Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.[OH-].[K+]>CO.O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]=2[O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:31])[C:3]([OH:32])=[O:2])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCOc1ccc(C(=O)C(=O)O)cc1
Yield: 66.7 %

Procedure:
As in Example 19, 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.186 g) in a mixture of methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 1N potassium hydroxide (0.52 mL). The usual work up gave 0.17 g of a solid, which after crystallization from diethyl ether-hexane afforded 0.12 g of 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid, mp 123°-125° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([OH:19])(=[O:18])[CH2:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CC#N>[CH2:26]([O:15][C:14]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]([O:19][CH2:8][C:9]2[CH:17]=[CH:16][CH:14]=[CH:11][CH:10]=2)=[O:18])=[CH:10][C:11]=1[O:12][CH3:13])[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
Cs2CO3 (17.88 g; 54.9 mmol) was added to a solution of homovanillic acid (2.0 g; 11 mmol) in CH3CN, whereafter BnBr (4.3 g; 24.15 mmol) was added dropwise over 10 minutes. The mixture was refluxed overnight, filtered through Hyflo and concentrated. The resulting mixture was dissolved in EtOAc (100 mL), water (30 mL) was added, and the aqueous layer was separated. The organic phase was washed with citric acid solution (5%, 1×20 mL) and brine, dried (Na2SO4), and evaporated to yield 4.25 g (quant.) of the sub-title compound.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([CH2:37][P:20]([OH:21])([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:22])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=1
Reactant: C=C(Cc1ccc(Br)cc1)C(=O)OCC
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Product: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 84.1 %

Procedure:
The process is performed according to the operating conditions described in 1.6., starting with 2 g (6.27 mmol) of [2-phenyl-1-[(phenylmethoxy)carbonyl]aminoethyl]phosphinic acid synthesized in 1.4. and 2 g (7.44 mol) of ethyl 4-bromo-α-methylenebenzenepropanoate. 3.1 g of product are recovered (yield=84.1%)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[N:36]=[CH:35][O:34][N:33]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]5[N:36]=[CH:35][O:34][N:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCc1ncon1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncon1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,2,4-oxadiazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-(chloromethyl)-1,2,4-oxadiazole following General Procedure H.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=1[O:7]2
Reactant: O=c1c2ccc(O)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: O=P(OCCBr)(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2ccc(OCCOP(=O)(OCc3ccccc3)OCc3ccccc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 1,6-dihydroxy-3-morpholin-4-yl-xanthen-9-one in anhydrous DMF (2.0 mL) was treated with sodium hydride (27.7 mg, 0.693 mmol). After 15 minutes, a solution of phosphoric acid dibenzyl ester 2-bromoethyl ester (267.0 mg, 0.693 mmol) in DMF (1.0 mL), was added, and reaction mixture was stirred overnight at room temperature. The reaction mixture then was dissolved in EtOAc (250 mL) and washed with water (6×50 mL) and brine (1×50 mL). The organics were dried. (Na2SO4) and concentrated. The residue then was purified via Biotage chromatography using 80% EtOAc in hexanes as, eluent to yield 132 mg (31%) of phosphoric acid dibenzyl ester 2-(8-hydroxy-6-morpholin-4-yl-9-oxo-9H-xanthen-3-yloxy)-ethyl ester as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 12.82 (s, 1H), 8.12 (d, 1H), 7.34 (m, 10H), 6.82 (d, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 5.04 (m, 4H), 4.38 (m, 2H), 4.18 (m, 2H), 3.83 (m, 4H), 3.38 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.O.[NH2:20][NH2:21].O>C(O)CCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5](=[N:20][NH2:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1C(=NN)c1ccccc1OC
Temperature: 25 °C

Procedure:
A stirred suspension of 2,2′-dimethoxybenzophenone (20.72 g, 0.0855 mol) and 20 mL (0.412 mol) of hydrazine monohydrate in 25 mL of 1-butanol was heated to reflux overnight. After cooling to room temperature the two phase reaction mixture was poured into water and cooled to induce crystallization. The white precipitate was filtered, washed with water and petroleum ether and dried in vacuo to yield 2,2′-dimethoxybenzophenone hydrazone (1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18](=[O:24])[CH2:19][Si](C)(C)C)([CH3:16])([CH3:15])[CH3:14].[CH3:25][C:26]1([C:29](N2C=CN=C2)=[O:30])[CH2:28][CH2:27]1.Cl>O1CCCC1>[CH3:25][C:26]1([C:29](=[O:30])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:24])[CH2:28][CH2:27]1
Reactant: CC1(C(=O)n2ccnc2)CC1
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C1(C)CC1
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium (2.5M in hexane, 36 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (9.09 g) in dry tetrahydrofuran (i.e. tetrahydofuran) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred for 0.25 hour and t-butyltrimethylsilylacetate (16.9 g) was added dropwise with stirring whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour. A suspension of 1-(1-methylcyclopropylcarbonyl)-imidazole (13.5 g) in dry tetrahydrofuran (120 ml) was added dropwise whilst maintaining the temperature below -60° C. The mixture was stirred at -78° C. for 3 hours and the temperature was allowed to rise to room temperature. Hydrochloric acid (2M, 100 ml) was added cautiously and the mixture was extracted with ether (2×100 ml). The combined extracts were washed with hydrochloric acid (2M, 3×50 ml) and water (3×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 3-(1-methylcyclopropyl)-3-oxopropionate as an orange oil NMR (CDCl3) 0.65(m,2H), 1.1(m,2H), 1.25(s,3H), 1.4(s,9H), 3.2(s,2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[N:10]=[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[O:13][N:12]=2)[CH:15]=1
Reactant: COc1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
3-[5-(3-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl)pyridine (4.0 g, 15.79 mM) and pyridine hydrochloride (37.6 g, 325 mM) were melted together at about 160° C. under an atmosphere of nitrogen for about 30 hours. This mixture was poured into H2O and stirred. The precipitated product was filtered and dried, 2.9 g, mp. >200° C.
Reaction SMILES: Cl.C(OC(=O)[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)C1C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:14][CH2:13][C:12]([NH2:11])([CH3:18])[CH2:17][CH2:16]2)=[N:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(N)CCN(c2ccc(S(C)(=O)=O)cn2)CC1
Yield: 72.6 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.37 g, 1.3 mmol, Example 30B), 2-bromo-5-(methylsulfonyl)pyridine (0.27 g, 1.15 mmol) and diisopropylethylamine (0.7 mL) in dioxane (4 mL) in a sealed tube was heated to 80° C. for 16 hours. The mixture was cooled, concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 5% hexane/ethyl acetate to 25% ethyl acetate/hexane) to provide the titled compound (0.225 g) as a white solid. MS (CI) m/z 404 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.63 (d, 1H), 7.86 (dd, 1H), 7.37 (m, 5H), 6.65 (d, 1H), 5.07 (s, 2H), 4.67 (s, 1H), 4.04-3.96 (m, 2H), 3.49-3.39 (m, 2H), 3.03 (s, 3H), 2.19-2.12 (m, 2H), 1.71-1.61 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([O:27]CC)=O)=[N:15][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1.O.[NH3:32]>C(O)CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([NH2:32])=[O:27])=[N:15][N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Solvent: O
Solvent: OCCO
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Temperature: 85 °C

Procedure:
Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate from Part B of example 6 (3.0 g, 5.8 mmol) was suspended in 8% NH3 in ethylene glycol (30 mL) in a 100 mL pressure tube. The mixture was heated at 85° C. for 18 hours. Water was added, and the precipitate was filtered and washed with water. The crude product was dried under vacuum to afford 3.2 g of final product. MS (ES+): 489.2 (M+H)+. 1HNMR (DMSO-d6) δ 7.72-7.68 (m, 3H), 7.49-7.41 (m, 3H), 7.15 (d, 2H), 6.97 (d, 2H), 4.00 (t, 2H), 3.77 (s, 3H), 3.16 (t, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[N:41]1([CH2:45][C@@H:46]([NH:50][CH3:51])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[N:41]1([CH2:45][C@@H:46]([N:50]([CH3:51])[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1
Reactant: CCC[C@@H](CN1CCC1)NC
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC[C@@H](CN1CCC1)N(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
2,4-Dichlorobenzoic acid (92 mg, 0.48 mmol) and TBTU (162 mg, 0.50 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.063 mL, 0.58 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(azetidin-1-yl)-N-methyl-pentan-2-amine (Compound J1) (75 mg, 0.48 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 2×5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (98 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6): 0.59-0.87, 0.90, 0.98-1.66, 1.72-2.11, 2.22-2.47, 2.5, 2.78, 4.26-4.70, 7.24-7.36, 7.43-7.64, 7.65-7.79. Total no of protons: 22. HRMS (M+H)+: calculated 329.1187. found 329.1161
Reaction SMILES: [F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=[CH:39][CH:40]=5)[NH:35][C:34]4=O)COC3=CC=2ON=1.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:33][C:41]4[CH:36]=[N:35][CH:34]=[CH:39][CH:40]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (57%) as a colorless solid: mp 175-177° C.; 1H NMR (300 MHz, CD3OD) δ 8.98 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.67 (d, J=8.4 Hz, 1H), 8.12 (dd, J=8.1, 6.0 Hz, 1H), 7.37 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.26 (d, J=6.9 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.93 (dd, J=10.5, 6.3 Hz, 1H), 6.76 (dd, J=9.6, 7.8 Hz, 1H), 5.27 (s, 1H), 5.26 (s, 1H), 5.00 (d, J=9.6 Hz, 1H), 4.83 (d, J=9.6 Hz, 1H); MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Cl)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:12][CH2:11][C:10]1[S:9][CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ncsc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncsc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
4-Ethoxycarbonyl-5-hydroxymethylthiazole (282 mg) was dissolved in 5 ml of DMF, 123 mg of imidazole and 250 mg of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 374 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][CH2:18][CH2:19]2
Reactant: Nc1ccc2c(c1)CCN2
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc2c(c1)CCN2

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (250 mg, 0.89 mmol), 2,3-dihydro-1H-indol-5-ylamine×2HCl (184 mg, 0.89 mmol) and Et3N (0.37 mL, 2.67 mmol) in N,N-dimethylformamide (DMF) (10 mL) is stirred for 4 days. The reaction mixture is concentrated in vacuo and the residue is triturated in H2O for 24 hours. The precipitate is filtered, washed with H2O and dried in vacuo to give 370 mg of the title compound as a brown solid. HRMS (ESI) m/z calcd for C18H14BrN3O2 (M+H)+1 384.03422. found: 384.03553. The compound is contains 29% of 4-(5-amino-2,3-dihydro-indol-1-ylmethylene)-6-bromo-4H-isoquinoline-1,3-dione.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH:9]=[C:8]([O:12]C)[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.C(OCC)(=O)C>O1CCCC1>[C:2]1(=[O:1])[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: COC1=CCC2=C(CCCC2=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC2=C(CCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
6.8 g (38.2 mmol) of 1,2,3,4,5,8-hexahydro-1-oxo-6-methoxynaphthalene was dissolved in 50 ml of tetrahydrofuran and 5 ml of 1 N hydrochloric acid was added thereto. After stirring at room temperature for 1 hour, ethyl acetate was added thereto. Then the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentrating, a small amount of a mixture of n-hexane with ethyl acetate (1:1) was added thereto and the obtained mixture was cooled in a dry ice-ether bath. The precipitate thus formed was recovered by filtration and washed with a small amount of n-hexane to thereby give 4.8 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([NH:16][C:17](=[O:31])[C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[C:20]([F:30])[CH:19]=3)=[CH:8][CH:7]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: CC(=O)N1CCN(CCCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and N-acetylpiperizine according to conditions described in general procedure L. A white powder (0.13 g, 75.5%). Mp: 210-211° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.22 (br s, 1H), 7.84 (br s, 1H), 7.55 (m, 2H), 7.44 (m, 2H), 7.15 (br s, 1H), 6.98 (br s, 2H), 4.23 (br s, 2H), 3.42 (br s, 4H), 3.30 (br s, 4H), 2.57 (br s, 2H), 2.42 (m, 4H), 2.04 (m, 2H), 1.98 (s, 3H), 1.60 (br s, 6H). MS: 533.5 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH:6]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)(=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:7]2[N:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:34]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The material of step 3 of Example 17 (15 g, 0.044 mol) was dissolved in 100 mL of glacial acetic acid and then 4-fluorophenyl hydrazine hydrochloride (7.15 g, 0.044 mol) was added. The reaction was then stirred at room temperature for 18 hours, under argon, and then concentrated to remove most of the acetic acid. The remaining viscous oil was triturated with 250 mL acetonitrile. The resulting solid was isolated by vacuum filtration and dried to yield the product as an orange/pink solid. 11 g (MW=424.38, 59% yield). LC/MS m/z=425.2 (m+1).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:25][CH:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[C:15]=3[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:38][Li].O.OO>CO>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:25][CH:26]4[CH2:27][CH2:28][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:30][CH2:31]4)[C:15]=3[C:14]1=2)[C:10]([NH2:11])=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21)C(N)=O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (300 mg, 0.55 mmol, 1.00 equiv) in methanol (20 mL) was added LiOH.H2O (47 mg, 1.12 mmol, 3.55 equiv) and H2O2 (30%, 0.8 mL). The solution was stirred for 2 hr in a water/ice bath. After completion, the reaction was quenched by the addition of 30 mL of saturated aqueous Na2SO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by column chromatography on silica gel with dichloromethane/methanol (20:1) afforded the 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (197 mg, 64%) as a colorless oil. MS (ES): m/z 561 [M+H]+.