Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.CSC>O1CCCC1>[CH:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][OH:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCC(c1ccccc1)C1CCCCC1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and N2 inlet were added 15 g (68.8 mmol) α-phenylcyclohexylacetic acid, 110 mL dry tetrahydrofuran, and 137 mL (275 mmol) of a 2M solution of borane-methyl sulfide in tetrahydrofuran. The solution was refluxed 60 hr, cooled, and evaporated. The residue was taken up carefully in 200 mL ethanol, treated with 2 g sodium carbonate, and refluxed 3 hr. The reaction was cooled, evaporated, taken up in ethyl acetate/water, separated, and the aqueous phase extracted with fresh ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and evaporated to an oil which solidified on standing. The yield was 12.27 g (87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([NH2:34])=[O:33])[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[S:10]([N:13]1[CH2:30][CH2:29][C:16]2([N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)[NH:18][C:17]2=[O:28])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[H][H]>C(#N)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([NH2:34])=[O:33])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][S:10]([N:13]1[CH2:14][CH2:15][C:16]2([N:20]=[C:19]([CH:21]3[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]3)[NH:18][C:17]2=[O:28])[CH2:29][CH2:30]1)(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: Cc1cc(CC(N)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CC(N)=O)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Yield: 72.3 %

Procedure:
20% palladium hydroxide (7.4 mg) was added to a solution of Compound 737 (14.7 mg, 0.030 mmol) in acetonitrile (1.0 mL), and the mixture was stirred at room temperature for one hour in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 2-(3-methyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-acetamide (Compound 750) as a white powder (10.6 mg, 72%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].C(N(CC)CC)C.Cl[CH2:26][CH:27]([OH:34])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH3:33].S(=O)(=O)(O)O>CN(C)C=O>[CH2:30]([O:29][CH2:28][CH:27]([OH:34])[CH2:26][N:6]1[C:4](=[O:5])[C:3]([CH2:2][CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: CCCCOCC(O)CCl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CC)(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A solution of phenobarbital (69.6 g, 0.3 mole) in dimethylformamide (60 ml) containing triethylamine (20.2 g, 0.2 mole) was stirred with 1-chloro-3-n-butoxy-2-propanol (33.2 g, 0.2 mole) for 6 hours at 70° C. The reaction mixture was then poured into 3% sulphuric acid (500 ml) and the precipitated product was extracted with toluene (200 ml) at 70° C. The toluene layer was separated, washed with 3% aqueous sulphuric acid (200 ml) and left overnight at 4° C. The precipitated phenobarbital was filtered off and filtrate extracted with 5% aqueous sodium carbonate (5×100 ml). The organic layer was then extracted with 1M aqueous sodium hydroxide (2×200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (38.5 g, 53%); purity by HPLC 96.5% .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:18][C:16]=2C=1.CCN=C=NCCCN(C)C.Cl.CN>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:18][CH3:16])=[O:11])=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 27.3 %

Procedure:
To a suspension of 5-bromo-pyridin-2-yl-acetic acid (0.87 g, 4.0 mmol) in THF (12 mL) was added HOBt (0.74 g, 4.8 mmol) and EDCI.HCl (0.85 g, 4.4 mmol). The resulting reaction mixture was stirred for 15-20 min at room temperature followed by drop-wise addition of methylamine (2.0 M in THF, 4.05 mL, 8.0 mmol). The resulting mixture was then continued to stir for 6-7 h at room temperature. After completion of reaction, water was added and extracted with EtOAc. The crude residue was purified over silica (60-120 M, 2.50% MeOH-DCM) to obtain the pale-yellow solid compound (0.25 g, 27%). 1H NMR (400 MHz, DMSO-d6): δ 2.58 (d, J=4.80 Hz, 3H), 3.57 (s, 2H), 7.33 (m, 1H), 7.96 (d, J=2.40 Hz and 8.40 Hz, 1H), 8.00 (br s, 1H) and 8.58 (d, J=2.40 Hz, 1H). MS: 229.11 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([CH2:8][C:9]([CH3:11])=O)=O)=[O:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:8][C:9]([CH3:11])=[N:14]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1C
Yield: 43.1 %

Procedure:
Ethyl acetopyruvate (Organic Syntheses, Coll. Vol. I, 1944, p. 238) (31.6 g) was dissolved in ethanol (100 ml) and treated with methyl hydrazine (12 g) in portions. The mixture was then refluxed gently for 1 hr, whereupon most of the ethanol was removed in vacuo. The residue was poured into 5% NaCl solution and the product extracted with chloroform (3×100 ml). The combined extracts were washed with water, dried and the solvent evaporated. The residue was then distilled in vacuo. 1,3-dimethyl-5-ethoxycarbonylpyrazole (14.5 g 43%) was obtained as a colourless oil, b.p.25 118°-121° C. (A mixture of the two isomers (1.5 g), followed by pure 1,5-dimethyl-3-ethoxycarbonylpyrazole (10.5 g, 31%), b.p.25 178°-180° C., was obtained on continued distillation).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]1[CH2:39][CH2:38][O:37][CH:36]1[O:40][CH3:41])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]1[CH2:39][CH2:38][O:37][CH:36]1[O:40][CH3:41])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17]
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1O2
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Product: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1O2
Yield: 72 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of intermediate 1.1, starting with 10H-phenoxazine-2-carboxylic acid (J. Org. Chem. 1960, 25, 747-753) and L-leucyl-N1-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide (intermediate 1.6). The condensation product is purified by chromatography on a silica column (eluent: heptane/ethyl acetate: 3/7). A yellow solid is obtained with a yield of 72%. Melting point: 178-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[O:30][CH2:31][O:32][C:25]=12.Cl[CH2:34][C:35]#[N:36]>>[C:35]([CH2:34][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]5[O:30][CH2:31][O:32][C:25]=45)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:18][CH2:19]1)#[N:36]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Reactant: N#CCCl
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 2.1 (m, 2H), 2.45–2.7 (m, 1H), 3.5 (s, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.0 (s, 2H), 6.7 (d, 1H), 6.9 (t, 1H), 7.0 (m, 21), 7.75 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]2)=[C:5]2[NH:17][CH:18]=[CH:19][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[OH:16][CH:14]([C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:19]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:18][NH:17][C:5]=23)[N:10]=1)[CH3:15]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]ccc12
Agent: CC[Mg]Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(C(C)O)n3)ncc(OC)c12
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)ethanol (100 mg, 0.386 mmol) in THF (8 mL) was added ethylmagnesium bromide (1.736 mL, 1.736 mmol) at −40° C. After stirring at −5° C. for 1 h, pyridine (0.016 mL, 0.193 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.176 mL, 1.543 mmol) was added. After stirring at −40° C. for 30 min, the reaction was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (100 mg, 0.278 mmol, 72.2% yield). LCMS: m/z 360.1 (M+H)+, 1.53 min (method 8).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([CH2:11][C:12]1[C:20]2[C:15](=[C:16]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.C>[OH-].[Na+]>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:29])=[O:3])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(Cc1c[nH]c2c(C(=O)c3ccccc3)cccc12)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1cccc2c(CC(C(=O)O)C(=O)O)c[nH]c12
Yield: 71.1 %

Procedure:
A mixture of 10.0 g (0.025 mole) of 2-[(7-benzoyl-1H-indol-3-yl)methyl]propanedioic acid diethyl ester in 150 ml of 3N sodium hydroxide was heated at reflux for 18 hr, then treated with charcoal, cooled and filtered. The dark yellow filtrate was acidified by the dropwise addition of 50 ml of concentrated hydrochloric acid. The addition of 20 ml of methylene chloride caused the formation of a ppt., which was collected and recrystallized from chloroform-methanol to give 6.0 g (70%) of off-white crystals, m.p. 188°-189° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]([C:16]#[N:17])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:31].[K+].[K+].OO>CS(C)=O.O>[C:1]1([N:7]2[C:11]3[C:12]([C:16]([NH2:17])=[O:31])=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:18]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C#N)c2n1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C(N)=O)c2n1-c1ccccc1
Reaction time: 2 h
Yield: 121.4 %

Procedure:
3-Phenyl-2-[(S)-1-(9H-purin-6-ylamino)ethyl]-3H-benzoimidazole-4-carbonitrile (70 mg, 0.18 mmol) was dissolved in DMSO (2 mL) and to this solution was added a solution of K2CO3 (10 mg) in water (0.1 mL). H2O2 (0.2 mL, 30% in water) was added dropwise and the resulting solution stirred for 2 h. Very slow hydrolysis occurred as observed by LCMS. The solution was heated at 60° C. over 2 days with additional aliquots of H2O2 (2×0.2 mL). The cooled mixture was poured onto water. The resulting aqueous solution was passed through an SCX cartridge, the cartridge was washed with water and MeOH and the product eluted with 2M NH3 in MeOH. The product fractions were combined and evaporated and the residue purified by chromatography (Si—PCC, 0-10% 2M methanolic NH3 in DCM). The product fractions were concentrated in vacuo to give white solid. This was triturated in ether, filtered and dried in vacuo to give 311 as a white solid (35 mg, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.00 (2H, m), 7.87-7.77 (1H, m), 7.66 (1H, d, J=7.4 Hz), 7.55-7.27 (6H, m), 7.23-7.13 (2H, m), 6.95 (1H, s), 5.38-5.18 (1H, m), 1.46 (3H, d, J=6.7 Hz). LCMS (Method K): RT 1.99 min; m/z 399 [M+H]+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24][C:23]([CH3:26])([CH3:25])[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:53][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=4)=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])(=[O:12])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccn2)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Yield: 63.1 %

Procedure:
0.1 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate, 0.03 g of o-picolylchloride-hydrochloride and 0.15 g of cesium carbonate were suspended in 0.5 mL of dimethyl formamide and heated to 60 degrees for 3 h. The mixture was diluted with ethyl acetate and washed with water. Chromatography on silica gel (9:1 ethyl acetate/hexanes) gave 72 mg of the desired material
Reaction SMILES: [NH2:1][NH2:2].O.[C:4]([CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](O)=[O:10])(=O)[CH3:5]>CCO>[CH3:5][C:4]1[CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](=[O:10])[NH:1][N:2]=1
Reactant: CCCC(CC(=O)O)C(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCC1CC(=O)NN=C1C
Temperature: 85 °C

Procedure:
NH2NH2—H2O (6.94 ml, 143 mmol) is added to a solution of 3-acetyl-hexanoic acid (18.8 g, 119 mmol) in EtOH (150 ml), and the mixture is refluxed (oil bath 85° C.) for 4 hours. The solvent is removed in vacuo and water (100 ml) and EtOAc (100 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (3×100ml). The combined extracts are washed with brine (150 ml), dried (Na2SO4) and evaporated. 6-methyl-5propyl-4,5-dihydropyridazin-3-one is obtained as a light yellow oil, and is used in the next step.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([OH:6])=[O:5].CCN(C(C)C)C(C)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC#N>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([O:6][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(O)(C(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (0.6 g, 3.80 mmol) was dissolved in MeCN (5 ml). DIPEA (0.663 ml, 3.80 mmol) was added and stirred for 5 min. Benzyl bromide (541 mg, 3.16 mmol) was added and the reaction mixture was stirred at RT for 16 h followed by 70° C. for 16 h. After cooling to RT, the solvent was removed in vacuo and the resulting residue was dissolved in DCM. The mixture was washed with water and the organic portion was separated by means of a phase separator. The solvent was removed in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)cnc2N1Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a suspension of 1K (80 mg, 0.17 mmol) in THF (1 mL) at RT under argon was added borane-tetrahydrofuran complex (0.85 mL, 0.85 mmol) dropwise. After the addition, the reaction became a clear solution. The reaction was allowed to stir at RT under argon for 30 min. After this time, no starting material was detected by LC-MS. MeOH (1 mL) was added carefully to the reaction and the reaction mixture was stirred at RT for 40 min, then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (10 g) column chromatography eluting with a gradient of EtOAc (0-50%) in hexane to give the title compound as a white foam (74 mg, 96%). LC/MS (method A): retention time=3.96 min, (M+H)+=456. 1H-NMR (CDCl3, 400 MHz): δ8.30 (s, 1H), 7.70 (dd, J1=8.2 Hz, J2=1.2 Hz, 2H), 7.52-7.60 (m, 1H), 7.40-7.52 (m, 6H), 7.20-7.40 (m, 7H), 4.75 (dd, J1=48.2. Hz, J2=15.0 Hz, 2H), 4.71 (d, J=8.6 Hz, 1H), 3.80-3.92 (m, 1H), 3.30 (dd, J1=15.9 Hz, J2=2.2 Hz, 1H), 3.00-3.13 (m, 2H), 2.75-2.85 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[CH2:11][CH2:10]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]2[NH:8][C:6]2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[N:7]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Combine 6-chloro-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-nitropyridin-2-amine (9.00 g, 29.34 mmol) and 3-amino-5-methylpyrazole (4.56 g, 46.95 mmol) in dimethylsulfoxide (60 mL). Add N,N-diisopropylethylamine (8.18 mL, 46.95 mmol) and heat the reaction under nitrogen at 120° C. for 90 minutes. Pour the reaction into ice water (200 mL) and stir 20 minutes, then filter. Suspend the solid obtained in a mixture of dichloromethane and methanol and stir at 40° C. for 20 minutes. Filter the mixture to give the title compound as a yellow solid (6.03 g, 56%). MS (ES) m/z=369 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](CCl)=[CH:7]2.[C-]#N.[Na+].[CH3:17][C:18]#[N:19]>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:17][C:18]#[N:19]
Reactant: CC#N
Reactant: ClCc1ccc2c(Cl)cccc2c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1cccc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 5-chloro-2-chloromethylnaphthalene (1.37 g crude product, 5.12 mmol), NaCN (0.275 g, 5.61 mmol), CH3CN (10 mL), and H2O (1 mL) was heated under reflux for 5.5 hours, cooled, and stirred at room temperature overnight. The mixture was partitioned between ether and H2O. The aqueous phase was extracted with ether, and the combined ether layers were washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (eluant EtOAc/hexane (10:90)) gave a pale yellow solid (600 mg, 58%), m.p. 95°-98° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]([NH:49][CH2:50][C:51](=O)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=O)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]3[S:10][C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:50][N:49]=3)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(CNC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2ncc(-c3ccccc3)s2)C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
600 mg (1.484 mmol) of Lawesson reagent were added to a solution of 300 mg (about 0.371 mmol) of the compound from Example 106A in 5 ml of dioxane. The reaction mixture was stirred at 50° C. for 5 h and, without any further purification, was purified by preparative HPLC. Yield: 5 mg (3% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:18]([O:17][C:11](=[O:16])/[CH:12]=[C:13](\[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)/[CH3:15])[CH3:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(N)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)/C=C(/C)Nc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
7.66 g (37.9 mmol) of 4-bromo-3-methoxy-phenylamine (preparation described in Tetrahedron Lett., 1995, 7583) were dissolved in 80 ml of cyclohexane at 70° C. and subsequently treated under stirring with 72 mg (0.38 mmol) of p-toluenesulfonic acid monohydrate and 4.93 g (37.9 mmol) of ethyl acetoacetate. The solution was then heated at reflux for 3.5 h with a water separator funnel connected. It was then cooled to RT and concentrated in vacuo. The residue was applied to a silica gel column with hexane/diethyl ether (3:1) as eluent. Combinations of the purified fractions and concentration in vacuo gave 8.2 g (68.8%) of the (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester, as a yellow solid. ISP mass spectrum, m/e: 316.2(M+1 calculated for C13H16BrNO3: 316).