Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][OH:20])[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCn1c(Oc2cccc(F)c2)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82), 3-fluorophenol (0.098 mL, 1.08 mmol) and potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (8 mL) and heated at 90° C. for 15 h. The reaction was cooled to room temperature and acidified with 6N HCl to pH=1. The reaction was stirred for 1 h then diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N LiCl (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a golden oil. The oil was purified using a 24 g silica gel flash column eluted with a gradient of 20% ethyl acetate/hexanes to 100% ethyl acetate to give 8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.20 g, 48% yield) as a white solid. LCMS retention time=3.524 min and 96% purity, LCMS MH+=405.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:19]([Br:23])=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][C:19]([Br:23])=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cc(Br)cc(Cl)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.75 g, 22.6 mmol) and 2-amino-5-bromo-3-chlorobenzonitrile (5.24 g, 22.6 mmol) in DCM (75 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (9.5 mL, 68 mmol) was added, followed by titanium (IV) chloride solution (1 N in DCM, 13.6 mL, 13.6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.S(=O)(=O)(O)[OH:24].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([NH2:16])=[O:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C#N)c12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(C(N)=O)c12
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carbonitrile (0.30 g, 1.1 mmol) and conc. sulfuric acid (1.0 mL) in acetic acid (6.0 mL) was heated under reflux for 31.5 hours. The solution was allowed to cool to room temperature, and poured into iced water. The resulting solution was neutralized with an aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/isopropylether to give the title compound (0.14 g, 44% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:30]
Reactant: COCc1ccc(C)c(NCC=O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COCc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxymethylanilino)-acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH:11]([C:29](=[O:30])[NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1=NN(c2ccc(Cl)cc2)C(=O)C1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
The stirred suspension of 4.2 g of 1-(p-chlorophenyl)-3-methyl-2-pyrazolin-5-one in 100 ml of benzene is gently warmed with 2.4 g of triethylamine until all solid is dissolved. The deep red solution is combined with 2.4 g of phenylisocyanate, and after 2 hours' standing at ambient temperature, a lower layer is present. The mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with water, dried, evaporated, the residue is triturated with diethyl ether and recrystallized from methanol to yield the 1-(p-chlorophenyl)-3-methyl-4-phenylcarbamoyl-2-pyrazolin-5-one of Formula II with R'=R"=H and R=Cl, melting at 212°-215° (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.O[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1
Reactant: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCC2CCN(c3cc(Cl)nnc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a 50 mL dry three-necked flask, 0.554 g (0.002 mol) of self-made 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, 0.20 g (0.002 mol) of p-hydroxybenzonitrile, 0.612 g of triphenylphosphine were added, 15 mL of anhydrous tetrahydrofuran was added under conditions of ice bath and nitrogen gas protection, then 0.35 mL of diethyl azodiformate (DEAD) dissolved in 5 mL of anhydrous tetrahydrofuran, was added dropwise into the flask. After the dropwise addition, the temperature was elevated to room temperature, the agitation was kept overnight. On the next day, the solvent was removed by evaporation using a rotation evaporator, the residue was poured into 100 mL of water, extracted for three times by using total 150 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by column chromatograph (eluent, petroleum ether:ethyl acetate:methanol=10:3:0.1) to obtain 0.26 g of 4-{2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethoxy}-benzonitrile, a white solid. Yield: 34.0%, m.p. 138 ˜139° C. 1HNMR(400 MHz, CDCl3) δppm: 1.49 ˜1.55(m, 2H), 1.83˜1.86(m, 3H), 1.91˜1.94(dbrs, 2H), 2.82˜2.87(dt, 2H, J=11.4 Hz), 3.76 ˜3.79(dbrs, 2H), 4.08 ˜4.11(t, 2H, J=5.8 Hz), 6.85(s, 1H), 6.94˜6.96(d, 2H, J=8.8 Hz), 7.58˜7.61(d, 2H, J=8.8 Hz), 7.40(s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2
Reactant: [H][H]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N)c21
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21

Procedure:
(Z)-4-azido-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.48 mmol) (from Example 44 above) was suspended in THF (40 mL) at r.t. Ammonium hydroxide was added (0.15 mL), followed by a catalytic amount of poisoned platinum on carbon (50 mg, 5% Pt/C.1/2S) (Engelhard Ind.). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 16 h. The mixture was filtered through a cake of Celite®, and the cake was washed twice with THF. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 1% MeOH/1% ET3N in THF) to afford (Z)-4,5-diamino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one as a dark red solid. (Yield 52 mg, 42%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[C:5]1=[O:14].[CH2:15]1[O:17][CH2:16]1>CO.Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([CH2:15][CH2:16][OH:17])[C:6]([CH3:13])([CH3:12])[C:5]1=[O:14]
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1CCO
Temperature: 130 °C

Procedure:
45.3 g (0.22 moles) of 1-(2-hydroxyethy)-3,3,5,5-tetramethyl-piperazin-2-one are dissolved in 450 ml of methanol in the presence of 2 ml of HCl 37% (% wiw). The solution is poured into an autoclave and 19.4 g (0.44 moles) of ethylene oxide are added. The solution is heated to 130° C. and maintained at 130° C. for 60 hours under stirring.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][N:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)cnc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
To a solution of 1J (120 mg, 0.36 mmol) in CH3CN (4 mL) at RT was added DIPEA (94 μL, 0.54 mmol), followed by benzenesulfonyl chloride (51 μL, 0.4 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (100 mg, 71%). LC/MS (method A): retention time=3.96 min, (M+H)+=470. 1H NMR (CD3SOCD3, 400 MHz): δ8.60 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J1=7.1 Hz, J2=1.5 Hz, 2H), 7.70 (dd, J1=8.5 Hz, J2=1.3 Hz, 2H), 7.66-7.69 (m, 1H), 7.61-7.64 (m, 2H), 7.54 (t, J =7.5 Hz, 2H), 7.34-7.46 (m, 1H), 7.25 -7.34 (m, 5H), 5.16 (dd, J1=47.0 Hz, J2=15.2 Hz, 2H), 4.44-4.50 (m, 1H), 3.20 (dd, J1=15.9 Hz, J2=6.0 Hz), 3.06-3.13 (m, 1H).
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:14]=[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[O:3][C:4]3[CH:14]=[C:13]4[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:7][C:5]=3[N:6]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: Sc1nc2cc3ccccc3cc2o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3cc4ccccc4cc3o2)CC1
Reaction time: 2.5 h

Procedure:
A 100 mg portion of 2-mercaptonaphtho[2,3-d]oxazole dissolved in 30 ml of anhydrous benzene was mixed with 130 mg of phosphorus pentachloride, and the mixture was refluxed under heating for 2 hours. To this was further added 90 mg of phosphorus pentachloride, followed by additional 2.5 hours of heating under reflux. Under cooling with ice, 995 mg of N-methylpiperazine was added to the resulting solution, and the reaction was carried out for 1 hour at the same temperature and then for 48 hours at room temperature. Precipitated materials in the reaction solution were removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue was dissolved in 300 ml of ethyl acetate, washed three times with water, dehydrated with sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol=50:1) to obtain 18 mg of the title compound.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[CH:11]([NH2:14])([CH3:13])[CH3:12]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:11]([NH:14][C:8]([NH2:10])=[NH:9])([CH3:13])[CH3:12]
Reactant: CSC(=N)N
Reactant: CC(C)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)NC(=N)N
Yield: 32.4 %

Procedure:
The solution of S-methylisothiourea sulfate (65.9 g, 250 mmol) in water (100 ml) was cooled with an ice/salt bath. To the solution was added isopropylamine (42.5 ml, 500 mmol) dropwise with stirring. The reaction mixture was allowed to stir at room temperature for 16 hours after the addition of amine was completed and was then refluxed for about 4 to about 5 hours. The solution was evaporated to dryness under the reduced pressure and the residue was crystallized from 95% EtOH, to give isopropylguanidine sulfate as colorless needles (16.12 g, 81.01 mmol, 32%). 1H NMR (300 MHz, D2O): δ 3.72 (m, 1H), 1.27 (d, J=6.4 Hz, 6H); 13C NMR: δ 158.45, 46.50, 24.11; IR: 1675, 1623, 1071 cm−1.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH:21]1[C:31]2C=C[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[C:26](=O)[C:25]=2[CH:24]=[CH:23][CH:22]=1.[Na+].[Cl-]>CS(C)=O>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[C:17]2[C:18]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[CH:27]=[CH:26][C:25]3[CH:31]=[CH:21][CH:22]=[CH:23][C:24]2=3)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
150 ml of dimethyl sulfoxide was admixed with 3.60 g (about 90 mmoles) of oily sodium hydride (about 60%) at room temperature. After the addition, the mixture was heated over an oil bath to an inside temperature of about 70° C., and stirred as such for about one hour. Then, the reaction mixture was cooled to room temperature, and a solution of 25.1 g (92 m moles) of the previously obtained diethyl-4-nitrobenzyl phosphonate and 10.0 g (48.5 m moles) of 5H-dibenzo[a,d]cycloheptene-5-on in 50 ml of dimethyl sulfoxide was added thereto dropwise. After the dropwise addition, the mixture was stirred at room temperature for 15 minutes, and then further stirred with heating at an inside temperature of 70° to 80° C. for 2 hours over an oil bath. After the end of reaction, the mixture was cooled to room temperature, poured into about 1 l of an aqueous saturated NaCl solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed therefrom under reduced pressure. The residue was admixed with methanol, and the thus precipitated crystal was recovered therefrom by filtration. The thus obtained crystal was recrystallized from methanol-acetone solvent mixture, whereby 10.94 g of 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene was obtained (yield: 69.3%). The melting point was 151.5°-152.5° C. The elemental analysis as C22H15NO2 was as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:15][CH2:16][C:17](Br)=[O:18]>O1CCOCC1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 4-aminobenzonitrile (5.0 g, 42.3 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (8.53 g, 3.7 mL, 42.3 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a pale brown solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.78 g (77%) of the title compound as a pale brown solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ10.81 (s, 1H), 7.81-7.74 (m, 4H), 4.08 (s, 2H); 13C NMR (DMSO-d6) δ165.60, 142.75, 133.39, 119.28, 118.89, 105.60, 30.17; MS (EI, m/z) 238 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]2[CH:26]=[CH:25][N:24]3[N:27]=[CH:28][C:29]([C:30]([OH:32])=O)=[C:23]3[N:22]=2)[CH2:4][O:3]1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:30]([C:29]2[CH:28]=[N:27][N:24]3[CH:25]=[CH:26][C:21]([N:17]4[CH2:18][CH2:19][CH2:20][C@@H:16]4[C:10]4[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][CH:5]4[CH2:4][O:3][C:2]([CH3:33])([CH3:1])[O:6]4)=[N:22][C:23]=23)=[O:32])[CH2:36][CH2:35]1
Reactant: CC1(C)OCC(COc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)O1
Reactant: NC1CC1
Product: CC1(C)OCC(COc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(C(=O)NC4CC4)c3n2)O1
Yield: 99 %

Procedure:
Prepared according to the method of Example 86, Step F, using 5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropyl amine to yield the title compound as a white solid (33.0 mg, 99% yield). MS (apci) m/z=496.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28]([O:27][CH3:26])=[O:29])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C1CCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)C1CCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(methyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.30 minutes; C23H22C12N4O4 (489.36); mass spectrum: (M−H)−=488/490/492 (chlorine isotope).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6](Cl)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6]([C:22]2[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CN(C)c1cc(-c2ccccc2)c(Cl)nn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Temperature: 110 °C

Procedure:
N,N-dimethyl 6-chloro-5-phenylpyridazin-3-amine (1-2; 120 mg, 0.51 mmol) was dissolved in dry dioxane (3 mL) and 4-formylphenyl boronic acid (136 mg, 0.91 mmol). 2 M aqueous Na2CO3 (0.75 mL) and palladium(0) tetrakis-triphenylphosphine (66 mg, 0.058 mmol) were then added. This mixture was degassed, the vessel sealed and heated at 110° C. for 24 hours. The cooled reaction was diluted with water and the product extracted into ethyl acetate, the extract dried over anhydrous NaSO4, filtered and evaporated. The product was purified by chromatography on silica gel and elution with a 25-65% ethyl acetate/hexane gradient to give 4-[6-(Dimethylamino)-4-phenylpyridazin-3-yl]benzaldehyde (1-3). NMR (CDCl3): δ9.98 (1H, s), 7.74 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.35 (3H, m), 7.19 (2H, d, J=8 Hz), 6.76 (1H, s), 3.29 (6H, s); m/e (m+1): 304.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Br:15]Br>>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: BrBr
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1F

Procedure:
12.5 g of 4'-fluoro-3'-sulfamoylacetophenone were reacted as described in Example 12 with 9.2 g of bromine to give the 2-bromo-4'-fluoro-3'-sulfamoylacetophenone, melting point: 125° C.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:3](=[O:10])[CH2:26][C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][CH:21]=1)=[O:27])[CH3:9]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 69.6 %

Procedure:
To a refluxing mixture of 7.0 g (175 mmol) of sodium hydride (NaH 60% dispersion in mineral oil) and 10.45 g (88.5 mmol) of diethyl carbonate (CO(OEt)2) in 100 mL of toluene was added dropwise via an addition funnel a mixture of 10 g (44.3 mmol) of 1-(4-benzyloxy-phenyl)-ethanone in 20 mL of toluene, and the resulting mixture was heated at reflux under argon for 1 h. The reaction mixture was then cooled to 0° C., quenched by the addition of 40 mL of acetic acid, during which time a yellow precipitate formed, and it dissolved upon subsequent addition of water. The separated organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated to give a residue which was chromatographed on silica gel (10% hexane in dichloromethane) to afford 9.2 g (70% yield) of desired 3-(4-benzyloxy-phenyl)-3-oxo-propionic acid ethyl ester as indicated by 1H NMR.