Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CC(F)=CC=1C1C(CN)=CC2C(=C(Cl)C=CC=2)N=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.ClC1N=CN=C2C=1NC=N2.N1C(N)=C2C(NC=N2)=NC=1.[Cl:58][C:59]1[CH:60]=[CH:61][CH:62]=[C:63]2[C:68]=1[N:67]=[C:66]([C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=1)[C:65]([C@H:76]([NH:78][C:79]1[N:87]=[CH:86][N:85]=[C:84]3[C:80]=1[N:81]=[CH:82][NH:83]3)[CH3:77])=[CH:64]2>C(O)CCC>[Cl:58][C:59]1[CH:60]=[CH:61][CH:62]=[C:63]2[C:68]=1[N:67]=[C:66]([C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[CH:70]=1)[C:65]([C@@H:76]([NH:78][C:79]1[N:87]=[CH:86][N:85]=[C:84]3[C:80]=1[N:81]=[CH:82][NH:83]3)[CH3:77])=[CH:64]2
Reactant: C[C@@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: Clc1ncnc2nc[nH]c12
Agent: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1OCc1ccccc1
Agent: Nc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1

Procedure:
A mixture of (2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)-methanamine (0.120 g, 0.40 mmol) in n-butanol (5 mL) was treated with DIEA (0.80 mmol, 2.0 eq) followed with 6-chloropurine (0.075 g, 0.48 mmol, 1.2 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide the mixture of N-(S)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine and N-((R)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine. Further separation by chiral HPLC with IA column at IPA/Hexane (10%) provides N-((S)-1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=6 nM] as a white solid. 1H-NMR (MeOD) δ ppm 8.43 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.73-7.80 (m, 2H), 7.48-7.53 (m, 1H), 7.44-7.49 (m, 1H), 7.35-7.44 (m, 2H), 7.04-7.11 (m, 1H), 1.44-1.47 (d, 3H), Mass Spectrum (ESI) m/e=419 (M+1), and N—((R)-1-(8-chloro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=424 nM] as a white solid. 1H-NMR (MeOD) δ ppm, 8.56 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.84-7.93 (m, 2H), 7.45-7.66 (m, 4H), 7.14-7.23 (m, 1H), 3.89-3.98 (m, 1H), 1.57-1.60 (d, 3H) Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:26][CH2:25]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCN(CCN2CCNCC2)CC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(CCN2CCCCC2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-[2-(1-piperidinyl)ethyl]piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: O1CCCCC1[N:7]1[CH:10]([CH2:11][CH2:12][O:13]C2CCCCO2)[CH:9]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]1=[O:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[C:23]1([CH2:22][C:21]([NH:20][CH:9]2[CH:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]2=[O:30])=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccccc1)NC1C(=O)NC1CCO
Reaction time: 2 h

Procedure:
A solution of 1-(2-tetrahydropyranyl)-3-phenylacetamido-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1 M pH 7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give 3-phenylacetamido-4-(2-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][NH:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:19])([CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)(C)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)NCCN

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (1.6 ml, 52.7 mmol) was added to a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methylpropanoate (intermediate 298, 1.45 g, 5.29 mmol) in 1,4-dioxane (9 ml) at room temperature. After stirring 1 day additional hydrogen chloride in 1,4-dioxane was added (5 ml). After a further 1 day the reaction mixture was evaporated to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].C(Cl)(=O)C([Cl:13])=O>ClCCl>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:13])=[O:7]
Reactant: CC(C)CCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)CCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) in dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-1,5-dimethyl-1H-imidazole (0.60 g, 1.76 mmole) in dichloromethane (15 mL) was added 5-methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.42 g, 85%) was treated with HCl in ether and recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 112°-114°; MS m/e 456 (M+ +H); 1H NMR (CDCl3 /TMS) δ 0.90(s,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m,3H,CH2CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,1H,CH), 7.33(m,2H,Harom), 8.00(m,2H,Harom).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To methyl 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (406 mg, 1.34 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (4.0 ml), and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.0 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (307 mg, 1.28 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylate (4.40 g) in tetrahydrofuran (20 mL) was gradually added lithium aluminum hydride (350 mg) at 0° C., and the mixture was stirred for 30 min. Sodium sulfate decahydrate (3.54 g) was added to the reaction mixture, the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)methanol (3.88 g, yield 97%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 108-109° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[C:37](Cl)(=[O:40])[O:38][CH3:39].FC1C(C(F)(F)F)=C(C2CCN(C(C3C4CCN(C([O-])=O)CC=4NN=3)=O)CC2)C=CC=1F>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:37]([O:38][CH3:39])=[O:40])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: COC(=O)Cl
Agent: O=C([O-])N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and methyl carbonochloridate were converted to 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridine-6-carboxylate as a light orange solid (30 mg, 60%): mp 238-240° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.13 (br s, 0.25H), 12.86 (br s, 0.75H), 7.78-7.70 (m, 1H), 7.51-7.48 (m, 1H), 4.82-4.80 (m, 1H), 4.67-4.65 (m, 1H), 4.54 (s, 1.5H), 4.50 (s, 0.5H), 3.64 (s, 3H), 3.60-3.57 (m, 2H), 3.15-3.13 (m, 2H), 2.79-2.78 (m, 1H), 2.64-2.59 (m, 2H), 1.76-1.68 (m, 4H); ESI MS m/z 473 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Product: N#Cc1ccc(Cn2cncn2)cc1

Procedure:
U.S. Pat. No. 4,978,672 (referred to herein as '672, Indian Reference not available) provides 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and the process of its preparation. The patent discloses reacting 4-bromomethylbenzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile. This patent does not disclose the purity of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compound of formula 1. When we followed the patented process we also get the unwanted isomer 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compound of formula 4 (20 to 40%) in step 1. When the reaction mixture of step 1 is treated with 4-fluorobenzonitrile it yields 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]-benzonitrile, a compound of formula 1, and its isomer, a compound of formula 5. Thus the impurity of formula 4 has to be separated before treating it with 4-fluorobenzonitrile, which involves an additional step of column purification, which is reported in '672 and makes the process tedious and commercially unviable.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:3].Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[Br:26][C:24]1[N:25]=[C:20]([NH:3][C:2]([CH3:18])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:1])[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 83.2 %

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d, 5.25 g) dissolved in dioxane (40 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252g, 9.14 g) and N,N-diisopropylethylamine (5.59 mL) under nitrogen. The resulting solution was stirred at 100° C. for 10 h. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The organic was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography eluting with 20% ethyl acetate in iso-hexane) to afford the subtitle product (10.50 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:21])[OH:19])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)cc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-n2cccn2)cc1
Reaction time: 1 h
Yield: 37.5 %

Procedure:
Under a nitrogen stream, to a solution of 1-(4-bromophenyl)-1H-pyrazole (995 mg, 4.46 mmol) in anhydrous THF (12 ml), a hexane solution of n-butyllithium (1.6 M, 2.79 ml, 4.46 mmol) was added dropwise at −78° C. After stirring at the same temperature for 1 hour, this solution was added dropwise at −78° C. to a solution of trimethyl borate (1.07 ml, 9.37 mmol) in anhydrous THF (8 ml). After stirring at the same temperature for 1 hour, the reaction mixture was stirred at room temperature for one day and a night. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (developing solution=methylene chloride:methanol (50:1)) to give the titled compound (314 mg, 37%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=O)=[N:6][CH:5]=[N:4]1)[CH3:2].Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:7]([CH:8]=[N:11][OH:12])=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncnc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCn1ncnc1C=NO
Yield: 31.1 %

Procedure:
A mixture of crude 1-ethyl-1H-1,2,4-triazole-5-carbaldehyde (17.7 g), hydroxylamine hydrochloride (12.7 g, 0.182 mol), sodium bicarbonate (15.3 g, 0.182 mol) and ethanol (60 mL) was heated at reflux for 3 hours. After cooling, the reaction was filtered and the filtrate concentrated in vacuo. The resulting residue was crystallised from ethanol to give the title compound (6.17 g) 1H-NMR (d6-DMSO) δ 1.32 (3H, t, J=7 Hz), 4.41 (2H, q, J=7 Hz), 8.02 (1H, s), 8.25 (1H, s), 12.70 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].[Si](I)(C)(C)C>C(#N)C>[F:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(C(F)(F)F)ccc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (3.54 g, 11.27 mmol) in acetonitrile (118.0 mL) was added TMSI (4.0 mL, 28.18 mmol). The reaction was stirred at 50° C. overnight. The acetonitrile was evaporated and the crude re-dissolved in ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography using a gradient of ethyl acetate in hexanes (0-100%) and then methanol in dichloromethane (0-20%) gave 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (3 g, 89%), as a brown solid. ESI-MS m/z calc. 300.05. found 301.3 (M+1)+; Retention time: 1.34 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.10 (dd, J=6.0, 2.2 Hz, 1H), 8.03 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.49 (d, J=7.1 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.57 (dd, J=7.2, 2.1 Hz, 1H), 5.07 (s, 2H) ppm.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:16][CH:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:14]2)=[O:12])=[CH:7][CH:6]=1)(=O)C.[Li+].[OH-].Cl>C1COCC1.CO.O>[C:25]1([C:23]([N:20]2[CH2:21][CH2:22][N:17]([CH:15]3[CH2:16][N:13]([C:11]([C:8]4[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=4)=[O:12])[CH2:14]3)[CH2:18][CH2:19]2)=[O:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)Oc1ccc(C(=O)N2CC(N3CCN(C(=O)c4ccccc4)CC3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 26c (420 mg, 1.03 mmol) and LiOH (100 mg, 4.0 mmol) in a solvent mixture of THF/MeOH/H2O (2/2/2 mL) was stirred at room temperature for 4 h, at which time it was brought to pH 5 by the addition of 2N HCl (aq). The mixture was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue (crude compound 26d) was dried under reduced pressure for 18 h, and used in the following step without further purification.
Reaction SMILES: C[O:2][C:3]1[C:11]2[C:7](=[CH:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1.Cl.Cl.COC1C2C(=CSN=2)C=CC=1.B(Br)(Br)Br>CCOCC.C(Cl)Cl>[OH:2][C:3]1[C:11]2[C:7](=[CH:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2csnc12
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Oc1cccc2csnc12

Procedure:
7-Methoxy-2,1-benzisothiazole was dissolved in ether and converted to the hydrochloride using dry hydrogen chloride gas. The 7-methoxy-2,1-benzisothiazole hydrochloride (6.0 g.) was refluxed 22 hours in a solution of 16 g. boron tribromide and 160 ml. methylene chloride to give 3.78 g. pure, yellow, crystalline 7-hydroxy-2,1-benzisothiazole, mp. 99°-100.5° after recrystallization from hexane. This structure was confirmed by nmr.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Yield: 69.4 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (109 mg, 0.277 mmol) and N-bromosuccinimide (54 mg, 0.304 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 91 mg of the title compound as a light yellow solid. MS: (+) m/z 473.29, 475.18 (M+1, 79/81Br).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: NS(=O)(=O)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
4-hydroxymethyl-benzene-sulphonamide (0.105 mg, 0.56 mmoles) was dissolved in DCM (5 mL). Polymer supported triphenylphosphine (294 mg, 2.4 mmoles/g, 1.12 mmoles) was added, and the mixture was stirred with a shaker at room temperature for 10 minutes. CBr4 (557 mg, 1.68 mmoles) was then added, and stirring was continued for 3 hours. The supported reagent was removed by filtration, the solvent was evaporated, and the crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt 9/1) to yield the title compound as a light-yellow solid (70 mg).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH3:25])=[C:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:14][C:15]=1[CH:16]=[O:17])=[O:10])[CH3:7]>O1CCCC1>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH3:25])=[C:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:14][C:15]=1[CH:16]([CH:1]1[CH2:3][CH2:2]1)[OH:17])=[O:10])[CH3:7]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)c1c(C=O)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(O)C2CC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: -10 °C
Yield: 39.6 %

Procedure:
Cyclopropylmagnesium bromide (15 m, 0.5 mol/L) was cooled down to −10° C. in an ice-salt bath under an argon atmosphere. 5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1b (1.26 g, 4.5 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, the resulting solution was added dropwise to the above solution while maintaining the temperature at −10° C. Upon completion of the addition, the ice-salt bath was removed, and the reaction mixture was stirred for 1 hour at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with water, added with sulfuric acid solution (20 ml, 10%) and stirred for 30 minutes, and extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-(cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60a (576 mg, yield 39.6%) as a white solid.