Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=2)([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:28]([C:30]1[CH:31]=[C:32]([NH:36][C:37]([C:39]2[N:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)#[CH:29]>>[C:23]([O:22][C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([CH3:13])(=[O:12])=[N:10][C:8](=[O:9])[C:4]2[CH:3]=[C:2]([C:29]#[C:28][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[N:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=4)=[O:38])[CH:31]=3)[CH:7]=[N:6][CH:5]=2)=[CH:15][CH:16]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)cc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(NC(=O)OC(C)(C)C)cc4)c3)c2)n(C)n1
Yield: 336.4 %

Procedure:
In a manner similar to that described in Example 460, tert-butyl (4-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)carbamate (0.158 g, 0.349 mmol) and 2,5-dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide (0.125 g, 0.0524 mmol) were reacted to give the title compound (0.108 g, 51%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1.[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.CCOCC>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: c1ccsc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Pd]
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
A solution of thiophene (12.6 g, 0.15 mol) in a mixture of anhydrous ether (230 mL) and anhydrous THF (70 mL) was treated dropwise at 0° C. with a 2.5M solution of n-butyllithium in hexane (54.0 mL, 0.134 mol). The mixture was stirred at 0° C. for 1.5 hours and then transferred by cannula into a -78° C. solution of 4-fluorobenzylbromide (23.6 g, 0.125 mol) containing tetrakis(triphenylphosphine) palladium (0) (1.25 g) in anhydrous THF (200 mL). The reaction mixture was stirred at ambient temperature under nitrogen overnight and then quenched with saturated NH4Cl solution (100 mL) and partitioned between ether and additional NH4Cl solution. The ether layer was dried over MgSO4, concentrated in vacuo and the residue subjected to vacuum distillation to give 19.4 g (81%) of 2-(4-fluorophenylmethyl)thiophene. b.p. 74°-83° C. at 0.6-0.7 mm of Hg.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:21]([NH:20][CH3:19])=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 61.3 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (54 mg, 0,19 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.03 mL, 0.47 mmol). The resulting solution was heated under reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 70/30 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-methyl-urea (40 mg, 63%) as a white solid: mp 124.8-127.5° C.; [α]23589=−21.2° (c=0.099, chloroform); EI-HRMS m/e calcd for C16H20Cl2N2O2 (M+) 342.0902, found 342.0902.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[O:7][C:6]([CH3:11])([CH3:10])[O:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:18])[CH2:16][SH:17]>CO>[CH3:10][C:6]1([CH3:11])[O:7][C:8](=[O:9])[C:3](=[CH:2][S:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])[C:4](=[O:12])[O:5]1
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Reactant: COC(=O)CS
Solvent: CO
Product: COC(=O)CSC=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(hydroxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.6 g, 50 mmole), described by Bihlmayer et al., supra, and mercaptoacetic acid methyl ester (13 g, 0.125 mole) in dry methanol (50 mL) was heated at reflux for 2 hr. Thereafter, the mixture was stirred for 18 hr at 20°-22° C., and then poured into ice-water. The resultant mixture was extracted with diethyl ether. The extract was dried (MgSO4) and concentrated to dryness under reduced pressure. The residue (8.0 g) was purified by chromatography on silica gel, using 30% ethyl acetate in hexane (v/v) as the eluant. The pure fractions were combined and the solvent removed under reduced pressure. Crystallization of the residue from ethyl acetate-hexane gave the title compound; mp 117°-118° C.; NMR (CDCl3) δ 1.7 (s, 6H), 3.65 (s, 2H), 3.75 (s, 3H), 8.95 (s, 1H); IR (CHCl3) 1735, 1700, 1535 cm-1 ; UVλmax (MeOH) 315 um (ε 8900), 260 (7950).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1CCCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1CCCCNC(=O)c1cccnc1

Procedure:
By treating 6-[3-methyl-4-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one and nicotinic acid in the same manner as in Example 87, 6-[3-methyl-4-[4-(pyridin-3-ylcarbonylamino)butyl]phenyl]-4,5-dihydropyridazin-3(2H)-one was obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:19])[CH3:20])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOc1ccc(C(C)(C)CC=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-pentene, 0.2 g of 5% pd-C and 40 ml of ethyl acetate was put in a 200 ml autoclave and pressed up to 10 kg/cm2G with hydrogen gas, and stirred at 80° C. for three hours. After cooling, the reaction mixture was filtered and the solvent was evaporated, and the residue was purified by column chromatography on silica gel to 1.7 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[CH2:12]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:15]3[C@@H:14]([CH2:12][CH3:13])[CH2:18][O:17][C:16]3=[O:19])=[N:7][C:6]=12
Reactant: CC[C@H]1COC(=O)N1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.375 g, 1.61 mmol) and (S)-4-ethyloxazolidin-2-one (0.279 g, 2.42 mmol) in DMF (10 mL) was added sodium hydride (0.0968 g, 2.42 mmol) at ambient temperature. The mixture was stirred for 18 hours. Saturated aqueous NH4Cl was added and the solids were collected by filtration. Purification of the crude material by column chromatography (1-10% EtOAc in DCM) provided (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-ethyloxazolidin-2-one (0.282 g, 56% yield) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])[CH2:16][CH2:15]4)=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:34])[CH3:23])[CH2:16][CH2:15]4)=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (375 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min and concentrated. Pyridine (5 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated, the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate), and the obtained solid was washed with diethyl ether-hexane to give the title compound (183 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])=[CH:9][N:10]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of acetyl chloride (0.11g) in dry tetrahydrofuran (2 cc) is added, in 3 minutes, to a solution, cooled to 0° C., of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.80 g) in dry tetrahydrofuran (10 cc), and a solution of triethylamine (0.18 cc) in dry tetrahydrofuran (2 cc) is then added. The mixture is stirred for 30 minutes at 0° C. and is then filtered over a diatomaceous earth powder. The filtrate is diluted with ethyl acetate (50 cc) and washed with distilled water (50 cc), a half-saturated sodium bicarbonate solution (50 cc) and a saturated sodium chloride solution (50 cc). The organic phase is dried over anhydrous sodium sulphate; it is filtered, the insoluble matter is washed with ethyl acetate (10 cc) and the organic solution is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue (0.89 g) is chromatographed on a column (height: 24 cm; diameter: 2.2 cm) of silica (0.04-0.06 mm), elution being carried out with a 40:60 (by volume) mixture of cyclohexane and ethyl acetate under 0.4 kPa, and 60 cc fractions being collected. Fractions 5 to 11 are combined and the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.55 g) is obtained in the form of a pale chestnut-coloured froth.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:32].B#B.[O:35]1CCCC1.[OH-].[Na+].OO.[Cl-].[NH4+]>O.C(O)C>[NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]([OH:35])[CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:32]
Reactant: Nc1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: C1CCOC1
Agent: B#B
Agent: OO
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
2-(4-((4-(4-Amino-3-fluorobenzylidene)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.384 mmol, 0.64 g) was cooled to 0° C. and 1M diborane solution in tetrahydrofuran (5.54 mmol, 5.54 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and ethanol slowly added. Sodium hydroxide (8.30 mmol, 0.332 g) in water (20 mL) was then added slowly with stirring, followed by hydrogen peroxide (24.91 mmol, 2.421 g). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride (50 mL) and the mixture extracted with dichloromethane (3×100 mL). The combined organic phase was then washed with water (50 mL) and brine (50 mL) and the organic phase dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 2% to 10% methanol/dichloromethane) to afford the title compound (60 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O>>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:5]2[S:4][C:3]([CH2:1][CH3:2])=[CH:7][CH:6]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCc1cccs1
Reactant: COc1ccc(C=O)cc1Br
Product: CCc1ccc(Cc2ccc(OC)c(Br)c2)s1

Procedure:
2-Ethylthiophene and 3-bromo-4-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.C1(C)C=CC(S(O[CH2:22][C@H:23]2[O:25][CH2:24]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:2][CH:1]=1)(=[O:9])[NH2:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: NC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Cc1ccc(OCC2CO2)cc1
Reaction time: 30 h

Procedure:
p-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and the solution was stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.).
Reaction SMILES: [C:1]([CH:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:25])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:25])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:3])[CH3:2]
Reactant: CCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)cc3)nn12

Procedure:
Analogously to Example 1, 340 mg (0.82 mmol) of 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}heptanamide (Example 26A) and 540 g (3.50 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetylhexyl)-2-(4-methoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.Br[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]>C(#N)C.ClCCl>[N:7]1([CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: c1nc[nH]n1
Reactant: O=C1c2ccccc2CCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1n1cncn1

Procedure:
To a mixture of 30 g. potassium carbonate, 15 g. 1,2,4-triazole and 250 ml acetonitrile at 40° C. was added a solution of 45 g. 3,4-dihydro-2-bromo-1(2H)-naphthalenone in 150 ml acetonitrile. The mixture was allowed to react for 5 hours at 40° C. and than at reflux temperature for 2 hours. The solid was removed by filtration and the filtrate concentrated to dryness leaving a solid residue. This was dissolved in dichloromethane and washed twice with water. The organic extract was dried over sodium sulfate and evaporated to give 42 grams of product having a melting point of 96°-98° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(Cl)cc2C(=O)O)cc1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-chlorobenzoic acid pretreated with n-butyllithium with 4-methoxy-N-methoxy-N-methyl-benzamide. It is used in crude form in the following reaction.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:25][CH:26]=2)=[CH:20][C:19]([C:37]([CH3:41])([CH3:40])[C:38]#[N:39])=[N:18]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=3)=[CH:25][CH:26]=2)=[CH:20][C:19]([C:37]([CH3:41])([CH3:40])[CH2:38][NH2:39])=[N:18]1
Reactant: CC(C)(C#N)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(CN)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
DIBAL-H (1.0M in hexanes, 1.5 mL, 1.5 mmol) was added dropwise at −78° C. to a stirred solution of 2-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-2-methyl propanenitrile (210 mg, 0.436 mmol) in dry DCM (10 mL) under N2, the resulting mixture was stirred at −78° C. for 3 h. At −78° C. 10% aqueous Rochelle's salt solution was added dropwise to quench the reaction, the mixture was allowed to warm to rt, and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH/DCM) to give the title compound as a white solid (160 mg, 76%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.83-7.80 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.42 (m, 5H), 7.20 (d, 1H), 6.71 (d, 1H), 6.52 (s, 1H0, 3.07 (s, 3H), 2.90 (s, 2H), 2.17 (brs, 2H), 1.39 (s, 6H). MS(ES): 486 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([O:27]C)=[O:26])=[CH:11][N:12]2[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.Cl>O1CCCC1>[C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)[N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:11]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Reaction time: 16 h
Yield: 97.3 %

Procedure:
0.57 g (13.6 mmol) of lithium hydroxide monohydrate and 70 cm3 of water are added at a temperature in the region of 20° C. to 1.45 g (4.53 mmol) of 6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 70 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 16 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 13.6 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at 60° C., 1.35 g of 3-carboxy-6-fluoro-1-(quinol-4-yl)-1H-indole are obtained in the form of a yellow solid melting at 190° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of cyclopropylamine (1.25 g, 22.0 mmol) in toluene (11 mL) was added over 10 min to an ice-cold solution of 2,6-dichloro-3-nitropyridine (2.00 g, 10.4 mmol) in toluene (10 mL). The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (50 mL) was added to the mixture and the phases were separated. The organic layer was washed with brine (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 3:2) to give the title compound (1.97 g, 89% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:28]=3[C:29]([O:31]CC)=[O:30])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:28]=3[C:29]([OH:31])=[O:30])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2nc3ccccn3c2C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2nc3ccccn3c2C(=O)O)cc1
Yield: 83.2 %

Procedure:
0.28 g of compound A from Example 1d) in 10 ml of ethanol is stirred with 0.25 g of sodium borohydride for 45 min. Dilution with 1 N NaOH is followed by extraction 2× with EtOAc. Washing of the organic phase with saturated NaCl solution is followed by drying with Na2SO and concentration. 0.22 g of the title compound is obtained.