Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
To a solution of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (2.1 g) in tetrahydrofuran (400 mL) was added Lawesson's reagent (2.3 g) and the mixture was stirred at 60° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was solidified with ethyl acetate and the resulting solid was washed with diethyl ether to give the title compound (2.06 g, 94%) as a pale yellow solid. MS 378 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([C:13](=[CH:18][O:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:21][CH3:22])[N:10]=[CH:9][N:8]=1.[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:29]([C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([C:13](=[CH:18][O:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:21][CH3:22])[N:10]=[CH:9][N:8]=1)#[N:30]
Reactant: N#Cc1ccccc1O
Reactant: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(COc2ccccc2C#N)c1
Yield: 86 %

Procedure:
Methyl α-[4-(3-bromomethylphenoxy)-6-methoxy-5-pyrimidinyl]-β-methoxyacrylate (3.2 g, 7.8 mmol), o-hydroxybenzonitril (0.93 g, 7.8 mmol) and potassium carbonate (2.1 g, 15 mmol) are stirred in dimethylformamide (20 ml) for 4 hours at room temperature. Dilution with ether, washing with brine, drying (MgSO4) and chromatography on silicagel (eluent: hexane/ethyl acetate 1:1) gives methyl α-[4-(3-(2-cyanophenoxymethyl)-phenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate as a colorless solid (3.0 g), m.p. 132°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6].[C:18]([Cl:21])(=O)[CH3:19].O1CCOCC1.Cl>O1CCOCC1>[ClH:21].[CH3:18][C:19]1[N:11]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc(C(=O)O)ccc1NC1CCOCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
3-Amino-4-((tetrahydropyran-4-yl)amino)benzoic acid (see Working Example 4-2) (90 g, 0.38 mol) was dissolved in dioxane (900 mL), and after cooling to 10° C., a solution of acetyl chloride (35.0 g, 0.45 mol) in dioxane (900 mL) was added dropwise over the course of 35 minutes. After heating to reflux with stirring for 2.5 h, another solution of acetyl chloride (15.8 g, 0.20 mol) in dioxane (200 mL) was added to the reaction solution, and this was further heated to reflux with stirring for 3 hours. Next, a 4N HCl dioxane solution (100 mL) was added, and after heating to reflux with stirring for 8 h, this was allowed to cool to room temperature, the solid obtained was filtered off and washed with hexane to yield the title compound (105 g, quant.) as a light purple solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:28]>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]([F:28])=[O:18])=[CH:5][N:4]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CSc1ncc(C(=O)O)c(Nc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(C(=O)F)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution containing 2.88 g (11.02 mmol) of the product prepared in step 20.2 and 2.1 mL (15.0 mmol) of triethylamine in 55 mL of CH2Cl2 are added 1.40 mL (16.53 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and washed twice with 50 mL of ice-cold aqueous NaHCO3 solution. The organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of the expected product are obtained in the form of a yellow solid. The yield is quantitative.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([NH:16][NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:28][C:18]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)=[N:17][N:16]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NNC(=O)CCc2cccc(F)c2)ccn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1
Yield: 73.4 %

Procedure:
A solution of tert-butyl[4-[[2-[3-(3-fluorophenyl)propanoyl]hydrazino]carbonyl]-2-pyridyl]carbamate (1.00 g, 2.48 mmol), p-toluenesulfonyl chloride (946 mg, 4.96 mmol) and triethylamine (1.72 mL, 12.4 mmol) in tetrahydrofuran (30 mL) was heated under reflux for 17 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100), and recrystallized from ethyl acetate to give the title compound (0.70 g, yield 73%) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([Cl:9])[CH:11]=2)=[CH:3][N:4]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: Nc1ncc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(N)nn2)cc1Cl
Temperature: 82 °C
Yield: 55.7 %

Procedure:
To a mixture of 6-bromo-1,2,4-triazin-3-amine (Step 1, 1.0 g, 5.7 mmol) and [3-chloro-4-(methoxycarbonyl)phenyl]boronic acid (1.5 g, 6.8 mmol) (VMR, Cat. #100013-404) in 1,4-dioxane (22 mL) was added a solution of potassium phosphate (2.4 g, 11 mmol) in water (5.1 mL). The mixture was degassed by purging nitrogen for 10 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and again was degassed with nitrogen. The mixture was stirred and heated at 82° C. (an oil bath) for 1 h. The mixture was cooled to r.t., diluted with water, stirred for 30 min, and a grey solid formed. The solid was isolated by filtration, rinsed several times with water, and dried in air. The solid was then triturated sequentially with hexanes, dichloromethane-hexanes (1:1), and hexanes to afford the desired product (840 mg, 55.54%). LCMS (M+H)+: m/z=264.9/267.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:25]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([OH:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:36])=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:6]=3[CH:25]=2)[CH:28]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of di-tert-butyl (5-bromo-1,2-benzoxazol-3-yl)imidodicarbonate (3.9 g, 9.3 mmol) in dimethoxyethane (100 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (1.6 g, 9.3 mmol), tetrakis(triphenylphosphine)palladium (1.1 g, 0.9 mmol) and 2 M aqueous sodium carbonate (9.3 mL, 18.6 mmol). The mixture was heated at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (75 mL), washed with water (2×40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10-50% gradient of ethyl acetate in hexanes to afford di-tert-butyl [5-(5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate as a colorless solid in 63% yield (2.69 g): 1H NMR (300 MHz, DMSO-d6) δ7.66 (m, 2H), 7.47-7.45 (s, 1H), 7.22-7.19 (m, 3H), 6.90-6.87 (m, 1H), 1.41 (s, 18H); MS (ES+) m/z 460.9 (M+1), 462.9 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)([CH3:11])[CH2:8][CH2:9][OH:10].C(Cl)Cl>>[CH3:1][S:2]([O:10][CH2:9][CH2:8][C:7]([CH3:6])([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)[CH3:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
TEA (38.0 μL, 0.000273 mol) and methanesulfonyl chloride (21.1 μL, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (87 mg). MS(ES): 479 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=23)[CH2:3][C:2]1=[O:15].C1COCC1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[OH:14][C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]2[C:5]3[N:4]([CH2:3][C:2](=[O:15])[NH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CN2C(=O)C(=O)c3cccc(c32)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CN2C(=O)C(O)(c3ccccc3)c3cccc(c32)N1
Reaction time: 8 h

Procedure:
A suspension was prepared from 4.3 g. of 1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16 ml. of a 2.83 M phenylmagnesium bromide solution in diethyl ether (phenyl Grignard reagent) were added thereto while maintaining the temperature in the range 10°-15° C. The resulting reaction mixture was stirred overnight after which time, 200 ml. of a saturated aqueous amonium chloride solution were added. An additional 1500 ml. of diethylether were added and the ethereal layer decanted from the solids. The ethereal layer was dried and the ether removed therefrom in vacuo. The resulting residue, comprising 6-hydroxy-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione melted at 259°-262° C. with decomposition after recrystallization from methanol; yield = 2.4 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][N:14]([CH2:17][CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[NH2:16])#[N:8].[F-].[Na+].O>O1CCCC1>[NH2:8][CH2:7][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([CH2:17][CH2:18][O:19][C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[NH2:16]
Reactant: N#C/C=C/c1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Yield: 90 %

Procedure:
To a suspension of lithium aluminum hydride (5.41 g) in tetrahydrofuran (200 ml) was added a solution of 4-[(E)-2-cyanoethenyl]-1-[2-(trityloxy)ethyl]-5-aminopyrazole (15 g) in tetrahydrofuran (100 ml) under ice-cooling. The mixture was refluxed for 3.5 hours. After cooling on an ice bath, sodium fluoride (24 g) and water (10.3 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 4-(3-aminopropyl)-1-(2-triphenylmethyloxyethyl)-5-aminopyrazole (13.7 g). This product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:18]([NH2:20])[CH3:19]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:20][CH2:18][CH3:19])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Reactant: CCN
Product: CCNc1nc(C#N)c(C#N)nc1-c1ccccc1
Yield: 88 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (12.03 g; 0.05 mole) and 7.07 g (0.11 mole) of a 70% aqueous solution of ethylamine were worked up in the same way as in Example 13, and recrystallized from toluene to afford 10.98 g (yield 88%) of 2,3-dicyano-5-ethylamino-6-phenylpyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])=O)[CH2:11][CH2:10]1.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:22])[NH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NNC(=O)Nc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2-c2ccccc2)CC1
Yield: 84.3 %

Procedure:
A suspension of 2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-N-phenyl-1-hydrazine carboxamide D5 (1.00 g, 2.50 mmol) in 2M NaOH aqueous solution (10 mL) was heated at reflux for 5 hrs. The pH of the solution was adjusted to 8 by the sequential addition of HCl 28% and NaOH, and the resulting white precipitate was filtered, washed with water and diethyl ether to afford 0.80 g (84%) 5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-4-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one E2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (259 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 124 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:5].[C:32](OC(=O)C)(=[O:34])[CH3:33].[OH-].[NH4+]>O>[C:32]([NH:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:15][NH:14][C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9 parts of 2-amino-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro [4,5]dec-8-yl]ethyl}-benzamide, 8.5 parts of acetic acid anhydride and 85 parts of water is stirred for 30 minutes in a water-bath at about 80° C. The reaction mixture is cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane. The combined organic phases are washed three times with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 5.2 parts of 2-(acetylamino)-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro-[4,5]dec-8-yl]ethyl}benzamide; mp. 195.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[H-].[Na+].Br[CH2:30][C:31](OC(C)(C)C)=[O:32].CC(C[AlH]CC(C)C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][O:26][CH2:30][CH2:31][OH:32])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(COCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.28 mmol) of 1-9 in 3 mL of DMF at 0° C. was added 20 mg of NaH (0.6 mmol of a 60% suspension in oil), followed by 80 μL (0.6 mmol) of tert-butyl bromoacetate. After stirring for 2 h at 0° C., the reaction was quenched with a saturated NH4Cl solution, and extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide a colorless oil. This residue was dissolved in 10 mL of CH2Cl2, cooled to −78° C., and 900 μL of a 1M DIBAL-H solution in CH2Cl2 was added dropwise. After stirring for 45 min, the reaction was quenched with 500 μL of acetone, the cooling bath was removed, 15 mL of a 0.5 M tartaric acid solution was added, and the biphasic mixture was stirred for 1 h. The layers were separated, the organic was washed with water, dried over Na2SO4, and concentrated: The residue was then dissolved in 5 mL of THF and 1 mL of MeOH, and a small amount of NaBH4 was added. After stirring for 15 min, the reaction was quenched with 1M HCl, extracted twice with EtOAc, washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide 2-2 as a sticky white taffy. Data for 2-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.4 (s, 1H), 4.8-4.6 (m, 3H), 4.2 (d, 1H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 2H), 2.85 (s, 6H) ppm. HRMS (ES) calc'd M+H for C22H24F2N2O3: 403.1828. Found: 403.1824.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][C:14](=[O:16])[S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: Sc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(CC(=O)Sc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10-mL, one-necked, round-bottomed flask was charged with 2.5 mL dichloromethane, (3,4,5-trimethoxyphenyl)acetic acid (566 mg, 2.5 mmol), DMAP (31 mg, 2.5 mmol) and thiophenol (1.0 mL, 9.9 mmol). The mixture was cooled in an ice bath while DCC (619 mg, 3.0 mmol) was added and stirred for 5 min. The reaction was allowed to warm up to room temperature and additionally stirred for 3 h.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
230 mg (0.409 mmol) of (2R*,4S*)-2-benzyl-1-(3-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 81 mg (2.14 mmol) of sodium borohydride in analogy to Example 2. The title compound of the formula ##STR48## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.26, FD-MS: M+ =465.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:17]([CH3:23])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[OH:22][C:18]1[C:17]([CH3:23])=[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(N)cccc1O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.81) and 3-amino-2-methylphenol (0.5 g) to give the title compound as a white solid (0.5 g).