Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[CH3:34]>COCCOC>[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:34]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)cc(F)c1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 66.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,6-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-ethylphenylboronic acid (71 mg, 0.468 mmol), and Pd[PPh3]4 (27 mg, 0.0234 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (70 mg, 66%). MS m/e 453.30 (M+H+)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1ccccc1
Product: O=C(CNC(=O)c1ccccc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[N:8]=[CH:7]1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[N:8]=[CH:7][N:6]1[CH2:5][C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)c1ccc2ncn(Cc3cccc(Br)c3)c(=O)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc2ncn(Cc3cccc(-c4ccncc4)c3)c(=O)c2c1
Temperature: 90 °C

Procedure:
To a microwave vial was added ethyl 3-(3-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.050 g, 0.13 mmol), pyridine-4-boronic acid (0.032 g, 0.26 mmol) in a solution of 1,4-dioxane (2 mL) and water (0.4 mL). Sodium carbonate (0.041 g, 0.39 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.013 g, 0.015 mmol). The reaction mixture was heated at 90° C. for 16 h. The mixture was then concentrated and to the residue was added dichloromethane (3 mL) and water (1 mL). After separation, the aqueous phase was extracted with dichloromethane (3 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford ethyl 4-oxo-3-(3-(pyridin-4-yl)benzyl)-3,4-dihydroquinazoline-6-carboxylate. LC-MS: (FA) ES+ 386.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].N=[O:13].Cl>>[N:1]1[C:2](=[O:11])[C:3](=[O:13])[CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: N=O
Reactant: O=c1ccc2ccccc2[nH]1
Agent: Cl
Product: O=C1C=c2ccccc2=NC1=O

Procedure:
Quinolinone compounds (e.g., Structure 16) may be converted into corresponding quinoline-diones (e.g., Structure 24), hydroxy quinolinones (e.g., Structure 25), and quinoline-thiones (e.g., Structures 26 and 27) by the processes shown in Scheme V. The process of Scheme V begins with the deprotection of the imino ether of Structure 16 by treatment with a mineral acid, for example, hydrochloric acid, to afford a quinoline-dione compound of Structure 24. Alternatively, this transformation can be carried out with a Lewis acid, for example, boron trichloride, to afford a quinoline-dione compound (e.g., Structure 24). See T. Sala, et al., supra. A quinoline-dione compound (e.g., Structure 24) can be converted to a hydroxy quinoline compound (e.g., Structure 25) by addition of an organometallic reagent, for example, methyl lithium, which affords a hydroxy quinoline compound (Structure 25).
Reaction SMILES: N[C@@H]1CCCC[C@H]1N.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:26]1[C:27]2[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:36][C:28]=2[N:29]([CH:31]([O:33][CH2:34][CH3:35])[CH3:32])[N:30]=1>O1CCOCC1.[Cu]I>[CH2:34]([O:33][CH:31]([N:29]1[C:28]2[S:36][C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:38][C:27]=2[C:26]([NH:16][C:14]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[O:15])=[N:30]1)[CH3:32])[CH3:35]
Reactant: NC(=O)c1cccs1
Reactant: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(NC(=O)c3cccs3)nn(C(C)OCC)c2s1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
1.1 g (5.8 mmol) of copper(I) iodide, 0.69 cm3 (5.8 mmol) of trans-1,2-diaminocyclohexane, 4.4 g (34.6 mmol) of 2-thiophenecarboxamide and then 12.2 g (57.6 mmol) of tripotassium phosphate are successively added to a solution of 10.0 g (28.8 mmol) of ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate in 167 cm3 of dioxane, stirred at a temperature in the region of 25° C., under argon. The reaction mixture is refluxed for 20 hours and is then cooled to a temperature in the region of 25° C. and filtered through Clarcel®. The solid is washed with twice 170 cm3 of ethyl acetate. The filtrate is extracted with three times 170 cm3 of saturated brine and the organic phase is then dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. The residue is purified by chromatography on a column of about 300 g of silica gel (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate mixture (90/10 and then 85/15 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 2.9 g of ethyl 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylate are thus obtained in the form of a yellow solid. (Rf=0.18, thin-layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (80/20 by volume)).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25]3=[C:26]([NH:28][C:29](=[S:30])[N:24]3[CH2:23][CH2:22][CH2:21]2)[CH:27]=1.[OH-].[Na+]>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25]3=[C:26]([N:28]=[C:29]([S:30][CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:5]=4)[N:24]3[CH2:23][CH2:22][CH2:21]2)[CH:27]=1
Reactant: COc1cc2c3c(c1)[nH]c(=S)n3CCC2
Reactant: ClCc1cccc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1cccc(-c4ccccc4)n1)n3CCC2
Temperature: 25 °C

Procedure:
2-Chloromethyl-6-phenylpyridine hydrochloride 1.942 g, 8.1 mmol) was added to a solution of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinoline-2[1H]-thione (1.78 g, 8.1 mmol) in ethanol (16 ml) and 1N-sodium hydroxide (16.2 ml). The mixture was heated under reflux for 15 seconds and cooled to room temperature. The ethanol was removed by evaporation in vacuo and the aqueous mixture extracted with dichloromethane (2×150 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give a brown solid which was recrystallised from MeOH to give the title compound as the quarter hydrate (2.77 g, 88%), mp 134°-135° C. (Found: C, 70.5; H, 5.8; N, 10.4; C23H21N3OS1/4H2O requires C, 70.5; H, 5.5; N, 10.7%).
Reaction SMILES: S(Cl)(Cl)=[O:2].[C:5]1(=[N:16]O)[CH:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:7]2[CH2:6]1>O1CCOCC1>[C:5]1(=[O:2])[CH:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:7]2[CH2:6][NH:16]1
Reactant: O=S(Cl)Cl
Reactant: ON=C1CC2c3ccccc3CC12
Solvent: C1COCCO1
Product: O=C1NCC2c3ccccc3CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (1.9 mL, 26.4 mmol) was added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime (1.5 g, 8.8 mmol) in 1,4-dioxane (44 mL), and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×50 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C(N(CC)CC)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CC(C)N=C=O
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Reaction time: 60 h

Procedure:
5 g (0.018 M) of 7-amino-1,3-dihydro-1-methyl-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one are heated at reflux for 5 hours with 15 ml of isopropylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature for 2.5 days, the product crystallising out partially. The solvent is concentrated partially, cooled with ice and the crystallised product is filtered off. After recrystallisation from methylene chloride/ethyl acetate, there is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-isopropylurea which melts at 185°-188° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Cl)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Cl)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester (3.8 g, 10.2 mmol) and triethylsilane (6.0 mL) at 25° C. was added trifluoroacetic acid (3.0 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.8 g, 50%) as a white solid: LC/MS m/e calcd for C20H21ClFNO2 (M+H)+: 362.85, observed: 362.2.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:36](N(CC)CC)[CH3:37].C(Cl)(=O)CC>Cl>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:37])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: CCN(CC)CC
Reactant: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Agent: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (29.04 g, 58.73 mmol) in 2-Me-THF (100 mL) was dropwise added into aqueous HCl solution (150 mL, 31%) over 15 min. The reaction mixture was partitioned between water (300 mL) and isopropyl acetate (100 mL) and the upper organic phase was discarded. The aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried. Triethylamine (16.32 mL, 117.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was washed with water (110 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum. The residue was recrystallized with isopropanol and methyl tert-butyl ether to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (17.2 g, 65% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.BrC1C=CC(C=O)=CC=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>COCCOC.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:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc2cnccc2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cnccc3c2)CC1
Yield: 70 %

Procedure:
A round bottom flask charged with 6-bromo isoquinoline (prepared from 4-bromobenzaldehyde according to the literature: Neiko Nerenz, et al. (1998) J. Chem. Soc. Perkin Trans. 2, 437-447, 0.200 g, 0.961 mmol), 1-Boc piperazine (0.215 g, 1.15 mmol), K3PO4 (0.286 g, 1.35 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (0.028 g, 0.072 mmol) and Pd2dba3 (0.022 g, 0.024 mmol) in dry DME (2 mL) was purged under N2 and heated at reflux for 5 hours. After cooling, the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (1:1 hexanes/EtOAc,) to give 4-Isoquinolin-6-yl-piperazine-1-carboxylic acid tert-butyl ester (0.210 g, 70%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 9.04 (s, 1H), 8.39 (dd, J=6.8 Hz, J=2.8 Hz, 1H), 7.83 (dd, J=9.2 Hz, J=2.8 Hz, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.32 (dd, J=9.2 Hz, J=2.4 Hz, 1H), 6.98 (s, 1H), 3.64 (m, 4H), 3.35 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 314 [M+H]+; Rt=2.14 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][CH2:20][S:21][CH3:22])[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH2:29][C:30](Cl)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:19][CH2:20][S:21][CH3:22])[CH2:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:30](=[O:31])[CH2:29]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@@H](CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CSCC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product from Step H (22.0 g, 63.8 mmol) in ethyl acetate (150 mL) was vigorously stirred at 0° C. with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwise, and the reaction stirred at 0° C. for 2h. The layers were separated, and the ethyl acetate phase was washed with 10% citric acid and saturated brine, and dried over sodium sulfate. After concentration in vacuo, the resulting crude product (27.6 g) was dissolved in DMF (300 mL) and cooled to 0° C. under argon. Cesium carbonate (63.9 g, 196 mmol) was added, and the reaction was stirred for two days, allowing it to warm to room temperature. Another portion of cesium carbonate (10 g, 30 mmol) was added, and the reaction was stirred for 16 hours. The DMF was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, and dried over sodium sulfate. The crude product was chromatographed on silica gel with 20-25% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.CC(C)=[O:26]>>[C:8]([OH:26])(=[O:7])[CH3:17].[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CC(C)=O
Agent: O[C@H]1CCC[C@@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[(1S,2S)-(2-Hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 5) (1.03 g) is dissolved in acetone (35 ml) with heating, and the solution is filtered, and to the filtrate is added acetic acid (0.20 ml), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(1S,2S)-(2-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline monoacetate (990 mg) as crystals.
Reaction SMILES: [CH:1]([CH:4]1[C:8]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH3:15])([CH3:14])[O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[F:32][CH:30]([F:31])[C:26]1[C:25]([C:33]([NH:13][C:9]2[C:8]3[CH:4]([CH:1]([CH3:3])[CH3:2])[O:5][C:6]([CH3:15])([CH3:14])[C:7]=3[CH:12]=[CH:11][CH:10]=2)=[O:34])=[C:24]([F:23])[N:28]([CH3:29])[N:27]=1
Reactant: CC(C)C1OC(C)(C)c2cccc(N)c21
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1OC(C)(C)c2cccc(NC(=O)c3c(C(F)F)nn(C)c3F)c21
Reaction time: 4 h
Yield: 78 %

Procedure:
In a 25 ml round bottom flask, a solution of 3-isopropyl-1,1-dimethyl-1,3-dihydro-2-benzofuran-4-amine (62 mg, 0.301 mmol, 1 eq) in 5 ml of DCM is cooled to 0° C. and triethylamine (0.05 ml, 0.361 mmol, 1.2 eq) is added. A solution of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (70 mg, 0.331 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (78%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:3]([N:9]=[C:10]=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1ncc(Cl)cc1Cl
Solvent: ClCCl
Product: S=C=Nc1ncc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To 3,5-dichloropyridin-2-amine (0.36 g, 2.209 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.523 g, 2.253 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature and the crude was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield to yield 3,5-dichloro-2-isothiocyanatopyridine (0.4 g, 1.951 mmol, 88% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.50 (t, J=2.59 Hz, 1H), 8.45 (t, J=2.59 Hz, 1H). MS (LC/MS) R.T.=2.07; [M+H]+=204.8.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[Cl:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([NH:28][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:19])=[N:25][CH:24]=1
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ncc(Cl)s2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 34 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5-chloro-2-thiazolamine with a yield of 34% of theory.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11](=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=[O:4].Cl>[OH-].[Na+]>[Cl:21][C:15]1[C:14]([CH3:22])=[C:13]([NH:12][C:11]([N:6]2[CH2:7][CH2:8][C@H:9]([OH:10])[C@H:5]2[C:3]([OH:4])=[O:2])=[O:23])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(NC(=O)N2CC[C@H](O)[C@H]2C(=O)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.3 %

Procedure:
A suspension of ester 54A (260 mg, 0.770 mmol) in 20 mL of 1.6 N NaOH was stirred at rt for 45 min. The reaction mixture was acidified to pH 2 with 10% HCl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to afford the title compound (260 mg) as a beige solid. A portion (50 mg) of the residue was purified by preparative HPLC (reverse phase silica gel, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA) to afford the title compound (25 mg) as a colorless oil. 1H NMR (CD3OD) 2.02-2.05 (m, 1H), 2.17-2.22 (m, 1H), 2.35 (s, 3H), 3.73-3.76 (m, 2H), 4.40 (br s, 1H), 4.49 (br s, 1H), 7.47 (d, J=8.80, 1H), 7.58 (d, J=8.25, 1H); 13C NMR (CD3OD) 15.83, 33.59, 45.61, 69.53, 74.73, 110.40, 117.45, 125.45, 132.34, 137.80, 144.42, 156.50, 159.95, 173.94; HPLC a) column: Phenomenex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 1.97 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 1.79 min retention time (92%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% isopropanol/hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 6.96 min retention time (98%); MS (ES) m/z 324 [M+H]+.