Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:25][NH:26][C:27](=[O:36])[CH:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[C:32]([CH:28]([C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30])[C:27]([NH:26][CH2:25][C:24]1[CH:23]=[C:22]([F:21])[CH:39]=[C:38]([F:40])[CH:37]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(C(=O)NCc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
The title compound, MS: m/e=533.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-tert-butyl-malonamic acid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[CH2:11]2)(=O)=O)=CC=1.O.[BrH:21]>C1(O)C=CC=CC=1>[BrH:21].[BrH:21].[C:17]12[CH2:18][NH:10][CH2:11][C:12]=1[CH2:13][CH2:14][NH:15][CH2:16]2
Reactant: Cc1ccc(S(=O)(=O)N2CC3=C(CNCC3)C2)cc1
Agent: Br
Solvent: O
Solvent: Oc1ccccc1
Product: C1CC2=C(CN1)CNC2
Yield: 98 %

Procedure:
1.5 g of N8 -(p-toluenesulfonyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene, prepared in Preparation 8, was suspended in 15 ml of 48% hydrobromic acid and 2 g of phenol, and the reaction mixture was refluxed for 4 hours. After cooling the reaction mixture, 20 ml of water was added. The mixture was washed with chloroform (40 ml×3). The aqueous phase was taken and decolorized by active carbon. The aqueous phase was concentrated under reduced pressure and thus resulting solid was washed with 1:1 methanol-ethylether solvent. 0.9 g of the title compound was obtained (yield 98%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=1.O>C(OCC)C>[OH:13][CH2:12][C:11]1[CH:17]=[CH:18][C:8]([CH3:7])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CO)cn1
Temperature: 0 °C
Yield: 80.4 %

Procedure:
To a stirred suspension of 11.4 g of lithium aluminum hydride in 500 ml of dry diethyl ether, 32.7 g of ethyl 6-methylnicotinate in 250 ml of dry diethyl ether is added dropwise at room temperature, and the mixture is refluxed for 1.5 hours. The reaction mixture is cooled to 0° C., and the remaining lithium aluminum hydride is decomposed by the cautious addition of 60 ml of water. The ether layer is decanted, and the residual solid is extracted with three 150-ml portions of diethyl ether. The combined extracts are dried over potassium carbonate and concentrated to give 19.6 g of crude 5-hydroxymethyl-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)oc2c1
Solvent: CCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5ccccc5)oc4c3)c2cc1OC

Procedure:
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzoxazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzoxazol-2-yl)benzamide (IM 1, 30 mg, 0.118 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 26.5 mg, 0.118 mmol) in ethanol (3 mL) to 80° C. for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 38 mg, 85 μmol, 72%). LC/ESI-MS: m/z=442 [M+H]+; m/z=440 [M−H]−; Rt=2.43 min.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([Cl:10])[CH:4]=1.[CH2:11]([O:13][C:14](=[O:20])[C:15](OCC)=[O:16])[CH3:12].[NH4+].[Cl-]>C(OCC)C.C(Br)C>[CH2:11]([O:13][C:14](=[O:20])[C:15]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[Cl:10])=[O:16])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1ccc(I)c(Cl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCOC(=O)C(=O)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Yield: 80.1 %

Procedure:
A suspension of magnesium (6.7 g; 0.275 moles) in ethyl ether (125 ml) under stirring and nitrogen flow was added with ethyl bromide (180 mg). A solution of 1,3-dichloro-4-iodobenzene (50 g; 0.183 moles) and ethyl bromide (180 mg) in ethyl ether (100 ml) was dropped in about 1 hour keeping the temperature at 15-20° C. The suspension was stirred for further 2 hours. After decanting the magnesium in excess, the solution was dropped in about 1 hour in a solution of diethyloxalate (29.32 g; 0.2 moles) in ethyl ether (125 ml) cooled to −70° C. At the end of the addition it was stirred at −70° C. for 1 hour, then the temperature was left to rise to 10° C. and the stirring was kept on for another hour. The suspension was added with a saturated solution of NH4Cl (125 ml), the phases were separated and the aqueous one extracted with ethyl acetate (50 ml). The organic phases were washed with a solution of sodium bisulfite and treated with discolouring charcoal. After filtration, the organic solution was distilled under vacuum to give a crude which was purified by chromatography (SiO2; hexane/ethyl ether 9/1) to give 36.2 g of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester (yield 80%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: N#Cc1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 4-amino-benzonitrile (11.8 g, 100 mmol) and 3-nitro-benzaldehyde (16.6 g, 110 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-nitro-benzylidene)-amino]-benzonitrile (21 g, 83%) as a white solid: LC/MS m/e calcd for C14H9N3O2 (M+H)+: 252.25, observed: 252.1.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C@@H:15]([C:20]([OH:22])=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)C)=O.[C:31]1([CH:37](N)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C@@H:15]([C:20]([O:22][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(C)ON=O
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
6β-Phenoxyacetamido-2,2-dimethylpenam-3α-carboxylic acid (3.50 g, 10 m.moles) was added to a mixture of isopropyl nitrite (2.40 g, 27 m.moles) and diphenylmethylamine (2.21 g, 12 m.moles) in tetrahydrofuran (50 ml) at 35° and stirred for 3 hours. The solvent was removed in vacuo and the gum dissolved in chloroform (50 ml), which solution was washed with 5% sodium bicarbonate solution (50 ml) and then water (50 ml) to leave a gum of the title ester. Yield 2.11 g (40.8% based on the input penicillin acid).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:38])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@H:20]([C:35](=O)[CH3:36])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][C@@H:18]([NH:17][C:16](=[O:38])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19][C@H:20]1[C:35]([CH3:36])=[CH2:1])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphoniumbromide (729 mg) was dissolved in THF (4 mL) and cooled to 0° C. prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (3.7 mL) in toluene. After 1 h, (1R,3R,4S)-(4-benzyloxycarbonylamino-3-acetylcyclohexyl)carbamic acid tert-butyl ester (400 mg) in THF (4 mL) was added dropwise. The reaction was warmed to rt over 2 h, before it was quenched with saturated NH4Cl solution and extracted with EtOAc (3×) The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to provide tert-butyl (1R,3S,4S)-4-benzyloxycarbonylamino-3-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS (ES+)=389.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[N:12]=[CH:11]3)[C:5]([CH3:18])=[CH:4][CH:3]=1.[Li+].[Cl-].Br[C:22]1[S:23][C:24]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=2[N:26]=1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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>[C:45]([O:44][C@@H:38]([C:29]1[C:28]([CH3:49])=[CH:27][C:25]2[N:26]=[C:22]([C:2]3[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]4[CH:9]=[C:10]5[C:14](=[CH:15][CH:16]=4)[N:13]([CH3:17])[N:12]=[CH:11]5)[N:7]=3)[S:23][C:24]=2[C:30]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]
Reactant: Cc1ccc(Cl)nc1-c1ccc2c(cnn2C)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(C)c(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In a 10 mL reaction vial, 5-(6-chloro-3-methylpyridin-2-yl)-1-methyl-1H-indazole (100 mg, 0.389 mmol) was dissolved in dioxane (5 mL) at rt. The solution was bubbled with argon for 5 min. Then Sn2(n-Bu)6 (0.253 mL, 0.508 mmol), LiCl (100 mg, 2.38 mmol), Pd(PPh3)2Cl2 (27 mg, 0.039 mmol) and Pd(PPh3)4 (45 mg, 0.039 mmol) were added sequentially. The resulting reaction mixture was sealed and heated to 90° C. in oil bath. To this mixture, a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (289 mg, 0.583 mmol) in dioxane (5 mL) was added slowly through syringe pump over 1.5 h. The resulting reaction mixture was stirred at 100° C. in oil bath for 16 h. The reaction was then diluted with EtOAc (20 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-20% EtOAc/Hex to afford product as. LCMS-ESI+: calc'd for: C36H35ClN4O3S: 639.2, 640.2, 641.2 (M+H+); found: 639.1, 640.1, 641.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N+:13][O-:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(C#N)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc2ccc(C#[N+][O-])nc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
7-Methylquinoline-2-carbonitrile (181 g, 1.1 mol, 1.0 equiv.) was dissolved in dichloromethane (3.3 L, 0.3 M). m-Chloroperbenzoic acid (500 g, 2.9 mol, 2.6 equiv) was added and the reaction mixture was heated to 40° C. After 3 hr mCPBA (7 g, 40 mmol, 0.04 equiv.) was added and the mixture was allowed to stir overnight at room temperature. The mixture was extracted with 3 L of 1N NaOH aq., washed twice with 20 ml of dichloromethane and the combined organic phases were washed with DI water then dried over MgSO4. The organics were filtered and the solvent was removed to give 192 g of 7-methylquinoline-2-carbonitrile N-oxide (1-4). LRMS m/z (M+H)4 185.2 found, 185.2 required.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:21]([NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NC(c1ccccc1)c1ccccc1
Product: c1ccc(C(Nc2nccc(-n3cnc4ccccc43)n2)c2ccccc2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with aminodiphenylmethane according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 378.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.41 (br s, 1H); 8.24 (br s, 1H); 7.33 (m, 2H); 6.79 (s, 1H); 6.45 (br s, 1H); 6.29 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]1([C:22]2[NH:23][C:24]3[C:25]([N:32]=2)=[N:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:32]3[C:25]4=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]4[N:23]=[C:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)cn2)CCCC1

Procedure:
The product of Example 10, Step 3, above (45), was alkylated as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to produce the title compound (48).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:37].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[OH:37])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: O=Cc1ccccc1O
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccccc3O)CC2)cc1

Procedure:
2-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-ylmethyl}-phenol was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with salicylaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-2.03 (m, 2H), 2.19-2.28 (m, 4H), 2.32-2.38 (m, 2H), 2.98-3.06 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.71 (s, 2H), 4.84-4.89 (m, 1H), 6.75-6.79 (m, 2H), 7.08-7.14 (m, 2H), 7.63-7.65 (m, 2H), 8.04-8.07 (m, 2H), 8.40 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=480.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.69 (dt, J=2.3, 1.4 Hz, 1H), 7.55 (t, J=2.7 Hz, 1H), 7.62-7.70 (m, 2H), 7.94 (dd, J=8.8, 1.7 Hz, 1H), 8.46 (dt, J=8.1, 1.9 Hz, 1H), 8.49-8.52 (m, 1H), 8.81 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9]C(=O)C(F)(F)F.[CH2:16]([OH:20])[CH2:17][C:18]#[CH:19].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:7]=1)[NH:9][C:18]([CH2:17][CH2:16][OH:20])=[CH:19]2
Reactant: O=C(Nc1ccc(Cl)cc1Br)C(F)(F)F
Reactant: C#CCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCc1cc2cc(Cl)ccc2[nH]1
Temperature: 120 °C
Yield: 67 %

Procedure:
N-(2-Bromo4-chlorophenyl)-2,2,2-trifluoroacetamide(step 1, 1.0 eq) was mixed with 3-butyn-1-ol(2.0 eq), dichlorobis(triphenylphosphine)palladium(lI) (2.5% eq), triethylamine(3.0 eq), Cul(5% eq) in DMF(0.2M) in a sealed vessel under N2 and heated to 120° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with brine and dried over Na2SO4. Furthermore, evaporate the solvent and the residue was purified by flash column chromatography with 2% MeOH/CH2Cl2 to give the described 2-(5-Chloro-1H-indol-2-yl)ethanol in 67% yield. m/z(M−H)194.09
Reaction SMILES: O.C([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)C.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c2ncccc2c1O

Procedure:
The water washings of the crude 5-ethoxy-6-methoxy-8-nitroquinoline were acidified with acetic acid and basified with sodium bicarbonate to give 0.44 g of 5-hydroxy-6-methoxy-8-nitroquinoline.
Reaction SMILES: [C:1](Cl)(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:13]=1[OH:38])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH:24][C:1](=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])=[C:14]([CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:13]=1[OH:38])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 12.3 ml of ethyl chlorooxalate in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g of 3-{3-[4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methylaniline and 15.3 ml of triethylamine in 400 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether gives ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:54][C:55]1([F:61])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:58]3[CH2:59][CH2:60][C:55]([F:61])([F:54])[CH2:56][CH2:57]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:29])[CH3:30])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)[Si](OC1CCN(N2CCC(Cc3ccc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Treat a solution of 3′-chloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.2 g, 0.34 mmol) in CH2Cl2 (15 mL) with 1,1′-carbonyldiimidazole (0.11 g, 0.68 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4,4-difluoropiperidine hydrochloride (0.08 g, 0.51 mmol) and diisopropylethylamine (0.07 g, 0.51 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column, flash with 0% to 50% ethyl acetate in hexanes to afford 0.15 g (64%) of the title compound. MS (m/z): 688 (M+).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@:18]3([OH:36])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[C:23](\[CH3:26])/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[C:23](/[CH3:26])=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:36])[C@H:17]3[C@H:30]([CH2:29][CH2:28][C@:27]12[CH3:35])[C@:31]1([CH3:34])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:33][CH2:32]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(/C=N/NC(=N)N)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.50 g of aminoguanidine hydrogencarbonate in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 0.95 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn. 1) in 10 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 0.75 g of the title compound (I-aa) as a white solid.