Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([Cl:13])[N:6]=1>C1COCC1>[Cl:13][C:7]1[C:8]([F:12])=[C:9]([O:2][CH3:1])[N:10]=[C:5]([CH3:4])[N:6]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(Cl)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
3.21 g of sodium methoxide are added to a solution of 9.8 g of 2-methyl-4,6-dichloro-5-fluoropyrimidine in 80 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 3 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 9 g of 4-chloro-5-fluoro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].C(O)(=O)C.[BrH:19].N([O-])=O.[Na+]>O>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 3-amino-4-trifluoromethyl-benzoic acid were dissolved using 50 ml of acetic acid. Then, 50 g of ice and 50 ml of a saturated aqueous HBr-solution were added and a solution of 2.0 g NaNO2 in 10 ml of water was added dropwise at 0° C. The reaction mixture was then stirred at room temperature for 10 minutes. Then, the reaction mixture was added dropwise to a suspension of 7.0 g CuBr and 10.9 g CuBr2 in 100 ml of a half-concentrated aqueous solution of HBr. The resulting mixture was then stirred for 2 h at room temperature, then diluted using 21 of water, stirred for 1 h and finally the precipitate was isolated by filtration. The precipitate was dried in vacuo to yield 5.2 g of the title compound that was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])=[N:14][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)nc3)CC2)c(C)c1
Yield: 20 %

Procedure:
Using piperidin-2-one (58 mg) and (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (42 mg) was obtained.
Reaction SMILES: [CH:1]1([N:4]([CH2:38][CH2:39]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:39][CH2:38][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (355) (120 mg, 0.22 mmol) and diisopropyl azodicarboxylate (0.22 mL, 1.12 mmol) in dichloromethane (30 mL) was added triphenyl phosphine (351 mg, 1.34 mmol) at room temperature and the reaction mixture was stirred for 15 min at the same temperature. The yellow color disappeared (silica TLC 5% methanol in ethyl acetate, Rf=0.2). The dichloromethane was removed in vacuo and the crude mass was purified by silica gel (normal, 100-200 mesh) column chromatography using a gradient eluent mixture of 1% to 5% methanol in dichloromethane to get pure 9-benzyloxy-2-cyclopropyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (356) (106 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].Cl.Cl[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CNCCN
Reactant: ClCc1ccccn1
Agent: Cl
Product: CN(CCN(Cc1ccccn1)Cc1ccccn1)Cc1ccccn1

Procedure:
Prepared from N-methylethane-1,2-diamine and 2-chloromethylpyridine hydrochloride using the procedure described by I. Bernal et al in J. Chem. Soc., Dalton. Trans., 1995, 3667.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13])([CH3:4])[CH3:3].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>>[C:2]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[N:13]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Reactant: BrCCCCBr
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, brown oil, MS: m/e=255.3 [(M+H)+], was prepared in accordance with the general method of intermediate E from [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) and 1,4-dibromobutane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21](O)=[O:22])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:39]1([C@H:45]2[CH2:49][O:48][C:47](=[O:50])[NH:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21]([N:46]4[C@@H:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:49][O:48][C:47]4=[O:50])=[O:22])[O:11][CH2:12][C:13]([CH3:16])([CH3:17])[CH2:14][O:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC1(C)COC(CSCC(=O)O)(c2ccc3c(c2)OCO3)OC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccc3c(c2)OCO3)OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
({[2-(1,3-Benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (Method 13) (12.7 g, 37.4 mmol) was dissolved in dry CH2Cl2 (150 ml) and given 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 8.48 g, 37.4 mmol) and 4-(dimethylamino)pyridine (DMAP, 9.13 g, 74.8 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (6.10 g, 37.4 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (heptane:EtOAc 2:1). This afforded the title compound.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH:15]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][C:20](=[O:24])[C:19]1([CH3:26])[CH3:25])=[O:17]>CO>[NH2:6][CH:15]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][C:20](=[O:24])[C:19]1([CH3:25])[CH3:26])=[O:17]
Reactant: CC1(C)C(=O)NCCN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC1(C)C(=O)NCCN1C(=O)C(N)Cc1ccccc1

Procedure:
Hydrazine hydrate (2.0 g., 0.04 mole) is added to a stirred solution of 4-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-3,3-dimethylpiperazinone (XXIII, Example 57, 10.0 g., 0.025 mole) in methanol (200 ml.). After refluxing for 2 hours the solution is cooled and filtered to remove the 2,3-dihydro-1,4-phthalazinedione by-product. The methanol is evaporated and the residual oil is recrystallized from water to give the title compound as the dihydrate, m.p. 70°-73°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=2[Cl:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: Fc1cccc(-c2cncc(Br)c2)c1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2-chloro-3-fluoro-phenylboronic acid. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])=[N+:2]=[N-:3].N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[C:22](=[O:23])([O:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)[O:14][CH2:13][CH2:12][S:9]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:11])=[O:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NCCOCCS(=O)(=O)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCS(=O)(=O)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A solution of alcohol 5 (4.0 g, 17.9 mmol) and pyridine (10 ml, 6.9 equiv.) in CH2Cl2 (100 ml) was cooled in an ice bath and p-nitrophenyl chloroformate (5.42 g, 1.5 equiv.) was added. The resulting solution was stirred at RT for 16 h then washed with a 1 M HCl aqueous solution (3×50 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 7:3 then 1:1) afforded carbonate 6 as a white amorphous solid (6.3 g, 91%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:14])([F:13])[C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1.[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C(F)(F)F)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C(F)(F)F)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-trifluoromethyl-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) was added to the reaction vessel and the resulting mixture was stirred for a period of about 16 hours resulting in the formation of precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover 48 grams of a white solid. This solid was recrystallized from dimethyl formamide to yield the desired product 5-trifluoromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23])C.Cl.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
1-(4,4-diethoxybutyl)-2-propyl-1H-imidazo[4,5-c]quinoline (25.3 g, 71.2 mmol) was added to a solution of concentrated hydrochloric acid (35 mL) and water (35 mL) cooled to 0° C. and the reaction mixture was allowed to warm to ambient temperature and was stirred for 30 minutes. The reaction mixture was diluted with water (100 mL) and dichloromethane (200 mL) and the pH of the reaction mixture was slowly made basic with addition of potassium carbonate. The aqueous and organic layers were separated and the organic layer was dried over potassium carbonate, filtered, and concentrated to afford 22.7 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:53][CH2:52]1)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:53][CH2:52]1)=[O:4]
Reactant: CCCc1nc(CN2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCc1nc(CN2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
5-Methoxycarbonyl-4-[4-(2-pyridyl)-piperazin-1-yl]methyl-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole (1.72 g, 2.10 mmol), obtained from Part B of Example 101, was stirred in 75 mL methanol at reflux for 2 hours. After evaporation of solvent under reduced pressure, the residue was stirred in 30 mL of 1:1 methanol/5% aqueous NaHCO3 for 6 h. The reaction mixture was extracted with 4×50 mL ethyl ether, and the residual organic solvent in the aqueous layer was evaporated under reduced pressure. The product was precipitated by adjusting the pH to 5 with aqueous HCl. The title compound (1.02 g, 84.2%) was collected as a white powder after filtering and drying in vacuo at 60° C. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=7.3 Hz, 3H); 1.61 (m, 2H); 2.54 (t, J=7.7 Hz, 2H); 2.76 (br s, 4H, piperazine); 3.54 (br s, 4H, piperazine); 3.63 (s, 3H); 3.88 (s, 2H); 5.27 (s, 2H); 6.57-8.13 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][C:5]([O:6][CH:7]4[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:8]4)=[CH:4][CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: CCN1CCCC(Oc2ccc(Br)cc2)C1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CCN1CCCC(Oc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)C1

Procedure:
Prepared according to general working method I from 3-(4-bromo-phenoxy)-1-ethyl-piperidine (90 mg, 0.32 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.[OH-].[K+].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(C)c2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
By a method similar to Preparation 3, using 5-methoxy-7-methyl-1H-indole (0.12 mole, 20.02 g), methanol (240 mL), potassium hydroxide (0.43 mole, 24.39 g) and 1-methyl-4-piperidone (0.13 mole, 14.76 g) afforded 24.72 (78%) of the title compound: Mass spectrum (ion spray): m/z=(ES+) 257 (M+1), (ES−) 255 (M−1); 1H NMR (DMSOd6): 7.32 (s, 1H), 7.06 (1H), 6.59 (1H), 6.05 (m, 1H), 3.75 (s, 3H), 3.04 (2H), 2.50 (m, 4H), 2.42 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure--Nonanoyl chloride (2.74 m, 14.6 mmol) was added dropwise to a cooled solution of tyramine (1 g, 7.29 mmol) and triethylamine (2.03 ml, 14.6 mmol) in THF (35 ml). The reaction mixture was stirred at room temperature for 48 hours. It was then poured into 10% HCl solution (70 ml) and the mixture was then extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give crude N-nonanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). m.p. 65.9° to 66.7° C. IR (KBr) 3306, 2922, 2851, 1638; 1H NMR δ 6.65-6.98 (d of d, 4 H, aromatic), 7.78 (t, 1 H, NH), 9.15 (s, 1 H, OH). Analysis calculated for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found C, 73.49; H, 9.661; N, 5.31.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.Cl>CN(C)C=O>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5.45, sodium hydride (55%) in mineral oil) in 100 ml N,N-dimethylformamide was added at 0-5° C. a solution of 16.8 g indole-5-carboxaldehyde in 100 ml N,N-dimethylformamide followed by 24.46 ml of 2-(trimethylsilyl)-ethoxymethyl chloride. The reaction mixture was then warmed up to ambient temperature and stirring continued for 16 hours. It was then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a brown oil, which was purified by chromatography (silicagel, eluent: gradient of n-heptane/EtOAc) to yield 25.52 g 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-5-carbaldehyde as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 89.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (104 mg, 0.16 mmol) prepared in Example 131a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (72.2 mg, 90%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:25]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:27]([CH3:29])[CH:28]=1)=[O:4].[OH-].[Li+]>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C@H:8]2[CH2:7][N:6]([C:24]3[N:25]([CH:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[N:26]=[C:27]([CH3:29])[CH:28]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])=[C:14]([C:20]([F:22])([F:21])[F:23])[CH:15]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide avoiding methanol as a cosolvent to give the title compound as yellow foam which was used in the next step without further purification. MS (ESI): m/z=506.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[OH-].[Na+].[Cl:18][C:19]1[N:23]2[N:24]=[C:25](Cl)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1.O>COCCOC>[Cl:18][C:19]1[N:23]2[N:24]=[C:25]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Cl)n3n2)cn1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
0.61 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5.3 cm3 of a 1N aqueous solution of sodium hydroxide are added to a mixture of 0.5 g of commercial 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine in 15 cm3 of 1,2-dimethoxyethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes before the addition of 92 mg of palladium dichlorobis(triphenylphosphine). The reaction mixture is then stirred at 65° C. for 30 minutes, and then brought back to a temperature in the region of 20° C. and poured into 20 cm3 of water. The mixture obtained is extracted with 3×100 cm3 of dichloromethane and the combined organic phases are washed with 2×100 cm3 of a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The yellow powder thus obtained is purified by chromatography on silica gel (eluent: 98/2 CH2Cl2/MeOH). 0.2 g of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo-[4,3-b]pyridazine is thus obtained in the form of a beige powder, the characteristics of which are as follows: