Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)=[CH:22][CH:21]=1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Reactant: Nc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) was added a few drops of DMF (0.05 mL). The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. This residue was dissolved in 2-propanol (30 mL), then 4-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (4-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.5 g, 70%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C=O)C>[CH2:21]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1)[CH2:22][CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (13 g, 53 mmol) in dry DMF (50 mL) was added molecular sieves (4A, 6 mL). The mixture was stirred for 30 min at rt. NaH (5.3 g 60% in oil, 132.5 mmol) was washed with hexanes before it was added in portions to the reaction mixture. The mixture was stirred for 30 min before propylbromide (48.1 mL, 530 mmol) was added. The reaction mixture was stirred for 16 hours before the reaction mixture was filtered. The filtrate was added water (100 mL) and extracted with Et2O (250 mL). The organic phase was washed with brine (3×50 mL) and dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, heptane-EtOAc (4:1). The first band was collected to give 6.6 g (43%) of trans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:10]2([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:16][CH:15]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Yield: 110.7 %

Procedure:
The title compound (D29) (819.5 mg) was prepared according to the experimental procedure described in Description 28 starting from 1-Boc-3-azetidinone (500 mg, 2.77 mmol) and 4-Fluorophenylmagnesiumbromide (2M in diethylether) (1.67 ml, 3.33 mmol)).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:26][O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]2)=[CH:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([C:24]4[C:25]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[N:26][O:27][C:28]=4[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 90 °C
Yield: 78 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 338 μL, 0.68 mmol) and cyclopropanemethylamine (60.4 μL, 0.68 mmol) in dioxane (9 mL) was stirred at room temperature for 1 h and then a solution of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) in dioxane (6 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=60:40) afforded the title compound (60 mg, 78%) which was obtained as a colourless oil. MS: m/e=453.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)C=CC=N1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:35]1[CH2:34][CH2:33][CH:32]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:9]=2)[CH2:37][CH2:36]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnn(C2CCNCC2)c1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Yield: 174.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.16 g, 0.47 mmol) obtained in Example 21, step 4 and 4-(pyrimidin-5-yl)piperidine (WO2004/094371, 0.09 g, 0.57 mmol), the title compound (0.20 g, 0.41 mmol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[CH3:14][O:15][C:16](=[O:32])[C:17](=[CH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:25]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: COC(=O)C(=Cc1cccnc1)C(=O)OC(C)(C)C
Reactant: COc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1cccnc1)n1ccc2cccc(OC)c21
Reaction time: 0.5 h

Procedure:
To a solution of 7-methoxyindole in DMF was added sodium hydride (0.086 g, 60% in oil) at 0° C. and the resulting mixture was stirred for 30 minutes. 2-Pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester (0.470 g) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed twice with water and once with brine, then dried over magnesium sulfate, filtered and evaporated to dryness to afford the crude 2-[(7-methoxy-indol-1-yl)-pyridin-3-yl-methyl]-malonic acid tert-butyl ester methyl ester, which was crystallized from a hexane-ether mixture (0.207 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH2:11][Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(CCl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 4 (963 g, 3.56 mol) in anhydrous DCM (2000 mL) was added slowly SOCl2 (535 g, 4.5 mol) at 0° C. The mixture was stirred at 20° C. for 2 hours, then concentrated in vacuo to give compound 5 as an oil, which was used in the next reaction without further drying or purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]2[CH3:27])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(OC(=O)C)C.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]2[CH3:27])=[O:12])=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc(N)cc1)CC2
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (38.3 g, 0.1035 m) in a mixture of methanol (500 ml), ethylacetate (500 ml) and conc HCl (8 ml) in a pressure bottle was treated with 5.0 g 5% Pd/C catalyst under nitrogen and the mixture hydrogenated on a Parr apparatus at 50 psi for 4 hr. The catalyst was removed by filtration and the solvent evaporated to a solid residue. The solid was dissolved in water (2 liters), filtered, then basified to pH with 50% NaOH. Extraction with CHCl3 (3×250 ml) and evaporation of the extracts gave N-(4-aminophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as an off-white solid, 30.4 g (86% yield).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:33])[C:13]#[C:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2/[C:17](=[CH:25]/[C:26]2[NH:27][CH:28]=[CH:29][C:30]=2[O:31][CH3:32])/[C:18](=[O:24])[NH:19]3)=[CH:8][C:7]=1[O:34][CH3:35].O[Li].O>C1COCC1.O>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][NH:27][C:26]=1/[CH:25]=[C:17]1\[C:18](=[O:24])[NH:19][C:20]2[C:16]\1=[C:15]([C:14]#[C:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([O:34][CH3:35])[CH:8]=1)[OH:33])[CH:23]=[CH:22][CH:21]=2
Reactant: COC(=O)COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)ccc1OCC(=O)O

Procedure:
rac-(Z)-[4-[3-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]-2-methoxyphenoxy]acetic acid methyl ester(28 mg, 0.057 mmol) (from Example 47) was hydrolyzed with LiOH.H2O (55 mg, 1.15 mmol) in THF (0.5 mL) and H2O (0.5 mL) at room temperature for 20 h according to Method F above to yield rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]-2-methoxyphenoxy]acetic acid. (Yield 22 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl.CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to 0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was added drop-wise, catalytic amount (2 drop) of dimethyl formamide was added to the reaction mixture. After the addition, reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. To this residue, solution of Piperidine (0.68 mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added under nitrogen at room temperature and reaction mass was stirred for 0.5 h at room temperature. The reaction mixture was quenched by ice water and extracted with Dichloromethane and purified by column chromatography to gives 0.8 g of desired compound as free base. The free base was converted into HCl salt by treatment with ethanolic HCl. Sodium hydride (0.8 g, 20 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol) in THF was added drop wise in react ion mixture. Then reaction mixture stirred at RT for 2 h. Reaction monitored by TLC. After completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to give 1 g of desired compound then it was stirred with ethanolic HCl to give HCl salt of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:12]([N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:16]=2[C:15]1=[O:35])[CH3:13]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:14]([CH2:12][CH3:13])[C:15](=[O:35])[C:16]2[CH:28]=[N:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:17]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCN1C(=O)c2cnc(-c3ccccc3)nc2Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21
Temperature: 100 °C
Reaction time: 20 h

Procedure:
28 g (250 mmol) of chloroacetyl chloride and 28 g (250 mmol) of sodium carbonate are added to a solution of 20 g (63 mmol) of 6-ethyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 500 ml of absolute toluene. The mixture is stirred for 20 hours at 100° C. The solvent is removed on a rotary evaporator, and the residue is neutralized with 2 N-hydrochloric acid. The mixture is extracted with chloroform, and the organic phase is washed with water, dried and concentrated in vacuo. The residue which remains is recrystallized from isopropanol; yield: 19.2 g (77%), m.p. 147° to 148° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:15][CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1.CN(C=[O:36])C>>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:16](=[O:36])[C:15]=4[CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)N(Cc1ccncc1)CC3
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccncc1)C2

Procedure:
Following the same procedure as outlined in Example 21, sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylenedioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carboline (192 mg, 0.50 mmol) (prepared as in Example 15) in DMF (10 mL, anhydrous) were reacted to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:15][CH2:14][CH:11]2[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Reactant: NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(NCC2CC2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.45 mmol), cyclopropylmethanamine (0.051 mL, 0.58 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.114 g, 98%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.46 (t, J=5.5 Hz, 1H), 3.33 (s, 3H), 3.19 (t, J=6.2 Hz, 2H), 1.12 (m, 1H), 0.43 (m, 2H), 0.24 (m, 2H). LRMS (ESI pos) m/e 258, 260 (M+1, Br pattern).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:13]([OH:15])=[O:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Product: COCCOc1ncc(C(=O)O)cc1-c1ccc(F)c(F)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2-methoxyethoxy)-3-pyridinecarboxylic acid (CAN 912454-34-3) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials; MS (ESI): 308.3 (M−H)−.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[N:33]=[CH:34][C:35]2[CH:40]=[CH:39][NH:38][C:36]=2[N:37]=1>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[N:33]=[CH:34][C:35]4[CH:40]=[CH:39][NH:38][C:36]=4[N:37]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Brc1ncc2cc[nH]c2n1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ncc3cc[nH]c3n2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 2-bromo-7H-pyrrolo[2,3-d]pyrimidine. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.31 (s, 1H), 8.82 (s, 1H), 8.15 (m, 1H), 7.90 (d, J=3.6, 1H), 7.68 (d, J=7.5, 1H), 7.63 (d, J=6.3, 1H), 7.50 (s, 1H), 7.42 (d, J=7.1, 1H), 7.02 (d, J=3.6, 1H), 6.66 (d, J=3.6, 1H), 1.12 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13](Cl)[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:37][NH2:38]>C1COCC1.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13]([NH:38][CH3:37])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: CN
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Solvent: C1CCOC1
Solvent: O
Product: CNc1nn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(trifluoromethyl)benzyl)-6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (50 mg, 0.091 mmol), prepared as described in Example 3, and 2.0 M methyl amine in THF (0.4 mL) was stirred at reflux for 12 h. After this time, the reaction mixture was cooled to RT and diluted with water (5 mL). The resultant solution was extracted with EtOAc (5 mL×3). The combined organic layers were washed with water (5 mL×2) followed by saturated aqueous NaCl (5 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative reverse phase HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl-7,8-bis(4-chlorophenyl)-6-(methylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (31.5 mg, 64%) as pale yellow solid. HPLC: 4.17 min; MS: M+H=544; 1H NMR (CDCl3), ppm: 7.55 (2H, d, J=10.0 Hz), 7.47 (2H, d, J=10.0 Hz), 7.34 (2H, d, J=10.0 Hz), 7.21 (2H, d, J=10.0 Hz), 7.09 (2H, d, J=10.0 Hz), 7.05 (2H, d, J=10.0 Hz), 5.18 (2H, s), 4.19-4-21 (1H, br), 2.95 (3H, d, J=5.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH:5]=[O:6]
Reactant: Oc1ccc(F)cc1F
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (4.06 g, 20 mmol), 2,4-difluorophenol (2.60 g, 20 mmol) and cesium carbonate (7.17 g, 22 mmol) in dimethyl sulfoxide (20 mL) was heated at 100° C. for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate in heptanes) to provide the title compound (5.94 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]O)[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:70]=[N+:71]=[N-:72])(C2C=CC=CC=2)=O)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:70]=[N+:71]=[N-:72])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCO)c3)c2)Cc2ccccc2C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN=[N+]=[N-])c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
300 mg (0.613 mmol) of 2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester (methyl ester intermediate of example 27) and triphenylphosphine (0.241 g, 0.920 mmol) were dissolved in THF (5 ml) and cooled in an ice bath. Diphenylphosphoryl azide (0.258 g, 0.920 mmol) and DIAD (0.198 g, 0.920 mmol) were added sequentially, the ice bath was removed and the mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness and purified by silica gel chromatography (HEP/EA gradient) to yield 0.188 g of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([CH3:15])([CH3:14])[O:10][C:11]([CH3:13])=[N:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:13][C:11]1[O:10][C:9]([CH3:14])([CH3:15])[C:8]2=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=[C:7]2[N:12]=1
Reactant: COc1cccc2c1C(C)(C)OC(C)=N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=Nc2cccc(O)c2C(C)(C)O1
Temperature: 25 °C
Yield: 103.3 %

Procedure:
5-Methoxy-2,4,4-trimethyl-4H-3,1-benzoxazine (Intermediate 201, 342 mg, 1.67 mmol) was dissolved in DCM (7 mL) and 1M BBr3 solution in DCM (1.67 ml, 1.67 mmol) was added. After 1.5 h at room temperature the mixture was heated to reflux and after 6 hours at reflux, some more 1M BBr3 solution in DCM (1.67 ml, 1.67 mmol) was added leaving the mixture at reflux overnight. The reaction mixture was quenched with an aqueous saturated solution of NaHCO3 while the pH was allowed to become basic. Two phases were separated and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness, to obtain the title compound (330 mg) as foam.