product of N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide (1.24 g) prepared using procedures similar to those for Example 151, was added anhydrous DMSO (10 mL), followed by sodium methoxide (273 mg). The resulting mixture was heated at 100° C. for 3 days. The mixture was diluted with EtOAc and water, and the pH was adjusted to about 4 by adding acetic acid. The product was extracted with EtOAc (3×). The combined extracts were washed with brine to give the crude product. A portion of the crude product was purified by prep HPLC to give N-(3-{[2-chloro-6-(methyloxy)pyridin-4-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.90 (s, 1H), 8.50 (d, 1H), 8.42 (d, 1H), 7.88-7.84 (m, 2H), 7.77 (s, 1H), 7.74 (s, 1H), 7.64 (d, 1H), 7.45-7.38 (m, 2H), 3.82 (s, 3H); MS (EI) m/z for C20H15ClN6O5S: 496.94 (MH+).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH:26]([CH3:28])[CH3:27])[CH:16]=2)[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:24]1[C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][C:17]([O:25][CH:26]([CH3:28])[CH3:27])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: COC(=O)c1ccc(C2CC2)cc1OC(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C2CC2)cc1OC(C)C
Reaction time: 1 h
Yield: 158.2 %

Procedure:
Dibromoisocyanuric acid (3.99 g) was added at room temperature to a DMF (80 mL) solution of methyl 4-cyclopropyl-2-isopropoxybenzoate (5.43 g), and the mixture was stirred at 90 C for 1 hour in a nitrogen atmosphere. An aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.89 g).
Reaction SMILES: [CH3:1][C:2]12[C:15](=[O:16])[CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=31)[NH:5][CH2:4][CH2:3]2.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:17]1([CH2:20][N:5]2[CH2:4][CH2:3][C:2]3([CH3:1])[C:15](=[O:16])[CH:6]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=23)[CH2:19][CH2:18]1
Reactant: CC12CCNC(Cc3ccc(O)cc31)C2=O
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCN(CC3CC3)C(Cc3ccc(O)cc31)C2=O

Procedure:
A mixture of 1,2,3,4,5,6-hexahydro-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (part A, 0.220 g.), cyclopropylmethyl bromide (0.200 g.) sodium bicarbonate (0.084 g.) and N,N-dimethylformamide (5 ml.) was stirred in a nitrogen atmosphere under reflux (for 2 hr.), then stripped of N,N-dimethylformamide. A solution of the residue in dilute hydrochloric acid (5%) was extracted with ether, neutralized and extracted with ether again. Desiccation and concentration of the latter ether extracts afforded 1,2,3,4,5,6-hexahydro-3-cyclopropylmethyl-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (I: ##STR13## R=CH3, X=HO, Y+Z=O) as a yellow oil, from which with methanesulfonic acid was obtained the methanesulfonate salt as another oil, from which with 1,5-naphthalenedisulfonic acid was obtained the crystalline 1,5-naphthalenedisulfonate tetrahydrate salt (220 mg., m.p. 287°-288° C.).
Reaction SMILES: C1C(Cl)=CC=C(Cl)C=1.Cl[C:10]1[CH:11]=[C:12]([C:19]([O-:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O.[Na+].[OH-].[Na+]>O.CN1C(=O)CCC1>[C:19]1(=[O:20])[O:21][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:10][CH:11]=[C:12]12
Reactant: O=C([O-])c1cc(Cl)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccc(Cl)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1OC(=O)c2ccccc21
Temperature: 255 °C

Procedure:
Then, 1116.5 g (7.59 moles) of p-dichlorobenzene, 1540.2 g of NMP and 32.7 g of water were fed to react the contents at a temperature of 220° C. for 4.5 hours. Thereafter, 282 g (15.7 moles) of water, 175.9 g (0.790 mole) of sodium hydrogen 4-chlorophthalate and 31.32 g (0.783 mole) of sodium hydroxide were additionally introduced under pressure in the autoclave. The contents were heated up to 255° C. to react them for 5 hours.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29].O>CN(C)C(=O)C.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>[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:28](=[O:30])[CH3:29])=[CH:32][CH:33]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: CC(=O)c1ccc(B(O)O)cc1
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: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 120 °C
Yield: 96.9 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (921 mg, 3.0 mmol) in N,N-dimethylacetamide (6 mL). Add potassium carbonate (996 mg, 7.2 mmol), 4-acetylbenzene boronic acid (590 mg, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0174 g, 0.015 mmol), then water (3 mL). Heat at 120° C. for 17 hr., then cool to room temperature, add water (15 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with 3.5 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 5:95 to 20:80 methanol:DCM), to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-ethanone as a yellow powder (1.135 g, 97%). MS (ES): m/z=391 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]2[C:20]3[C:21]4[CH:27]=[CH:26][NH:25][C:22]=4[N:23]=[CH:24][C:19]=3[CH2:18][O:17][CH2:16]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.Cl.[C].[Pd]>[CH3:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[N:15]1[C:20]2[C:21]3[CH:27]=[CH:26][NH:25][C:22]=3[N:23]=[CH:24][C:19]=2[CH2:18][O:17][CH2:16]1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N1COCc2cnc3[nH]ccc3c21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@@H]1CCNC[C@@H]1N1COCc2cnc3[nH]ccc3c21
Temperature: 25 °C
Yield: 100.2 %

Procedure:
rac-1-[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine (28.2 mg, 0.0777 mmol) in ethanol was stirred with 5% palladium-carbon (30 mg) and concentrated hydrochloric acid (2 drops) at 50° C. for 2 hours under a hydrogen atmosphere. The reaction mixture was allowed to cool to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (21.2 mg, yield 100%).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:12]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2)=[O:13])[CH:16]=1
Reactant: CCOC(=O)C1CCN(C(=O)Oc2cccnc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
4-Ethyl 1-pyridin-3-yl piperidine-1,4-dicarboxylate (0.732 g) was dissolved in THF (15 ml) and ethanol (8.0 ml), and under ice cooling, an aqueous 1 M sodium hydroxide solution (3.9 ml) was dropwise added thereto. This was stirred at room temperature for 2 hours, and neutralized with 1 M hydrochloric acid (0.5 ml). The reaction liquid was concentrated under reduced pressure, methanol was added to the residue, and the precipitated salt was removed through suction filtration. The filtrate was concentrated to obtain 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (0.727 g) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:28])[F:27])[C:21]([N+:33]([O-])=O)=[C:20]([F:36])[CH:19]=2)[CH2:13][S@:12](=[O:37])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO>[NH2:33][C:21]1[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:27])[F:28])=[CH:23][C:18]([CH2:17][C@H:14]2[C@H:15]([OH:16])[C@@H:10]([NH:9][CH2:8][C:7]3[CH:38]=[CH:39][CH:40]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[CH2:11][S@@:12](=[O:37])[CH2:13]2)=[CH:19][C:20]=1[F:36]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 41d) from (1S,3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol as an amorphous solid: TLC (EtOAc-MeOH 9:1) Rf=0.48; HPLC RtH1=0.91 min; ESIMS [M+H]+=561; 1H NMR (600 MHz, CDCl3): δ 7.36 (s, 1H), 7.24 (m, 2H), 7.13 (d, 1H), 6.74 (s, 1H), 6.65 (d, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.58 (s, 2H), 3.83-3.79 (m, 2H), 3.73 (m, 2H), 3.63 (dd, 1H), 3.53 (d, 1H), 3.30 (s, 3H), 3.03 (m, 1H), 2.97 (m, 2H), 2.49-2.32 (m, 4H), 1.70-2.62 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.II.CON(C)[C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:18](=[O:29])[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH3:20])[CH:8]=[CH:7][C:6]=1[S:9][CH3:10]
Reactant: COc1cc(Br)ccc1SC
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(C(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1SC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Magnesium (17 μg, 0.69 mmol) was placed in a screwcap reaction tube, and a solution of (4-bromo-2-methoxyphenyl)(methyl)sulfane (308e, 100 μg, 0.43 mmol) in tetrahydrofuran (1 mL) was added, followed by a small crystal of iodine. The tube was sealed and flushed with argon. The mixture was stirred at 60° C. overnight. After cooling (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (35 μg, 150 μmol) was added as a solid, and the mixture was stirred at r.t. for 1 h. Then the solvent was evaporated, the mixture was partitioned between aq. HCl (1N) and ethyl acetate. The organic layer was separated and dried. The product was isolated by HPLC to afford 10 mg (10%).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:11]([F:25])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:26])=[O:5])[CH:14]=[CH:13][C:12]=1[CH:15]=[CH:16][C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2cccnc2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2cccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 138 %

Procedure:
3-[3-Fluoro-4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid tert-butyl ester (550 mg, 1.55 mmol) was dissolved in DCM (15 ml) and TFA (5 ml). The resulting solution was stirred at RT for 4 h then the solvent was removed under vacuo giving 636 mg of 3-[3-fluoro-4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid as trifluoro acetate salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:10][C:9]=2[CH:20]=1)=O.FC1C=C(C2OC3C=CC(CO)=CC=3N=2)C=CC=1>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:3][OH:2])=[CH:20][C:9]=2[N:10]=1
Reactant: COC(=O)c1ccc2oc(-c3ccccc3F)nc2c1
Agent: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Product: OCc1ccc2oc(-c3ccccc3F)nc2c1

Procedure:
Compound 75A was reacted in a manner analogous to Compound 69B to give the title product. MS m/z 244 (M+1).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:33]([CH3:35])[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[CH:20]=[C:19]1[CH:33]([CH3:35])[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 38, 0.727 g, 1.42 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an off-white foam (0.65 g, 87%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=CC=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)cc2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)c(F)c1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)cc2F)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:12]2[CH2:13][CH2:14]3)=[CH:5][CH:4]=1)#[CH:2].I[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.C(N(CC)CC)C>[O:17]=[C:16]1[CH:15]2[CH2:18][CH2:19][CH:12]([CH2:13][CH2:14]2)[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(OCCCN2C(=O)C3CCC2CC3)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(OCCCN3C(=O)C4CCC3CC4)cc2)cc1

Procedure:
In the a) route of scheme 3, compound 5 is reacted with ethyl 4-iodo-benzoate in the presence of triethylamine (Et3N), trimethyl-benzylammonium chloride (Me3N (Bn) Cl) and tetrakistriphenylphosphine palladium (Pd(PPh3)4) to give ethyl 4-[4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylethynyl]-benzoate (compound 15), then 4-[4-[3-(3-oxo-2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylethynyl]-benzoic acid (compound 16 ) is provided by hydrolysis of compound 15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[C:5]2[N:6]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:32][N:33](C)CCN(C)C.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>CN(C=O)C.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:32]([C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[C:5]2[N:6]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1)#[N:33]
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Reactant: CN(C)CCN(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C#N)cn12
Temperature: 160 °C

Procedure:
Under argon, 500 mg (1.0 mmol) of 6-bromo-8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 70.9 mg of zinc(II) cyanide (0.6 mmol, 0.6 equivalents), 30.4 μl of 1,2-bis(dimethylamino)ethane (TMEDA; 0.2 mmol, 0.2 equivalents), 65 mg of tris(dibenzylideneacetone)dipalladium Pd2 dba3 (0.07 mmol, 7 mol %) and 29 mg of xantphos ligand (0.05 mmol, 5 mol %) were dissolved in 2 ml of DMF and, divided into 5 microwave reaction vessels, heated at 160° C. for 5 min (CEM Discovery microwave, 300 Watt irratiation). The combined reaction mixtures were diluted with ethyl acetate and filtered through kieselguhr. The filter cake was washed thoroughly and the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The residue was chromatographed on a 50 g silica gel cartridge (Biotage Isolera, cyclohexane/ethyl acetate gradient as mobile phase). This gave 289 mg of the target compound (64% of theory).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][N:4]=1>Cl>[NH2:10][CH2:9][C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=1
Reactant: COc1cc(CN)ccn1
Agent: Cl
Product: NCc1cc[nH]c(=O)c1

Procedure:
The starting material (2-methoxypyridin-4-yl)methanamine 56-2 in 3N HCl was refluxed at 110° C. for 12 hours. The reaction was taken to dryness by rotary evaporation to give crude 4-(aminomethyl)pyridin-2(1H)-one 56-3.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.I[C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:38]4[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(OC(F)(F)F)cc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenanthroline with 3,4,7,8-tetramethylphenanthroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.19 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (86 mg, 0.3 mmol) gave the title compound as colourless oil after purification by preparative HPLC (44 mg, 52%).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(N[C@H]2CC[C@H](CC)CC2)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:1]1([N:6]([C@H:20]2[CH2:21][CH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][CH2:25]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:28][CH2:5]1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-ethyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.