Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1[N:49]=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1(N)CCCC1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][N:48]5[CH2:43][CH2:44][CH2:45][CH2:46]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCC1
Product: COc1cc(C(=O)NN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and pyrrolidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.75 (m, 6H) 1.90-2.02 (m, 2H) 2.67-3.03 (m, 4H) 3.57 (s, 3H) 3.95 (s, 3H) 4.05 (t, 2H) 4.73-4.81 (m, 1H) 7.48-7.54 (m, 2H) 8.00 (s, 1H) 8.20 (d, 1H) 8.27 (s, 1H) 8.30 (d, 1H). [M+H] calc'd for C25H31F2N7O3, 516. found 516.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19](O)[CH3:20])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:29])=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19]([Cl:29])[CH3:20])[CH:3]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CC(OC)C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CC(OC)C1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile (30 mg, 0.1 mmol) (racemic mixture) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (100 μL, 1 mmol). Thionyl chloride (18 μL, 0.24 mmol) was added dropwise at room temperature and the reaction was stirred for 2 hrs. The reaction was diluted with EtOAc, washed with water and saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give the crude 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (0.030 g, 100%). LCMS calculated for C15H19Cl2N2O3(M+H)+: m/z=329.1; found: 329.1.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][NH2:14].CCN(C(C)C)C(C)C.[CH2:24]([OH:26])[CH3:25]>CCOC(C)=O>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:14]([CH2:25][CH2:24][OH:26])[N:13]=[CH:4]2)([O-:12])=[O:11]
Reactant: NN
Reactant: CCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCO)c1

Procedure:
To a solution of 2-chloro-5-nitrobenzaldehyde (4 mmol) in ethanol (10 mL) was added aqueous hydrazine (5 mmol), and the resulting solution was heated at reflux for 2 h to complete hydrazone formation. DIEA (10 mmol) was added to the reaction mixture, and the reaction was subjected to microwave irradiation at 150° C. for 8-10 h. After removal of volatiles in vacuo, the residue obtained was dissolved in EtOAc (30 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield the product, 2-(5-nitroindazol-1-yl)-ethanol.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([O:25][CH3:26])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(CNCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of benzylamine (13.1 mL, 0.12 mol) and 4-benzyloxy-3-methoxybenzaldehyde (24.2 g, 0.1 mol) in 1,2-dichloroethane (50 mL) and chloroform (250 mL) was added sodium triacetoxyborohydride (31.79 g, 0.15 mol). The mixture was stirred at room temperature for 18 hrs, saturated NaHCO3 was added. The organic phase was separated and aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil in 76% yield (25.2 g). Rf: 0.17 (petrol:ethyl acetate; 1:1). 1H NMR (270 MHz, CDCl3) δ 3.73 (2H, s), 3.79 (2H, s), 3.89 (3H, s), 5.13 (2H, s), 6.75-6.84 (2H, m), 6.91 (1H, d, J=1.4), 7.23-7.44 (10H, m); HRMS (ESI+) calcd. for C22H24NO2 (M++H) 334.1802, found 334.1787; LC/MS (ES+) tr=1.19 min, m/z 334.5 (M++H);
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:12][C:11]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:10]=2[CH3:9])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1

Procedure:
4,6-Dichloropyrimidine (5.37 g, 36.0 mmol) and 2-methyl-5-nitroaniline (5.48 g, 36.0 mmol) are heated in n-butanol (58 mL) with diisopropylethylamine (4.66 g, 36 mmol) for 3 days at 110° C. The mixture is evaporated and the product is purified by standard methods.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[CH3:12][NH2+]C.C=O>>[CH:2]([C:3](=[CH2:12])[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:1]
Reactant: CCOC(=O)CCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCC(=O)OCC

Procedure:
With stirring, 14.4 g (100 mmol) of ethyl 5-oxopentanoate, 9.2 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37% formaldehyde solution are heated to 100° C. The mixture is cooled and extracted with 3×30 ml of diethyl ether. The batch is cooled and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness, giving ethyl 4-formylpent-4-enoate as a colorless oil which can be further reacted without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[O:14])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[BH4-].[Na+].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([O:14][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1CCn2c1cc1cc(Br)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCn2c1cc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (1.1 g, 4.4 mmol) in MeOH (20 mL), cooled to 0° C., was added NaBH4 (0.33 g, 8.8 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with H2O and then extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford a white solid which was used without further purification. The crude solid was dissolved in CH2Cl2 (20 mL) and TBSCl (0.7 g, 4.4 mmol) and imidazole (0.33 g, 4.4 mmol) were added. After stirring at room temperature for 1 h, the reaction mixture was poured into H2O and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid (1.26 g, 79%).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:39][CH3:38])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and methylamine (45 uL, 0.09 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.6 mg, 31%). LC-MS m/z 521 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1cc(Cl)ccc1CO
Product: Cc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.18 (2H, s), 5.77 (1H, d, J=2.0 Hz), 7.18-7.22 (2H, m), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.58 (1H, d, J=2.0 Hz), 8.00 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O, 325. Found, 325.
Reaction SMILES: COC([C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][C:7]([CH2:11][C:12]([Cl:14])=[CH2:13])([CH3:10])[C:6]1=[O:15])=O.[OH-].[Na+]>CC(O)C.O>[Cl:14][C:12](=[CH2:13])[CH2:11][C:7]1([CH3:10])[CH2:8][CH2:9][CH:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:6]1=[O:15]
Reactant: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2.5 h

Procedure:
3-(2-Chloro-2-propenyl)-1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XIII), R1═CH3, (Rb)Xbnb=CH2CCl═CH2, R2═CH3) (2.90 g, 8.16 mmol) was dissolved in i-PrOH (5 ml), and then an aqueous solution of NaOH (0.65 g, 16.3 mmol) dissolved in water (5.4 ml) was added, and stirring under reflux was conducted for 2.5 hours. Water (50 ml) was added, and extraction with hexane (50 ml×2) was conducted. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain the desired substance
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[N+:19]([O-])=O.[H][H]>[Pt].C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[NH2:19]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Oc2ccccc2)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c(Oc2ccccc2)n1
Reaction time: 2 h

Procedure:
Toluene (150 ml), 5% platinum on carbon (1.55 g), and N-(2-methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine (31.00 g) from Part C were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 2 hours with shaking. The reaction was monitored by TLC and HPLC. More 5% platinum on carbon (5 g) was added. After 2 hours, another 4 g of 5% platinum on carbon was added and the reaction was continued overnight. The resulting reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. After one hour the resulting brown oil solidified. NMR analysis of the solid (26.37 g) indicated sufficient purity for carrying the product on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (77 mg, 351 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.35 mL, 0.70 mmol) at RT followed by 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (90 mg, 350 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 19 mg of 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 37 as a brown solid (22 mg, 13% yield).
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC=CC=1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:43]([O-:45])=[O:44].[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>N1C=CC=CC=1>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:26]([N+:43]([O-:45])=[O:44])[CH:27]=1)(=[O:33])=[O:32]
Reactant: C1CNCCN1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(N2CCNCC2)c([N+](=O)[O-])c1

Procedure:
The compound was prepared from 4-chloro-3-nitrobenzenesulfonyl chloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2CL2 (2 mL). 4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 g) was reacted with piperazine (0.111 g) to afford N-(2-methoxyphenyl)-4-(piperazinyl)-3-nitrobenzenesulfonamide. This was then treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt. 1H NMR (DMSO-d6) δ 7.18–7.20 (m, 1H), 7.08–7.10 (m, 2H), 6.93–6.96 (m, 1H), 6.91–6.93 (m, 2H); 6.84 (dt, 1H), 3.56 (s, 3H), 3.22–3.27 (m, 4H), 3.00–3.02 (m, 4H); MS (posESI) m/z=362.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.OS(O)(=O)=O.[C:20](=O)([O-])O.[Na+]>CO>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH3:20])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc2c1C(=O)CCC2
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2c1C(=O)CCC2

Procedure:
A solution of 3.466 g of 8-oxo-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid in 30 ml of methanol is admixed with 1.850 ml of conc. H2SO4 and the reaction solution is subsequently heated to reflux over 18 hours. The reaction solution is subsequently cooled and poured onto 200 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2×200 ml of ethyl acetate. The combined organic phases are washed with 150 ml of saturated aqueous sodium hydrogencarbonate solution and 150 ml of water, dried over sodium sulphate and concentrated. The crude product is obtained as a brown oil and is used without further purification. Rt=3.42
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH3:35][S:36]([NH:1][CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:38])=[O:37]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1ccoc1[Si](CC)(CC)CC
Reactant: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCC(NS(C)(=O)=O)c1ccoc1[Si](CC)(CC)CC

Procedure:
Reducing 3-(1-azidotridecyl)-2-triethylsilylfuran with lithium aluminum hydride, as in Example 8, followed by reacting the intermediate with methanesulfonyl chloride, gives 3-(1-methanesulfonamidotridecyl)-2-triethylsilylfuran. Oxidizing this sulfonamide followed by reduction with sodium borohydride gives 3-(1-methanesulfonamidotridecyl)-2(5H)-furanone.
Reaction SMILES: Cl.[CH3:2][P:3]([CH2:6][CH2:7][NH2:8])([CH3:5])=[O:4].Br[CH2:10][C:11]1[CH:39]=[CH:38][C:14]([C:15]([NH:17][C:18]2[CH:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=[CH:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:27]([O:26][C:25](=[O:31])[NH:24][C:23]1[CH:22]=[CH:21][C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C:14]1[CH:38]=[CH:39][C:11]([CH2:10][NH:8][CH2:7][CH2:6][P:3]([CH3:5])([CH3:2])=[O:4])=[CH:12][CH:13]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CBr)cc1
Reactant: CP(C)(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CNCCP(C)(C)=O)cc1

Procedure:
2-(Dimethylphosphoryl)ethanamine hydrochloride (393 mg, 2.493 mmol), tert-butyl (3-{[4-(bromomethyl)benzoyl]amino}biphenyl-4-yl)carbamate (400 mg, 0.831 mmol), and DIEA (581 μl, 3.32 mmol) were combined in DMF (8 mL) and water (0.50 mL) and stirred at 60° C. overnight. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (4×). The combined organics were dried (MgSO4), evaporated, and purified by reverse phase HPLC (25-95% MeCN/water w/0.025% TFA). Product fractions were neutralized with saturated NaHCO3, extracted with EtOAc (2×), dried (MgSO4), and evaporated to give a colorless solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][NH:5]1)([OH:3])=[O:2].Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].[OH-].[Na+].[Cl-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:14]([O:13][C:11]([N:5]1[CH2:6][C@H:7]([OH:9])[CH2:8][C@H:4]1[C:1]([OH:3])=[O:2])=[O:12])[CH:15]=[CH2:16]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of (2S,4R)-2-carboxy-4-hydroxypyrrolidine (300 g) in a mixture of tetrahydrofuran (1.5 l) and water (1.5 l) was added dropwise a solution of allyl chloroformate (292 ml) in tetrahydrofuran (300 ml) at 0° C. while adjusting pH to around 9 with 4N aqueous sodium hydroxide. After stirring at 0° C. for 1 hour at pH 9, the aqueous layer was saturated with sodium chloride, and the mixture was diluted with ethyl acetate (1 l). The aqueous layer was separated, washed with ethyl acetate (1 l). After adjusting pH to around 2 with 12N hydrochloric acid, the emulsion was extracted with two portions of ethyl acetate (1 l×2). The combined extract was dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (426.2 g)
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[NH2:8][C:9]1C=C[C:12]([S:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)=[CH:11][C:10]=1O>C(OCC)(=O)C>[CH:21]1[C:22]2[C:17](=[C:16]([S:15][C:12]3[CH:11]=[CH:10][C:9]4[N:8]=[C:5]([CH3:6])[O:4][C:1]=4[CH:2]=3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: Nc1ccc(Sc2cccc3cnccc23)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Sc3cccc4cnccc34)cc2o1
Temperature: 200 °C
Yield: 50.6 %

Procedure:
Acetic anhydride 0.6 ml was added to 2-amino-5-(5-isoquinolylsulfanyl)phenol 210 mg (0.8 mmol), and the mixture was heated for 1 hour at 200° C. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 0.5 N sodium hydroxide, water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH-silica gel, hexane:ethyl acetate=1:1), and 6-(5-isoquinolylsulfanyl)-2-methylbenzo[d][1,3]oxazole 120 mg (50.6%) was obtained.