Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22](I)=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N(CC(O)=O)C.[CH3:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.C(OCC)C.CO>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([N:48]([CH3:47])[S:49]([CH3:52])(=[O:51])=[O:50])=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(Cc3ccc(F)cc3)c1=O)N2)S(C)(=O)=O
Temperature: 100 °C
Yield: 65 %

Procedure:
1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6 benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 9b, 0.269 g, 0.477 mmol), potassium phosphate (tribasic) (0.506 g, 2.38 mmol), copper (I) iodide (0.023 g, 0.119 mmol), sarcosine (0.026 g, 0.290 mmol, and N-methyl-methanesulfonamide (0.520 g, 4.77 mmol) were dissolved in N,N-dimethylformamide (9 mL) at 25° C. The mixture was heated to 100° C. for 6 h, then was allowed to cool to 25° C., diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→10% methanol in dichloromethane) to afford a yellow solid. Sequential trituration of this material with methanol and diethyl ether afforded the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6 benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.169 g, 0.31 mmol, 65% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.02 (3H, s), 3.31 (3H, s), 5.65 (2H, s), 6.59-6.61 (1H, m), 7.01-7.03 (1H, m), 7.14-7.19 (2H, m), 7.42-7.46 (2H, m), 7.68-7.71 (2H, m), 7.75 (1H, dd, J1=2.4 Hz, J2=8.7 Hz), 7.90 (1H, d, J=2.2 Hz), 13.72 (1H, s). LC-MS (ESI) calcd for C23H20FN5O6S2 545.08. found 546.15 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[NH:24][C:25]2=[O:26])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(N2C(=O)NC3CCCCC32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of compound {4-(2-aminocyclohexylamino)-piperidine-1-carboxylic acid benzyl ester)} (1.48 g, 4.47 mmoles) in acetonitrile (50 mL), 1,1′-carbonyldiimidazole (0.86 g, 5.36 mmole) was added and the reaction mixture was stirred at room temperature for 18 h. Reaction mixture was concentrated under reduced pressure, dissolved again in dichloromethane (60 mL) washed with water (2×100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a solid (1.45 g, 90%). MS: (M+1): 358.13
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:32])[NH:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[C:2]=[S:3].C[N:34](C=O)C.N>C(O)C>[CH3:30][N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:20]2[C:19](=[O:31])[NH:18][C:17](=[O:32])[C:16]=2[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH2:34])=[S:3])[CH:8]=2)=[CH:22]1
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cn(CCCN=C=S)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: N
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=S)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h

Procedure:
A suspension of 100 mg of the product of Example 48 in 10 ml of ethanol was treated with 4 ml of DMF and then with 10 ml of a saturated solution of ammonia in ethanol. The mixture was left to stand at room temperature for 1 hour and the solvent was then evaporated. The residue was crystallized from ethanol to give 18 mg of 3-(1-methyl-3-indolyl)-4-[1-(3-thioureidopropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 166°-168° C. (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]1>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:26][CH2:27]1)[CH3:36]
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: CCOC(=O)CC1CCNCC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2ccccc2)CC1
Yield: 65.1 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (1.0 g, 3.10 mmol) using ethyl 4-piperidine acetate (1.59 g, 9.31 mmol) to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid ethyl ester (0.96 g, 65.1%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20](C#N)=[CH:19][CH:18]=1>>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COCCCc1ccc(C#N)cc1
Product: COCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 26.9 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (3.75 g) and 4-(3-methoxypropyl)benzonitrile (4.40 g) were reacted, to give 3-[4-(3-methoxypropyl)phenyl]isoquinolin-1-one (1.98 g).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.Br[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1.C[C:41]([N:43](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH3:37][Si:36]([CH3:39])([CH3:38])[CH2:35][CH2:34][O:33][CH2:32][N:29]1[C:26]2=[N:27][CH:28]=[C:23]([C:41]#[N:43])[CH:24]=[C:25]2[CH:31]=[CH:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: C[Si](C)(C)CCOCn1ccc2cc(C#N)cnc21
Reaction time: 0.08 h

Procedure:
Zinc cyanide (900 mg), biphenyl-2-yl(di-tert-butyl)phosphine (610 mg) and zinc (67 mg) were added to a solution of 5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.917 g) in DMA (25 ml), followed by stirring for 5 minutes while degassing under ice cooling, and palladium (II) trifluoroacetate (338 mg) was added thereto, followed by stirring at 80° C. overnight after making it under an argon atmosphere. Ethyl acetate was added thereto, an insoluble substance was separated by celite filtration, and water was added to the filtrate, followed by extraction. The organic layer was washed with a 3M aqueous ammonia solution and then saturated brine in this order and was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100 to 0:100) to obtain, as a colorless amorphous solid, 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (377 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:10]([OH:19])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.[ClH:27]>CO>[ClH:27].[NH2:8][C@@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:10]([OH:19])[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C(=O)N1CCOCC1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC1CCCCC1)C(O)C(=O)N1CCOCC1

Procedure:
To a solution of 290 mg of the amide compound in 5 ml of methyl alcohol was added 1.0 ml of a 2N-hydrochloric acid, and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated under reduced pressure to obtain 206 mg of 4-[(2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyryl]morpholine hydrochloride as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1.O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([C:41]([F:40])([F:52])[F:53])[CH:43]=3)(=[O:50])=[O:49])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (76 μL, 0.474 mmol). After stirring for ˜10 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then was stirred for overnight at room temperature. Water (˜25 mL) was added and the mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. Silica gel chromatography (25-33% ethyl acetate in hexanes) afforded {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (104 mg, 84%). MS cald. for C26H26F4NO4S [(M+H)+]: 524, obsd. 524.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:40])=[CH:33][CH:34]=2)[N:7]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 62.9 %

Procedure:
Under the conditions of example 5 A, 1 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 384 mg of 4-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-7% ethyl acetate. 670 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[CH2:13]([N:15]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].C(O)(C)C>O>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][C@@H:17]([OH:20])[C@H:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][C@@H:17]([OH:20])[C@H:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14]
Reactant: CCN1CC2OC2C1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1C[C@@H](O)[C@H](Oc2ccc(C(C)=O)cc2OC)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of acetovanillone and 1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml. of methylene chloride and extracted with three 150-ml. portions of 5% sodium hydroxide and one 100-ml. portion of water. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 19.0 g. crude oil. This oil was chromatographed on 400 g. of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g. of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystallized twice from isopropyl alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p. 121-3° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)N.[CH3:17][CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(O)(=O)C>[C:21]1([C:19]2[C:18]([CH3:27])([CH3:17])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]4[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=4)[CH:8]=3)[N:2]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C(=O)c1ccccc1
Reactant: NNc1ccc(C2=NNC(=O)CC2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C)C(c2ccccc2)=Nc2ccc(C3=NNC(=O)CC3)cc21

Procedure:
3 g. (12.5 mMole) 6-(4-hydrazinophenyl)-2,3,4,5-tetrahydropyridazin-3-one hydrochloride, 2.4 g. (16.2 mMole) α-methylpropiophenone and 40 ml. glacial acetic acid were stirred for 8 hours at 100° C. under an atmosphere of nitrogen. The glacial acetic acid was subsequently distilled off and the residue suspended in water, neutralised and filtered with suction. After recrystallisation from ethanol, there was obtained 1.6 g. (40% of theory) of the title compound; m.p. 200°-201° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[N+:17]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[OH-].[Na+]>CO.O.[Zn]>[CH2:1]([N:8]1[C:9](=[O:20])[C:10]2[C:11](=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[NH:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]n1Cc1ccccc1
Yield: 19.4 %

Procedure:
N-(Benzyl)-4-chloro-2-nitrobenzamide (obtained by reaction of benzylamine with 4-chloro-2-nitrobenzoyl chloride) (1.16 g) was dissolved in a mixture of methanol (20 ml) and water (4 ml). Zinc dust (520 mg) was then added in one portion. Ammonium acetate (1.23 g) was then added in portions to the rapidly stirred reaction mixture. After the addition was complete, 2M sodium hydroxide solution (8 ml) was added and the mixture was heated under reflux for 4 hours. The cooled mixture was then concentrated in vacuo to remove methanol and then acidified to pH6 with 2M hydrochloric acid. This mixture was extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using an increasing gradient of ether in methylene chloride to give 1,2-dihydro-2-benzyl-6-chloro-3H-indazol-3-one (Ex. 43) as a solid (0.2 g), m.p. 209-214° C.
Reaction SMILES: [C:1]([O:12]C)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[OH-].[K+].[OH-].Cl>O.C(O)(C)C>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C=CCCCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
In a 5 L 5-neck round bottom flask, 1108.5 g of methyl 9-decenoate, 540 mL water, and 300 mL isopropanol were combined. The flask was connected to a mechanical stirrer, addition funnel, condenser, thermocouple, and stopper. Nitrogen was passed over the headspace for 20 minutes. An aqueous solution of potassium hydroxide (6.6 moles in 660 mL water) was added over 30 minutes, under an atmosphere of nitrogen, at ambient pressure. The reaction temperature peaked at 54° C. The mixture was stirred for a further 4 hours following the addition of aqueous hydroxide addition. After 4 hours, the temperature of the reaction was 28° C. The flask was placed in a water bath and aqueous hydrochloric acid (HCl, 37% (v/v)) was added in portions over 1 hr until the pH was 1-2. The temperature was kept below 40° C. by adding ice to the water bath during the addition of aqueous HCl. The solution was then transferred to a separatory funnel where the organic layer was washed three times with saturated sodium chloride and dried over magnesium sulfate. The magnesium sulfate was removed via vacuum filtration, and the solution was concentrated on the rotary evaporator. The crude product was distilled under reduced pressure (140° C., 2 torr) to provide 9-decenoic acid (995.2 g, 97% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[O:42][CH2:41][CH2:40][C@H:39]2[NH2:46].O>CS(C)=O.CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:46][C@H:39]2[C:38]3[C:43](=[CH:44][CH:45]=[C:36]([F:35])[CH:37]=3)[O:42][CH2:41][CH2:40]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: N[C@@H]1CCOc2ccc(F)cc21
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile (139 mg) in anhydrous DMSO (3 mL) was added to solution of (R)-6-fluorochroman-4-amine hydrochloride (79 mg) in anhydrous DMSO (3 mL) and DIEA (0.21 mL), the resulting dark red solution was stirred at RT under an atmosphere of Ar over which time the solution lighten to yellow. Upon completion of the reaction, the mixture was cooled to 0° C. with an ice bath, and water (25 mL) was added (exotherm). The resulting yellow solid was collected via filtration, washed with additional water, air dried, then dissolved in CH2Cl2, the organic solution was dried (MgSO4), filtered and evaporated to yield the titled compound (quant.), NMR CDCl3 1H δ 9.0 (s, 1H), 8.6 (d, 1H), 7.7 (br s, 1H), 7.4 (dd, 1H), 7.1 (d, 1H), 7.0-6.8 (m, 4H), 6.5-6.4 (m, 2H), 5.2 (br s, 1H), 4.3 (s, 2H), 4.2 (br s, 2H), 3.8 (s, 6H), 2.2 (br s, 1H), 1.8 (br s, 1H); 19F δ −123 ppm; MH+=572.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH:16][CH3:17].C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][N:16]([CH3:17])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
Crude N-t-butyloxycarbonyl-(S)-prolinal (2.34 g, 11.7 mmol) was dissolved in dichloromethane (90 ml). A 5.6 M solution of dimethylamine in ethanol (4.19 ml, 23.5 mmol) was added. 0.4 nm Mol sieves (10.0 g) was added. Sodium triacetoxyborohydride 7.47 g, 35.2 mmol) and glacial acetic acid (1.34 ml, 23.5 mmol) were added successively. The reaction mixture was stirred for 3 days. It was filtered through a plug of celite. The celite was washed with methanol (150 ml). An 1N aqueous solution of sodium hydroxide (150 ml) and tert-butyl methyl ether (150 ml) were added. The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.29 g of (2S)-2-((dimethylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:55]=[CH:54][C:40]([C:41]([NH:43][CH2:44][C:45]([CH3:53])([CH3:52])[CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:42])=[CH:39][C:38]=1[O:56][CH3:57].CC(C)CC(O)C>CO>[CH:13]1([N:10]2[CH2:9][C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:7](=[O:22])[N:6]([CH3:23])[C:5]3[C:11]2=[N:12][C:2]([NH:36][C:37]2[CH:55]=[CH:54][C:40]([C:41]([NH:43][CH2:44][C:45]([CH3:52])([CH3:53])[CH2:46][N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:42])=[CH:39][C:38]=2[O:56][CH3:57])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Reactant: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NCC(C)(C)CN4CCCC4)cc3OC)ncc2N(C)C1=O
Temperature: 120 °C
Yield: 27.5 %

Procedure:
10-chloro-2-cyclopentyl-4,4-diethyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 250; 111 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-1-yl-propyl)-3-methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (55 mg, 27%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
To a mixture of tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.89 mmol, 1 equiv.), 4-fluorophenylboronic acid (529 mg, 3.78 mmol, 2 equiv.) and copper acetate (517 mg, 2.83 mmol, 1.5 equiv.) in dichloromethane (28 mL) was added pyridine (301 mg, 0.301 mL, 3.78 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with 250 mL of dichloromethane and the solvent of the filtrate was evaporated to give tert-butyl (1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (501 mg, 74%).