Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:14]=2)=[O:11])=[CH:8][C:7]=1[O:28]C)(=[O:4])=[O:3].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:28][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][C:6]=1[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH:14]=1)=[O:11]
Reactant: COc1ccc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(O)c(NS(C)(=O)=O)c2)cc1O
Reaction time: 20 h
Yield: 12.2 %

Procedure:
To a stirred suspension of 4-methanesulfonylamino-3-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.25 g) in dry CH2Cl2 (50 ml) under nitrogen, was added boron tribromide (1.5 ml) then stirring continued for a further 20 hours. Methanol (50 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this was repeated 2 more times. Purification by column chromatography over silica gel eluting with chloroform containing methanol (10-20%) gave 3-hydroxy-4-methanesulfonylamino-N-(3-methanesulfonylamino-4-hydroxyphenyl)benzamide (143 mg, 15%) as an off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)C>[CH2:15]([NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=NCc1ccccc1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc(CNC(=S)NCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and benzylisothiocyanate (0.11 g) in dry tetrahydrofuran (10 ml) was added triethylamine (10 drops) and the mixture stirred at room temperature for 12 hours. The solvent was evaporated and ethyl acetate added. The mixture was washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution. The organic layer was separated and the solvent removed to give the title product. 1H N.M.R. δ(ppm) 4.7 (2H, broad s), 4.95 (2H, d), 6.9 (1H, broad s), 7.3-7.55 (6H, m), 7.95 (1H, s) and 8.58 (1H, s).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][N:11]=1>>[N:11]1[CH:10]=[CH:15][CH:14]=[C:13]([O:16][C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH:12]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1ccc(O)cn1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-215a and I-215b were prepared in 2 steps compound from racemic compound I-21. Bromo-4,5-dihydroisoxazole I-21 was reacted with 5-hydroxy picolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=418.3 m/z. Activity: B
Reaction SMILES: Br[CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[C:8]3[CH3:18].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[C:8]3[CH3:18])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Temperature: 25 °C
Reaction time: 4 h
Yield: 1 %

Procedure:
2-Bromomethyl-5,8,9-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.07 g, 3.32 mmol) was dissolved in N,N-dimethylformamide (30 ml). To the obtained solution, sodium azide (1.29 g, 19.9 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was subjected to distillation under reduced pressure for removing the solvent. To the resultant residue, chloroform and water were added. The mixture was extracted, dried, and condensed. Recrystallization from chloroform--n-hexane yielded 8.99 mg of the title compound as yellow needles (95.2%).
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[C:16]([OH:32])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH:27]([CH3:28])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])=[C:16]([CH:15]=2)[O:32][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:34]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(c1ccccc1)C(C)C
Temperature: 70 °C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide (250 mg, 0.55 mmol) in 2.5 mL of N,N-dimethylformamide is treated with 60% sodium hydride (22 mg, 0.55 mmol), and ethyl bromoacetate (67 μL, 0.60 mmol) and heated at 70° C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 50-70% ethyl acetate/hexane as the eluent to afford ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N-(1-methylethyl)-N-phenylaminocarbonyl]phenoxyacetate as colorless foam.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To 1.00 g (3.53 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10.0 ml of acetonitrile and 0.54 g (3.53 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene, was added 1.70 g (19.7 mmol) of piperazine. The mixture was refluxed for one hour and then stirred overnight. It was concentrated, dissolved in ammonium hydroxide and filtered. The filtrate was then concentrated to one-half volume and filtered to give 0.67 g of the title compound, mp >270° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Methane sulphonyl chloride (7.0 g) was added to a stirred, cooled mixture of methyl 4-chlorosalicylate (10.0 g) and triethylamine (8.0 g) in dichloromethane while maintaining the temperature at 0° C. The mixture was then stirred at room temperature for one-half hour and left to stand overnight. The mixture was washed with hydrochloric acid (2M), saturated aqueous sodium bicarbonate solution, water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(methylsulphonyloxy)benzoate (11.7 g) as an orange solid m.p. 82.5°-84.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16](=[O:32])[CH:17]([NH:24]C(=O)OC(C)(C)C)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:33]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([NH:15][C@@H:8]1[C:7]2[CH:33]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])=[O:32]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing (3S-trans)-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]-2-oxo-1-phenylethyl]carbamic acid, 1,1-dimethylethyl ester (2.27 g, 5.03 mmol; the title compound of Example 1) in dichloromethane (20 mL) was added trifluoroacetic acid (5.0 mL) and the reaction mixture was stirred at room temperature for 16 hours. The volatile materials were removed under vacuum and the residue in chloroform was washed with sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography (7.5% methanol in dichloromethane) to give two diastereomers. The faster moving material was triturated with ether to give (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide, isomer A (620 mg, 35.2%) as a colorless solid, mp 243°-246° C. Analysis calculated for C20H21N3O3.0.3H2O: C, 67.32; H, 6.10; N, 11.78. Found: C, 67.50; H, 5.99; N, 11.65. [α]D =-17.2° (c=1, Dimethylformamide). The slower moving material was triturated with ether to give (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-benzeneacetamide, isomer B (940 mg, 53.4%) as a colorless solid, mp 109°-111° C. (with foaming). Analysis calculated for C20H21N3O3.0.45H2O: C, 66.82; H, 6.14; N, 11.69. Found: C, 67.14; H, 6.32; N, 11.14. [α]D=+29.2° (c=1, Dimethylformamide).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:24]
Reactant: CON
Reactant: O=C=NC1CCCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)NC1CCCc2ccccc21
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
To an ice-cold, stirred mixture of 6.7 grams (0.080 mole) of methoxyamine hydrochloride in 80 ml of methylene chloride is added a solution of 8.1 grams (0.080 mole) of triethylamine in 20 ml of methylene chloride. The mixture is stirred at 15°C. for 15 minutes, and is then allowed to warm to 15°C. to 25°C. while a solution of 6.94 grams (0.04 mole) of 1,2,3,4-tetrahydro-1-naphthyl isocyanate in 25 ml of methylene chloride is added dropwise. The mixture is stirred for 30 minutes at room temperature and then filtered. The filtrate is washed with water, dried (sodium sulfate), and the solvent evaporated at reduced pressure to give a solid. Recrystallization of the solid from acetone/hexane gives 6.75 grams of the product, melting point 122°C. to 125°C. Recrystallization of the product from acetone/hexane gives the analytical sample, melting point 123.5°C. to 125°C.
Reaction SMILES: [CH:1](=[O:17])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[CH:1](=[O:17])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:18][CH3:20]
Reactant: CCCCCCCCCCCCCC=CC=O
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCC/C=C/C=O

Procedure:
12 g (50 mmol) of hexadecenal and 15.2 g (50 mmol) of formylmethylenetriphenylphosphorane in 250 ml of anhydrous toluene are boiled under reflux for 8 hours. The mixture is evaporated to dryness. The residue is extracted five times with 100 ml of ether. The extract is evaporated to dryness and chromatographed on silica gel using toluene. Yield: 8.2 g (62%). Melting point: 35° C.; RF =0.8, toluene/ethyl acetate 8:2.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1>CCOCC>[CH2:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]=[CH:1][C:2](=[O:3])[CH3:4])[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)C=O
Solvent: CCOCC
Product: CC(=O)C=NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 0.49 mL, 0.57 g, 3.19 mmol) in 10 mL of Et2O at room temperature was added dropwise 4-amino-1-benzylpiperidine (0.5 mL, 0.46 g, 2.45 mmol). After 20 min, the solution was diluted with 40 mL of Et2O and washed with 2×5 mL of water. The solution was concentrated in vacuo to yield the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.62 (1H, s), 7.29 (5H, m), 3.53 (2H, s), 3.28 (1H, m), 2.91 (2H, m), 2.38 (3H, s), 2.15 (2H, m), 1.84 (2H, m), 1.69 (2H, m).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:17](=[O:18])[C:12]3[N:13]=[C:14]([CH3:16])[S:15][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:19]=1>CO.ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:17]([OH:18])[C:12]3[N:13]=[C:14]([CH3:16])[S:15][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:19]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2O

Procedure:
Sodium borohydride (0.3 g) was added portionwaise to a suspension of the product from step (ii) (1 g) in a mixture of methanol (40 ml) and dichloromethane (30 ml) at room temperature. After 1 hour the reaction mixture was partitioned between dichloromethane and brine. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to leave a beige foam. Yield: 1 g. Used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:17]1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].[CH:30](=O)[CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15]3)=[CH:7][N:6]=1)=[O:4])[CH2:24]2)[CH3:31]
Reactant: CN(C(=O)c1ccc(OCC2CC2)cn1)[C@@H]1Cc2ccc(C3CCCN3)cc2C1
Reactant: CC=O
Product: CCN1CCCC1c1ccc2c(c1)C[C@H](N(C)C(=O)c1ccc(OCC3CC3)cn1)C2

Procedure:
According to method A, N-methyl-N-((R)-5-pyrrolidin-2-ylindan-2-yl)-5-cyclopropylmethoxypyridine-2-carboxamide was reacted with acetaldehyde. The product was thus obtained with the monoisotopic molecular weight of 419.26 (C26H33N3O2); MS (ESI): 420.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[CH:4][S:5][C:6]=1[CH2:7][CH3:8].[ClH:12].[CH:13](O)([CH3:15])[CH3:14]>>[ClH:12].[CH:13]([O:10][C:9]([C:3]1[C:2]([NH2:1])=[C:6]([CH2:7][CH3:8])[S:5][CH:4]=1)=[O:11])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: CCc1scc(C(=O)O)c1N
Agent: Cl
Product: CCc1scc(C(=O)OC(C)C)c1N

Procedure:
A sample of 1.02 g. (4.610 mmols) of 4-amino-5-ethyl-3-thiophenecarboxylic acid was dissolved in 50 ml. of isopropanol which had been previously saturated with gaseous hydrogen chloride. The resulting reaction was heated under reflux for 48 hours, cooled and evaporated to afford 0.927 g. (81%) of pure 4-amino-5-ethyl-3-thiophenecarboxylic acid isopropyl ester hydrochloride, m.p. 159° C. (dec.) after recrystallization from isoprpopanol/ether.
Reaction SMILES: [CH:1]([N:4]([CH2:17][CH2:18][NH:19][CH3:20])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:3])[CH3:2].[CH3:21][Si:22]([CH2:25]Cl)([CH3:24])[CH3:23].[OH-].[Na+]>CO>[CH:1]([N:4]([CH2:17][CH2:18][N:19]([CH3:20])[CH2:25][Si:22]([CH3:23])([CH3:24])[CH3:21])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCl
Reactant: CNCCN(CCNC(=O)CN1CCCC1=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCNC(=O)CN1CCCC1=O)CCN(C)C[Si](C)(C)C
Reaction time: 30 h
Yield: 28.1 %

Procedure:
A mixture of 8.71 g (30.7 mmol) of N-[2-[(isopropyl)[2-(methylamino)ethyl]amino]ethyl]-2-oxo-1-pyrrolidineacetamide and 3.76 g (30.7 mmol) of trimethylsilylmethyl chloride was stirred at 80°-90° C. for 30 hours. The reaction mixture was neutralized with methanol solution of NaOH and concentrated in vacuo. The residue was chromatographed on alumina column and distilled in vacuo to afford 3.20 g (Yield: 28.1%) of the desired compound.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9][N:8]=1.[CH3:21][CH2:22]O>>[CH2:21]([O:18][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([Br:6])=[N:8][NH:9][C:10]2=[O:20])=[O:19])[CH3:22]
Reactant: CCO
Reactant: O=C(O)c1ccc2c(Br)n[nH]c(=O)c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Yield: 31 %

Procedure:
Concentrated sulfuric acid (40 ml) was added to a stirred solution of 1-bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (85 g, 0.32 mol) in EtOH (500 ml) and the mixture was heated to reflux for 48 hours. After this time, the reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was partitioned between EtOAc (1 L) and saturated NaHCO3 (500 ml), the organic layer was separated and washed with water (500 ml) before being dried (MgSO4), filtered and concentrated under vacuum to give the title compound (30 g, 31% yield) as a white solid. Tr=1.23 min, m/z (ES+) (M+H)+ 297 & 299
Reaction SMILES: [CH:1](OC)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][OH:33])=[C:25]([CH3:34])[CH:24]=2)=[CH:8][CH:7]=1>CCO>[OH:33][CH2:32][CH2:31][O:30][C:26]1[C:25]([CH3:34])=[CH:24][C:23]([C:13]2[N:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][CH:1]=[O:2])=[CH:7][CH:8]=3)[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:28][C:27]=1[CH3:29]
Reactant: COC=O
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(NC=O)cc2)cc(C)c1OCCO
Yield: 33.5 %

Procedure:
Methyl formate (10 mL, 162 mmol) was added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.200 g, 0.50 mmol) in EtOH (10 mL) and heated at reflux. More methyl formate (5 mL, 81 mmol) was added and the mixture was heated at reflux for 2 more days, before being concentrated in vacuo and purification by flash chromatography on silica gel eluting with 2% to 8% MeOH in CH2Cl2. Further purification was effected by reverse phase chromatography eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, extracted, and concentrated, to afford the title compound as a white solid (0.072 g, 33%). 1H-NMR (300 MHz, DMSO-d6, mixture of rotamers): δ 10.24 (s, 0.8H), 10.18 (m, 0.2H), 8.72-8.87 (m, 0.2H), 8.25 (d, J=1.7 Hz, 0.8H), 8.18 (dd, J=6.9, 1.1 Hz, 1H), 7.83-7.96 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.51-7.59 (m, 2.5H), 7.24 (d, J=8.7 Hz, 2H), 7.11-7.19 (m, 0.5H), 7.03 (s, 2H), 4.81 (t, J=5.4 Hz, 1H), 3.63-3.71 (m, 4H), 2.09 (s, 6H). MS (APCI) m/z: 430 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)cc1
Temperature: 95 °C
Yield: 60 %

Procedure:
A mixture of compound 3 (4.01 g, 10.1 mmol), 1-bromo-4-iodobenzene (5.73 g, 20.2 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and potassium carbonate (4.2 g, 30 mmol) in dioxane/water (60 ml/10 ml) was degassed and heated at 95° C. overnight. After being cooled to RT, the mixture was filtered to collect the precipitate, which was redissolved in hot dichloromethane. The dichloromethane solution was filtered and concentrated with presence of methanol until a large amount of white precipitate forms. Filtration and drying in air gave a white solid (2.58 g, in 60% yield).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17](=[N:22][OH:23])[NH2:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: N#Cc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile (730 mg, Example 65), hydroxylamine hydrochloride (0.4 g), sodium carbonate (0.8 g) and ethanol (30 ml) was boiled under reflux for about 16 hours. The solvent was removed under reduced pressure at about 50° C. and the residue stirred with water (70 ml). The mixture was extracted with ethyl acetate and the combined organic phases dried, filtered and evaporated to give a solid. The solid was purified by flash column chromatography on silica using ethyl acetate as eluant to give a solid which was washed with diethyl ether and dried to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide oxime, m.p.>300° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].S(=O)(=O)(O)O>O1CCOCC1>[C:1]([NH:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
119 ml. (1.025 moles) of benzoyl chloride and 760 ml. of 2N. sodium hydroxide solution (1.52 moles) are simultaneously added to a mixture of 100 g. (0.854 mole) of DL-valine, 200 ml. of dioxane and 350 ml. of 2N. sodium hydroxide solution (0.7 mole) stirred at 0°-5° C., the additions being at rates such that the pH of the reaction mixture is always basic and the temperature does not exceed 5° C., the reaction being exothermic. the reaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C. for 2 hours, cooled to 0° C. and acidified with about 40 ml. of concentrated sulfuric acid. The precipitate is collected by filtration, washed with water, air dried for 16 hours and dissolved in ethyl acetate. The ethyl acetate solution is decanted from some residual water, and petroleum ether is added to obtain a precipitate. The precipitate is subjected to high vacuum for 8 hours to remove some residual dioxane and obtain the product (165.81 g. (88%)), m.p. 125°-128° C. Lit.: 132° C.