Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1([CH3:24])[C:18]2[C:11]([CH:12]=[C:13]3[C:17]=2[CH:16]=[N:15][N:14]3[CH2:19][CH:20](O)[CH3:21])=[C:10]([CH3:23])[CH:9]=[CH:8]1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:20]([CH3:21])[CH2:19][N:14]1[C:13]2=[CH:12][C:11]3[C:18]([C:7]([CH3:24])([CH3:6])[CH:8]=[CH:9][C:10]=3[CH3:23])=[C:17]2[CH:16]=[N:15]1)=[N+:33]=[N-:34]
Reactant: CC1=C2C=c3c(cnn3CC(C)O)=C2C(C)(C)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 63.1 %

Procedure:
1 ml (12.5 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.6 g (6.2 mmol) of (RS)-1-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 3.5 ml (25 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.81 g (12.5 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The yellow oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.1 g (63%) of (RS)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=O)(C)(C)C.[C:31]1([C:37]2[N:41]=[C:40]([CH2:42][NH2:43])[NH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:12]1[NH:8][C@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:43][CH2:42][C:40]3[NH:39][N:38]=[C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:41]=3)=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: NCc1nc(-c2ccccc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(-c2ccccc2)n[nH]1)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1, 0.020 g, 0.049 mmol) in N,N-dimethylformamide (0.5 ml) was added to 1-(3-phenyl-1H-1,2,4-triazol-5-yl)methanamine (0.018 g, 0.073 mmol) followed by 1-hydroxybenzotriazole (0.0099 g, 0.073 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (0.014 g, 0.073 mmol) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol). The reaction mixture was stirred at ambient temperature for 4 h. The mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The resulting pure fractions were lyophilized overnight to give the titled compound as a white solid. LC-MS 590.2 (M+23).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pt](=O)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCN2C=CN=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CCO
Product: O=S1(=O)CCN2CCNC(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33 %

Procedure:
A mixture of 9-(4-phenoxyphenyl)-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (96.0 mg), and platinum(IV) oxide (15.0 mg) in EtOH (5 ml) was stirred at room temperature for 2.5 hr under H2. The mixture was added with NH silica gel, concentrated, purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), then recrystallized from EtOAc-IPE to give the title compound (32.0 mg) as white powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:48][O:49][CH3:50])[CH2:26][CH2:25][N:24]([C:27](=[O:47])[CH2:28][N:29]6[CH2:34][CH:33]=[C:32]([C:35]7[CH:40]=[CH:39][C:38]([C:41]8[N:46]=[CH:45][CH:44]=[CH:43][N:42]=8)=[CH:37][CH:36]=7)[CH2:31][CH2:30]6)[CH2:23]5)=[O:21])[CH:17]=4)[N:12](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.ClCCl.O>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]5([CH2:48][O:49][CH3:50])[CH2:26][CH2:25][N:24]([C:27](=[O:47])[CH2:28][N:29]6[CH2:30][CH:31]=[C:32]([C:35]7[CH:36]=[CH:37][C:38]([C:41]8[N:42]=[CH:43][CH:44]=[CH:45][N:46]=8)=[CH:39][CH:40]=7)[CH2:33][CH2:34]6)[CH2:23]5)=[O:21])[CH:17]=4)[NH:12][N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COCC1(C(=O)Nc2ccc3c(c2)c(-c2ccnc(C4CC4)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C5CC5)c4)c3c2)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Yield: 105.4 %

Procedure:
3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-yl]-amide (570 mg, 0.63 mmol) was dissolved in 4 ml of trifluoroacetic acid (TFA), 10 ml dichloromethane and 2 ml of water and the reaction mixture was stirred for 18 hrs. The reaction mixture was evaporated and chromatographed on silica gel using 3-5% 2N NH3/methanol/dichlormethane to obtain 444 mg of title product. MS (M+1)=669. Retention time (minutes) 2.67.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[ClH:41].COC(C)(C)C>CC(O)C.O1CCOCC1>[ClH:41].[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-[({4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e1 (2.72 g; 4.95 mmol) is dissolved in dry 2-propanol (50 mL). After addition of 4M HCl in dioxane (5.0 mL) the stirred reaction mixture is heated to 80° C. for two hours. At ambient temperature tert.-butyl methyl ether (100 mL) is added. The precipitated product is isolated by suction filtration, washed with several portions of tert.-butyl methyl ether and dried in high vacuo at 40° C. to yield the title compound as yellow solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:26][N:27]([CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C.[ClH:39].O1CCOCC1>C(O)C>[ClH:39].[CH3:38][O:37][CH2:36][CH2:35][N:27]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:3]=2[CH:2]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1C(=O)C2=CO
Reactant: COCCN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COCCn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of tert-butyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (200 mg, 0.58 mmol) and tert-butyl N-amino-N-(2-methoxyethyl)carbamate (130 mg, 0.70 mmol) in ethanol (5 mL) was allowed to stir at rt for 2 h. A solution of hydrogen chloride in 1,4-dioxane (150 μL of 4.0 M, 0.60 mmol) was added and the mixture was stirred at 50° C. for 1.5 h before it was concentrated in vacuo to give 1-(2-methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (85 mg, 44%). ESI-MS m/z calc. 299.2. found 300.3 (M+1)+; Retention time: 0.95 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1.C(Cl)CCl.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:28][C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[NH:19][N:20]=[CH:21]3)=[O:18])=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2)CC(=O)N1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)CC(=O)N1
Temperature: 80 °C
Yield: 13.3 %

Procedure:
The product of step 2 (128 mg, 0.514 mmol, 1.00 equiv), 1H-indazol-5-amine (82.0 mg, 0.617 mmol, 1.20 equiv), EDC (118 mg, 0.617 mmol, 1.20 equiv), and DMAP (10 mg, catalytic) were suspended in 2.0 mL DMF. Et3N (0.086 mL, 1.35 mmol, 2.4 equiv) was added and the solution was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (100% EtOAc) to provide 25.0 mg (13%) of the title compound as a white solid. MS (ES+) m/e 365 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>O1CCOCC1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:13][C:5]2[N:4]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:3]=[C:2]([CH3:1])[C:6]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1[nH]n(Cc2ccc(Cl)cc2)c(=O)c1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccc(Cl)cc2)c(OC(=O)c2ccc(Cl)cc2)c1-c1ccccc1

Procedure:
0.1 mol (29.9 g) of 3-methyl-4-phenyl-1-(p-chlorobenzyl)-5-pyrazolone were dissolved in 400 ml of absolute dioxane. After adding 15 ml of triethylamine, 0.11 mol (17.6 g) of 4-chlorobenzoyl chloride in dioxane was added dropwise. After heating for several hours under reflux, the reaction batch was worked up as follows:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1)#[CH:14].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(OC)c(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To the mixture of diisopropylamine (0.262 mL, 1.87 mmol) in tetrahydrofuran (5 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (1.17 mL, 1.87 mmol, 1.6M in hexanes). After stifling for 30 minutes, the solution of 4-ethynyl-2-fluoro-1-methoxybenzene (622) (0.180 g, 0.94 mmol) in tetrahydrofuran (1 mL) was added slowly into the reaction mixture. The mixture was allowed to reach 0° C. over 1 hour and ethyl chloroformate (0.134 mL, 1.4 mmol) was added. The resulting mixture was stirred to room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide ethyl 3-(3-fluoro-4-methoxyphenyl)propiolate (623) (0.070 g, 6.3%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:10]O)[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH2:10][Cl:16])[C:3]=1[CH2:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(Br)c(CC)c1CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(Br)c(CC)c1CCl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5.84 g (24 mmol) (3-bromo-2,6-diethyl-phenyl)-methanol in 60 ml dichloromethane were added 10 drops N,N-dimethylformamide and drop-wise within 5 minutes 5.71 g (3.5 ml, 5.71 mmol) thionyl chloride. The mixture was stirred at ambient temperature over night, then the volatile parts distilled off under reduced pressure. 1-Bromo-3-chloromethyl-2,4-diethyl-benzene was obtained as an oily residue which was used immediately for the following reaction.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:35]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH:40]=O)([OH:37])=[O:36]>O1CCCC1>[C:35]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH:40]=[CH:9][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:8])([OH:37])=[O:36]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (t-butoxycarbonylmethyl)-triphenylphosphonium chloride (20.7 g) in tetrahydrofuran (200 ml) was added potassium t-butoxide (5.60 g) portionwise and the mixture was stirred for 30 minutes at ambient temperature. 2-Carboxybenzaldehyde was added to the mixture. After being stirred for 1 hour the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified by conc. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to afford t-butyl 3-(2-carboxyphenyl)acrylate (8.3 g).
Reaction SMILES: CCCCCC.Br[C:8]1[C:9]([O:16][CH3:17])=[N:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1.[CH:18](OCC)=[O:19].O>CCOCC>[CH:18]([C:8]1[C:9]([O:16][CH3:17])=[N:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1)=[O:19]
Reactant: CCOC=O
Reactant: COc1ncc(Br)c(OC)n1
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ncc(C=O)c(OC)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 1.6M n-Buli in hexane (48 ml, 73.6 mmol) was added over 5 min. to a stirred suspension of 5-bromo-2,4-dimethoxypyrimidine (16 g; 72.9 mmol) in dry Et2O (240 ml) at -70° C. under an atmosphere of dry N2. Dry ethyl formate (28 g: 377 mmol) was added and the orange solution stirred at -70° C. for 1 h then allowed to warm slowly to ambient temperature. Water (400 ml) was added and the aqueous layer separated and extracted with Et2O (3×200 ml). The ether layer was combined with the extracts and dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography by preloading in SiO2 and eluting with EtOAc-hexane (3:7, v/v). Product fractions were combined and evaporated to give fine white needles, yield 6.89 g, (56%). Mass spectrum m/z 169 (M+H)+Analysis, found: C, 50:1;H,4.5;N,16.9%;C7H8N2O3 requires C,50.00; H,4.79; N, 16.66%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:35][C:36]1[N:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([NH:43][CH2:42][C:39]1[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=1)=[O:7]
Reactant: Cc1ccc(CN)cn1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CNC(=O)c2cc(Br)cc(I)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 3-bromo-5-iodo-benzoic acid (1.4 g, 4.4 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmol), 1-hydroxybenzotriazole hydrate (0.20 g, 1.3 mmol), and CH2Cl2 (50 mL) were added (6-methylpyridin-3-yl)methanamine (0.65 g, 5.3 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The precipitated solid was washed with water and ethyl ether and dried to afford the product as a white solid. LC-MS: 432.7 [M+l].
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([C:11]([C:13]2[C:22]([F:23])=[C:21]([F:24])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH2:12])=[O:10])C=CC=CC=1.FC(F)(F)C(O)=O.CCCCCC.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[C:9]([C:11]([C:13]1[C:14]([F:26])=[C:15]([F:25])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([F:24])[C:22]=1[F:23])=[CH2:12])([OH:10])=[O:8]
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C(=O)O)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In 15 ml of anisole was dissolved 3.2 g of methyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5,6-tetrafluorobenzoate. To the resulting solution was added 15 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was mixed with 20 ml of n-hexane. The resulting mixture was adjusted to pH 7.5 with a saturated aqueous sodium hydrogencarbonate solution. The aqueous layer was separated and mixed with 50 ml of ethyl acetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.9 g (yield: 95.0%) of methyl 4-(1-carboxyvinyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:23]=5[F:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Product: Fc1ccc(F)c(CN2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl) -1-cyclohexyl]piperazine and 2,5-difluorobenzyl bromide by the method described in example 15 to give the product (59%, top: 110°-111° C.). Calc'd for C24H28F2N2O2 : C, 69.55%; H, 6.81%; N, 6.76%. Found: C, 69.55%; H, 6.74%; N, 6.63%.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N.Cl>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Agent: Cl
Product: COc1ccccc1-n1nccc1-c1nn(-c2ccccc2)ccc1=O
Yield: 61 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-methoxy-phenylhydrazine×HCl according to the method described for Example 1 in 61% yield. MS: M=345.1 (M+H)+
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2-(methylsulphonyl)-ethyl chloroformate. Yield: 66% of theory, C32H36N6O7S (648.8) Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1) ##EQU65##
Reaction SMILES: [O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([NH:15][CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:24]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:23])=[CH:10][C:11]([N:15]3[CH2:16][C@H:17]([C:18]([O:20][CH3:21])=[O:19])[O:22][C:32]3=[O:33])=[CH:12][C:13]=2[F:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of methyl (2R)-3-{[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]amino}-2-hydroxypropanoate (Step 1, 1.02 g, 2.90 mmol) in CH2Cl2 (25 mL) and triethylamine (1.0 g, 1.5 mL, 10.5 mmol) is cooled to 0° C. and treated with phosgene (1.94 mL of a 20% solution in toluene, 3.6 mmol). After stirring at room temperature for one hour, the reaction mixture is diluted with CH2Cl2 and washed with dilute NaHCO3, saline, and dried (MgSO4), filtered and concentrated. Chromatography on silica gel (10% acetonitrile-dichloromethane) provides the title compound (0.91 g, 83%), MS (m/z): [M+H]+=391; 1H NMR (300 MHz, CDCl3): δ 3.16-3.20 (m, 4H), 3.64 (m, 4H), 3.88 (s, 3H), 4.06-4.11 (m, 1H), 4.23 (t, 1H), 5.06-5.11 (m, 1H), 7.16 (d, 2H).