Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O1CCOCC1>[N:23]1([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCl)c2ccccc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCCN2CCCC2)c2ccccc21

Procedure:
5.5 gm of 11-(4-chlorobutyryl)-5,11-dihydro-6H-pyrido [2,3-b][1,4]-benzodiazepin-6-one, 1.4 gm of pyrrolidine and 2.1 gm of sodium carbonate were refluxed in a mixture of 80 ml of absolute ethanol and 20 ml of absolute dioxane for 10 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was purified on a silica gel column. The eluate was evaporated in vacuo to dryness, and the residue was recrystallized from acetonitrile.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[O:13][C@H:5]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([C@@:15]1([OH:25])[C@@H:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[O:13][C@@H:5]([S:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:40])[CH3:39]
Reactant: [N-]=[N+]=N[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@H]1Sc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)[C@]1(O)[C@H](OCc2ccccc2)[C@@H](N=[N+]=[N-])[C@H](Sc2ccccc2)O[C@@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 72 h
Yield: 597.5 %

Procedure:
Under an argon atmosphere, 19 (5.28 g, 10.2 mmol) was dissolved in pyridine (100 ml), and the solution was added with acetic anhydride (1.5 ml, 1.59 mmol, 1.56 equiv) with stirring. After three days, stirring was terminated, and the solvent was evaporated. The residue was dissolved in chloroform, and the solution was washed three times with saturated aqueous sodium hydrogencarbonate in a separating funnel. The organic layer was dried over anhydrous sodium sulfate, then recrystallization was performed by using ethanol (50 ml), and primary crystals were collected to obtain 20 as colorless solid (5.29 g, 9.5 mmol, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8](Br)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:25].C(OCC)(=O)C.O>CC1CCCO1>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8]([NH2:25])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Benzyl-(2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (7.50 g) was dissolved in 2-methyl-tetrahydrofuran (15 ml) and the solution placed in a sealable vessel. Concentrated aqueous ammonia solution (15 ml) was added and the vial was then sealed and the bi-phasic mixture left to stir vigorously at room temperature for 36 hours. The reaction mixture was then transferred to a separating funnel and ethyl acetate (120 ml) and water (120 ml) were added. The phases were separated, and then the organics washed with brine (100 ml), dried (MgSO4), and evaporated to a yellow oil. Upon standing, a yellow solid crystallised. This was collected by filtration and washed with pentane, providing the title compound (6.64 g) as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][C:20]1([C:33]#[C:34][CH2:35][O:36][Si](C)(C)C)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1>O1CCCC1>[OH:19][C:20]1([C:33]#[C:34][CH2:35][OH:36])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80 mL, 80 mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate (Description 71, 24.4 g, 75 mmol) in tetrahydrofuran (300 mL) and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and water (200 mL) was added, The mixture was extracted with ethyl acetate (2×200 mL) and the combined organic fractions were washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (16.8 g, 88%). 1H NMR (400 MHz, CDCl3) δ 4.32 (2H, s), 3.80–3.68 (2H, m), 3.32–3.22 (2H, m), 1.93–1.83 (2H, m), 1.75–1.65 (2H, m), 1.62 (1H, br s), and 1.46 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)nc1
Reaction time: 23 h
Yield: 21.4 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.299 g, 1.23 mmol), 1-(4-fluoro-phenyl)-piperizine, bis hydrochloride salt (0.314 g, 1.24 mmol), triethylamine (0.36 mL, 2.58 mmol) in methanol (12 mL) and stir. After 23 h, add sodium borohydride (0.108 g, 2.85 mmol). After 1 d, concentrate and purify the residue by silica gel chromatography (25:1→4:1 methylene chloride:methanol) to provide 0.107 g (21%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H24FN4O2 407.1883, found 407.1883; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz) 7.52-7.47 (m, 2H), 7.20-7.15 (m, 2H), 7.05 (d, 1H, J=7.8 Hz), 7.01 (d, 4H, J=6.3 Hz), 3.66 (s, 2H), 3.21-3.16 (m, 4H), 2.74-2.68 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@@H:10]3[CH2:14][CH2:13][N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH3:18])=[O:22])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)N1CC[C@@H](Nc2nc3ccc(Cl)cc3o2)C1
Yield: 61.4 %

Procedure:
A mixture of 32.9 mg (0.12 mmol) (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride, 19.6 mg (0.144 mmol) 2-methyl-benzoic acid, 53.9 mg (0.168 mmol) TBTU and 77.5 mg (0.6 mmol) DIPEA in 2 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated, taken up in methanol and formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 26.2 mg (61%) of the title compound. (MH+) 356.1.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=2[CH:32]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([N:17]([CH:13]1[CH2:12][C:11]2[CH:32]=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2-[8-(N-benzyl-N-tert-butoxycarbonyl-amino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (1.6 g) in ethanol (16 ml) was added aqueous 1N sodium hydroxide at 5° C., and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of aqueous 0.1N hydrochloric acid and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane and dried in vacuo to give 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (1.3 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:18]([F:33])[CH:17]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[F:33][C:18]1[CH:17]=[C:16]([C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([F:15])[CH:11]=2)[CH:21]=[CH:20][C:19]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3OCc3ccccc3)cc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
A suspension of the product of step (ii) (838 mg) in acetic acid (30 ml) and 10% Pd/C (200 mg) was stirred under 2 bar pressure of hydrogen for 30 min. The catalyst was removed by filtration and the filtrate was evaporated to give the subtitle compound, yield 630 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: COc1cccc(N)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-6-methoxy-benzoic acid (3.00 g, 17.9 mmol) in THF (90 mL), EDCl (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9 mmol) were added and stirred at room temperature for 30 minutes then N-methylmorpholine (6.15 g, 60.0 mmol) and aqueous 50% v/v NH4OH (12 mL, 171.4 mmol) was added. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was extracted with ethylacetate (4×100 mL), the combined organic phase was washed with water and brine, and dried over anhydrous sodium sulfate; the solvent was evaporated to give 2-amino-6-methoxy-benzamide as an off-white solid. Yield: 1.90 g, (65%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][C:21](O)=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:21](=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:41][CH:40]=1)([O:37][CH2:38][CH3:39])=[O:36]
Reactant: O=C(O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)C=CC=Cc2cn(Cc3ccccc3)c3ccccc23)cc1
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
To a suspension of 5-(1-benzylindol-3-yl)-2,4-pentadienoic acid (0.9 g, 2.9 mmol) in 20 ml of methylene chloride was added dropwise with stirring at room temperature 0.26 ml (0.38 g, 3 mmol) of oxalyl chloride, followed by four drops of N,N-dimethyl-formamide (DMF). The reaction mixture was stirred for an additional 90 min. and concentrated on rotary evaporator. The residue was dissolved in 10 ml of anhydrous methylene chloride and added dropwise to a solution of ethyl p-aminobenzoate (0.44 g, 2.7 mmol) in 5 ml of methylene chloride and 1.3 ml of pyridine. The resulting mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate solution and water, dried (MgSO4) and mixture. Purification by a dry column (hexane:ethyl acetate, 2:1) followed by crystallization (acetone-petroleum ether) afforded 250 mg of yellow crystals, m.p. 162-166. MS(EI)=450(M+), 286 (M+--HNC6H4CO2C2H5 ); nmr (CDCl3): δ1.35 (t, J=7 Hz, 3), δ4.28(q, J=7 Hz, 2), δ5.22(s, 2), δ5.95(d, J=15 Hz, 1).
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([S:33][CH3:34])=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[S:30]([CH3:32])=[O:31])(=[O:3])[NH2:2].[NH3:36]>O1CCOCC1>[NH2:36][C:5]1[C:4]([C:1](=[O:3])[NH2:2])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[S:30]([CH3:32])=[O:31])[CH:8]=[C:7]([S:33][CH3:34])[N:6]=1
Reactant: N
Reactant: CSc1cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)=O)c(C(N)=O)c(Cl)n1
Solvent: C1COCCO1
Product: CSc1cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)=O)c(C(N)=O)c(N)n1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 14E (637 mg, 1.18 mmol) and 25% aqueous ammonia (2 mL) in 1,4-dioxane (3 mL) was heated in a seated tube at 80° C. for 24 hours. After cooling to ambient temperature, the mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25/1 dichloromethane/methanol to give the title compound. MS: 521 (M+H+).
Reaction SMILES: Cl.[CH2:2]([C:9]1[O:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]=1[C:14]1[CH:38]=[CH:37][C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:36])[CH2:25][CH:26]3C(=O)OC(C)(C)[O:28][C:27]3=[O:35])=[CH:20][CH:19]=2)=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([C:9]1[O:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:36])[CH2:25][CH2:26][C:27]([OH:35])=[O:28])=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
2N Hydrochloric acid (1 mL) was added to a stirred solution of 5-{2-[4′-(2-benzyl-benzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione (200 mg, 0.36 mmol) in THF (10 mL), and the resultant solution was heated at 70° C. for 6 hrs and then cooled to room temperature and concentrated in vacuo. The resulting solid was redissolved in DMSO (10 mL), and heated to 150° C. for 3 hrs before being cooled to room temperature, and diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water (2×10 mL), brine (3×10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by trituration and filtration from MeOH afforded the title compound as a white solid (105 mg, 62%). Rf: 0.20 (5% methanol in dichloromethane); 1H-NMR (CDCl3, 300 MHz): δ 8.10 (2H, d, J=8 Hz, Ar—H), 7.80 (5H, m, Ar—H), 7.62 (1H, d, J=8 Hz, Ar—H), 7.48 (1H, d, J=8 Hz, Ar—H), 7.29 (6H, m, Ar—H), 4.26 (2H, s, PhCH2), 3.86 (2H, t, J=6 Hz), 2.86 (2H, t, J=6 Hz); ESI-LCMS e/z calcd for C31H24O4: 460.527, found 461 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18](OC)=[O:19].CC(C[AlH]CC(C)C)C>C1COCC1.Cl>[OH:19][CH2:18][C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a solution of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (2.00 g, 6.70 mmol) in THF (134 mL) was added DIBAL (1.5 M in toluene, 13.4 mL, 20.1 mmol) at −78° C. The solution was stirred at −78° C. for 1 h, gradually warmed to room temperature, stirred at room temperature for 18 h, diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30) to yield the title compound (509 mg, 28% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 4.53 (2H, d, J=6.0 Hz), 5.11-5.16 (1H, m), 6.48 (1H, d, J=8.0 Hz), 7.76-7.84 (2H, m), 8.08-8.16 (1H, m), 8.19 (1H, s), 8.94 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:31])([F:42])[F:43])[CH:35]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.5 g, 0.0012 mol) in DMF (10 mL), was added 3-(trifluoromethoxy)benzyl bromide (0.47 g, 0.0018 mol) and powdered potassium carbonate (1.16 g, 0.0084 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.61 g in 88% yield. 1H NMR (CDCl3) δ 7.20 (s, 1H), 7.19 (m, 11H), 7.04 (s, 1H), 7.01 (t, 2H), 6.88 (d, 1H), 6.69 (m 2H), 4.20 (t, 1H), 3.70 (s, 3H), 3.63 (s, 2H), 3.59 (s, 2H), 3.13 (d, 2H), 2.67 (t, 2H), 1.84 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.5, 149.6, 144.8, 136.7, 131.0, 130.9, 130.0, 129.8, 129.7, 129.6, 128.4, 127.8, 122.8, 122.7, 122.5, 120.6, 116.9, 114.5, 66.8, 61.3, 60.1, 53.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[C:23]([F:26])([F:25])[F:24]>>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=2)[C:5]#[N:6])=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:17]=1)=[O:20]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1cc(O)cc(C(F)(F)F)c1
Product: N#Cc1cc(Oc2ccc(C=O)cc2C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-hydroxy-5-(trifluoromethyl)benzonitrile and 4-fluoro-3-(trifluoromethyl)benzaldehyde.
Reaction SMILES: C(O)(=[O:3])C.OO.C(OO)(=O)C.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[N:18][CH:17]=[CH:16]2>O>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[N+:18]([O-:3])[CH:17]=[CH:16]2
Reactant: Brc1ccc2cnccc2c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: OO
Solvent: O
Product: [O-][n+]1ccc2cc(Br)ccc2c1
Temperature: 80 °C

Procedure:
Acetic acid (8 mL) and 30% hydrogen peroxide (4 mL) were heated at 80° C. for 1 h. The cooled solution of peracetic acid was added to 6-bromoisoquinoline (Tyson, F. T. J. Am. Chem. Soc., 1939, 61, 183) (0.389 g, 1.87 mmol) and the mixture was then heated at 80° C. for 18 h. The mixture was diluted with water (15 mL) and concentrated in vacuo to ca. half the volume and the residue was extracted with CH2Cl2 (2×25 mL). The combined organics were washed with saturated aqueous NaHCO3 (25 mL), dried over MgSO4 and evaporated to leave an oil. Azeotroping with PhMe (×3) and then CH2Cl2 (×3) gave 6-bromoisoquinoline N-oxide (0.420 g, quant) as a cream-coloured solid. 1H (δ, CDCl3, 300 MHz) 7.6-7.65 (2H, m), 7.77 (1H, dd), 8.0 (1H, s), 8.2 (1H, dd), 8.85 (1H, s);
Reaction SMILES: [C:1]([C:3]([NH:6][S:7]([CH2:10][CH2:11][S:12]([CH3:14])=[O:13])(=[O:9])=[O:8])([CH3:5])[CH3:4])#[N:2].[Cl:15][C:16]([Cl:22])([S:20]Cl)[CH:17]([Cl:19])[Cl:18].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Cl:15][C:16]([Cl:22])([S:20][N:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[S:7]([CH2:10][CH2:11][S:12]([CH3:14])=[O:13])(=[O:9])=[O:8])[CH:17]([Cl:19])[Cl:18]
Reactant: CS(=O)CCS(=O)(=O)NC(C)(C)C#N
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)CCS(=O)(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(C)(C)C#N
Yield: 65.3 %

Procedure:
A stirred mixture of 2.38 g (0.01 moles) N-(2-cyano-2-propyl)-2-methylsulfinylethylsulfonamide (Example 29), 2.85 g (0.0109 moles) of 89.9% technical 1,1,2,2-tetrachloroethylsulfenyl chloride and a catalytic amount (about 0.25 g) of benzyltriethylammonium chloride in 30 ml methylene chloride was warmed until a solution was obtained. To that mixture, 0.96 g of a 50% solution of sodium hydroxide which had been diluted to 5 ml was added at once. The reaction mixture was stirred at reflux for four hours, then cooled and poured into a separatory funnel. The methylene chloride layer was separated, washed three times with 25 ml water, dried and evaporated to about 10 ml. The oily residue was transferred to a 50 ml Erlenmeyer flask and then diluted with about 25 ml hexane. The white precipitate which formed was recovered by filtration and washed with hexane to give 2.85 g of a white powder. Chromatography on silica gel, followed by recrystallization from ethanol gave 1.7 g of the above-identified product as white crystals, melting point 119°-120° C.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13]=2[NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]([NH2:25])=[N:7]1)=O)C>CN(C)C=O>[CH2:19]([O:18][C:16]([N:7]1[C:8]([NH2:25])=[C:9]2[C:14]([C:13]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([C:21]([F:23])([F:24])[F:22])=[CH:10]2)=[N:6]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)cc2c(N)nn(C(=O)OCC)c12
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc(C(F)(F)F)cc2c(N)n(C(=O)OCC)nc12

Procedure:
Analogously to Example 24, 0.025 mol of 3-amino-5-trifluoromethyl-7-ethoxycarbonylaminoindazole-2-carboxylic acid ethyl ester in 30 ml of dimethylformamide gives 3-amino-5-trifluoromethyl-7-ethoxycarbonylaminoindazole-1-carboxylic acid ethyl ester (melting point: 236°-237° C; 65% of theory) in 1 hour at 155° C.