Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-:3])=[O:2].[K+].C(N(CC)CC)C.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([C@@H:33]2[CH2:35][C@H:34]2[C:36]2[CH:41]=[CH:40][C:39](I)=[CH:38][CH:37]=2)[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Li+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]([N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([C@@H:33]2[CH2:35][C@H:34]2[C:36]2[CH:37]=[CH:38][C:39]([C:1]([OH:3])=[O:2])=[CH:40][CH:41]=2)[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23][CH2:24]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N(CC1CCN(Cc2ccccc2)CC1)[C@@H]1C[C@H]1c1ccc(I)cc1)C(F)(F)F
Reactant: O=C[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc([C@@H]2C[C@H]2N(CC2CCN(Cc3ccccc3)CC2)C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a 10-mL of microwave tube were added potassium formate (88 mg, 1.051 mmol), triethylamine (0.098 mL, 0.701 mmol) acetic anhydride (0.066 mL, 0.701 mmol) and DMF (1 mL), the resulting solution was stirred at room temperature for 1 h. N-((1-benzylpiperidin-4-yl)methyl)-2,2,2-trifluoro-N-((trans)-2-(4-iodophenyl)cyclopropyl)acetamide (190 mg, 0.350 mmol), Pd2(dba)3 (8.02 mg, 8.76 μmol), and lithium chloride (44.6 mg, 1.051 mmol) in DMF (1 mL) were added. The tube was sealed and the mixture was stirred at 80° C. for 4 h. The mixture was concentrated and the residue was taken up in methanol and filtered. The filtrate was purified using reverse-phase HPLC to give 20 mg of product as off-white solid. MS: (M+H)+=461.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.40-1.62 (m, 3H), 1.65-1.78 (m, 1H), 1.87-2.01 (m, 2H), 2.07 (d, J=13.39 Hz, 1H), 2.51-2.62 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.71 (m, 6H), 4.23 (s, 2H), 7.21 (d, J=8.34 Hz, 2H), 7.42-7.54 (m, 5H), 7.95 (d, J=8.34 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 67.1 %

Procedure:
A mixture of methyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A3) (14.28 g, 1 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (19.6 g, 0.85 equiv), DCE (300 ml), acetic acid (3.8 ml, 0.90 equiv) and sodium triacetoxyborohydride (20.7 g, 1.25 equiv) was stirred at room temperature under nitrogen for 17.5 h. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 4 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, dried over sodium sulfate and filtered through a pad of silica gel which was rinsed with 2.5% methanol in DCM. After evaporation in vacuo, the crude product was crystallised from ether/hexane, finally at ice bath temperature, which after drying yielded a white solid (20.9 g).
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[CH2:21]1COC[CH2:22]1>>[CH2:21]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:22]
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: C1CCOC1
Product: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 355 mg (1.17 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml THF were added at <10° C. drop-wise over 20 min 2.35 ml (4.7 mmol) 2-Methylmagnesium chloride solution in THF. The resulting brown solution was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NH4Cl solution (cooling with ice bath) and extracted three times with tert-butyl methyl ether. The combined organic phases were washed three times with brine, dried over Na2SO4, filtered and evaporated. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as yellow oil: MS (ISP): 286.1 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: C#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CC#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
250 mg (0.85 mmol) of (S)-8-chloro-1-ethynyl-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was suspended in 5 ml of N,N-dimethylformamide. 50 mg (1 mmol) of sodium hydride dispersion (55% in oil) was washed with n-hexane and then introduced into the above suspension. After 10 minutes 0.1 ml (1.5 mmol) of methyl iodide was added thereto and the mixture was stirred at room temperature for a further 4.5 hours. The mixture was poured into 50 ml of water and extracted four times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-propynyl-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 205°-20°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8](Cl)[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.[CH3:14][O-:15].[Na+]>CO>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8]([O:15][CH3:14])[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2c1ccnc2Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2c1ccnc2OC
Temperature: 90 °C

Procedure:
To a suspension of 7-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime (1.01 mmol) (A.2.7.2) in 4 mL MeOH were added 0.56 mL of NaOMe (30% solution in MeOH). The mixture was heated to 90° C. for 12 h in a closed vessel and it was then concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1) gives the desired product as beige solid;
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.Cl.Cl.[CH3:15][NH:16][NH:17][CH:18]([CH3:20])[CH3:19]>C(O)(=O)C.N1C=CC=CC=1.O>[CH3:15][N:16]1[C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5](=[O:7])[N:17]1[CH:18]([CH3:20])[CH3:19]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CNNC(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)N1C(=O)c2ccccc2CC(=O)N1C
Yield: 51.4 %

Procedure:
To the solution of homophthalic anhydride (6.80 g, 41.9 mmol) in 70 mL of glacial acetic acid was added 1-methyl-2-(1-methylethyl)hydrazine, dihydrochloride (6.75 g, 41.9 mmol) in 35 mL of pyridine (Rosen, et al., J. Heterocyclic Chem., 1969, 6, 9-12). The solution was refluxed for 12 h, cooled, diluted with water (300 mL), and extracted with chloroform (3×400 mL). The chloroform extract was washed with 10% hydrochloric acid (600 mL) and 5% sodium bicarbonate (600 mL) , dried over magnesium sulfate and concentrated to dryness. The mixture was purified by silica gel chromatography (hexane/ethyl acetate, 3/1) to afford 2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (5 g, 51%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:1]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1cc2nc[nH]c2cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2cnccc21
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a stirred solution of 5-azabenzimidazole (0.300 g, 2.51 mmol) in anhydrous DMF (5 mL) was added N,N-diisopropylethylamine (0.66 mL, 3.80 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.54 mL, 3.02 mmol). The resultant solution was heated to 80° C. for 2 h then cooled to room temperature. The reaction mixture was poured into brine (20 mL) and diluted with ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (3×5 mL), dried (MgSO4), and concentrated under reduced pressure. Purification of the crude brown oil through a plug of silica gel (CH2Cl2/MeOH, 9:1) provided the 1-(2-trimethylsilylethoxymethyl)-5-azabenzimidazole (0.586 g, 93%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CS(C)=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 74.1 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid morpholin-4-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 11 at 100° C. for 20 hours and allowed to cool to room temperature 2 mL of water was added, and the precipitated solid was collected by filtration, washed with chloroform and dried Synthesis was carried out in the same manner as in Reference Synthetic Example by using to give 40 mg of the desired product (yield 73%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]>CO>[CH3:3][O:4][C:5]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8]
Reactant: COc1c(C=O)cccc1Sc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(CO)cccc1Sc1ccccc1Cl
Yield: 98.2 %

Procedure:
Sodium borohydride (550 mg) was added in 10 minutes to a solution of 2-methoxy-3-(2-chlorophenylthio)benzaldehyde (9.1 g) in methanol (50 ml) with stirring at temperature below 15° C. After stirring the mixture at room temperature for 30 minutes, methanol was distilled off under reduced pressure. The residue was dissolved in water, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 2-methoxy-3-(2-chlorophenylthio)benzyl alcohol (9 g).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[C:10]2[CH:9]=[N:8]1.[ClH:32]>O1CCOCC1>[ClH:32].[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[NH:7][N:8]=[CH:9][C:10]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(N[C@H]2CCCNC2)c2cn[nH]c2n1
Reaction time: 0.5 h

Procedure:
To a solution of compound (S)-tert-butyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1 g, 2.22 mmol) in dioxane (10 mL) at 0° C., was added a solution of HCl in dioxane (10 mL) until the pH was acidic at 0° C. and stirred for 30 min at the same temperature. The reaction mixture was concentrated in vacuo to give a residue that was triturated with ether to give (S)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride as a free flowing solid. Then the compound was dissolved in MeOH, and to the reaction mixture resin was added until the mixture turns basic (Checked by pH paper). The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the titled intermediate (350 mg, 72%). 1H NMR (400 MHz, DMSO-d6): δ 13.1 (bs, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 4.46 (bs, 2H), 3.36-3.34 (m, 2H), 3.16-3.08 (m, 1H), 2.99-2.86 (m, 2H), 2.50 (bs, 1H), 1.97-1.81 (m, 2H), 1.68-1.58 (m, 2H). LC-MS: m/z [M+1]=219.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[C].[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[N:12][NH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of 4-[(E)-2-phenylvinyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (50 mg) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder (25 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-(2-phenylethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (50 mg). This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.065 mL), and the mixture was stirred at 50° C. overnight. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give the title compound (21 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].CON=[C:15]([CH2:21][C:22](=O)[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C:22]([CH3:23])=[N:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: Cc1ccc(NN)cc1C#N
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)nn1-c1ccc(C)c(C#N)c1

Procedure:
Part A: Ethyl 1-(3-cyano-4-methylphenyl)-3-methyl-5-pyrazole-carboxylate was prepared as colorless crystals following the standard condensation (3-cyano-4-methylphenyl-hydrazine and ethyl 2-(N-(methoxy)imino)-4-oxopentanoate in acetic acid) reaction protocol discussed previously. 1HNMR (CDCl3) δ: 7.68 (s, 1H), 7.57 (dd, 1H), 7.58 (d, 1H), 6.82 (s, 1H), 4.24 (q, 2H), 2.40 (s, 3H0, 2.37 (s, 3H), 1.27 (t, 3H) ppm; ESI mass spectrum analysis (270 (M+H, 100).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]5[CH2:20][CH2:19]5)[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)nc1N
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:36])[CH2:21][CH2:22][CH2:23][C:24]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:46]N1C(=O)C(C)(C)N(Br)C1=O>CCCCCC>[Br:46][CH:14]1[CH:13]=[C:12]2[C@:41]([CH3:44])([CH2:42][CH2:43][C@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11]2)[C@@H:40]2[C@@H:15]1[C@H:16]1[C@:37]([CH3:45])([CH2:38][CH2:39]2)[C@@H:19]([C@H:20]([CH3:36])[CH2:21][CH2:22][CH2:23][C:24]([O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCCCCC
Product: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3C(Br)C=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
To a boiling solution of 2.02 gm. of 3β,25-dibenzoyloxycholest- 5-ene (3.3 mmole) in 90 ml. of hexane, and 720 mg. (2.52 mmole) of dibromo-dimethylhydantoin. Reflux for 30 minutes, cool to room temperature, filter and wash with 2 ml. of carbontetrachloride. Concentrate the combined filtrate to dryness to obtain the title product. (2.3 gm.)
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][CH:5]([C:8]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:9]=2/[C:10](/[NH:13][OH:14])=[N:11]/[H])[O:4][CH2:3]1.[CH2:24]1CCN2C(=NCCC2)C[CH2:25]1.C(OC(=O)C)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[CH2:7][O:6][CH:5]([C:8]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:9]=2[C:10]2[N:11]=[C:24]([CH3:25])[O:14][N:13]=2)[O:4][CH2:3]1
Reactant: [H]/N=C(\NO)c1cc(OC)c(OC)cc1C1OCC(C)(C)CO1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C2OCC(C)(C)CO2)cc1OC
Reaction time: 1 h

Procedure:
A mixture of 1.34 g of (E)- and/or (Z)-2-(5,5-dimethyl-[1,3]dioxan-2-yl)-N-hydroxy-4,5-dimethoxy-benzamidine, 1.20 ml of DBU and 0.61 ml of acetic anhydride in 50 ml of DMF was stirred for 1 hr. at room temperature and subsequently for 2 hrs. at 80° C. Subsequently, the DMF was removed in a vacuum and the residue was taken up in ethyl acetate. The ethyl acetate phase was washed with water and saturated NaCl solution and, after removal of the solvent, the residue was purified by column chromatography (CH2Cl2/ethyl acetate). There were obtained 0.43 g of 3-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4,5-dimethoxy-phenyl]-5-methyl-[1,2,4]oxadiazole as a white solid; MS: 334 ([M]+).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)cc1
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OC(C)C)cc2)cc1

Procedure:
N—{(S)-2-[4-(4-Hydroxyphenoxy)phenoxy]-1-methylethyl}acetamide (139 mg, 0.46 mmol) was reacted with 2-iodopropane in analogy to example 10b. Yield: 51 mg (32%), M+H+: 344.23.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:31]3[CH:36]=[CH:35][C:34](Cl)=[CH:33][CH:32]=3)[C:18](=[O:30])[N:19]([C:23]3[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=3)[CH2:20][C:21]=2[N:22]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[N:7]([CH3:8])[C@H:9]([C:11](=[O:38])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:18](=[O:30])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][C:21]=2[N:22]=1)[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](C(=O)Nc1ccc2c(n1)CN(c1ccc(Cl)cc1)C(=O)N2c1ccc(Cl)cc1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](C(=O)Nc1ccc2c(n1)CN(c1ccccc1)C(=O)N2c1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of {(S)-1-[1,3-bis-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Example 21, product from Step 3) (100 mg, 0.18 mmol) in MeOH (10 mL) were added triethylamine (100 μL, 0.7 mmol, 4 equiv) and Pd/C (10%, 30 mg) and the mixture was hydrogenated overnight. The catalyst was filtered, the filtrate evaporated. The residue was dissolved in EtOAc and washed with H2O. The organic phase was dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-60%) to afford methyl-[(S)-1-(2-oxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (35 mg). MS: [M+H]+=502.