Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][NH:31][CH3:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]([CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[CH3:32])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CNCCN(C)C
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (56 mg, 0.15 mmol) in DMF (1 mL) were added N1,N1,N2-trimethylethane-1,2-diamine (17 mg, 0.17 mmol), diisopropylethylamine (DIPEA) (59 μL, 0.34 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (70 mg, 0.18 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 53 as a solid (11 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([Cl:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:16][C:15]1[C:10]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:11][C:12](=[O:17])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1Cl
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
400 mg (purity 91%, 1.37 mmol) of 4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 421 mg (80% of theory)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Li]CCCC.[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:17])[CH3:16].CN([CH:34]=[O:35])C>C1COCC1>[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH:34]=[O:35])=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C=O)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylethylamine (7.4 mL, 53.2 mmol) in THF was added n-BuLi (18.8 mL, 47.1 mmol, 2.5 M solution in hexanes) at −78° C., and allowed to stir at 0° C. of 30 minutes. The reaction mixture was again cooled to −78° C. and a solution compound tert-butyl(4,6-dichloropyridin-2-yl)carbamate (4.0 g, 15.2 mmol) in THF (20.0 mL) was added dropwise and stirred for 1 h at the same temperature. After 1 h, DMF (8.08 g, 36.7 mmol) was added at the same temperature and stirred for 30 minutes. After confirming the completion of starting material by TLC, the reaction mixture was quenched with saturated ammonium chloride solution extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product which was purified by column chromatography (hexanes:ethyl acetate=4:1) to afford product. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.22 (s, 1H), 7.95 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: COc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (1661 mg) was added to N,N-dimethylformamide (50 mL). Sodium hydride (60% in mineral oil, 430 mg) was added, the solution stirred for 15 minutes at room temperature, and 1-(bromomethyl)-4-methoxybenzene (2061 mg) was added. The solution was stirred at room temperature for three days, added to 0.01M aqueous HCl, and extracted with ethyl acetate. The organic phase was washed with water twice, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[O:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1.O1CCN(CC[N+]#[C-])CC1.O[N:45]1[C:49](=[O:50])[CH2:48][CH2:47][C:46]1=[O:51]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33][N:45]2[C:49](=[O:50])[CH2:48][CH2:47][C:46]2=[O:51])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[O:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3occc23)S(=O)(=O)CCCC(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: [C-]#[N+]CCN1CCOCC1
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3occc23)S(=O)(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of 140 mg (0.26 mmol) N-(4-Methoxy-phenyl)-N-(carboxypropyl-sulfonyl)-furo[2,3-b]quinoline-4-carboxamide 10, 54 μl (0.37 mmol) 2-Morpholino-ethyl-isocyanide (MEI) and 44 mg (0.37 mmol) N-Hydroxysuccinimide (HOSu) was stirred overnight at room temperature. The solvent was removed under vacuum and the oily residue was purified by silica gel column chromatography (eluent: methylene chloride/acetone 9:1+0.1% acetic acid). The appropriate fractions were combined and evaporated to yield 94 mg of 11.
Reaction SMILES: C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[C:11]([C@@:14]1([OH:25])[C:19](=[O:20])[O:18][C:16](=[O:17])[C@@:15]1([C:22](=[O:24])[CH3:23])[OH:21])(=[O:13])[CH3:12].C(O)(=O)C(C(C(O)=O)O)O.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[C:11]([C@:14]1([OH:25])[C:19](=[O:20])[O:18][C:16](=[O:17])[C@:15]1([C:22](=[O:24])[CH3:23])[OH:21])(=[O:13])[CH3:12]
Reactant: CC(=O)[C@@]1(O)C(=O)OC(=O)[C@]1(O)C(C)=O
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)[C@]1(O)C(=O)OC(=O)[C@@]1(O)C(C)=O

Procedure:
Diacetyl-L-tartaric anhydride is prepared from D-tartaric acid in the manner described in "DIACETYL-d-TARTARIC ANHYDRIDE (Tartaric anhydride, diacetate of d-)", Organic Synthesis, Collective Volume 4, 242-243 (1963). Briefly, a tartaric acid isomer or mixture of isomers is treated with acetic anhydride with a catalytic amount of sulfuric acid. The solution is heated gently for about 10 minutes and poured into an ice bath. The crystalline material formed is collected on a filter and is washed with toluene and ether and dried over phosphorus pentoxide and paraffin shavings. The crystalline bisacetyltartaric anhydride is used as is described in the following paragraph.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]1[C:12](=[O:13])[O:11][C:10](C)(C)[O:9]1>CO>[CH3:10][O:11][C:12](=[O:13])[C:8]([OH:9])=[CH:7][C:6](=[O:16])[N:5]([CH2:4][C:3]1[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=1[F:1])[O:17][CH3:18]
Reactant: CON(Cc1ccccc1F)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccccc1F)OC
Yield: 59 %

Procedure:
N-(2-Fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (59% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.93 (2H, s, NCH2), 6.47 (1H, s, CH), 7.05–7.36 (4H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 54.91; H, 5.23; N, 4.86.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14](C#N)=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O.CCCCCC>CC(N(C)C)=O.CCOC(C)=O>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:5]1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Temperature: 82.5 °C

Procedure:
A mixture of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (343 mg) and (4-methoxybenzyl)amine (0.137 ml) in DMA (1 ml) was heated at 80-85° C. for 25 hours. After addition of water, a precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarbonitrile as an amorphous solid (227 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:14]#[N:15]
Reactant: Cc1cc(C)c(Cl)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for 5 h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#CCOc1cc(C=O)ccc1OC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC#CCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 54.9 %

Procedure:
Piperidine (0.24 mL, 2.5 mmol) was added to a suspension of 4-methoxy-3-(pent-2-ynyl)oxybenzaldehyde (0.54 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.53 g, 2.4 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(4-Methoxy-3-(pent-2-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.50 g, 60%) was obtained as a yellow crystalline solid; mp 124-125° C.; δH (400 MHz, DMSO-d6) 1.06 (t, J=7.4 Hz, 2H, CH2CH3), 2.23 (q, J=7.4 Hz, 3H, CH2CH3), 3.80 (s, 3H, OCH3), 4.81 (s, 2H, OCH2), 6.73 (d, J=15.6 Hz, 1H, CH═CHCO), 7.01 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.28 (dd, J5′,6′=8.4, J2′,6′=1.6 Hz, 1H, H6′), 7.42 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.57 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 13.6, 55.6, 56.6, 74.9, 89.3, 111.9, 112.5, 116.5, 119.9, 120.3, 122.7, 123.3, 127.0, 131.1, 134.0, 141.1, 141.6, 146.8, 151.0, 164.1, 169.5; HRMS (ESI) calculated for C22H21NO6 [M+Na]+ 402.1312. found 402.1317; vmax 753, 1015, 1257, 1506, 1584, 1659, 2920, 3246, 3520 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]#[N:12])[CH:5]=1.Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(C#N)c1
Yield: 94 %

Procedure:
To a stirred solution of 24.0 g (134 mmol) 2b and 240 ml dimethylsulphoxid were added 13.2 g (161 mmol) dimethylamine hydrochloride and 38.9 g (281 mmol) potassium carbonate. The reaction mixture was stirred over night and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 2c was obtained in 94% yield (25.7 g, 126 mmol) and was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:23][CH3:24].[CH:25](OCC)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH2:12][CH2:13][N:14]([CH:25]=[O:26])[CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:23][CH3:24]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CNCC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CN(C=O)CC1

Procedure:
To a solution of the free base 7,8-dimethoxy-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline, (390 mg, 1.2 mmol, from Example 200) in THF (25 mL) was added ethyl formate (40 mL). The resulting solution was heated at reflux for 17 hours, concentrated, and the concentrate was chased with THF. The crude product was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=3[S:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH2:13][CH3:14]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C(F)(F)F)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (50 mg, 0.242 mmol) was reacted with the product from Example 35a (79.0 mg, 0.242 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the ditrifluoroacetic acid salt (10.5 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H), 1.81-1.92 (m, J=7.35 Hz, 2H), 2.07 (s, 3H), 3.01 (t, J=7.54 Hz, 2H), 6.44 (d, J=6.99 Hz, 1H), 7.11 (d, J=8.46 Hz, 1H), 7.42-7.49 (m, J=8.46 Hz, 2H), 7.69 (d, J=8.82 Hz, 2H), 7.78 (dd, J=8.82, 1.47 Hz, 1H), 7.87 (d, J=8.82 Hz, 1H), 7.91 (d, J=1.10 Hz, 1H), 8.52 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 11.14 (s, 1H); MS (ESI+) m/z 497 (M+H)+, ESI− m/z 495 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2].[OH-].[Na+:18].O>C(O)C>[CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2].[Na+:18]
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1Cc2ccc(C(C)C(=O)[O-])cc2C1

Procedure:
To 12.2g. of 2-(2-ethylindan-5-yl)propionic acid was added a solution of 2.2g. of sodium hydroxide in 9 ml. of water and 21 ml. of ethanol. After complete dissolution, the solvent was distilled off under reduced pressure and to the residue was added ether. The precipitates thus separated were recovered by filtration and washed with either to give 12.9g. of a white powder. The powder was recrystallized from a mixture of ethanol and ether to give the desired product as white needles of m.p. 178° - 181° C.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][CH:9](CC(C)=O)[CH3:10]>>[CH3:6][C:5](=[CH:4][C:2](=[O:1])[CH:3]=[C:9]([CH3:10])[CH3:8])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CC(=O)CC(C)C
Product: CC(C)=CC(=O)C=C(C)C

Procedure:
Mesityl oxide isomer→MIBK→MIBC  (7)
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:18].[Na+].C(OO)=O>C(O)=O.O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:18]
Reactant: Cn1nnnc1SCc1ccccn1
Reactant: O=S([O-])O
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)Cc1ccccn1
Reaction time: 5 h

Procedure:
1-Methyl-5-(2-pyridyl)methylthio-1,2,3,4-tetrazole (2.0 g) is dissolved in formic acid (20 ml), and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. Sodium hydrogensulfite is added to the mixture under ice-cooling in order to decompose excess performic acid. Water is added to the mixture and it is extracted with chloroform. Chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 1-methyl-1,2,3,4-tetrazol-5-yl 2-pyridylmethyl sulfoxide as brown liquid, nD26.5 =1.5810.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[NH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:33][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[N:12][N:13]=1
Reactant: COc1ncc(Cc2n[nH]c(=O)c3ccccc23)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: COc1ncc(Cc2nnc(Cl)c3ccccc23)cc1Br
Temperature: 25 °C

Procedure:
To a suspension of 1.38 g (4.00 mMol) of 4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazin-1(2H)-one and 1.33 g (8.0 mMol) of Et4NCl in 75 ml of acetonitrile under N2-atmosphere, 1.01 ml (8.0 mMol) of N,N-dimethyl-aniline and 8.79 ml (96 mMol) of POCl3 are added. After heating the mixture for 1 h to 90° C., the resulting solution is cooled to RT, pored into 400 ml of icewater and 500 ml sat. NaHCO3 solution and extracted with 3 portions of EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated to the title compound containing some 1-chloro-4-[5-bromo-6-hydroxy-(pyridin-3-yl)-methyl]phthalazine: FAB-MS: (M+H)+=364/366; HPLC(Grad20-100) tRet=14.5.
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:22])([F:24])[F:23])[CH:12]=2)[C:3]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Yield: 55.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (395 mg, 1.04 mmol) and 2-aminothiazole (209 mg, 1.38 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.09 mL, 1.38 mmol) was heated at 110° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (256.7 mg, 55.1%) as a white solid: mp 95–100° C.; EI-HRMS m/e calcd for C19H21F3N2O3S2 (M+) 446.0946, found 446.0944.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][C@@H:13]([CH3:15])[N:12]([S:16]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH:22]([C:28]([O:30]C)=[O:29])[CH2:23]4)(=[O:18])=[O:17])[C@@H:11]([CH3:32])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[OH-].O1CCCC1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][C@@H:11]([CH3:32])[N:12]([S:16]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH:22]([C:28]([OH:30])=[O:29])[CH2:23]4)(=[O:18])=[O:17])[C@@H:13]([CH3:15])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)N3[C@H](C)CN(c4ccc(Cl)c(Br)c4)C[C@@H]3C)c2C1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Cl)c(Br)c2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(4-(3-bromo-4-chlorophenyl)-cis-2,6-dimethylpiperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2(R,S)-carboxylate (194 mg, 0.36 mmol), 1N LiOH (2 mL), tetrahydrofuran (8 mL), and methanol (2 mL) was stirred at rt for 2 h. The reaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic extracts were dried, filtered, and concentrated to give 4-(4-(3-bromo-4-chlorophenyl)-cis-2,6-dimethylpiperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2-carboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ 12.30 (br s, 1H), 7.63 (d, 1H), 7.49 (d, 1H), 7.37-7.31 (m, 2H), 7.16 (d, 1H), 6.88 (dd, 1H), 4.04-3.97 (m, 1H), 3.95-3.87 (m, 1H), 3.52-3.44 (m, 2H), 3.40-3.28 (m, 3H), 3.24-3.10 (m, 2H), 2.75-2.64 (m, 2H), 1.35 (d, 6H); MS (ESI): 527.3 (M+H).