Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[H-].[Na+]>CN(C=O)C>[N:16]1([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[N:19][CH:18]=[N:17]1.[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(n2cncn2)CC1
Product: c1ncn(C2CCC3(CC2)OCCO3)n1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A solution of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (567 mg, 2.40 mmol) and 1,2,4-triazole (232 mg, 3.36 mmol) in dry DMF (5.00 mL) is treated with sodium hydride 60% (125 mg, 3.12 mmol) at room temperature under nitrogen. The resulting mixture is stirred at 65° C. for 72 h. It is poured in ice water (75 mL), extracted 3 portions of 75 mL of EtOAc. The organic portions are combined, dried over anhydrous Na2SO4 and concentrated. The solid is purified by silica gel column chromatography using a gradient from 100% EtOAc to 5% MeOH:EtOAc as eluent to furnish the final compound 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole as a white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C@@H:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[O:5][CH2:4]1.[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>>[Br:27][C:28]1[N:33]=[C:32]([C:34]([NH:23][C:22]2[CH:21]=[N:20][N:19]([CH3:26])[C:18]=2[C@H:6]2[O:5][CH2:4][C@H:3]([O:2][CH3:1])[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7]2)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3ccc(F)c(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Example 65, starting from tert-butyl N-[(3R,4R,7S)-3-methoxy-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (intermediate 93) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 6-bromo-5-fluoro-pyridine-2-carboxylic acid (see US2010/56576 A1) gave tert-butyl N-[(3R,4R,7S)-7-[4-[(6-bromo-5-fluoro-pyridine-2-carbonyl)amino]-2-methyl-pyrazol-3-yl]-3-methoxy-oxepan-4-yl]carbamate (contaminated with tetramethylurea) as a clear oil (169 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.26-8.17 (m, 2H), 7.63-7.55 (m, 1H), 5.02 (br s, 1H), 4.96 (dd, J=9.0, 3.6 Hz, 1H), 4.32 (dd, J=13.2, 4.4 Hz, 1H), 4.05-3.94 (m, 2H), 3.85-3.80 (m, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 2.10-1.91 (m, 3H), 1.86-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: Br[C:2]1[C:26]([F:27])=[C:25]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]2[C:6](=[O:24])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=3)[O:9][C:4]=2[C:3]=1[F:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][Si:56]([C:59]#[CH:60])([CH3:58])[CH3:57].O>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:27][C:26]1[C:2]([C:60]#[C:59][Si:56]([CH3:58])([CH3:57])[CH3:55])=[C:3]([F:35])[C:4]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=3)=[CH:7][C:6](=[O:24])[C:5]=2[C:25]=1[NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(Br)c(F)c3o2)cc1F
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(C#C[Si](C)(C)C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
30 mg (0.054mmol) of 7-bromo-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 84 (2) was dissolved in a mixed solvent of 0.5 mL of dimethylformamide and 0.5 mL of triethylamine, 1 mg (0.004 mmol) of palladium (II) acetate, 2 mg (0.008 mmol) of triphenylphosphine and 38 μL (0.27 mmol) of trimethylsilylacetylene were added and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled to room temperature, water was added thereto and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with 2N hydrochloric acid, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (chloroform:acetonitrile=19:1) to give 12 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-7-(2-trimethylsilylethynyl)-4H-1-benzopyran-4-one (yield: 39%).
Reaction SMILES: C(Cl)(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=2)[CH:10]=1.N1C=CC=CC=1.CC[O:32]CC>C(Cl)(Cl)Cl>[CH3:5][CH:3]([CH3:4])[C:2]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=1)=[O:32]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOCC
Reactant: CSc1nccc(-c2cc(C)ccc2N)n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2cc(C)ccc2NC(=O)C(C)C)n1
Reaction time: 1 h

Procedure:
A solution of 11.7 g (0.11 mol) isovaleryl chloride in 15 mL dry chloroform was added dropwise with stirring to a solution of 23.1 g (0.10 mol) 4-methyl-2-[2-(methylthio)-4-pyrimidinyl]benzenamine and 12 g pyridine in 60 mL dry chloroform. Stirring was continued for 1 h at room temperature, after which the reaction mixture was diluted with 200 mL ether and washed successively with water, 0.5N hydrochloric acid solution, and brine. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 10:1 chlorobutane/ethyl acetate mixture as eluent to yield 28.3 g of the title compound as white crystals melting at 134°-135° C. 1H NMR (CDCl3): δ 1.23 (d,6H), 2.30 (s,3H), 2.40 (s,3H) 2.47 (m,1H), 7.40-8.6 (5H), 10.7(s,1H,NH).
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:16])([CH2:10]4)[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]#[N:33])=[O:26]>CS(C)=O.CCOC(C)=O>[C:1]1([C:7]23[CH2:15][CH:11]4[CH2:10][C:9]([NH:16][CH2:24][C:25]([N:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]#[N:33])=[O:26])([CH2:8]2)[CH:13]([CH2:12]4)[CH2:14]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccccc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.2 g, 0.94 mmol) and K2CO3 (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol) was added. After stirring the reaction mixture for 3 h at r.t., it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as off-white solid (0.16 g) in 48% yield. m/z (M+1) 350; 1H NMR (CDCl3) 300 MHz δ 7.35-7.16 (m, 5H), 4.4.85-4.76 (m, 1H), 3.76-3.40 (m, 2H), 3.50 (s, 2H), 2.48-2.41 (m, 1H), 2.36-2.27 (m, 2H), 2.23-2.0 (m, 6H), 1.94-1.68 (m, 4H), 1.66-1.60 (m, 1H).
Reaction SMILES: [OH:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[S-:21][C:22]#[N:23].[NH4+].[NH2:25][C:26]1[C:27]([Cl:34])=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C(OCC)(=O)C.CCCCCC>CC(C)=O>[Cl:34][C:27]1[C:26]([NH:25][C:22]([NH:23][C:8]([N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH2:3][CH2:4]2)=[O:9])=[S:21])=[C:31]([O:32][CH3:33])[CH:30]=[CH:29][N:28]=1
Reactant: COc1ccnc(Cl)c1N
Reactant: N#C[S-]
Reactant: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccnc(Cl)c1NC(=S)NC(=O)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Yield: 15.9 %

Procedure:
To a magnetically stirred mixture of 4-Hydroxy-4-[3-(trifluoromethyl)phenyl]piperidine-1-carbonyl chloride (465 mg, 1.51 mmol) in acetone (15 mL) was added ammonium thiocyanate (105 mg, 1.39 mmole). The reaction is stirred at reflux for 30 min. 3-Amino-2-chloro-4 methoxypyridine (200 mg, 1.26 mmole) was added and the reaction was allowed to continue to stir at reflux overnight. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. The reaction was poured into water and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were washed with 2N HCl (2×) and saturated sodium chloride solution and then dried over magnesium sulfate. Purification by flash chromatography gave 1-(2-Chloro-4-methoxy-pyridin-3-yl)-3-[4-hydroxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbonyl]-thiourea (100 mg, 0.20 mmole, 16% yield) as a light yellow solid. (LRMS for C20H20ClF3N4O3S (M+H)+ at m/z=488. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)c1c(O)c(=O)cc(C)n1C
Yield: 100.4 %

Procedure:
Pd(OH)2 on charcoal (0.2 g) was added to a solution of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed with ethanol (3×25 ml). The Celite cake was further stirred with ethanol (100 ml). and then filtered through Celite. The combined ethanol filtrate was evaporated to give a solid (0.86 g, quantitative yield). Melting point: >250° C. H-NMR (CDCl3: DMSO-d6 [2:11]) δ: 1.81 (s, 3H, Me), 2.34 (d, 3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH). Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. Found. C 54.67; H 6.31; N 14.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH2:18][O:19][C:20]([F:23])([F:22])[F:21])=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCCOC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CCOC(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of N-(5-bromo-2-[2-(trifluoromethoxy)ethyl]amino]phenyl)-3,3-dimethylbutanamide (step C, 728 mg, 1.83 mmol) and p-toluenesulfonic acid monohydrate (350 mg, 1.83 mmol) in toluene (20 mL) was stirred at 120° C. for 8 h. Then, the mixture was allowed to cool to room temperature overnight to afford crystalline precipitates. The precipitates were collected by filtration, and dissolved in ethyl acetate and saturated sodium hydrogencarbonate aqueous solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (555 mg, 80%) as an amber solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[CH:16]([Mg]Br)=[CH2:17].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:17]=[CH:16]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccc(OCC2CC2)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1c(OCC2CC2)ccc2cc[nH]c12
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A 250 mL roundbottom flask with stirbar was charged with a solution of Example 98A (6.18 g, 22.7 mmol) in tetrahydrofuran (80 mL) and cooled to −45° C. under nitrogen. A solution of 0.7 M vinylmagnesium bromide in tetrahydrofuran (100 mL, 70.0 mmol) was added over 20 minutes and the mixture stirred at −45° C. for 30 minutes. The mixture was then poured into aqueous ammonium chloride and extracted with 3×150 mL of ether. The combined organics were dried over anhydrous magnesium sulfate. After filtration and solvent removal the residues were adsorbed on silica gel and chromatographed on a 150 g silica cartridge eluting with 0-10-100% ethyl acetate/heptane to provide 3.087 g, (51%) of the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[C:17]([OH:24])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O1CCCC1>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([CH2:19][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]=1[OH:24]
Reactant: O=Cc1cccc(Br)c1O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1c(Br)cccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (3.18 g) was added to a solution of 3-bromo-2-hydroxybenzaldehyde (2.0 g) and morpholine (1.04 ml) in tetrahydrofuran (30 ml) and the mixture stirred at ambient temperature for 18 h. After filtering from a little insoluble material, the filtrate was evaporated. The residue was partitioned between dichloromethane and water and the solvent phase was washed with water, dried and evaporated to an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:32]([O:34][CH3:35])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1.[H-].[Na+].[CH3:39]I>CN(C=O)C>[CH2:16]([N:14]([CH2:13][C:10]1[N:9]=[C:8]([C:7]2[CH:6]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:5]([C:32]([O:34][CH3:35])=[O:33])=[C:4]([CH3:36])[N:3]([CH3:39])[C:2]=2[CH3:1])[O:12][N:11]=1)[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 250 mg of methyl 1,4-dihydro-2,6-dimetyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate in 5 ml of dry DMF was added 24 mg of 60% sodium hydride with ice-cooling. After the mixture was stirred for 10 minutes, there was added 76 mg of methyl iodide. The reaction mixture was allowed to stand at room temperature for 6 hours, diluted by addition of ice-water and then extracted with ethyl acetate. The extracts were washed with water, dried and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (30:1) as eluent to give 190 mg of methyl 1,4-dihydro-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-1,2,6-trimethyl-4-(3-nitrophenyl)pyridine-5-carboxylate, IR νmaxneat cm-1 : 1690, 1635, 1580, 1520, 1340, 900.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (56.4 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=C[CH:27]=1>>[CH3:27][N:1]([S:22]([C:18]1[N:17]([CH3:16])[CH:21]=[CH:20][N:19]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: Cn1ccnc1S(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of ethyl 7-amino-1H-indole-2-carboxylate (3 g) in pyridine (30 mL) was added 1-methyl-1H-imidazole-2-sulfonyl chloride (3.6 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with water. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated brine and saturated aqueous sodium hydrogencarbonate solution, dried (MgSO4), and concentrated. The obtained residue was dissolved in DMF (30 mL), potassium carbonate (2.1 g) and methyl iodide (2.1 g) were added at room temperature, and the mixture was stirred for 3 hr at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated brine and saturated aqueous sodium hydrogencarbonate solution, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (3.0 g, yield 59%) as white crystals from a fraction eluted with ethyl acetate:hexane=50:50. melting point 120° C.
Reaction SMILES: C([Li])CCC.O1CCCC1.[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH3:21])[C:14]=2[CH:13]=1.[C:30](=[O:32])=[O:31]>CO>[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][C:17]([C:30]([OH:32])=[O:31])=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH3:21])[C:14]=2[CH:13]=1
Reactant: COC(CN(C)Cc1csc2ccc(Cl)cc12)OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Temperature: -30 °C
Yield: 54 %

Procedure:
Butyllithium in tetrahydrofuran (2.6 M, 0.04 mol) was added slowly to a solution of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]-thiophene (10 g, 0.033 mol) in freshly distilled tetrahydrofuran (100 ml) stirred at -30° C. under argon. The mixture was stirred for 30 minutes, treated with dry carbon dioxide for 5 minutes and allowed to warm to 25° C. The mixture was treated with methanol, poured into ice water and extracted with ethyl ether. The aqueous phase was adjusted to pH 7.5 and extracted with methylene chloride. The organic phase was washed with water, dried with magnesium sulfate and concentrated to give 6.0 g (54%) of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl-(aminomethyl)]benzo[b]thiophene-2-carboxylic acid.
Reaction SMILES: C([N:8]1[C:13]2[N:14]([CH3:29])[C:15](=[O:28])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:30])[CH:10]=[C:9]1[CH3:31])C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[CH3:29][N:14]1[C:13]2[NH:8][C:9]([CH3:31])=[CH:10][C:11](=[O:30])[C:12]=2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[C:15]1=[O:28]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2[nH]1
Yield: 117.4 %

Procedure:
A mixture of (R)-8-benzyl-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (80 mg), acetic acid (10 ml) and 10% Pd/C (20 mg) was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. The mixture was filtered through a pad of celite and the solids were rinsed with acetic acid. The combined filtrates were concentrated under reduced pressure and then coevaporated with toluene (2×50 ml) to remove remaining acetic acid to provide (R)-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (74 mg, 99% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 3H), 1.20-1.50 (m, 3H), 1.52-2.00 (m, 3H), 1.97 (s, 3H), 2.40 (s, 3H), 2.55(s, 6H), 3.15 (m, 1H), 3.58 (s, 3H), 3.97 (t, 2H), 6.40 (s, 1H), 9.50 (broad s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])=[CH:27][CH:28]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 1-bromo-4-fluorobenzene
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]N)[CH:25]=2)=[CH:20][C:19]=1[CH3:32].CC1C=C(B(O)O)C=CC=1[F:40].ClC1C(F)=C(C=CC=1)N>>[F:40][C:25]1[C:26]2[NH:30][C:2]3[C:10]4[C:5]([CH2:4][C:3]=3[C:27]=2[CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[C:19]([CH3:32])[CH:20]=1)=[CH:6][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:9]=4
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1cc(-c2cccc(NN)c2)ccc1F
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCC2=O
Agent: Cl
Agent: Nc1cccc(Cl)c1F
Product: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(NS(C)(=O)=O)cc2C4)ccc1F
Yield: 29 %

Procedure:
The title material is prepared in 29% yield by reacting N-(1-Oxo-indan-5-yl)-methanesulfonamide and (4′-Fluoro-3′-methyl-biphenyl-3-yl)-hydrazine hydrochloride (prepared as in example 70, steps 1 and 2 except using 3-methyl-4-fluorophenylboronic acid and 3-chloro-2-fluoroaniline as the coupling partners) in an analogous manner to example 1, step 3 except that purification is accomplished by reverse phase UV triggered HPLC: 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H), 9.75 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.48-7.40 (m, 3H), 7.28-7.22 (m, 2H), 7.14-7.09 (m, 1H), 3.74 (s, 2H), 3.01 (s, 3H), 2.34-2.31 (m, 3H); LC/MS calculated for [M+H]+ C23H18F2N2O2S: 425.1, found: 425.1.