Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C@@H:16]([CH2:21][OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([N+:23]([O-])=O)[CH:10]=1)=[O:8].NN.CC(O)C>[Pd].ClCCl.CO>[NH2:23][C:11]1[CH:10]=[C:9]([C:7]([C:6]2[S:5][C:4]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)=[N:3][C:2]=2[NH2:1])=[O:8])[CH:14]=[CH:13][C:12]=1[NH:15][C@@H:16]([CH2:21][OH:22])[CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C[C@H](CO)Nc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](CO)Nc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1N
Yield: 57.3 %

Procedure:
A solution of (R)-[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl]methanone (of Example 63; 30 mg, 0.05 mmol), NH2NH2 (0.5 mL), 10% Pd/C (5 mg), and 2-propanol (2 mL) was heated at reflux for 1 h. The mixture was filtered through a Celite™ pad and concentrated in vacuo. Flash chromatography with 4:1 dichloromethane/methanol furnished (R)-[3-amino-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl][4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]methanone (15 mg, 53% yield).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH3:10][C:11]([CH2:16][CH2:17][CH3:18])=[CH:12][C:13](Cl)=[O:14]>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([C:13](=[O:14])[CH2:12][C:11]([CH3:10])([CH2:16][CH2:17][CH3:18])[O:9]2)=[CH:6][CH:5]=1
Reactant: CCCC(C)=CC(=O)Cl
Reactant: Cc1c(O)cccc1O
Product: CCCC1(C)CC(=O)c2ccc(O)c(C)c2O1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To the mixture of 19.8 g. of 2-methyl resorcinol and 50 ml of boron trifluoride-ethyl ether complex were added dropwise 30 g. of 3-methyl-2-hexenoyl chloride with stirring at 45° C. for about 30 minutes. After stirring for 2 hours at about 60° C., the reaction mixture was poured into ice water, and extracted with ether. After washing with water, the ether layer was extracted with 5% aqueous solution of sodium hydroxide. After acidification with hydrochloric acid, the aqueous solution of sodium hydroxide was extracted with ether. The ether layer was washed with water, and dried over magnesium sulfate. The product was purified by subjecting to column chromatography filled with silica gel to obtain 26.1 g. (yield: 69.7%) of the subject compound as oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]([C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9])[CH3:36]
Reactant: CNc1ccccc1C(=O)OC
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), 2-methylamino-benzoic acid methyl ester (119 mg, 0.722 mmol), BOP (137 mg, 0.312 mmol), DIEA (265 μL, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoic acid methyl ester: MS m/z: (M+H) 562.1.
Reaction SMILES: C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[Br:17]Br.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:27])=[CH:22][CH:21]=1>C(OCC)C>[Br:17][CH:28]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: BrBr
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1

Procedure:
The benzoin starting material can be prepared by adding bromine (18.1g) dropwise to a stirred solution of 4,4'-dichlorodeoxybenzoin (30g) in dry diethylether (400ml). The solution is stirred for a further hour and evaporated to provide crude α-bromo-4,4'-dichlorodeoxybenzoin (40g) which when recrystallised from methanol has a melting point of 81°-83°.
Reaction SMILES: C[CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1>>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH2:2][CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:31])[N:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Nc1nc(C(=O)O)c(-c2ccccc2)s1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[F:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]3[NH:15][C:14](=[O:25])[O:13][C:12]([CH3:26])([CH3:11])[C:17]=3[CH:18]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: COc1ccc(Br)cc1F
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)cc1F

Procedure:
Prepared according to procedure B from 4-bromo-2-fluoroanisole and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 210-211° C. 1H-NMR (DMSO-d6), δ10.27 (s,1H), 7.52-7.60 (m, 3H), 7.45(d, 1H, J=8.6 Hz), 7.22 (t, 1H, J=8.9 Hz), 6.94 (d, 1H, J=8.8 Hz), 3.87 (s, 3H), 1.66 (s, 6H). MS [M−H]− m/z=300. Anal. Calc. For C17H16FNO3: C, 67.76; H, 5.35; N, 4.65. Found: C, 67.88; H, 5.39; N, 4.70.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: C1CNCCN1
Product: O=C(O)c1c(CC(=O)N2CCNCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with piperazine at 22° C. to give the title compound as a white solid. MS: 446.1 ([M+H]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]I>C1COCC1>[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: CC[C@H](C)CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (10.6 g, 0.13 mol) in dry THF (100 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (28.0 mL, 2.5 M, 70.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of (S)-2-methylbutyliodide (10.0 g, 50.5 mmol) in dry THF (20 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction was quenched by water and the mixture was poured into water (100 mL), and the resulting mixture was extracted with ether (300 mL). The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (4.27 g, 54.8%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH:24]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][CH2:31][C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=O>O1CCCC1>[CH2:2]([O:3][C:4]([C:6]([CH3:7])=[CH:24][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH2:31][C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:42]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(CCc2cccc3cncn23)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(CCc2cccc3cncn23)cc1
Reaction time: 1 h

Procedure:
Triethyl 2-phosphonopropionate (0.61 g) is added to a solution of lithium diisopropylamide (from 0.32 g of diisopropylamine and 1.7 ml of 1.64M n-butyllithium) in 20 ml of dry tetrahydrofuran at 0° under nitrogen. After stirring at 0° for 15 minutes 5-(p-formylphenethyl)-imidazo[1,5-a]pyridine (0.55 g) is added in 5 ml of tetrahydrofuran and the reaction mixture is stirred for 1 hour at 0° and 1 hour at 25° before quenching with 25 ml of water. The layers are separated and the organic phase is dried and evaporated. The resulting oil is redissolved in ethyl acetate and passed through a column of silica gel to remove the excess phosphonate and to yield 5-[p-(2-ethoxycarbonylprop-1-enyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12]>C(O)C>[CH2:11]([C:10]1[S:14][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:13]=1)[CH3:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(CC)n1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (4.10 mL, 32.67 mmol) was added dropwise over 10 min to a stirred solution of propanethioamide (3 g, 33.65 mmol) in ethanol (40 mL) cooled in an ice bath. After 16 h the reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with EtOAc:iso-hexanes, 1:3 to give the sub-title compound as a yellow oil. Yield: 2.78 g
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH3:9].Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([O:10][P:11]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=2)[N:20]=[CH:19][CH:18]=1)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: CCOP([O-])OCC
Reactant: FC(F)(F)c1ccc2nccc(Br)c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccnc2ccc(C(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1.73 g of tetrakis-(triphenylphosphine)-palladium(O) in 20 ml of toluene is mixed with 4.6 ml of triethylamine, 4.3 ml of diethylphosphite and 8.28 g of 4-bromo-6-trifluoromethyl-quinoline and stirred for three hours at 90° C. Another 0.17 g of tetrakis-(triphenylphosphine)-palladium(O) and 0.4 ml of triethylamine and diethylphosphite each are added and stirred for one hour at 90° C. After cooling, it is diluted with ether, suctioned off, washed with ether and the filtrate is concentrated by evaporation. The product is purified by column chromatography. 8.33 g of 6-trifluoromethyl-quinoline-4-phosphonic acid diethyl ester is obtained as colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH3:24])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:27]([S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28].COCCOC.[F-].[Cs+]>CN(C=O)C.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>[CH2:27]([S:29]([C:32]1[CH:37]=[C:36]([C:18]2[C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=[C:16]([C:15]([NH:14][C:5]3([C:3]([OH:2])=[O:4])[CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)=[O:26])[CH:17]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)cc(F)c2OC)c1
Temperature: 130 °C

Procedure:
300 mg (0.71 mmol) of the compound of step 4 and 175 mg (1.07 mmol) of 3-ethanesulfonylphenylboronic acid were dissolved in 4 ml of DMF and 4 ml of 1,2-dimethoxyethane under an argon atmosphere. 216 mg (1.42 mmol) of cesium fluoride and 41.08 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was heated to 130° C. in a microwave reactor for 15 min. After cooling, the solvent was evaporated and the residue purified by preparative RP HPLC (water/ACN gradient) to yield the methyl ester of the title compound. 135.1 mg (0.26 mmol) methyl ester were dissolved in 5 ml of a mixture of THF and water (9:1), 12.65 mg (0.53 mmol) of lithium hydroxide were added and the mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 123 mg of the title compound were obtained.
Reaction SMILES: C([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])(=O)C1C=CC=CC=1.Cl>>[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19]
Reactant: Cc1[nH]cnc1CCCCNC(=O)c1ccccc1
Agent: Cl
Product: Cc1[nH]cnc1CCCCN

Procedure:
4-(4-Benzamidobutyl)-5-methylimidazole is hydrolysed by heating with 6 N Hydrochloride Acid to give 4-(4-aminobutyl)-5-methylimidazole which may be converted into N-methyl-N'-[4-(5-methyl-4-imidazolyl)butyl]thiourea by the procedure of Example 7 (ii).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10](C(OC)=O)[C:9]2=[O:19])[CH:2]=1.C(#N)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]2=[O:19])[CH:2]=1
Reactant: COC(=O)C1C(=O)CCN(Cc2cccnc2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CCN(Cc2cccnc2)C(=O)C1
Yield: 100.6 %

Procedure:
A mixture of methyl 1-(3-pyridylmethyl)-2,4-dioxopiperidine-3-carboxylate (8.50 g), acetonitrile (100 ml) and water (1.4 ml) is refluxed for one hour. The mixture is distilled to remove the solvent to give 1-(3-pyridylmethyl)-2,4-dioxopiperidine (6.66 g, quantitative) as crystals, m.p. 55°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[CH2:29]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH:36]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:34])[CH:30]=[CH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:38]2[CH2:39][CH2:40][N:35]([C:33]([O:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: C=CCOC(=O)N1CCNCC1C(=O)OC(C)(C)C
Product: C=CCOC(=O)N1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1C(=O)OC(C)(C)C

Procedure:
The 1-allyl 2-tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperazine-1,2-dicarboxylate was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (INTERMEDIATE AAA1) and 1-allyloxycarbonyl-2-t-butyloxycarbonyl piperazine as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): 1.34 (s, 9H), 1.92 (m, 1H), 2.26 (m, 1H), 2.70 (m, 1H), 3.12 (m, 1H), 3.30 (m, 3H), 3.50 (m, 1H), 3.83 (m, 1H), 4.34 (abq, 2H, J=14.4 Hz), 4.54 (m, 1H), 4.62 (brs, 2H), 5.03 (s, 1H), 5.16-5.36 (m, 2H), 5.93 (brs, 1H), 6.11 (s, 1H), 6.85 (d, 1H, J=10.1 Hz), 7.32-7.56 (m, 7H). MS (API-ES+): 687 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]#[N:22].Cl.[NH2:24][OH:25]>C(O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](=[N:24][OH:25])[NH2:22]
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl)=NO
Reaction time: 11 h
Yield: 86 %

Procedure:
To a hot solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile in 75 ml of ethanol a solution of 0.42 g of hydroxylamine hydrochloride in 6.05 ml of 1 N sodium bicarbonate solution is added and heating is carried out at boiling for 11 hours under reflux. The solution is evaporated to dryness and recrystallised from methanol/water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime is obtained with a yield of 86%; F 184-186° (from toluene).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Phenoxybenzoic acid (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-phenoxybenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added methanesulfonyl chloride (280 mg) and the reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining solid yellow material was dissolved in a mixture of hot EtOAc (50 ml) and DMF (4 ml). On cooling a solid material formed, that was isolated by filtration and dried under vacuum, affording N-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-methanesulfonamide. Step 2: This anhydride intermediate was converted into the title compound by reaction with O-cyclopentylmethyl-hydroxylamine hydrochloride (see preparation 66), using general procedure 1A. 13C-NMR (DMSO-d6) δ 166.8, 152.9, 152.6, 148.3, 132.4, 127.9, 115.2, 114.8, 113.3, 111.4, 110.1, 79.4, 45.0, 41.5, 37.6, 28.9, 24.9.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH2:28])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2([NH:28][CH2:16][CH2:15][C:2]3([OH:1])[CH2:3][CH2:4][C:5]4([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]4)[CH2:13][CH2:14]3)[CH2:26][CH2:27]2)=[CH:23][CH:24]=1
Reactant: NC1(c2ccc(Br)cc2)CC1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC1(C)COC2(CCC(O)(CCNC3(c4ccc(Br)cc4)CC3)CC2)OC1
Yield: 42 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and 1-(4-bromo-phenyl)-cyclopropylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 42% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=438/440 (Br) [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.[Pt]=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Yield: 91.4 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (19.45 g, 61.39 mmol), prepared as described in Example 46, platinum oxide (10.00 g) and trifluoroacetic acid (200 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 2 days. The reaction mixture was filtered through CELITE filter aid. The filtrate was concentrated under reduced pressure to provide a dark oil. The oil was chilled in an ice bath, ice was added, and the mixture was made basic (pH 14) by the addition of 1 N potassium hydroxide. The resulting solid was isolated by filtration and then dissolved in dichloromethane. The solution was washed sequentially with 1 N potassium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under vacuum for 2 days to provide 18.0 g of 1-(4-chlorobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C1(=O)O[CH2:16][CH2:15][O:14]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:16][CH2:15][OH:14]
Reactant: O=C1OCCO1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1OCCO
Temperature: 160 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-Methoxy-4-nitrophenol (10.2 g), ethylene carbonate (5.66 g) and tetrabutylammonium iodide (2.1 g) were mixed and stirred for 2 hours at 160° C. After being cooled, all solids were dissolved into chloroform (300 ml) and the solution was washed with water (300 ml) two times. The organic layer was dehydrated with anhydrous magnesium sulfate (10 g) and concentrated under vacuum to obtain 2-(2-methoxy-4-nitrophenoxy)ethanol (12.0 g) as yellowish solid.