Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:16][CH2:15][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:17])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCSc1cc(C)c(N)c(C(C)(C)C)c1
Yield: 71.9 %

Procedure:
A stirred solution of 4.5 g (23 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 7.5 g (23 mmol) of octadecyl acrylate and 0.2 g (2 mmol) of triethylamine in 50 mL of toluene is heated at 50° C. for 18 hrs. The solvent is removed in vacuo and the residue is purified by preparative HPLC (silica gel, 9:1, heptane:ethyl acetate eluent) to give 8.6 g (72%) of the title compound as a colorless liquid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=1[C:36](OC)=[O:37])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:20])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O>C1COCC1>[NH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:20])=[C:29]([CH2:36][OH:37])[CH:30]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C(C)c1ccccn1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(c1ccccn1)N(Cc1nc2ccccc2[nH]1)Cc1ccc(CN)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
To a solution of 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (0.5065 g, 1.0 mmol) in dry THF (5 mL) under Ar at 0° C. was slowly added 1.0 M LiAlH4 in THF (9.6 mL, 9.6 mmol). The reaction was stirred at room temperature for 3 hours, then cooled to 0° C. Saturated aqueous KNa Tartrate (Rochelle's salt, 30 mL) was slowly added, and the phases were separated. The aqueous phase was extracted with CH2Cl2 (3×35 mL), and the combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2-MeOH—NH4OH) provided 28.0 mg (7%) of COMPOUND 398 as a white solid. 1H NMR (CDCl3) δ 1.55 (d, 7H), 3.72 (s, 2H), 3.79-3.97 (m, 4H), 4.08-4.15 (m, 1H), 4.61 (s, 2H), 7.00-7.03 (m, 1H), 7.12-7.22 (m, 4H), 7.30-7.34 (m, 2H), 7.39-7.548 (m, 2H), 7.66-7.73 (m, 1H), 8.63 (d, 1H, J=4.3 Hz). 13C NMR (CDCl3) δ 12.64, 46.30, 48.93, 56.11, 60.76, 63.68, 122.24, 122.64, 123.03, 126.86, 130.49, 132.06, 135.86, 137.63, 140.79, 140.79, 143.92, 149.44, 153.77, 161.45. ES-MS m/z 402 (M+H). Anal. Calcd. for C24H27N5O.0.6H2O.0.2CH2Cl2: C, 67.71; H, 6.71; N, 16.31. Found: C, 68.05; H, 6.75; N, 16.38.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH2:22])[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4].CC(C)([O-])C.[Na+].Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[C@H:9]([NH:22][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=2)[CH2:8][C@@H:7]1[CH3:23])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](N)C[C@@H]1C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 14 %

Procedure:
A mixture of (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride (for a preparation see intermediate 61) (250 mg, 0.700 mmol), sodium tert-butoxide (235 mg, 2.449 mmol), 2-bromo-5-fluoropyridine (123 mg, 0.700 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (55.0 mg, 0.140 mmol) and tris(dibenzylideneacetone)dipalladium(0) (64.1 mg, 0.070 mmol) was stirred in toluene (12 mL) at 70° C. under nitrogen for 2 h. An extra portion of 2-bromo-5-fluoropyridine (123 mg, 0.700 mmol), sodium tert-butoxyde (81 mg, 0.84 mmol), Davephos (55.0 mg, 0.140 mmol) and tris(dibenzylideneacetone)dipalladium(0) (64.1 mg, 0.070 mmol) was added after having cooled the mixture down. The resulting mixture was stirred at 70° C. under nitrogen for 12 h then was cooled to room temperature and concentrated in vacuo. The residue was suspended in 10% MeOH in DCM (100 mL) and filtered through celite. The insoluble material was rinsed with 10% MeOH in DCM (2×50 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between DCM (50 mL) and a saturated NaHCO3 aqueous solution and the layers were separated. The aqueous phase was extracted with DCM (50 mL) and AcOEt (50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient:0 to 5% MeOH in DCM) gave a residue which was further purified by MDAP (modifier: ammonium formate) to give (cis)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine (36.5 mg, 0.096 mmol, 14%) as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1([CH3:26])[C:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH:6]1[CH3:25])=[O:4].C(OCC(=O)[C@]1(C)[C@]2(C)C(C3C(=CC2)[C@]2(C)C(=CC(=O)CC2)CC3)C[C@H]1C)(=O)C.C[O-].[Na+]>CO>[OH:1][CH2:2][C:3]([C@:5]1([CH3:26])[C@:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C@:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][C@H:6]1[CH3:25])=[O:4]
Reactant: CC1CC2C3CCC4=CC(=O)CCC4(C)C3=CCC2(C)C1(C)C(=O)CO
Agent: CC(=O)OCC(=O)[C@@]1(C)[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@@]1(C)C(=O)CO

Procedure:
10S,13S,16R,17S)-17-(2-hydroxyacetyl)-10,13,16,17-tetramethyl-6,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one: 2-oxo-2-((10S,13S,16R,17S)-10,13,16,17-tetramethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl acetate (144 g) is stirred in 1500 ml methanol and treated with sodium methoxide (25%, 5 ml) for 30 minutes. The mixture is partitioned between methylene chloride and sodium bicarbonate. The organic phase is separated and washed with sodium bicarbonate, dried over sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]([C:15]1[O:16][CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:14].CO>COCCOC.C(=O)(O)[O-].[Na+].C(OCC)(=O)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>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[C:15]([CH:13]=[O:14])[O:16][CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
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: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1-c1coc(C=O)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a mixture of 2-iodo-4-nitroanisole (565 mg, 2.02 mmol) and 2-formylfuran-4-boronic acid pinacol ester (670 mg, 3.03 mmol) in 20 mL of ethylene glycol dimethyl ether and 12 mL of aqueous saturated sodium bicarbonate was added 80 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was heated at reflux overnight then allowed to cool to room temperature and added to a biphasic mixture of 10% methanol in ethyl acetate and water. The solid was collected by filtration, washed with ethyl acetate and water to provide 259 mg (52%) of 4-(2-methoxy-5-nitrophenyl)-2-furaldehyde as a light brown solid, 1H NMR (DMSO-d6) d 4.07 (s, 3H), 7.37 (d, J=9 Hz, 1H), 1H), 8.20-8.29 (m, 2H), 8.55 (d, J=3 Hz, 1H), 8.69 (s, 1H), 9.68 (s, 1H); MS 247.1 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])=[CH:29][CH:30]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN1CCNCC1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (30 mg, 0.07 mmol), 1-methyl-piperazine (8.3 μL, 0.074 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.4 mg, 0.089 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (31 μL, 0.18 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture (28 mg, 82%). LCMS (M+H) 485.5.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+].Cl.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:32]>O1CCOCC1.C(Cl)Cl>[N+:17]([C:5]1[CH:6]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([F:32])=[O:2])([O-:19])=[O:18]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)F)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
To a stirred solution of the above di-ester ((7), 7.28 g, 26 mmol) in dioxane (100 mL) was added aq. 1N NaOH (30 mL). The reaction was stirred for 6 h, acidified with aq. 1N HCl (30 mL), extracted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the corresponding acid which was used as is in the next reaction. To a stirred solution of the above acid (6.68 g, 25 mMol) under Ar in dry CH2Cl2 (75 mL) was added pyridine (2.1 mL, 25 mMol) followed by cyanuric fluoride (1.56 mL, 17 mMol). After stirring for 2 h the reaction became a thick suspension. The reaction was then evaporated under reduced pressure, taken up in ether (150 mL) and filtered through a pad of celite to remove insoluble materials. The filtrate was washed with cold water, dried (MgSO4), filtered and evaporated under reduced pressure to give the crude acid fluoride (8) as a clear oil.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[C:15]([F:20])=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[C:15]([F:20])=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc2sc(NCC3CCCCC3)nc2cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc2sc(NCC3CCCCC3)nc2cc1F
Reaction time: 2 h

Procedure:
To the solution of N-(cyclohexylmethyl)-5-fluoro-6-methoxybenzo[d]thiazol-2-amine (114 mg, 0.387 mmol, 1.0 eq) in 10 mL of DCM was added 1M solution of boron tribromide (ca. 1.0 mL, 0.775 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred for 2 hours, thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) till PH=7 and aqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [281.1] (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([N:10]1[CH:19](NC(C(OC(C)(C)C)=O)CC)[CH2:18][C:17]2[C:12](=[CH:13][C:14]([Cl:31])=[CH:15][CH:16]=2)[C:11]1=[O:32])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl>C(O)(C)C.C(OCC)(=O)C.O>[Cl:31][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:19][N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:33])[C:11]2=[O:32])=[CH:16][CH:15]=1
Reactant: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1C(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1ccc2ccc(Cl)cc2c1=O
Reaction time: 18 h

Procedure:
To a stirred solution of 2-[3-(1-tertbutoxycarbonyl-propylamino)-7-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-butyric acid tert-butyl ester (8.58 g) in isopropanol (180 ml) at 0° C. was added concentrated hydrochloric acid (20 ml). The resulting mixture was allowed to warm to ambient and stirred for 18 hours. The mixture was then diluted with ethyl acetate (500 ml) and water (150 ml). The organic phase was separated and washed with water, then brine, dried (magnesium sulfate), filtered and concentrated. The sub-title product was obtained as a yellow solid (5.57 g, 97%); m.p. 111.3-111.8° C.; [α]25D−52.3° (c=1, CHCl3); IR (solid) 1731.4, 1649.5, 1593.2, 1229.6, 1152.8, 901.9 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.95 (3H, t), 1.48 (9H, s), 1.95 (1H, m), 2.30 (1H, m), 5.55 (1H, m), 6.40 (1H, m), 7.15 (1H, m), 7.49 (1H, m), 7.61 (1H, m), 8.40 (1H, m); 13C NMR (100 MHz, CDCl3) δ 10.9, 24,8, 28.1, 59.2, 82,8, 105.7, 127.3, 127.8, 128.1, 129.5, 133.1, 133.2, 135.4, 161.8, 170.2; MS ES(+) 322.4 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1)[CH3:2].C(N1CC[C@@H](C(OCC2C=CC=CC=2)=O)C1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](C(=O)O)C1
Agent: CCN1CC[C@@H](C(=O)OCc2ccccc2)C1
Product: CCN1CC[C@@H](C(=O)O)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 189, starting from benzyl (R)-1-ethylpyrrolidine-3-carboxylate (Intermediate 197).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[N:11]=2)[N:9]=1)[NH2:3].Cl>O1CCCC1>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NCc2cccc(-c3csc(N=C(N)N)n3)n2)C1
Agent: Cl
Solvent: C1CCOC1
Product: NC(N)=Nc1nc(-c2cccc(CNC(=O)C3CCCNC3)n2)cs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.6 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(1-tert-butoxycarbonylpiperidin-3-yl)carbonylaminomethylpyridin-2-yl]thiazole (1.9 g) and 4N-methanolic hydrogen chloride (40 ml) was stirred for 7 hours at ambient temperature. To the reaction mixture was added a tetrahydrofuran (40 ml) and the isolated precipitate was collected by filtration. The precipitate was added to water and adjusted to pH 13 with 5N-sodium hydroxide. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-[6-(3-piperidyl)carbonylaminomethylpyridin-2-yl]thiazole (0.47 g).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:26]Br.C(OCC)(=O)C>C(O)(=O)C.CCCCCC.O>[Br:26][CH:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(Br)c1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 7.084 g 2-ethyl-3-(4-fluorophenyl)-3H-quinazoline-4-one (IV) (26.40 mmol, 1.000 equiv) and 2.60 g sodium acetate (31.7 mmol, 1.20 equiv) dissolved in 30 mL glacial acetic acid at 40° C. (external temperature; oil bath) was added dropwise by addition funnel a solution of 1.36 mL bromine (26.4 mmol, 1.00 equiv) in 5 mL glacial acetic acid over 60 min. Upon completed addition of the bromine solution, the reaction was stirred an additional 60 min, after which time TLC indicated no IV remained (Rf=0.44; 40% ethyl acetate in hexane) and the heterogeneous mixture was poured into 400 mL water. The resulting aqueous, acidic mixture, with precipitate, was stirred vigorously at ambient temperature for two h. The precipitate was collected by vacuum filtration, rinsing with warm (ca. 40° C.) water (2×50 mL) and cold isopropyl alcohol (50 mL). The solid was dried in vacuo over phosphorous pentoxide overnight, affording 8.81 g of a white solid.m.p. 179.8° C. 1H NMR (CDCl3) δ2.06 (d, J=0.016p, 3H), 4.55 (q, 0.016p, 2H), 7.16 (ddd, 1H, J1=2.4 Hz, J2=4.8 Hz, J3=8.4 Hz), 7.24 (dt, 1H, J1=2.8 Hz, J2=8.0 Hz), 7.28 (dt, 1H, J1=2.8 Hz, J2=8.4 Hz), 7.51-7.58 (m, 2H), 7.80-7.81 (m, 2H), 8.28 (dt, 1H, J1=0.8 Hz, J2=8.0 Hz) ppm. MS (ESI+) 348.0 [MH]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[Cl-:22].[Cl-].[CH3:24][Zr:25]([CH3:47])(=[SiH2:46])([CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:45])[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:35]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O-:11])([CH3:3])[CH3:2].[Cl-:22].[CH3:47][Zr:25]([CH3:24])(=[SiH2:46])([CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:45])[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:35]
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)C)c([O-])c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.2 g (21 mmol) of 2-isopropyl-5-methylphenol in 20 ml of toluene/2 ml of THF were admixed at room temperature with 7.8 ml (21 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 5.0 g (10.5 mmol) of dimethylsilanediylbis(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred for 2 hours at 100° C. and subsequently filtered hot through Celite. The filter cake was extracted twice with 25 ml each time of toluene (100° C.). After evaporation of part of the solvent, the yellow solid which precipitated was filtered off and dried under reduced pressure. This gave 1.36 g (22%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2-isopropyl-5-methylphenoxide) (4).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(C(=O)C=Cc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(C(O)CCc2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 61.4 %

Procedure:
To a solution of 2.72 g of methyl 4-[4-(4-fluorocinnamoyl)phenyl]butyrate in 28 ml of methanol, 140 mg of 5% palladium on carbon was added, and hydrogenation was carried out at an ordinary temperature and under ordinary pressure for 4 hours. The catalyst was filtered off and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride→ethyl acetate) to yield 1.69 g of colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=O)[CH3:2].[H-].[Na+].C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C>C1COCC1>[CH3:14][C:10]1([CH3:15])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]2[CH:5]=[C:4](/[C:1](/[CH3:2])=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:13]=[CH:12][C:11]1=2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
6-Acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (5.07 g) was added to a cooled (0° C.) mixture of NaH (60% oil dispersion, 1.10 g) and ethyl diethylphosphonoacetate (6.49 g) in THF (50 ml). The mixture was stirred at room temperature for 14 hours. The reaction was quenched by the addition of water and the mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to give the titled compound (6.50 g) as a colorless oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.[C:18](=O)([O:21]C)[O:19][CH3:20]>C1COCC1>[CH3:9][O:10][C:11]1[N:12]=[C:13]([CH2:17][C:18]([O:19][CH3:20])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)OC
Reactant: COc1cccc(C)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OC)n1
Reaction time: 2 h

Procedure:
To the solution of LDA (18.3 mL, 36.5 mmol) in THF (120 mL) cooled to −78° C. was added 2-methoxy-6-methylpyridine (1.5 g, 12.2 mmol) in THF (15 mL) dropwise, and then the mixture was stirred at −78 degree for 2 h. Dimethyl carbonate (1.2 mL, 14.6 mmol) was added quickly and continued to stir at −78° C. for 15 min. The reaction was quenched by H2O at −78° C. The solution was extracted with ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified with a standard method to give desired compound.