Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:36][CH3:37])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23](C(OCC2C=CC=CC=2)=O)[CH2:24][CH3:25])[CH:11]=1)[CH3:2].C([O-])=O.[NH4+].N#N>[Pd].CO>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:36][CH3:37])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: N#N
Agent: O=C[O-]
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)cnc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(5-{2-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester (0.700 g, 1.3 mmol), ammonium formate (0.164 g, 2.6 mmol), and palladium on carbon (10%; 0.138 g) were combined in an evacuated flask that was backfilled with N2. MeOH (10 mL) was added, and the resulting suspension was stirred at room temperature for 3 hours. A balloon of H2 was added, and the reaction was stirred under an atmosphere of H2 overnight at room temperature. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with H2O and brine, and then dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give [5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester, which was subsequently reacted with acetyl chloride as described in Example 5, Step 4 to provide (5-{2-[(N-acetyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.58 min; [M+H]+=436.28.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[C:38](Cl)(=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[N:28]5[C:38](=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (0.3 g) synthesized in the same manner as in WO2006/112464 (Example 11) in methylene chloride (10 ml) was added pyridine (0.11 ml), with stirring under ice-cooling, dodecanoylchloride (0.24 ml) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with methylene chloride, and dried over sodium sulfate. The solvent was evaporated under reduced to pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-dodecanoyl-3,4-dihydro-1H-quinolin-2-one (0.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-])=O)[C:5](O)=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[C:23]=1[C:24]([NH2:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl.C1COCC1.CCOC(C)=O.CN(C=O)C>[NH2:11][C:10]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]2[NH:26][C:24](=[O:25])[C:23]3[C:22](=[CH:30][C:29]([O:31][CH3:32])=[CH:28][C:27]=3[O:33][CH3:34])[N:21]=2)=[CH:8][C:9]=1[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(N)c(C)c3)nc2c1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) in CH2Cl2 (25.6 mL) cooled to 0-5° C. was added oxalyl chloride (0.626 mL, 7.17 mmol) followed by dropwise addition of DMF (39.8 μL). The mixture was stirred for 2 h, the volatiles were removed under vacuum, and the crude acid chloride was used immediately without further purification. To a mixture of 2-amino-4,6-dimethoxybenzamide (0.913 g, 4.65 mmol) and pyridine (414 μL, 5.12 mmol) in THF (18.6 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (8.53 mL). After 16 h, the mixture was diluted with EtOAc (500 mL), washed with saturated aqueous NH4Cl (3×100 mL), saturated aqueous NaHCO3 (3×100 mL), and brine (100 mL). The insoluble yellow solid was isolated by filtration to provide the amide (1.51 g, 87%). A mixture of the amide (1.50 g, 4.03 mmol) and 2 M aqueous NaOH (25.0 mL) was heated at 85° C. for 17 h, then added THF (50 mL) and stirred at reflux for 25 h. The volatiles were removed under vacuum, the mixture was cooled to 5° C., and neutralized with 4 M HCl in dioxanes. After stirring for 30 min, the white solid was filtered and lyophilized from MeCN/H2O to afford the cyclized compound (1.36 g, 95%). A mixture of the cyclized compound (0.200 g, 0.563 mmol), Na2S2O4 (0.980 g, 5.63 mmol), water (5.00 mL) and MeOH (15.0 mL) was stirred at 70° C. for 2 h. The volatiles were removed under vacuum, then diluted with EtOAc (200 mL), washed with saturated NaHCO3 (2×100 mL) and brine (75 mL). The organic layer was dried over sodium sulfate, filtered, and the volatiles were removed under vacuum to provide 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.062 g, 34%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.78 (s, 2H), 6.66 (d, J=2.25 Hz, 1H), 6.42 (d, J=2.24 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.14 (s, 6H); MS (APCI) m/z 326 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.C([N:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([OH:33])=[O:32])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])C1C=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[NH:15][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
In an autoclave, 55 ml of toluene, 4 ml of o-dichlorobenzene, 10.0 g of N-benzyl-o-(2,6-dichloroanilino)phenylacetic acid and 2.0 g of 5% Pd-alumina were charged and it was purged with hydrogen gas and hydrogen gas was fed at 70° to 75° C. under a pressure of 10 to 20 cm H2O for 1.5 hours. The reaction mixture at the same temperature was filtered to remove 5% Pd-alumina and catalyst was washed with 35 ml of THF. The filtrate and the washing were combined and THF and toluene were distilled off. The residue was admixed with 200 ml of n-hexane and cooled to obtain 7.0 g of o-(2,6-dichloroanilino)phenylacetic acid as colorless crystals. Yield: 91.2%
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:26])/[C:11](/[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:26])/[C:11](/[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(/C(=C/c1cccnc1)c1ccc(F)cc1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(/C(=C/c1cccnc1)c1ccc(F)cc1)c1ccccc1Cl
Reaction time: 2 h

Procedure:
7.6 g (0.20 mol) of sodium borohydride were added a little at a time, at 0° C., to a solution of 33.75 g (0.10 mol) of the E-1-(2-chlorophenyl)-2-(4-fluorophenyl)-3-(3-pyridyl)-2-propen-1-one, prepared under 2.), in 500 ml of methanol. Stirring was carried out for 2 hours at 0° C., excess sodium borohydride was destroyed by the dropwise addition of acetic acid and the mixture was evaporated down under reduced pressure. The residue was taken up in a water/dichloromethane mixture, and the organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure. Trituration with 9:1 methyl tert-butyl ether/pentane gave 27.0 g (79% of theory) of crystalline product of melting point 82°-83°C.(cf. Table, Example No. 682).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:20])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCN1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
This compound was synthesised in a method analogous to the method described for intermediates 1 to 3 and prepared according to the method below. To a suspension of 2-piperazinone (2 g, 19.98 mmol, commercially available from e.g. Sigma-Aldrich) in dry dichloromethane (DCM) (28.5 ml) was added triethylamine (6.13 ml, 43.9 mmol), the mixture was cooled to 0° C. and 3,4-dichlorobenzoyl chloride (4.60 g, 21.97 mmol, commercially available from e.g.Sigma-Aldrich, Acros or Alfa Aesar) was added dropwise. The mixture was stirred at 0° C. for 15 minutes then warmed to room temperature overnight. The mixture was diluted with DCM (100 mL) and sat. NaHCO3 (100 ml), the phases separated and the aqueous extracted with DCM (2×100 ml). The combined organics were washed with brine and dried over MgSO4. The crude material (3.37 g) was triturated with iso-hexane and Et2O to the desired product in 3.02 g as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:14]=2[NH:15][N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O>>[NH:15]1[C:14]2[CH2:17][NH:18][CH2:19][C:13]=2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(NC(=O)OCc3ccccc3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1n[nH]c2c1CNC2)OCc1ccccc1
Reaction time: 1 h

Procedure:
To the product from Step B was added 4 mL of 1:1 dichloromethane/trifluoroacetic acid, and the solution was stirred for 60 min then concentrated in vacuo. The crude oil was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (10% methanol/ethyl acetate, 1% concentrated ammonium hydroxide) to give the title compound as a white solid. LC/MS 259.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([Cl:28])=[CH:25][C:26]=2[CH3:27])[NH2:23])=[C:13]([CH2:31][CH2:32][CH3:33])[C:12]=1[OH:34])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([Cl:28])=[CH:25][C:26]([CH3:27])=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:29]=[CH:30][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:34])[C:13]=2[CH2:31][CH2:32][CH3:33])[CH:21]=1)=[O:5]
Reactant: CCCc1c(OCCCOc2cc(N)c(Cl)cc2C)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(Cl)cc2C)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 1.9 ml (21 mmol) of chloro-oxalic acid methyl ester in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.0 g (17.8 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chloroaniline and 22.2 g (21.4 mmol) of triethylamine in 100 ml of methylene chloride. The reaction mixture is stirred for a further 90 minutes at room temperature, poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid methyl ester having a melting point of 101°-102°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[N:30][CH:31]=3)=[CH:23][C:22]=2[CH2:37][NH:38][CH3:39])=[CH:7][CH:8]=[C:9]([C:11]2[NH:12]C(C3CCCN3)=[N:14][CH:15]=2)[CH:10]=1)=O.C([N:43]([CH:46]([CH3:48])[CH3:47])[CH2:44][CH3:45])(C)C>N1C=CC=CC=1>[CH3:39][N:38]1[CH2:37][C:22]2[CH:23]=[C:24]([C:27]3[NH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[N:30][CH:31]=3)[CH:25]=[CH:26][C:21]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[NH:12][C:48]([CH:46]4[CH2:47][CH2:45][CH2:44][NH:43]4)=[N:14][CH:15]=3)=[CH:10][C:5]=2[C:3]1=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCc1cc(-c2cnc(C3CCCN3)[nH]2)ccc1-c1ccc(-c2cnc(C3CCCN3)[nH]2)cc1C(=O)OC
Solvent: c1ccncc1
Product: CN1Cc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4)[nH]3)cc2C1=O
Temperature: 100 °C

Procedure:
To the solution of 2′-methylaminomethyl-4,4′-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-2-carboxylic acid methyl ester (90 mg) in pyridine (5 ml) was added diisopropylethylamine (1 ml). The mixture was heated at 100° C. for 2 hours. The solvents were evaporated. The mixture was diluted with acetonitrile and water, was freezer-dried to give 6-Methyl-3,9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-6,7-dihydro-dibenzo[c,e]azepin-5-one as brown powder. m/z: 494.1 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:30][C:31](=[NH:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[CH:34][CH:33]=1>CN(C=O)C.O1CCOCC1.CCOC(C)=O>[CH:1]([NH:4][C:5]1[N:6]=[C:7]([CH3:14])[CH:8]=[C:9]([C:11]2[O:13][N:40]=[C:31]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[CH:34][CH:33]=3)[N:30]=2)[N:10]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Reactant: C=Cc1ccc(C(=N)NO)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 81.1 %

Procedure:
To a suspension of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (1.9 g, 11.8 mmol) in DMF (25 mL) is added HOBt (1.8 g, 13.4 mmol) followed by EDC (2.6 g, 13.4 mmol). The reaction mixture is stirred for 40 min until a clear solution is obtained and a solution of N-hydroxy-4-vinyl-benzamidine (2.09 g, 10.7 mmol) in DMF (20 mL) is added. After 2 h, EtOAc (320 mL) is added to the reaction mixture and the solution is then washed with sat. aq. NaHCO3 (3×100 mL), with brine, dried over MgSO4, filtered and evaporated to give a red oil. The oil is dissolved in dioxane (50 mL) and the solution is heated to 95° C. for 2 h. The reaction mixture is evaporated and purification by CC on silica gel affords the title compound as a yellow oil (2.79 g); LC-MS: tR=1.12; [M+H]+=321.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[N:6][CH:7]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12.O>CN(C=O)C>[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([N:9]3[C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)[CH2:12][O:11][C:10]3=[O:13])=[N:22][C:21]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: O=C1N[C@@H](c2ccc(F)cn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of (S)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (4.3 g, 24 mmol) in DMF (75 mL) was added sodium hydride (0.94 g, 24 mmol) in portions and the reaction stirred for 15 minutes at room temperature, followed by the addition of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (5.5 g, 24 mmol) in a solution of DMF (50 mL) and the reaction was stirred for an additional 1 hour. The reaction was poured into water (400 mL) and extracted into ether (400 mL). The water layer was separated and washed with ether (200 mL). The combined organic layers were washed with water (100 mL) and brine (200 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 15% EtOAc/DCM as eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (6.7 g, 18 mmol, 75% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:37])([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([C:26](OC)=[O:27])=[CH:14][CH:15]=2)[N:10]=1.O.[OH-].[Na+]>C1COCC1>[F:37][C:8]([F:7])([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([CH2:26][OH:27])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(CO)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (LAH, 3 equiv) in THF at 0° C. is slowly added a suspension of methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carboxylate (1 equiv) in THF. The mixture is stirred at 0° C. for 0.5 h and then at rt for 4 h. To the stirring mixture at 0° C. are added successively in dropwise fashion water (1 mL per g of LAH), 15% NaOH (1 mL per g of LAH), and water (3 mL per gram of LAH) and the mixture is stirred at rt overnight. The mixture is filtered through Celite washing with 20% MeOH/DCM (500 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by reverse phase HPLC to afford (2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yl)methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=3)[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:34][S-:35].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH2:32]([C:29]1[N:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([S:35][CH3:34])[CH:7]=3)[C:9]2=[CH:31][CH:30]=1)[CH3:33]
Reactant: CCOC(=O)CCCCc1c(-c2ccccc2)nn2c(CC)ccc2c1-c1ccnc(Cl)c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1ccc2c(-c3ccnc(SC)c3)c(CCCCC(=O)O)c(-c3ccccc3)nn12
Yield: 73.4 %

Procedure:
To a solution of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (120 mg) in toluene (5 mL) and tetrahydrofuran (10 mL) was added sodium thiomethoxide (91.0 mg) and the mixture was heated under reflux for 4 hours. The solution was acidfied with 1N hydrochloric acid and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1–3:1) to give 5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl}pentanoic acid as an yellow powder (85.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:19]1[CH:24]=[C:23]2[CH:25]=[CH:26][C:27]3[C:32](=O)[O:31][C:29](=[O:30])[C:28]=3[C:22]2=[CH:21][CH:20]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:30])[C:28]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=4[CH:25]=[CH:26][C:27]=3[C:32]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.31 g, 4.79 mmol) and 1,2-naphthalic anhydride (950 mg, 4.79 mmol) in acetic acid (15 mL). The product was obtained as a yellow solid (1.65 g, 76% yield): mp, 158.0-159.5° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H, CH3), 3.03 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.03 (q, J=6.9 Hz, 2H, CH2), 4.18 (dd, J=4.3, 14.3 Hz, 1H, CHH), 4.41 (dd, J=10.7, 14.4 Hz, 1H, CHH), 5.86 (dd, J=4.2, 10.3 Hz, 1H, NCH), 6.83-6.96 (m, 1H, Ar), 7.03-7.07 (m, 1H, Ar), 7.15 (br s, 1H, Ar), 7.70-7.9 (m, 3H, Ar), 8.15 (d, J=8.0 Hz, 1H, Ar), 8.39 (d, J=8.3 Hz, 1H, Ar), 8.76 (d, J=8.2 Hz, 1H, Ar); 13C NMR (DMSO-d6) δ 19.86, 46.29, 52.48, 58.35, 60.67, 69.03, 116.96, 117.57, 123.65, 124.97, 128.97, 131.40, 132.30, 134.15, 134.36, 134.94, 135.16, 135.89, 140.85, 11.42, 153.09, 154.06, 173.09, 173.82; Anal Calcd for C24H23NO6S: C, 63.56; H, 5.11; N, 3.09. Found: C, 63.33; H, 5.06; N, 2.95.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[S:2]1.[S:14]([NH2:18])([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:17][S:14]([NH2:18])(=[O:16])=[O:15])=[O:13])[S:2]1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CCCCCC1CCSS1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)NC(=O)CCCCCC1CCSS1
Yield: 19.3 %

Procedure:
The reaction was carried out as described in Example 107, but using 5 ml of a solution of 1.6 mmol of 6(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 308 mg of N,N'-carbonyldiimidazole, 365 mg of sulfamide and 83 mg of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3:2 and 2:1 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 92 mg of the title compound as pale yellow crystals, melting at 130 to 132° C.