Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1

Procedure:
4-Nitrobenzyl bromide is treated with morpholine and potassium carbonate in acetone to give 4-(4-Nitrobenzyl)morpholine (G-1). The nitro group is reduced with platinum and hydrogen gas to afford the aniline (G-2) which is then treated with [(1-ethoxycyclopropyl)-oxy]trimethylsilane and sodium cyanoborohydride to give the N-cyclopropyl aniline (G-3). Reaction with diethyl ethoxymethylenemalonate in pyridine affords the enamine (G-4) which is cyclized with polyphosphoric acid to the quinoline (G-5). Treatment with p-chlorobenzylamine at elevated temperature converts the ester to the amide (G-6).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[C:33]([F:40])=[CH:32][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[C:6]1=[O:31].Cl[C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N:43]1[CH:44]=[CH:45][CH:46]=[N:47][C:42]=1[C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([N:7]3[CH2:8][CH2:9][C@H:5]([O:4][C:3]4[CH:32]=[C:33]([F:40])[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:2]=4[F:1])[C:6]3=[O:31])[CH2:11][CH2:12]2)=[N:21][CH:20]=1
Reactant: CC1(C)OB(c2cnc(N3CCC(N4CC[C@H](Oc5cc(F)c(S(C)(=O)=O)cc5F)C4=O)CC3)nc2)OC1(C)C
Reactant: Clc1ncccn1
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: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(-c5ncccn5)cn4)CC3)C2=O)cc1F
Temperature: 80 °C
Yield: 47.8 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (173 mg, 0.299 mmol), 2-chloropyrimidine (41.1 mg, 0.359 mmol) and 2M Na2CO3 (748 μL, 1.50 mmol) were dissolved in dioxane (3 mL) and purged with nitrogen. Pd(PPh3)4 (34.6 mg, 0.0299 mmol) was added and the reaction was heated to 80° C. for 3 hours. The reaction was cooled to ambient temperature, partitioned between water and CH2Cl2, extracted twice, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (eluting with 90 to 100% EtOAc in hexanes) to afford (S)-1-(1-(2,5′-bipyrimidin-2′-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (76 mg, 0.143 mmol, 47.9% yield) as a white solid. Mass spectrum (apci) m/z=531.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Reactant: COC(=O)CNCc1ccc(N(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 49.4 g (222 mmol) of [(4-dimethylamino-benzylamino)-acetic acid methyl ester], 41.4 ml (244 mmol) of diisopropylethyl amine and 0.271 g (2.2 mmol) of DMAP in 600 ml of CH2Cl2, 54.8 g (222 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 100 ml of CH2Cl2 are added at 0–5° C. After stirring for 15 h at r.t., the reaction mixture is quenched with ice water and sat. aqueous NH4CO3. The mixture is extracted with AcOEt and combined extracts are washed with sat. aqueous NH4CO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane: AcOEt=4:1) to give the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:20]1[CH:21]=[C:22]([C:27]2[N:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=2)[C:23]([NH2:26])=[N:24][CH:25]=1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[C:2]([F:1])[CH:3]=2)=[CH:21][C:22]=1[C:27]1[N:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)c(F)c3)cnc2N)nn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of (3-fluoro-4-(morpholine-4-carbonyl)phenyl)boronic acid (269 mg, 1.06 mmol) and of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (250 mg, 0.886 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (863 mg, 2.65 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (51 mg, 0.04 mmol) was added and allowed to stir at 120° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 125 mg (yield: 34.43%) of the title compound as pale yellow solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:2]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]=1[OH:33])[CH:28]=O)[CH3:23].[NH2:37][C:38]([NH2:40])=[O:39].Cl>C(O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:28]([C:27]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]([OH:33])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[NH:37][C:38](=[O:39])[NH:40][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(-c3ccccc3)c2)cc([N+](=O)[O-])c1O
Yield: 11.2 %

Procedure:
To a solution of 2-(biphenyl-3-yl)-1-phenylethanone (Intermediate 28) (120 mg, 0.44 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (86.9 mg, 0.44 mmol), and urea (79.3 mg, 1.32 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution. The mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 60 (25 mg, yield 11.2%). 1H NMR (DMSO-d6 400 MHz) δ 10.24 (s, 1H), 8.74 (s, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.32-7.12 (m, 12H), 7.10 (t, J=8.0 Hz, 1H), 7.00 (m, 1H), 6.82 (d, J=6.8 Hz, 1H), 5.30 (d, J=2.8 Hz, 1H), 4.00 (m, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI): m/z 508.1 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li].[CH2:12]([O:19][C:20]([NH:22][CH2:23][C@H:24]([NH:30][C:31](=[O:36])[CH2:32][C:33](O)=[O:34])[C@@H:25]([OH:29])[C:26]#[C:27][CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:12]([O:19][C:20](=[O:21])[NH:22][CH2:23][C@H:24]([NH:30][C:31](=[O:36])[CH2:32][C:33](=[O:34])[NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1)[C@@H:25]([OH:29])[C:26]#[C:27][CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.9 %

Procedure:
The compound 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (67 mg, 0.43 mmol) was dissolved in 6 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid (151 mg, 0.43 mmol, see procedure 21a), N, N-diisopropylethylamine (0.38 mL, 2.1 mmol) and HATU (194 mg, 0.51 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester as a colorless oil (90 mg, 43% yield). MS found: (M+Na)+=510.4. (23b) A solution of {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (90 mg, 0.19 mmol) in MeOH (4 mL) was charged with 5% Pd/C, Degussa style (18 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.02 mL, 0.14 mmol) and sodium cyanoborohydride (11 mg, 0.18 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=476.5.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:19])([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)[OH:8].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:8][C:7]([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)([CH3:19])[CH3:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(O)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(C)(C)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A total of 15 mmole of acrylic chloride was added dropwise to a mixture containing 10 mmole of the above-prepared α,α-dimethyl-1-adamantanemethanol, 20 mmole of triethylamine, and 40 ml of tetrahydrofuran, over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the resulting mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 76%.
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]/[CH3:23])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]\[CH3:23])[CH3:21]
Reactant: ClCCl
Reactant: C/C=C(/c1cccc(OC)c1)C(C)CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C/C=C(/c1cccc(O)c1)C(C)CN(C)C
Yield: 73 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (5), which was prepared according to Example 5, and after drying the solution dichloromethane was removed by distillation. Hydrochloride (6), which had a melting point of 80° C., was obtained in a yield of 73% theoretical from the base obtained, under the conditions given in Example 2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]1=[O:38]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:24]2=[O:38])[CH2:13][CH2:12]1
Reactant: Cc1cn(-c2ccc(F)cc2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cc1cn(-c2ccc(F)cc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-1-(4-fluorophenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 166°-168° C.; Anal.: Calcd. for C26H28F4N4O3HCl.(C4H10O)0.3 ; C, 56.34; H, 5.56; N, 9.66%; Found: C, 56.06; H, 5.76; N, 9.36%;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[O:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[OH:23])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:27]1[C:1]([C:3]2[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=2)[O:6][C:7]2[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[OH:23])=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:2][N:29]=[N:28]1
Reactant: N#Cc1cccc(Oc2ncccc2OCCCc2ccncc2O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(-c2nnn[nH]2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
2-(3-Cyanophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.85 g, 2.5 mmol) obtained in Example 28 is dissolved in DMF (10 ml), and thereto are added sodium azide (0.20 g, 3.0 mmol) and ammonium chloride (0.16 g, 3.0 mmol). The mixture is stirred at 130° C. for one hour, and the reaction solution is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent: acetic acid/ethanol), and recrystallized from ethanol to give the title compound (0.31 g) as pale brown crystals, m.p. 220-240° C. (decomposed).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.[C:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[N:39][CH:40]=1)#[C:33][CH3:34]>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[N:11]=1)=[CH:3][C:2]([C:37]1[CH:38]=[N:39][CH:40]=[C:35]([C:32]#[C:33][CH3:34])[CH:36]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(-c4cccnc4)nc(F)c2O3)c1

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method BB33), pyridin-3-ylboronic acid and 5-(prop-1-ynyl)pyridin-3-ylboronic acid
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]OC[CH2:41]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH:25]([CH2:41][CH2:40][CH3:44])[C:26]([O:28][CH3:29])=[O:27]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Yield: 62.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.330 g; 0.8 mmol), LHMDS 1N in THF (1.2 mL; 1.2 mmol), 1-iodopropane (0.156 mL; 1.6 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-80%) in heptane furnished 0.226 g (62%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(OCCOCC)C>C(OCC)C>[FH:10].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCOCCOCC
Solvent: CCOCC
Product: F
Product: O=[N+]([O-])c1ccc(N2CCN3CCC2CC3)cc1
Temperature: 135 °C
Reaction time: 18 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (20.2 g, 160 mmol), 1-fluoro-4-nitrobenzene (17.5 ml, 163.3 mmol) and ethylene glycol diethyl ether (160 ml) was stirred at 135° C. for 18 hours. The mixture was cooled to room-temperature and diethyl ether (100 ml) was added. The mixture was filtered and the product was isolated by filtration. Yield 24.8 g (58%). Mp. 122-129° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[C:22]([CH3:29])[C:23]=3[CH3:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2cccnc2SC2CCCC2)c1C
Yield: 96 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.10 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (27 mg, 0.12 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (37 mg, 84%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](Cl)(=[O:24])=[O:23])[C:18](=[O:26])[CH2:17][CH2:16]2>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](=[O:23])(=[O:24])[NH:4][CH2:1][CH2:2][CH3:3])[C:18](=[O:26])[CH2:17][CH2:16]2
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCNS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.95 g (33 mmoles) of n-propylamine and 3.04 g (30 mmoles) of triethylamine in 50 ml of acetone is added to a solution of 7.95 g (30 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone in 50 ml of acetone, and the whole is stirred for 6 hours at room temperature, thereafter for 1 hour at boiling temperature. The solution is largely concentrated, 200 ml of water are added, and the mixture is then acidified with 2N hydrochloric acid to a pH of 2. The precipitate is filtered off with suction and washed with water. The product melts at 122° to 123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(CC(=O)[O-])c1-c1ccccc1
Reactant: CCI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-6-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated under reduced pressure and crystallized to give ethyl 2-amino-6-biphenylacetate.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]1([C:15]2[N:16]=[C:17]([CH2:26][CH2:27][C:28]([OH:30])=O)[NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:31]([N:33](CC)CC)C.Cl.CN.N12CCCN=C1CCCCC2>CN(C)C=O.O>[CH3:31][NH:33][C:28](=[O:30])[CH2:27][CH2:26][C:17]1[NH:16][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:18]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 20 h
Yield: 65.5 %

Procedure:
3.2 ml (0.024 mol) of isobutyl chloroformate are added dropwise at -5° to a solution of 7.0 g (0.024 mol) of 4,5-diphenylimidazole-2-propionic acid and 3.36 ml (0.024 mol) of triethylamine in 80 ml of dimethylformamide. After stirring at 0°-5° for 30 minutes 1.64 g (0.024 mol) of methylamine hydrochloride and 3.36 ml (0.024 mol) of triethylamine in 32 ml of dimethylformamide and 1.65 ml of water are added. The temperature is then left to rise to room temperature and the mixture is stirred for a further 20 hours. After concentration under reduced pressure the residue is boiled up in 250 ml of methanol and treated with 3.6 ml (0.024 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), whereby a clear solution results. 4.8 g of N-methyl-4.5-diphenylimidazole-2-propionamide, m.p. 195°-200° (dec.), result by cooling in an ice-bath. From the mother liquor there are obtained by concentration and treatment with water a further 2 g of the same product, m.p. 195°-200°. Total yield: 6.8 g (93%).