Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH3:46])([CH3:45])[C:37]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CO.ClCCl>[CH3:46][C:38]1([CH3:45])[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]([CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:30][CH:31]=4)[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:37]1=[O:47]
Reactant: CC1(C)C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C(C)(C)c5ccccc54)CC3)C2=O)cc1
Yield: 83.9 %

Procedure:
tert-Butyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.14 g, 0.593 mmol), sodium iodide (0.026 g, 0.18 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.31 g, 85%); MS for C38H46N4O4 m/z 623 (M+H)+.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:18]1[N:22]=[N:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].IC>C1COCC1>[CH2:6]([N:18]1[N:22]=[N:21][C:20]([C:23]([CH3:2])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 1073.2 %

Procedure:
To a THF solution (30 mL) of n-BuLi (0.0055 mol, 1.6M in hexanes) at -78° C. under N2 with stirring was added 1.0 g (0.00027 mol) of (±)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetic acid (Compound d, Example 13). The resulting yellow solution was stirred at -78° C. for 30 minutes before iodomethane (0.34 mL, 0.0055 mol) was added. This solution was stirred for 3 hours before quenching with 1N HCl (20 mL). The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 1.12 g of pure product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14]C(C#N)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[ClH:18].[C:19]([OH:22])(=[O:21])[CH3:20]>>[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:20]([C:19]([OH:22])=[O:21])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CC(=O)O
Reactant: N#Cc1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Product: O=C(O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.10 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-carbonitrile and concentrated hydrochloric acid in acetic acid is heated at reflux temperature for 16 hours. The solvent is removed to give 7-(3-pyridyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate hydrochloride. The preceding compound is added portionwise to a chilled solution of 0.30 mole of diborane in tetrahydrofuran. After the addition the mixture is stirred for 16 hours and poured onto ice to give the product of the example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[NH:9]2)=[CH:5][CH:4]=1.O.[OH-].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(C(=O)O)[nH]c2c1
Reaction time: 1.5 h

Procedure:
Methyl 6-methoxyindole-2-carboxylate (PREPARATION 62, 5.71 g) is dissolved in 70 ml of dioxane and 7 ml of water and 1.87 g of crushed potassium hydroxide are added. The reaction is heated to 50° and stirred 1.5 hr. The reaction mixture is acidified to pH 4-5 and extracted several times with methanol/chloroform (10/90). The organic layers are combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title acid, NMR (300 MHz, d4-CD3OD) 7.47, 7.08, 6.90, 6.72 and 3.82 δ.
Reaction SMILES: Cl[C:2]1[N:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5].[Cl-].Cl.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH2:42][CH2:43][NH2:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:33][C:31]1[CH:30]=[CH:29][C:3]([C:4]([NH:6][CH2:7][C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:5])=[C:2]([NH:44][CH2:43][CH2:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)[N:32]=1
Reactant: O=C(NCCCC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(Cl)nc1Cl)OCc1ccccc1
Reactant: NCCC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(NCCCC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(Cl)nc1NCCC1CCCCO1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 34.8 %

Procedure:
A mixture of chloride (R)-benzyl 4-(2-((2,6-dichloronicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (150 mg, 0.304 mmol), 2-(tetrahydro-2H-pyran-2-yl)ethanamine HCl salt (76 mg, 0.459 mmol), K2CO3 (125 mg, 0.905 mmol) and DMF (1 mL) was stirred at 100° C. for 10 hrs. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give benzyl 4-((R)-2-((6-chloro-2-(2-(tetrahydro-2H-pyran-2-yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (62 mg, 35%). LRMS (M+H+) m/z 586.3.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][N:10](C(C3C=CC=CC=3)CC3C=C(C)C=CC=3)[CH2:9][CH2:8]2)CCCCC1.[OH2:28].[C:29]([C@:37]([C:52]([OH:54])=[O:53])([OH:51])[C@:38]([C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([OH:42])[C:39]([OH:41])=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[OH2:36].[C:43]([C@:38]([C:39]([OH:41])=[O:40])([OH:42])[C@:37]([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:51])[C:52]([OH:54])=[O:53])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[OH2:28].[OH2:36].[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:43]([C@:38]([C:39]([OH:41])=[O:40])([OH:42])[C@:37]([C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:51])[C:52]([OH:54])=[O:53])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: C1CNCCN1

Procedure:
A warmed mixture of dl-1-cyclohexyl-4-[1-phenyl-2-(3-tolyl)ethyl]piperazine (3.0 g), dibenzoyl-d-tartaric acid monohydrate (3.2 g) and ethanol (100 ml) is allowed to cool. The precipitated crystals are separated by filtration and fractionally recrystallized from 95% ethanol to give l-1-cyclohexyl-4-[1-phenyl-2-(3-tolyl)ethyl[piperazine dibenzoyl-d-tartarate sesquihydrate (1.2 g), melting point: 150°- 151° C. (decomp.), [α D28 = -83.0° (c=1.0, methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([F:22])[CH:15]=[CH:16][C:17]=2Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([F:22])[CH:15]=[CH:16][C:17]=2[C:30]2[CH:29]=[C:28]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:45])[CH:33]=[CH:32][C:31]=2[O:34][CH3:35])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(OCc1ccccc1)N1CCc2c(Br)ccc(F)c2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CCN(C(=O)OCc2ccccc2)C3)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a mixture under N2 of 5-bromo-8-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (529 mg, 1.45 mmol, 1.00 eq.), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (659 mg, 1.45 mmol, 1.00 eq.) and sodium carbonate (616 mg, 5.81 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (29 mL), tetrakis(triphenylphosphine) palladium (0) (84 mg, 0.07 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (60 mL) and water (60 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×60 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 40 fractions of 40 mL, Heptane 100% to Heptane+30% AcOEt) to yield the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5](O)=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=O)OC(=O)[C:14]2=[CH:20][C:21]=1[Cl:22].O>CS(O)(=O)=O>[Cl:22][C:21]1[C:11]([Cl:10])=[C:12]([C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH2:18][C:4]3[C:3]([O:9][C:14]=2[CH:20]=1)=[CH:2][CH:8]=[CH:7][CH:5]=3
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: Oc1ccc(Cl)c(O)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: Clc1cc2c(c(-c3ccccc3)c1Cl)Cc1ccccc1O2
Temperature: 180 °C
Reaction time: 24 h

Procedure:
4-Chlororesorcinol (33 g) was mixed with 4,5-dichlorophthalic anhydride in methane sulfonic acid (100 mL) according to the procedure of Menchen, et. al, (U.S. Pat. No. 5,654,442). Briefly, with magnetic stirring, the solution was heated to 180° C. over 30 min and maintained for an additional 30 minutes. The mixture was allowed to cool to ˜100° C. and was cautiously poured into water (1 L). The solid was collected by filtration and air dried for several days, followed by 24 h of high vacuum and was characterized as having the structure above.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(C(N)=O)cc1)nn2C1CCCC1
Yield: 90.5 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (120 mg) obtained in Step C of Example 12, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg), tetrakis(triphenylphosphine)palladium(0) (38.0 mg) and 2M aqueous sodium carbonate solution (0.821 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.C1OCCOCCOCCOCCOCCOC1.[C-:47]#[N:48].[K+]>CS(C)=O.O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:47]#[N:48])[CH2:5]1
Reactant: [C-]#N
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
5 (13.76 g, 0.034 mol) was dissolved in DMSO (17 mL). 18-Crown-6 (5 eq) and finely ground KCN (5 eq) were added and the reaction mixture was stirred for 6 h at 80° C. The reaction solution was diluted with H2O (17 mL) and then extracted with ethyl acetate. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (4/1, v/v) to afford 13.76 g (69% yield) of the desired product 6 as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N+:13]([O-:28])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccnc2ccccc12)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(Cc1cc[n+]([O-])c2ccccc12)OCC
Reaction time: 0.75 h

Procedure:
To a solution of 5.7 g of 4-(diethylphosphonomethyl)-quinoline in 100 ml of methylene chloride at room temperature is added 3.2 g of m-chloroperberzoic acid. After reacting for 45 minutes, an additional 1.5 g portion of m-chloroperbenzoic acid is added, and the reaction mixture is stirred for one hour. The reaction mixture is washed with saturated potassium carbonate solution, dried over sodium sulfate and evaporated to dryness to give 4-(diethylphosphonomethyl)-quinoline-N-oxide.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[CH2:29](N)CC.CC1C=C(NCC2(C(F)(F)F)CO2)C2C=NN(C3C=CC=CC=3)C=2C=1>>[F:7][C:6]([F:9])([F:8])[C:5]([CH2:4][NH:3][CH2:1][CH2:2][CH3:29])([OH:10])[CH2:11][NH:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCN
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccccc3)c2c1
Product: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 18 from n-propylamine and 6-methyl-1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][NH:30][CH3:31].[BH4-].[Na+]>CO>[CH3:29][N:30]([CH2:18][C:17]1[CH:16]=[C:15]([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:31]
Reactant: CNC
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (45 mg, 0.12 mmol) and 33% dimethylamine solution (50.2 mg, 0.366 mmol) in methanol (5 mL) was stirred at room temperature for 1 h. Then the mixture was cooled to 0° C., sodium borohydride (6.95 mg, 0.184 mmol) was added portionwise. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was purified by prep-HPLC to give 9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (21 mg, yield 44%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.59 (s, 3H), 2.75 (s, 3H), 4.11-4.27 (q, 2H), 4.31-4.34 (d, J=10.4 Hz, 1H), 4.68-4.71 (d, J=10.4 Hz, 1H), 7.17-7.30 (m, 9H), 7.33-7.37 (t, J=7.6 Hz, 1H), 7.56-7.58 (d, J=7.6 Hz, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C.[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@@H:49]([OH:52])[CH2:50][OH:51])=[C:43]3[C:39]=2[C:40]2[CH:56]=[C:55]([CH3:57])[CH:54]=[N:53][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])=[C:43]3[C:39]=2[C:40]2[CH:56]=[C:55]([CH3:57])[CH:54]=[N:53][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@@H](O)CO)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@H](O)CO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 157 using an analogous procedure to the procedure described for the preparation of Compound 230. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 2.27 (s, 3 H) 3.41 (q, J=7.41 Hz, 2 H) 3.60 (t, J=5.81 Hz, 2 H) 3.96 (m, 1 H) 4.11 (dd, J=9.60, 6.06 Hz, 1 H) 4.27 (dd, J=9.60, 4.29 Hz, 1 H) 4.73 (t, J=5.68 Hz, 1 H) 4.99 (d, J=5.31 Hz, 1 H) 7.07-7.15 (m, 2 H) 7.57 (d, J=1.77 Hz, 1 H) 7.85 (t, J=7.71 Hz, 1 H) 7.97 (t, J=1.64 Hz, 1 H) 7.99 (m, 1 H) 8.09 (t, J=1.64 Hz, 1 H) 8.28 (d, J=2.02 Hz, 1 H) 11.93 (s, 1 H); [M+H] calc'd for C23H25N2O5S, 441.1; found, 441.4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([OH:10])=O.O=S(Cl)[Cl:13]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCOCCCBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(3-bromopropoxy)propionic acid (15.2 g, 72.2 mmol) in CCl4 (250 mL) was added SOCl2 (5.5 mL, 76.0 mmol) and DMF (20 drops) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title intermediate, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
120.00 g (0.33 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) of triethylamine were stirred in 1200 ml of toluene at 60° C. for 2 days. The precipitated solid was filtered off with suction and recrystallized from acetone/n-hexane. 102.10 g (71%) of the title compound having a melting point of 243-245° C. were obtained.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10].[S:11]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+]>CO.[Cu]>[F:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][S:11]1(=[O:18])=[O:17]
Reactant: O=S1(=O)CCCCN1
Reactant: COc1cccc(F)c1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cccc(F)c1N1CCCCS1(=O)=O
Reaction time: 18 h

Procedure:
2-Bromo-1-fluoro-3-methoxybenzene (200 mg, 0.975 mmol), 1,2-thiazinane 1,1-dioxide (264 mg, 1.951 mmol), copper (62 mg, 0.975 mmol) and potassium carbonate (270 mg, 1.95 1 mmol) were combined and heated to 170 C for 5 hours. After this time, the mixture was suspended in methanol (15 ml) and vortexed for 18 hours. This mixture was filtered through Gelman Acrodisc and evaporated in vacuo. The resulting residue was partitioned between EtOAc (2×10 ml) and aq NH4Cl (5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. This residue was purified by column chromatography eluting with a 0-10% EtOAc/CH2Cl2 to give 2-(2-fluoro-6-methoxyphenyl)-1,2-thiazinane 1,1-dioxide. Low resolution mass spectrometry: (M+H+)=260.1. 1H NMR (400 MHz, CDCl3) δ 7.21 (dt, 1H, J=8.1 and 4.3 Hz), 6.69-6.77 (m, 21), 3.88 (s, 3H), 3.75-8.74 (m, 1H), 3.65 (dq, 1H, J=4.6, 6.0 and 14 Hz), 3.24 (dd, 2H, J=5.6 and 7.4 Hz), 3.27 (quin, 2H, J=6.1 Hz) and 1.78-1.90 (m, 2H) ppm.