Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl {4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate (153) (0.20 g, 0.51 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and trituration with hot hexanes (containing 1% methanol), the title compound 154 was obtained as a white solid (0.185 g, 96%). mp 220-221° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 3.49 (s, 2H), 6.64 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 9.24 (s, 1H), 12.26 (s, 1H). LCMS (ESI): m/z 401 (M+Na)+, 377 (M−H)−. Anal. Calcd for C25H30O3.⅙H2O: C, 78.71; H, 8.01. Found: C, 78.73; H, 7.98.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C([Li])CCC.CN([CH:31]=[O:32])C>>[CH:31]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2)=[O:32]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[C:14]2[C:9](=[C:10]([N+:16]([O-])=O)[C:11]([CH3:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1>C(O)C.C(Cl)Cl.C(Cl)Cl>[Cl:4][C:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc2c(Cl)nccc2c1N
Temperature: 70 °C
Yield: 40.4 %

Procedure:
Tin (II) chloride (0.43 g, 2.2 mmol) was added to a solution of 1-chloro-6-methyl-5-nitroisoquinoline (0.100 g, 0.45 mmol) in ethanol/DCM (10.0 mL, 4:1). The solution was heated at 70° C. for 16 h. The reaction mixture was diluted with DCM and the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid which was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 1-chloro-6-methylisoquinolin-5-amine (0.035 g, 40% yield) as a brown solid. MS (ESI, pos. ion) m/z: 193 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COCCC(=O)Nc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COCCC(=O)Nc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
The above 1.26 g N-(3-Hydroxymethyl-phenyl)-3-methoxy-propionamide were dissolved in 50 ml acetone, 12.60 g manganese dioxide were added and the mixture stirred at room temperature over night. The mixture was filtered and the filtrate evaporated and further purified by chromatography on silica in ethyl acetate/heptane mixtures. Yield 0.77 g of the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:21][C:20]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[O:19][N:18]=2)=O)=[C:10]([N+:27]([O-])=O)[CH:9]=1.[OH-].[Na+]>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([C:17]3[CH2:21][C:20]4([CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[O:19][N:18]=3)=[N:27][C:10]=2[CH:9]=1
Reactant: O=C(Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-])C1=NOC2(CCOCC2)C1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccccc1-c1ccc2[nH]c(C3=NOC4(CCOCC4)C3)nc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of 1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (2′-fluoro-3-nitro-biphenyl-4-yl)-amide (131 mg, 0.327 mmol, as prepared in the previous step) in glacial acetic acid (10 mL) was treated with Fe powder (91.2 mg, 1.36 mmol) and heated to 100° C. under a reflux condenser for 4 h. The pH of the mixture was adjusted to 7 with 6M aq NaOH. The resulting aqueous mixture was extracted three times with EtOAc (50 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g Sepra Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:9 v/v for 10 min, then 1:9 to 2:3 v/v over 40 min) to afford the title compound (98.8 mg, 86%) as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.78-7.90 (m, 1H), 7.55-7.68 (m, 1H), 7.46-7.54 (m, 2H), 7.29-7.39 (m, 1H), 7.14-7.26 (m, 2H), 3.97 (ddd, J=11.7, 8.1, 3.4 Hz, 2H), 3.70-3.81 (m, 2H), 3.47 (s, 2H), 1.99-2.08 (m, 3H), 1.87-1.98 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18FN3O2: 352.1 (M+H). found: 352.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1ccc(S(=O)(=O)Oc2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 40 °C

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 35 ml methoxyethylamine in 100 ml dioxane in a round bottom flask. The reaction mixture was heated to reflux for 8 hours and then cooled to 40° C. and extracted two times with 250 ml water. Concentrate was solubilized with ethyl acetate and extracted with 2N aqueous HCl and water, the organic phase was then dried under reduced pressure, yielding 19.2 g of 2-amino-5-(4-[2-methoxyethyl]aminophenylsulfonyloxy)nitrobenzene (melting point 105° C.).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=O)[C:20]=1[O:41][CH2:42][CH3:43]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:29])([CH3:30])[CH2:26][CH:25]=[C:24]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:41][CH2:42][CH3:43]
Reactant: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)(C)C

Procedure:
Following General Procedure I-1, ethyl 4(diethoxyphosphoryl)-3-methyl-but-2E-enoate (92-mg, 0.35 mmol) and (2E)-3-(4-bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-152, 37 mg, 0.09 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]3[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=3[N:33]=2)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:16][C:2]([F:1])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[S:30][C:31]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=4[N:33]=3)=[CH:27][CH:28]=2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCCC(F)(F)F)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 4-(4,4,4-trifluorobutoxy)benzoic acid (0.20 g, 0.806 mmol) and thionyl chloride (0.42 g, 3.54 mmol) in chloroform (5 ml) was heated under reflux for 8 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.206 g, 0.806 mmol) in dry pyridine (10 ml) to give the title compound (0.343 g, 87%) as a colourless solid after work-up.
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[N:54]1([CH2:59][CH2:60][NH2:61])[CH:58]=[CH:57][N:56]=[CH:55]1>O1CCOCC1.C(OCC)(=O)C>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:61][CH2:60][CH2:59][N:54]4[CH:58]=[CH:57][N:56]=[CH:55]4)=[O:43])=[CH:8][CH:7]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: NCCn1ccnc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)NCCn2ccnc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (50 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added 2-(1H-imidazol-1-yl)ethanamine (50 mg, 0.45 mmol, Synthetic Communications 1991, 21, 535-544) and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated and purified by chromatography (silica gel, dichloromethane/2M ethanolic ammonia, 93:7) to provide the title compound as a white solid (25 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.4 (1H, t), 2.55-2.80 (3H, m), 2.9-3.0 (2H, m), 3.3-3.4 (3H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.03-4.07 (2H, m), 4.8 (1H, dt), 0.505 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.87 (1H, s), 6.9 (2H, d), 7.05 (1H, d), 7.15 (1H, s), 7.2 (2H, d), 7.23 (1H, s), 7.25-7.30 (2H, m), 7.6 (1H, s), 7.8 (1H, t); MS: 730 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:51]([CH3:53])[CH3:52])[C:45]([O:47][CH:48](Cl)[CH3:49])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17](=[O:18])[C:19]4[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=4[F:33])=[CH:15][N:14]([CH:48]([O:47][C:45](=[O:46])[CH:44]([NH:43][C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH:51]([CH3:52])[CH3:53])[CH3:49])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(Cl)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 64.8 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.22 mmol) and a solution of 1-chloroethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (172 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as orange oil (0.29 g, 65%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.O>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cc(Cl)ncn3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.34 mL (2.43 mmol) TEA are added to a mixture of 181 mg (1.22 mmol) 4,6-dichloropyrimidine and 300 mg (1.22 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 3 mL THF. The mixture is stirred for 5 min at 80° C. and for 2 h at rt. After that time, water is added and the mixture is extracted with dichloromethane (2×). The combined organic layers are dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; dichloromethane/methanol, gradient 98:2-95:5) to yield the desired product.
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[N:6][CH:5]=[CH:4][NH:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:1][N:2]2[CH:7]=[N:6][CH:5]=[CH:4][NH:3]2)=[CH:10][CH:11]=1)#[N:14]
Reactant: NN1C=NC=CN1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(NN2C=NC=CN2)cc1

Procedure:
Starting compounds: 2-amino-1,2,4-triazine and 4-fluorobenzonitrile
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:15]=[CH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH:18]1(B(O)O)[CH2:20][CH2:19]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([CH:18]3[CH2:20][CH2:19]3)[C:3]3[N:4]([CH:15]=[CH:16][N:17]=3)[CH:5]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2cc(Br)c3nccn3c2)cc1
Reactant: OB(O)C1CC1
Product: Clc1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Yield: 59.2 %

Procedure:
Prepared from 8-bromo-6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine (example C.27 step 3) (6.15 g, 20 mmol) and cyclopropylboronic acid (2.23 g, 26 mmol) as described in example C.25 step 4. Obtained the title compound as an orange solid (3.18 g, 59%; 88% pure, contains 12% 8-cyclopropyl-6-(4-cyclopropyl-phenyl)-imidazo[1,2-a]pyridine). MS (ISP) 269.3 [(M+H)+], 271.3 [(M+2+H)+].
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.C(OC1C(C(O)=O)=NC(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 112.3 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (218) (300.0 mg, crude) was synthesized as a white solid from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (217) (300.0 mg, 0.588 mmol) following the procedure described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (205).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[I-].[K+].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>O.C(#N)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: N#Cc1ccc(OCCCCCCCCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(OCCCCCCCCOC(=O)c2cc(O)ccc2O)cc1
Yield: 83.5 %

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.2 g; 27.5 mmol), 1.8-diazabicyclo[5.4.0]undec-7-ene (4.2 g; 27.5 mmol), potassium iodide (41.0 g; 247 mmol), p-[(8-chlorooctyl)oxy]benzonitrile (6.6 g; 25 mmol) and acetonitrile (100 ml) was heated under reflux for 72 h. The reaction mixture was cooled, poured into water (500 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×150 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuo. The residue was purified by column flash chromatography on silica gel using a toluene/ethyl acetate 80:20 as eluent to give 8.0 g (84%) of 8-(p-cyanophenoxy)octyl 2,5-dihydroxybenzoate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([CH:29]=1)[NH2:28]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:28][C:27]4[CH:29]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:30])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1ccc(F)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.32 mmol), 5-fluoro-2-methylaniline (60 mg, 0.48 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (50 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.96 (m, 9H) 2.22 (s, 3H) 3.99 (t, J=14 Hz, 2H) 4.62 (t, J=8 Hz, 1H) 6.81 (td, J=8, 3 Hz, 1H) 7.19 (t, J=8 Hz, 1H) 7.58 (dd, J=12, 3 Hz, 1H) 8.20 (s, 1H) 8.57 (s, 1H). [M+H] calc'd for C20H22F3N5O, 406. found 406.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[C:49]#[N:50]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][CH:53]=[C:46]([C:45]#[N:44])[CH:47]=3)=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: N#Cc1cccc(CN)c1
Agent: Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4cccc(C#N)c4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 3-(aminomethyl)benzonitrile-HCl.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][NH:7][C:6]=2[N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[N:16]=1
Reactant: CN1C(=O)C(F)(F)CNc2nc(Cl)ncc21
Reactant: ICCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(CCOc2ccccc2)c2nc(Cl)ncc21
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 0.20 g (0.8 mmole) of 2-chloro-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292) in 2 mL of dimethylformamide was added 0.53 g (1.6 mmole) of cesium carbonate, followed by 0.8 g (3.2 mole) of (2-iodo-ethoxy)-benzene. After stirring at 50 degrees overnight, the mixture was filtered and then concentrated under reduced pressure. Dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.28 g of 2-chloro-7,7-difluoro-5-methyl-9-(2-phenoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-304) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:12][N:11]([CH:13](C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH2:29])[C:27]#[CH:28].C(C1C=CC(C2CN(C(NCC=C)=[O:45])C2)=CC=1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:13]([NH:29][CH2:26][C:27]#[CH:28])=[O:45])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCNC(=O)N1CC(c2ccc(C(C)(C)C)cc2)C1
Reactant: C#CCN
Reactant: Clc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Product: C#CCNC(=O)N1CC(c2ccc(Cl)c(Cl)c2)C1

Procedure:
This compound was prepared from compound (26) and propargylamine using the procedure described for compound (12). mp. 105.5-107.5° C.