Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[Mg].[CH2:12]([Si@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[CH:33][C:32](I)=[C:31]([F:36])[CH:30]=3)[CH2:25][CH2:24]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14]>C1COCC1>[CH2:12]([Si@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[CH:33][C:32]([C:2]4[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=4)=[C:31]([F:36])[CH:30]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:20]1)[CH2:13][CH3:14]
Reactant: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(I)c(F)c3)CC2)CC1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4cc(F)c(F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
21.1 g (0.1 mol) of 1-bromo-3,4,5-trifluorobenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 47.3 g (0.1 mol) of 4-(trans -4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl) -2-fluorophenyl iodide. After a conventional after treatment, purification was conducted by means of chromatography to obtain 37.7 g (yield 79.1%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,3',4',5'-tetrafluorobiphenyl was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].O>O1CCCC1>[C:29]([NH:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH3:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCN)CC3
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCNC(C)=O)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of ethyl 9-(2-aminoethyl)-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (50.0 mg, 0.174 mmol) and triethylamine (36.4 μL, 0.261 mmol) in tetrahydrofuran (2 mL) was added acetic anhydride (24.7 μL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (diisopropyl ether) to give the title compound (32.1 mg, yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.CC(=CC)C.Cl([O-])=[O:15].[Na+].Cl>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:15])=[O:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Yield: 100.5 %

Procedure:
To a cooled (0° C.) solution of 10.0 g (47.1 mmol based on 90% purity) of 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company, Milwaukee, Wis.) in 200 mL of t-butanol was added 100 mL of 20 % (w/v) NaH2PO4 followed by 60 mL (0.566 mol) of 2-methyl-2-butene. Sodium chlorite (70.8 mmol based on 80% purity) in 60 mL of water was added with stirring. After stirring the two-phase mixture vigorously for 16 h at room temperature, the pH of the aqueous layer was adjusted to 1-2 with 20% HCl. The layers were separated and the aqueous layer extracted with EtOAc (2×120 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 9.8 g of an off-white solid. Recrystallization from a minimum of MeCN (three crops) gave the title compound as a white solid (9.02 g, 93%). 1H-NMR (300 MHz, CDCl3) δ7.79 (d, 1H, J=1.5 Hz), and 7.55 (d, 1H, J=1.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([O:29][CH2:30][CH2:31]OS(C)(=O)=O)[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:37]([CH2:31][CH2:30][O:29][CH:15]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:17]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(-c2c(F)cccc2C(OCCOS(C)(=O)=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2c(F)cccc2C(OCCN=[N+]=[N-])[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
(3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(2-(methanesulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (1.1 g, 2 mmol) was dissolved in anhydrous DMF (15 mL), solid NaN3 (280 mg, 4 mmol) was added and the reaction mixture was heated to 80° C. for 5 h. The mixture was cooled to rt and diluted with EtOAc and water. The organic phase was separated, washed with water and dried over MgSO4. Removal of the solvent gave (3R)-tert-butyl 3-((2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (0.89 g, yield 90%) which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH2:29][CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:31]=1.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCO[C@@H](Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)C(=O)O
Yield: 94.4 %

Procedure:
(S)-Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (1.7 g, 1 eq, 3.95 mmol) obtained in example 45, was hydrolyzed using lithium hydroxide monohydrate (249 mg, 1.5 eq, 5.93 mmol), in methanol-THF-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes→methanol and chloroform to afford the title compound (1.5 g, yield 94%) as viscous liquid.
Reaction SMILES: [C:1]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=3)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])=O.[Na+]>C(O)C>[OH:8][CH:1]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([CH:23]([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=3)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc2nc3ccc(C(=O)c4ccccc4)cc3c(-c3ccccc3)c2c1
Agent: O=B[O-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)c1ccc2nc3ccc(C(O)c4ccccc4)cc3c(-c3ccccc3)c2c1
Reaction time: 24 h

Procedure:
1 pbw of 2,7-dibenzoyl-9-phenylacridine is suspended in 4 pbw of ethanol and reduced by adding 0.1 pbw of sodium boranate in portions at 20°-50° C. After 24 hours, the reaction product is precipitated with water, purified and dried (m.p. above 280° C.).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
Following the procedure described in Preparation 58, 100 mg of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 49) were dissolved in 2 ml of methanol and, in the presence of 20 mg of 10% w/w palladium-on-carbon, the compound was reduced under 1 atmosphere (about 1 bar) pressure of hydrogen, to give the title compound melting at 138°-140° C.
Reaction SMILES: [OH-].[Na+].OO.[OH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]1[C:15]([NH2:16])=[C:14]([C:17]#[N:18])[C:13]([CH3:19])=[N:12]1.C(O)(=[O:22])C>O>[OH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]1[C:15]([NH2:16])=[C:14]([C:17]([NH2:18])=[O:22])[C:13]([CH3:19])=[N:12]1
Reactant: Cc1nn(C2CCCC2O)c(N)c1C#N
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C2CCCC2O)c(N)c1C(N)=O
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of sodium hydroxide (1.2 g, 30 mmol) in water (50 ml) in an ice-bath was added 30% hydrogen peroxide (3.3 ml, 29 mmol). The reaction mixture was stirred for 5 minutes then 1-(2-hydroxycyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.5 g, 12 mmol) was added. The reaction mixture was stirred in an ice-bath for 5 hours, additional 30% hydrogen peroxide (1.5 ml) was added and stirring was continued for 2 hours. Acetic acid (2 ml) was added to the reaction mixture, all but approximately 25 ml of the solvent was removed in vacuo and the resulting solid was collected by filtration and washed with water. The solid was air dried to afford 2.4 g (90%) of 1-(2-hydroxycyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carboxamide as a white solid, m.p. 120°-124° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:3][CH:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(C)O)nn1
Temperature: -70 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of methyl 6-acetylpyridazine-3-carboxylate (0.8 g, 4.4 mmol) in methanol (30 mL) was added sodium borohydride (340 mg, 8.8 mmol) at −70° C. under nitrogen gas protected. The mixture solution was stirred for 3 hours at −70° C., then poured into ethyl acetate (50 mL) and water (50 mL). Separated organic layer was dried over sodium sulfate and concentrated to dry. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=5:) to give methyl 6-(1-hydroxyethyl)pyridazine-3-carboxylate as a white solid (200 mg, 25%). 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 5.07 (m, 1H), 3.96 (s, 3H), 1.46 (d, J=6 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([SH:16])[S:15][C:9]2=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+]>O>[C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([SH:16])[S:15][C:9]2=[N:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2sc(S)nn2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2sc(S)nn2c1=O
Temperature: 60 °C
Yield: 80.2 %

Procedure:
The product obtained in Step 1 (9.1 g) was added to a solution of 4.0 g of potassium hydroxide in 200 ml of water, and the mixture was heated at 60° C. for 30 minutes. After cooling to room temperature, the solution was washed with 200 ml of ethyl acetate and the pH was adjusted to 1.0 with hydrochloric acid. The formed crystals were collected by filtration and washed with ether, affording 6.5 g of the objective compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:43][OH:44])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:33]=[N:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=5)=[CH:30][CH:31]=[C:26]4[C:25]([C:41]#[N:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:47])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:43][OH:44])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:33]=[N:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=5)=[CH:30][CH:31]=[C:26]4[C:25]([C:41]([NH2:42])=[O:47])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(-c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)cn1
Reactant: CCO
Solvent: O
Product: CCOc1ccc(-c2ccc3c(C(N)=O)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)cn1
Temperature: 45 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (36 mg, 61.2 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (263 μg, 0.612 μmol, Eq: 0.01) were combined with ethanol (480 μl) and water (480 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(6-ethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (31 mg, 84%, [M+H]+ 607).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>C(O)C>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH:17][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: Cc1cccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c1
Yield: 63.3 %

Procedure:
2-Chloro-N-(2-chloro-4-sulphamoylphenyl)-acetamide (28.3 g) and m-toluidine (31.8 g) were heated 7 hours at 175°C (oil bath) and worked up as in Example 15 to yield 22.4 g product, m.p. 185°-189°C (ethanol).
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH:1]1([N:5]2[C:9]([C:10]([Cl:16])=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)O)n(C2CCC2)n1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(C(=O)Cl)n(C2CCC2)n1
Yield: 96.1 %

Procedure:
To 3.02 g of 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylic acid were added 60 ml of benzene and 10 ml of thionyl chloride. The mixture was refluxed for two hours. Then the solvent was distilled off under reduced pressure and thus 3.2 g of 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylic acid chloride was obtained (yield: 96.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]1[CH2:30][CH2:29]1.[I-].[Na+]>CN(C=O)C.O>[CH:28]1([N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:30][CH2:29]1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(C2CC2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 150 °C
Reaction time: 30 h

Procedure:
To a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (1.0 g) in DMF (20 ml) were added cesium carbonate (2.429 g), bromocyclopropane (0.597 ml) and sodium iodide (0.559 g) at room temperature. The reaction mixture was stirred at 150° C. for 30 hr in an autoclave, allowed to cool to room temperature, and poured into water (100 ml). The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate). The fraction containing the title compound was purified again by silica gel column chromatography (NH, methanol/ethyl acetate), and crystallized from methanol/ethyl acetate to give the title compound (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24]C(OC(C)(C)C)=O)[CH3:23])=[CH:18][CH:17]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:20][CH:21]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Temperature: 25 °C

Procedure:
To 630 mg (1.48 mmol) 2-[4-((S)-1-tert-butoxycarbonylamino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester (example XXXIV) in 6 mL dioxane are added 1.48 mL (5.94 mmol) HCl solution in dioxane (c=4 mol/L). After stirring over night at r.t. the reaction is neutralised by the addition of a sat. aq. NaHCO3 solution and extracted three times with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(#N)C.[N+:8]([C:11]1[CH:12]=[C:13]([N:20]=[C:21]=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]>O>[N+:8]([C:11]1[CH:12]=[C:13]([NH:20][C:21]([NH:1][CH2:2][CH2:3][OH:4])=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]
Reactant: NCCO
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Solvent: CC#N
Product: O=C(NCCO)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
11.0 g (0.180 mol) of 2-aminoethanol was placed, in a nitrogen current, in a 0.3-l four-necked flask equipped with a nitrogen inlet tube, a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added 50 ml of acetonitrile, followed by stirring for dissolution. While the flask was being cooled with ice water, the flask contents were stirred. Thereto was dropwise added 50 ml of the above-obtained acetonitrile solution containing 3,5-dinitrophenyl isocyanate (compound 7). The mixture was stirred at room temperature for 1 hour and then poured into 0.7 l of water. The separated crystals were collected by suction filtration, washed with water and vacuum-dried at 35° C. for 12 hours to obtain N-(3,5-dinitrophenyl)-N′-(2-hydroxyethyl)urea (compound 11) as a yellow powder. Yield: 16.7 g (74%) Melting point: 192-194° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[CH3:24][C:21]([CH3:25])([CH2:22][CH3:23])[CH:20]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[O:26][CH3:30]
Reactant: CI
Reactant: CCC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 66.62A (0.39 g, 1.1 mmol) in DMF (5 mL), was added NaH (0.034 g, 1.4 mmol). The mixture was stirred at room temperature for 10 minutes and then iodomethane (0.20 mL, 3.2 mmol) was added. The mixture was stirred at room temperature for 60 minutes and then it was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:9 EtOAc/hexane) and gave 66.62B, colorless oil, in 64% yield (260 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:20])=[O:19]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:10][C:9](=[O:8])[CH:16]=[CH:15][C:14]2[CH:11]=[CH:12][CH:20]=[C:18]([O:19][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CC(C)=O
Solvent: CCO
Product: O=C(C=Cc1cccc(OCc2ccccc2)c1)C=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
The title compound was prepared as described in General Method 2 using 5.03 g (23.7 mmol) of 3-benzyloxy-benzaldehyde, 150 mL of EtOH, 0.65 mL (11.2 mmol) of acetone, and 0.31 g of Ba(OH)2.(H2O)8. The mixture was heated at room temperature overnight and filtered to give the title compound. 1H NMR (CDCl3) δ 5.08 (s, 4 H), 7.03-7.07 (m, 4 H), 7.22-7.47 (m, 16 H), 7.69 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>O1CCCC1.O.C(O)(C)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:11])[CH2:7]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)N2CC(Oc3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
A stirred solution of 2.8 g (0.01 mole) of crude 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml of tetrahydrofuran was treated with 1 g (0.01 mole) of 1-methylpiperazine then with 1.42 g (0.01 mole) of potassium carbonate. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and an oil separated. Upon standing, this oil solidified and was collected by filtration, yielding 3.3 g of crude product. The solid was dissolved in 20 ml of isopropanol and treated with 1.16 g of fumaric acid dissolved in 25 ml of boiling isopropanol. The volume was reduced to 30 ml by heating under a stream of nitrogen and upon cooling, the precipitated salt was collected by filtration, yielding 1.35 g (95.9%) of white crystals, m.p. 187°-188° C.