Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:35](=[O:37])[CH3:36]>>[CH3:45][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:43][CH:44]=1)[C:35](=[O:37])[CH3:36]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-aniline Rf value: 0.2 (aluminium oxide, methylene chloride/ethanol=40:1) C31H34N4O4
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:40][CH2:41][C:42]#[CH:43])[CH3:39].CCO>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:43]=[C:42]([CH2:41][S:40][CH2:38][CH3:39])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCSCC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCSCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and propargyl ethyl sulfide (0.066 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluting with 1% to 2% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.1 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 2% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.12 g of the title compound as light tan product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([OH:7])=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:22][CH2:21]1)[N:14]=2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)N1CCOCC1

Procedure:
The title compound was synthesized using the described in Example 105 above using 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (101 mg, 0.259 mmol) and morpholine. MS (ESI) m/z: Calculated: 459.1; Observed: 460.1 (M++1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:17][C:18]1[C:19](Cl)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]>CC#N.CCOCC>[Br:17][C:18]1[C:19]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:20]([C:26](=[O:33])[C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[C:21]([CH3:25])=[N:22][C:23]=1[CH3:24]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To a solution of 4-methylpiperidine (593 mg, 5.98 mmol) and DIEA (2.1 mL, 12 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.0 g, 5.98 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 1.99 g (84%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.41-3.39 (m, 2H), 2.83 (br. s, 2H), 2.60 (s, 3H), 2.29 (s, 3H), 1.58 (d, J=12.5 Hz, 2H), 1.44 (br. s, 1H), 1.29 (d, J=6.2 Hz, 6H), 1.09-1.07 (m, 2H), 0.92 (d, J=6.2 Hz, 3H). UPLC (M+H)=399.2.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.287 g (1.1 mmol) of 4-(4-chlorobenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1), after which it was recrystallized from hexane-methanol to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]
Reactant: CSC1=C([N+](=O)[O-])CCCN1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC1=C([N+](=O)[O-])CCCN1
Yield: 74 %

Procedure:
A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.51 g, 0.003 mol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.49 g, 0.003 mol) in ethanol (50 ml) was refluxed for 6 hours. The mixture was cooled, and the solvent was removed in vacuo. The residue was dissolved in hot propan-2-ol and the product crystallised on cooling. Recrystallisation of the product from propan-2-ol/methanol gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridine (0.66 g, 82%) m.p. 205.5°-206.5°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:48]=[CH:47][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>ClCCl>[CH3:12][N+:13]1([O-:6])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:47][CH:48]=2)[CH2:15][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[N+](C)([O-])CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-Chloroperoxybenzoic acid (Fluka, Buchs, Switzerland; 2.06 g of 55%, 4.27 mmol) is added to a stirred mixture of 4-[(4-methyl-1-piperazinyl)-methyl]-N-{4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl}-benzamide (prepared as described in EP 0 564 409 B1, Example 21; 2.00 g, 4.05 mmol) in dichloromethane (70 mL) at −20° C. The resulting mixture is then stirred at RT for 72 h. The solvent is then evaporated off under reduced pressure to yield a mixture which is purified by column chromatography on silica gel, eluent dichloromethane-methanol-water (70:30:5), to give the title compound as a yellow crystalline solid, m.p. 154-158° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].C([O-])([O-])=O.[Na+].[Na+]>Br.CC(O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCOc2ccc(O)cc21

Procedure:
A solution of 6-methoxy-2,3-dihydro-4H-chromen-4-one in 48% aqueous HBr (250 mL) and HOAc (250 mL) was heated to 75° C. for 6 hours. The reaction mixture was cooled, adjusted to pH≈5 by the addition of saturated aqueous Na2CO3 and extracted with CHCl3 (2×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:18][C:19](=[O:31])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:25]3[C:24]([F:30])=[CH:23][C:22]([CH2:21][CH2:20][C:19]([OH:31])=[O:18])=[CH:27][C:26]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCCC1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCCCC2)c(F)c1
Yield: 76.3 %

Procedure:
3-Chloromethyl-2-cyclohexylsulfanyl-pyridine (0.074 mmol) obtained in Step C of Preparation Example 22 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (17.5 mg, 0.074 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (23 mg, 74%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:11]([CH3:13])=[O:12]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:11]([NH:10][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:15]=1)(=[O:12])[CH3:13]
Reactant: C1=Cc2ccccc2C1
Reactant: CC(=O)Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2=Cc3ccccc3C2)cc1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmol) of indene, 5.22 , (20 mmol) of para-acetamino-iodo-benzene and 0.134 g (0.6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. After that all triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of dichloromethane and 50 ml of water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yield of product was 13%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].C(Cl)(=O)C(Cl)=O.[C:23]1([CH3:29])[CH:28]=CC=C[CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][C:23]([CH3:29])([CH3:28])[CH3:24])=[O:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred suspension of the above acid ((6), 7.0 g, 31 mMol) in toluene (25 mL) was added oxalylchloride (5 mL) followed by one drop of dry DMF. After stirring for 16 h (the solution became clear after ~30 minutes) the reaction was evaporated to dryness and re-evaporated from fresh toluene (2×100 mL). To the resulting acid chloride in CHCl3 (10 mL) with stirring at 0° C. was added t-BuOH (1 mL) followed by pyridine (0.6 mL). The reaction was allowed to warm to room temperature and stirred for 6 h. The resulting reaction was stripped of solvent, taken up in ethyl acetate, washed with aq. 1N NaHCO3, brine, dried (MgSO4) and evaporated under reduced pressure. Purification by flash chromatography on silica gel eluted with 10% ethyl acetate in hexane gave product (7) (7.28 g, 83%) as a clear oil.
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22]CC3C=CC=CC=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[ClH:1].[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline hydrochloride (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml ) and trichloromethane (50 ml) was stirred at ambient temperature under an atmosphere of hydrogen (1.5 atmospheres) for 30 minutes. The catalyst was filtered off and the filtrate evaporated. The residual solid was triturated in ether, filtered off and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (2.1 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>CN(C=O)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#N)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.49 g, 17.3 mmol) was dissolved in DMF (35 ml) and cooled to 0° C. NaH (1.19 g, 24.8 mmol) was added in small portions over 20 minutes. The reaction was stirred for 30 minutes at 0° C. and 3-fluorobenzonitrile (3.1 ml, 29.0 mmol) added. The reaction was allowed to warm to r.t. over 1 h, stirred for a further 16 h and then quenched by addition of water. The reaction mixture was separated between water (500 ml) and DCM (2×500 ml). The combined organics were washed with water (500 ml), dried through a phase separator and evaporated in vacuo. Purification by flash silica gel chromatography using a 100 g Biotage column with a gradient of 5-40% EtOAc in heptane yielded the title compound as a white solid. Yield: 4.2 g (81%). 1H NMR (400 MHz, CDCl3) δ 7.34 (t, 1H, J=7.9 Hz), 7.21 (d, 1H, J=7.7), 7.14-7.08 (m, 2H), 4.46 (m, 1H), 3.67 (m, 2H), 3.33 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Li]CCCC.[Li+].CC([N-]C(C)C)C.[Cl:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21].[Br:23]CCBr.Cl>C1COCC1>[Br:23][C:18]1[S:17][C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:14])[CH:19]=1
Reactant: BrCCBr
Reactant: O=C(O)c1sccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1sc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 39816.9 %

Procedure:
To a solution of DIPA (26.3 g, 0.26 mol) in 400 mL of dry THF was added a solution of n-BuLi (104 mL, 0.26 mol, 2.5M in n-hexane) at −78° C. under nitrogen. After the addition was completed, the mixture was stirring for 1 h and then warmed to 0° C. and stirred for 30 min. To above LDA solution was added a solution of 3-chlorothiophene-2-carboxylic acid (21 g, 0.13 mol) in THF (50 mL) at −78° C. After stirring for 1 h, a solution of 1,2-dibromo-ethane (48.9 g, 0.26 mmol) in THF (50 mL) was added at −78° C. The mixture was stirred at −78° C. for 1.5 h and slowly warm to RT. The mixture was poured into aq. HCl solution, and then extracted with EtOAc. The combined extracts were dried over Na2SO4, concentrated to give 25 g of 5-bromo-3-chlorothiophene-2-carboxylic acid. MS (M+H): 241, 243. 1H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([O:38][CH3:39])[CH:3]=1.[OH:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.N#N>[Cu]I.O1CCOCC1>[F:8][C:7]1[C:2]([N:42]2[CH:43]=[CH:44][C:45]([CH3:47])=[CH:46][C:41]2=[O:40])=[CH:3][C:4]([O:38][CH3:39])=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)[CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])[CH:6]=1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OC)c2)cc1
Reactant: Cc1ccnc(O)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-n4ccc(C)cc4=O)cc3OC)c2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 3.5 %

Procedure:
A blue-green dioxane (2.2 mL) slurry of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.683 g, 1.11 mmol), 2-hydroxy-4-methylpyridine (1.21 g, 11.1 mmol), cesium carbonate (0.543 g, 1.67 mmol), copper(I) iodide (0.212 g, 1.11 mmol), and trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.18 mL, 1.17 mmol) was sparged with N2 for 45 min in a 40-mL vial. The sealed flask was then heated to 110° C. After stirring for 2 h, the reaction was then quenched with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (25 g Snap Ultra column, 0% to 80% [3:1 EtOAc/EtOH]/hept gradient with 10% DCM) followed by additional column chromatography (55 g Interchim C18 PuriFlash column, 0-100% MeCN/H2O with 0.1% NH4OH) afforded 1-(5-fluoro-2-methoxy-4-(4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (25 mg, 0.039 mmol, 3.5% yield). m/z (ESI) 643.2 (M+H)+.
Reaction SMILES: C([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5]1)=O.[OH-].[Na+].Cl>CO>[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:5]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(OC=O)C4)nc3c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
The tert-butyl (E)-3-{2-(3-formyloxypiperidino)-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (184 mg, 0.334 mmol) obtained in (G) was dissolved in methanol (3.0 ml), added with 1 N aqueous sodium hydroxide (1.0 ml), and then the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with 1 N hydrochloric acid (1.0 ml) and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→2:1→1:2, v/v) to obtain the title compound (174 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.BrN1C(=O)CCC1=O.C(O)(=O)C>C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])=[O:20])[C:15]([Br:17])=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2c(ccc3nc(N)[nH]c(=O)c32)cc1Br
Temperature: 25 °C
Yield: 33.2 %

Procedure:
3-Amino-8-bromo-N,N,-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide (0.165 g, 0.39 mmole) was suspended in pivalic anhydride (5 ml) (Aldrich) and heated under nitrogen until dissolved. The solution was heated under reflux for 10 minutes, cooled, and the pivalic anhydride removed in vacuo. The dried solid was dissolved in benzene (20 ml), pyridine (0.05 ml) added, and the solution heated to boiling under nitrogen. N-Bromosuccinimide (0.07 g, 0.47 mmole) was added, and the mixture refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, solvent removed in vacuo, and the solid residue crystallized from methanol. The pivalamide (0.105 g) was dissolved in methanol (2 ml), 1N NaOH (4 ml) added, and the solution heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was neutralized with dilute acetic acid, the crystals collected by filtration and suspended in methanol. The collected crystals were dried in vacuo to give 3-amino-8-bromo-N,N-diethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-9-sulfonamide (0.055 g, 33%). Mp>250° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, J=7 Hz, 6H, ethylCH3), 3.38 (q, J=7 Hz, 4H, ethylCH2), 6.78 (br s, 2H, NH2), 7.47 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=9 Hz, 1H, Ar), 8.40 (s, 1H, Ar), 10.30 (s, 1H, Ar), 11.32 (br s 1H, NH). Anal Calculated for C16H17BrN4O3S: C, 45.19; H, 4.03; Br, 18.79; N, 13.17; S, 7.54. Found: C, 45.10; H, 4.03; Br, 18.74; N, 13.07; S, 7.56.