Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C([Li])CCC.[Br-].[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:13])=[O:12].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([CH:53]=O)=[CH:45]2)[CH:39]=1>O>[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:53][C:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:44]([C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)[CH:45]=1)([OH:13])=[O:12]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cn(-c2cccnc2)c2ccccc12
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCCC=Cc1cn(-c2cccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of dimsyllithium (from 80 ml of dimethylsulfoxide and 13 ml of 2.1M n-butyllithium) is stirred under nitrogen at room temperature, and 6.2 g of 5-carboxypentyltriphenylphosphonium bromide is added in portions. The reaction mixture is stirred for 30 minutes and 3.0 g of N-(3-pyridyl)indole-3-carboxaldehyde is added. After 18 hours at room temperature, the reaction mixture is diluted with 240 ml of water and extracted with 100 ml of ethyl acetate. The aqueous phase is neutralized with 1.1 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are dried over sodium sulfate and evaporated to an oil which is triturated with ether to give a semi-solid which is recrystallized from methanol to yield 3-(6-carboxyhex-1-enyl)-N-(3-pyridyl)indole, m.p. 124°-125°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(F)ccn1
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(F)ccn12
Temperature: 60 °C

Procedure:
4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40 mL) in a reaction flask under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL; commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 4 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (300 mL) and sodium bicarbonate solution (75 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate to give ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=2)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][C:26]([C:30]([F:32])([F:33])[F:31])=[CH:25][N:24]=2)(=[O:38])=[O:36])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccncc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
217 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 146 mg of 2-(4-ethylsulfanylpyridin-3-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine and 5 ml of chloroform under ice cooling, then the mixture was stirred at room temperature for 8 hours. An aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 81 mg of 2-(4-ethylsulfonylpyridin-3-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as Compound of Present Invention 43) and 29 mg of 2-(4-ethylsulfonyl-1-oxypyridin-3-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as Compound of Present Invention 44).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(C(C)C)CC)(C)C>C(#N)C>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
A mixture of 3,6-dichloro-4-phenyl-pyridazine (0.41 g, 1.82 mmol), prepared by following the procedure described in WO-2005/013907, N-Boc-piperazine (0.509 g, 2.73 mmol) and diisopropylethylamine (0.634 ml, 3.64 mmol) in acetonitrile (7.5 ml) was stirred at 180° C. for 40 min., under microwave irradiation, and then for a further 30 min. After this period, additional amounts of diisopropylethylamine (0.1 ml, 0.57 mmol) and N-Boc-piperazine (0.1 g, 0.54 mmol) were added and the resulting mixture was stirred at 180° C. for 40 min. The solvent was evaporated in vacuo and then, dichloromethane and a saturated solution of ammonium chloride were added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane and heptane/ethyl acetate 8:2 to 7:3). The desired fractions were collected and evaporated in vacuo to yield D13 (0.137 g, 20%) as a white solid. C19H23ClN4O2 requires 374; Found 375 (MH+).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([O:33][C:34]2[N:39]=[CH:38][C:37]3[N:40]=[C:41]([C:45]4[C:46]([NH2:50])=[N:47][O:48][N:49]=4)[N:42]([CH2:43][CH3:44])[C:36]=3[CH:35]=2)[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[NH2:50][C:46]1[C:45]([C:41]2[N:42]([CH2:43][CH3:44])[C:36]3[CH:35]=[C:34]([O:33][C:29]4[CH:28]=[C:27]([NH:26][C:15](=[O:17])[C:14]5[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]6[CH2:3][CH2:4][O:5][CH2:6][CH2:7]6)=[CH:19][CH:18]=5)[CH:32]=[CH:31][CH:30]=4)[N:39]=[CH:38][C:37]=3[N:40]=2)=[N:49][O:48][N:47]=1
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OCCN5CCOCC5)cc4)c3)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Under argon, to a suspension of the HCl salt of 4-{[2-(4-morpholinyl)ethyl]oxy}benzoic acid (3.98 g, 13.8 mmol) in CH2Cl2 (100 ml) was added DMF (40 μl), followed with oxalylchloride (3.6 ml, 41.4 mmol). This mixture was then heated to reflux until a clear solution resulted. The reaction mixture was then concentrated, added CH2Cl2 (20 mL) and reconcentrated. A suspension of the above product in CH2Cl2 (100 mL), was added to a suspension of the product of Example 3 (3.96 g, 11.7 mmol) in pyridine (30 mL). This mixture was then heated to 70° C., the CH2Cl2 was distilled off, then stirred for 1 h. CH2Cl2 (200 mL) was added to the cooled reaction mixture, stirred for 15 min and then filtered to provide a first crop of product (crop 1). The filtrate was concentrated in vacuo and the residue taken up in EtOAc, washed with water (4×), brine, dried over Na2SO4, filtered and concentrated to provide Crop 2. Crops 1 and 2 were combined and recrystallized from MeOH to afforded a off white solid (5.54 g, 83%). 1H NMR (400 MHz, DMSO) δ ppm 11.35 (bs, 1H), 10.22 (s, 1H), 8.79 (d, 1H, 0.8 Hz), 7.99 (d, 2H, 8.8 Hz), 7.58-7.64 (m, 3H), 7.37 (t, 1H, 8.0 Hz), 7.12 (d, 2H, 8.8 Hz), 6.95 (s, 2H), 6.84-6.87 (m, 1H), 4.70 (q, 2H, 7.2 Hz), 4.53 (bs, 2H), 3.81-3.98 (m, 4H), 3.49-3.58 (m, 4H), 3.18-3.36 (m, 2H), 1.41 (t, 3H, 7.2 Hz). MS (ES+) m/e 571 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-].C(O)(C(F)(F)F)=[O:15]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:7]=[C:8]([CH2:12][OH:15])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(C2OCCO2)[n+]1[O-]
Solvent: ClCCl
Product: OCc1cccc(C2OCCO2)n1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a stirred solution of 2-(1,3-dioxolan-2-yl)-6-methylpyridine 1-oxide (2.3 g, 12.69 mmol, 1 eq.) in 200 ml dry DCM was added TFA (6.66 g, 31.73 mmol, 2.5 eq.) via syringe, The reaction was stirred 2 hrs and was evaporated on RFE. The residue was redissolved in 200 ml DCM and 200 ml of 2M aqueous K2CO3 solution was added. Vigorously stirring was allowed for 2 hrs. The aqueous layer was separated and extracted with fresh DCM (2×100 ml). The organics were combined, washed with water (50 ml), brine (50 ml), dried over MgSO4 and concentrated to give [6-(1,3-dioxolan-2-yl)pyridin-2-yl]methanol (2.25 g, 84% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]([CH3:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH2:14]Cl)=[CH2:13]>>[CH3:13][C:12]([CH2:14][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8](=[O:9])[CH3:10])=[CH2:11]
Reactant: CC(=O)Cc1ccccc1
Reactant: C=C(C)CCl
Product: C=C(C)CC(C(C)=O)c1ccccc1

Procedure:
Reaction of methyl benzyl ketone with β-methallyl chloride in accordance with the foregoing process yields 2-methyl-4-phenyl-hex-1-en-5-one of boiling point 85° C./3 mmHg; nD20 =1.5151.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][C:5]=1[O:16][CH3:17].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([C:8]=1[CH3:15])=[CH:6][C:5]([O:16][CH3:17])=[C:4]([OH:3])[CH:13]=2
Reactant: BrBr
Reactant: COc1cc2c(C)cc(=O)oc2cc1O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2c(C)c(Br)c(=O)oc2cc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A bromine (2.55 g, 15.96 mmol) solution in acetic acid (8 mL) was added dropwise to a stirred suspension of 7-hydroxy-6-methoxy-4-methyl-chromen-2-one (3.20 g, 15.5 mmol) in glacial acetic acid (31 mL) at room temperature. The mixture was stirred for 10 min, then poured onto crushed ice (400 mL). To the resultant, light, yellow suspension, 1 mL of saturated sodium bisulphite solution was added and the mixture was allowed to reach room temperature. The precipitated solids were filtered off, washed with water, dried and recrystallized from glacial acetic acid. The obtained white powder (3.39 g, 11.88 mmol, 76%) was used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 81.9 %

Procedure:
The 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(4-methyl---piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 35 but starting from 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 3 g of 1-methylpiperazine. methylpiperazine. 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 230° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH:30]([CH3:33])[C:29]=2[CH:34]=1)=[O:24]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:19][CH:20]=2)[S:6][C:22]=1[C:23]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH:30]([CH3:33])[C:29]=2[CH:34]=1)=[O:24]
Reactant: N#CN
Reactant: CC1COc2ccc(C(=O)CBr)cc21
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: CC1COc2ccc(C(=O)c3sc(Nc4ccc(OCCN5CCCC5)cc4)nc3N)cc21

Procedure:
This compound was prepared from cyanamide, 1-[2-(4-Isothiocyanato-phenoxy)-ethyl]-pyrrolidine (from Example 5) and 2-bromo-1-(3-methyl-2,3-dihydro-benzofuran-5-yl)ethanone (from Example 138) following a procedure similar to Example 130. Mass spectrum (ES) MH+=465.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24](CC5C=CC=CC=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:34]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)n2ccc3cc(N4CCN(Cc5ccccc5)CC4)ccc32)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2ccc3cc(N4CCNCC4)ccc32)cc1
Product: Cl
Reaction time: 2 h
Yield: 99.9 %

Procedure:
N-(4-Methoxybenzenesulfonyl)-5-(4-benzylpiperazin-1-yl)-indole (0.25 g, 0.54 mmol) was dissolved in DCM (4 mL), α-chloroethyl chloroformate (0.150 g, 1.05 mmol) was added and the mixture left at room temperature for 2 h after which it was concentrated. MeOH (10 mL) was added and the mixture refluxed for 2 hrs and then concentrated to give the product (0.22 g, quantitative yield). 1H NMR (MeOH d6) δ 3.39-3.47 (8H, m), 3.77 (3H, s), 6.64 (1H, d, J=3), 6.94 (2H, d, J=9), 7.15 (1H, dd, J=9, 2), 7.26 (1H, d, J=2), 7.59 (1H, d, J=4), 7.80 (2H, d, J=9) and 7.90 (1, H, d, J=9); MS (posES-FIA) 371.1304 M+; Purity (HPLC chromsil C18) >98%.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:31])[C:6](=[O:30])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[CH:11][C:10]([O:26][CH3:27])=[C:9]([O:28][CH3:29])[CH:8]=2)(O)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:27][O:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:28][CH3:29])[C:6](=[O:30])[N:5]([CH3:31])[C:4]([C:1]([CH:59]1[O:60][CH2:61][CH2:62][NH:57][CH2:58]1)=[O:2])=[C:13]2[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)n(C)c(=O)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)C3CNCCO3)n(C)c(=O)c2cc1OC
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of the compound obtained in Example 128 (1.50 g), 1,3-dicyclohexylcarbodiimide (793 mg) and 1-hydroxybenzotriazole (588 mg) in dimethylformamide (30 ml) is stirred at room temperature for one hour, and thereto is added morpholine (335 mg), and the mixture is stirred for two hours. The mixture is further stirred at 50° C. for four hours. To the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether-ethyl acetate to give 6,7-dimethoxy-2-methyl-3-morphlino-carbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (893 mg) as listed in Table 12.
Reaction SMILES: Br[C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:4]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:5](=[O:20])[N:6]([CH2:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:7]=1.[NH2:36][NH2:37]>N1C=CC=CC=1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:3]2[C:2]([NH:36][NH2:37])=[N:7][N:6]([CH2:8][C:9]3[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[C:5](=[O:20])[C:4]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:30][CH:31]=1
Reactant: NN
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(Br)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: c1ccncc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
To a microwave flask was added 4-(6-bromo-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (105 mg, 0.187 mmol), pyridine (10 ml) and anhydrous hydrazine (60 mg, 1.87 mmol). The reaction was subjected to microwaves with heating to 200° C. and the conditions were continued at that temperature for 1.5 hr. After this time, the reaction was cooled to rt and the solvent was removed to give product as yellow solid. The product was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.COC(OC)[N:13]([CH3:15])C.O.[NH2:19]N>CCO>[CH2:8]([O:7][C:1]([C:2]1[CH:15]=[N:13][NH:19][C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of ethyl acetoacetate (8.0 mL, 63 mmol) and dimethylformamide-dimethylacetal (8.3 mL, 63 mmol) is heated to reflux for 1 hour. The reaction mixture is cooled to room temperature and diluted with EtOH (70 mL). Hydrazine hydrate (3.0 mL, 63 mmol) is then added and the reaction is heated at 80° C. for 2 hours. The resultant solution is cooled to room temperature and concentrated in vacuo to afford crude 5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1F)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.[F:48][P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[F:48][C:33]1[CH:32]=[C:31]([CH2:30][C@H:17]([NH:16][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([C:10]3[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=3)[CH:4]=2)=[O:9])[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH:36]=[CH:35][C:34]=1[F:37]
Reactant: N[C@@H](Cc1ccc(F)cc1F)CN1C(=O)c2ccccc2C1=O
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Cc1oc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (200 mg, 0.97 mmol), 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (322 mg, 1.02 mmol)[prepared according to the procedure of Preparation 6] and N,N-diisopropylethylamine (0.51 ml, 2.91 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (678 mg, 1.46 mmol). After stirring at ambient temperature for 20 h, the mixture was concentrated and purified using silica gel and eluting with a 0-50% ethyl acetate/hexane gradient to afford the title compound as an off-white foamy solid (181 mg, 0.36 mmol, 37% yield): LCMS (ES) m/e 505 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:19])[NH:35][C:26]3([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CN(C(=O)OC(C)(C)C)CC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 3,4-dihydro-1H-isoquinoline-2,8-dicarboxylic acid 2-tert-butyl ester (2.0 g, 7.2 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (1.5 g, 7.2 mmol), HATU (3.3 g, 8.6 mmol) in anhydrous DMF (70 mL) is added DIPEA (1.4 mL, 8.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (217) as white solid (3.3 g, 99%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:24][C:22](=[O:23])[C:21]4[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=4[O:31][CH3:32])[N:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)C(C)C4)cc3)nc2c1
Temperature: 155 °C
Yield: 21.9 %

Procedure:
To a solution of 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.400 g, 1.62 mmol) in DMA (15 mL) was added 2-amino-4,6-dimethoxybenzamide (0.349 g, 1.78 mmol), NaHSO3 (0.201 g, 1.94 mmol) and p-TsOH (0.030 g, 0.16 mmol). The resulting solution was heated to 155° C. for 5 hours. The mixture was cooled to room temperature, diluted with water, extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.150 g, 21%). 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.57 (s, 1H), 8.10 (d, J=8.9 Hz, 2H), 6.90-7.14 (m, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.42-4.75 (m, 0.5H), 4.03-4.42 (m, 1H), 3.61-4.02 (m, 8H), 3.41-3.60 (m, 1H), 2.85-3.13 (m, 2H), 2.63-2.85 (m, 0.5H), 1.88-2.13 (m, 3H), 1.04-1.31 (m, 3H). ESI MS m/z 423 [M+H]+.