Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>ClCCl>[CH:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC([C@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine by treatment with isopropyl chloroformate in the presence of triethylamine using dichloromethane as a solvent. LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C@@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)[NH:22][C:23]=2[CH2:24][CH2:25][C:26]23[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]4)[CH2:27]2)[CH2:33]3)=[O:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:44])[NH:22][C:23]=2[CH2:24][CH2:25][C:26]23[CH2:35][CH:30]4[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]4)[CH2:33]2)[CH2:27]3)=[O:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc([C@@H]3CCCN3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CN1CCC[C@H]1c1nc(C(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a rapidly stirred solution of (S)-3-{[5-(2-adamantan-1-yl-ethyl)-2-pyrrolidin-2-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester (Example 136, step d) (180 mg, 0.33 mmol) and formaldehyde (100 μl, 37% aqueous) in dichloroethane (5 ml) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol). After stirring for 1 h at room temperature the reaction mixture was diluted with DCM and the solution was washed with saturated sodium bicarbonate. The organic layer was dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/IPA, 9:9:2) to afford the product as a white solid (130 mg, 71%). 1H NMR (300 MHz, CDCl3) 9.70 (1H, br s), 9.12 (1H, s), 8.17 (1H, d), 8.12 (1H, s), 7.77 (1H, d), 7.47-7.35 (6H, m), 5.37 (2H, s), 3.41 (1H, m), 3.20 (1H, m), 3.06 (2H, m), 2.30 (4H, s+m),1.96-1.55 (19H, m), 1.42 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+]>Cl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.13 g tert-butyl 4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylate are dissolved in 20 ml of a 5 M solution of HCl in isopropanol and stirred for 12 hours at ambient temperature. Then the mixture is adjusted to pH 9 with saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The combined organic phases are dried on magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH3:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]([CH3:16])[CH3:15])[C:5]=2[N:4]([CH2:17][C:18]([N:20]2[CH2:26][CH:25]3[CH2:27][CH2:28][CH:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:19])[C:3]1=[O:29].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1.[ClH:40]>O1CCCC1.C(OCC)(=O)C>[ClH:40].[CH:25]12[CH2:24][CH2:23][CH:22]([CH2:28][CH2:27]1)[CH2:21][N:20]([C:18]([CH2:17][N:4]1[C:5]3[C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=3[C:7]([CH3:9])=[N:8][CH:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)=[O:38])[C:3]1=[O:29])=[O:19])[CH2:26]2
Reactant: CC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c1cccc2N(C)C
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c1cccc2N(C)C
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (285 mg) in tetrahydrofuran (4 ml) was added dropwise 3-tolyl isocyanate (100 mg) under stirring at room temperature. The mixture was stirred at room temperature for 2 hours. Removal of the solvent in vacuo afforded a residue, which was triturated in diisopropyl ether and collected by filtration to give a white powder. To a solution of the powder in ethyl acetate was added 4N-hydrogen chloride in ethyl acetate (0.25 ml) under cooling. The mixture was evaporated in vacuo to dryness. The residue was washed with diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methyl-9-(N,N-dimethylamino )-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea hydrochloride (250 mg,61.5%) as a crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C1(O)C=CC=CC=1.[CH3:19][O:20][C:21](=[O:25])[CH:22](Br)[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:22]([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Using 4-bromo-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a dark red oil: 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.13 (d, J=2.5 Hz, 1H), 7.80 (dd, J=8.8, 2.5 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 5.29 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 1.52 (d, J=6.6 Hz, 3H). ESI-MS: m/z 305.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][C:3]=1[CH3:36].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][C:3]=1[CH3:36]
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)ccc1F
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 65.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-3-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.61 mmol), the title compound (0.038 g, 64%) was obtained.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][NH2:5])[CH3:2].N[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[NH:5][CH2:4][C:3]([CH2:1][CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])[CH3:24]
Reactant: CCN(CC)CCC(CC)(CN)c1ccccc1
Reactant: CCOC(N)=O
Product: CCOC(=O)NCC(CC)(CCN(CC)CC)c1ccccc1

Procedure:
From 2-ethyl-2-phenyl-4-diethylamino-butylamine in analogy to 3a. The urethane was further reacted in a pure state.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Yield: 86.2 %

Procedure:
A mixture of 2.77 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine and 1.20 g of ethyl acrylate in 14 ml of ethanol was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give 3.25 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 133°-134° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:21]([Si:23]([O:28][C:29](=[O:39])[CH2:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([CH2:26]C)[CH2:24]C)C>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:39][C:29]([O:28][Si:23]([CH3:26])([CH3:24])[CH3:21])=[CH:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:33][CH3:34])[CH2:35][CH3:36])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC[Si](CC)(CC)OCC(=O)O[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC=C(O[Si](C)(C)C)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of triethylsilyl-2-(triethylsiloxy)acetate (37.6 g, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath and the THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 minutes and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give a clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a 1:1 mixture of geometrical isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>ClCCl>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 0 °C

Procedure:
In a 2.5 l sulfation flask, 260.2 g (2.0 mol) of 2,4-difluorophenol and 242.9 g (2.4 mol) of triethylamine are dissolved in 700 ml of dichloromethane and cooled to 0° C. 239 g (2.2 mol) of trimethylchlorosilane are added dropwise in the course of about 3 hours. The white suspension is allowed to react to completion for 8 hours (check using GC and TLC). The suspension is filtered, the residue is washed with a little dichloromethane, and the filtrate is evaporated on a rotary evaporator. The oil obtained is distilled at 56°-62° C. in vacuo (22 mbar). 280 g of a clear, colourless liquid are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.[Na+].[Cl-]>CN(C=O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:12]1=[O:19])[CH2:10]2
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1CC1CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1-Adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) was dissolved in dry DMF under argon and sodium hydride (55% in mineral oil) was added. The mixture was allowed to stir for 45 minutes and then bromomethylcyclopropane (0.04 ml) was added drop by drop. Stirring was continued at RT for another 4 hours. The reaction mixture was poured into ice/water, saturated with NaCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated to give a residue that was purified by flash chromatography using a gradient of 10 to 80% ethyl acetate in heptane as an eluent. Fractions containing the desired material were combined and evaporated to give 1-adamantan-2-yl-3-cyclopropylmethyl-4-isopropyl-1,3-dihydro-imidazol-2-one as a colorless oil (87 mg). MS (ESI): 315.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCOc2cc(N)ccc2C1=O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCN(C)C3=O)ncc1Cl
Yield: 40.8 %

Procedure:
Following the procedure of 512f, 8-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.04 g, 0.0002 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.062 g, 0.0002 mol) were reacted giving 2[5-chloro-2-(4-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.037 g, 41%) as a white solid. MP: 288-9° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.78 (d, 1H), 8.70-2 (d, 1H), 8.29 9s, 1H), 7.75-7 (d, 1H), 7.53-8 (m, 3H), 7.35-8 (d, 1H), 7.17-9 (t, 1H), 4.32-4 (m, 2H), 3.06 (s, 3H), 2.80-1 (d, 3H); LC/MS (ESI+): 453 (M+H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]([Br:14])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.N12CCN(CC1)CC2>>[Br:3][C:4]([Br:14])=[CH:5][CH:6]1[CH:8]([C:9]([O:11][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:10])[C:7]1([CH3:12])[CH3:13]
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)O
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)OCc1cccc(-c2ccccc2)c1

Procedure:
[1,1'-Biphenyl]-3-ylmethyl 3-(2,2-dibromoethenyl)-2,2-dimethycyclopropanecarboxylate was prepared by the method described in Example 1B above using potassium hydroxide (0.66 g, 0.12 mole), 3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid (5.3 g, 0.12 mole), which may be prepared according to the method of Elliott, et al., U.S. Pat. No. 4,024,163, 3-bromomethylbiphenyl (2.7 g, 0.12 mole), and 0.1 g of 1,4-diazabicyclo[2.2.2]octane.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Yield: 83.5 %

Procedure:
{1-Benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.167 g, 0.357 mmol), and potassium hydroxide (0.103 g, 1.84 mmol) in THF (5 mL) and water (5 mL), according to the procedure described in Step 4 of Example 5. Drying for 12 hours at 90° C. furnished the title compound as a light yellow solid (0.131 g, 83%), mp: 167-169° C. (dec.). Mass spectrum (+ESI, [M+H]+) m/z 440; 1HNMR (500 MHz, DMSO-d6): δ 13.5-14.0 (br s, 1H), 8.65 (s, 1H), 7.65 (d, 1H, J=8.2 Hz), 7.25-7.4 (m, 10H), 7.15 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27]([OH:29])[CH3:28]>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:29][CH2:27][CH3:28])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)Oc1ccccc1CC2=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)Oc1ccccc1CC2=O
Reaction time: 5 h

Procedure:
To 50 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-3-yl)-propionamide in 2 ml of ethanol was added 0.2 ml of conc. sulfuric acid and the mixture was refluxed with stirring for 5 hours. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow oil, which was chromatographed over silica gel, eluted with chloroform and there was obtained 55 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@@H:8]([CH3:36])[C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][CH:29]([O:31][CH2:32][CH3:33])[CH3:30])[C:17]4([CH3:35])[CH3:34])=[CH:11][CH2:10]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:32]([O:31][CH:29]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:8]([CH3:36])[CH2:7][OH:6])[CH2:10][CH:11]=4)[C:17]1([CH3:35])[CH3:34])[CH3:30])[CH3:33]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO[Si](C)(C)C(C)(C)C)[C@@]1(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO)[C@@]1(C)CC3
Yield: 99.4 %

Procedure:
vi)—A solution of (3β,5α,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-diene (11.6 g) in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (43 ml) was stirred at 50° C. for 1 h. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S)-3-[(1 -ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-dien-21-ol (9.11 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:19][C:18]([NH:20][C:21](=[O:35])[C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH3:24])[CH3:23])=[N:17][C:16]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:22]([CH3:24])([C:21](=[O:35])[NH:20][C:18]2[S:19][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)[CH3:23])=[O:34])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(CN2CCNCC2)s1

Procedure:
A solution of 4-{2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazol-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg) and TFA (1.5 mL) in dichloromethane (3 mL) was stirred at RT for 2 h and concentrated. The residue was partitioned between dichloromethane and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and purified by HPLC to give the title compound. m/z 482.2 (MH+). 1H NMR (CD3OD) 7.98-7.96 (m, 2H), 7.57 (d, J=8 Hz, 2H), 7.41 (t, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.21 (t, J=8 Hz, 2H), 3.75 (s, 2H), 2.88-2.85 (m, 4H), 2.55-2.45 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)C1N2N=C(N3CCN([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([CH:44]([F:46])[F:45])=[CH:40][CH:39]=4)CC3)C=CC2=NN=1>>[F:45][CH:44]([F:46])[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:39][CH:40]=1
Reactant: FC(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 23 %

Procedure:
Obtained in 23% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 4-difluoromethylbenzaldehyde (obtained as described in Example 826, preparation of starting materials).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A suspension of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (3.1 g, 16.73 mmol) and manganese dioxide (7.27 g, 83.67 mmol) in DCM (40 mL) was stirred at room temperature for 12 hours. The resulting precipitate was filtered off, and the filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.8 g, 91%) as a yellowish solid. MS (ES+) C7H9N3OS requires: 183. found: 184 [M+H]+.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17])([OH:11])=[O:10]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O

Procedure:
To a hot stirred solution of 20.5 g. (134 mM) of phthalaldehydic acid and 17.95 g. (135 mM) of rhodanine in 90 ml. of glacial acetic acid is added 36.0 g. (438 mM) of sodium acetate. While heating the resulting solution to reflux, a precipitate forms and an additional 30 ml. of acetic acid is added. After refluxing the mixture for 0.5 hour, it is cooled, poured into water, and filtered to separate a yellow solid. The solid is washed with water and boiled with 500 ml. of isopropanol. The resulting mixture is cooled and filtered to separate 31.14 g. (87.5%) of the 5-o-carboxybenzylidenerhodanine as yellow needles, m.p. 276°-278°.