Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>O.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([O:34][CH2:33][CH2:32][O:31][CH3:30])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cc1)OCC
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 120 °C

Procedure:
To a solution of diethyl 4-((6-amino-2-chloro-9H-purin-9-yl)methyl)benzylphosphonate (1 equiv.) in 2-methoxyethanol (0.10 M) was added sodium hydride (1.3 equiv.). The reaction mixture was then heated to 120° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature. The mixture was then diluted with water and EtOAc. This mixture was transferred to a separatory funnel and washed with water three times. The organic layer was then separated, dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound in quantitative yield as a solid.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)C[C@@H]3O)=CC=4)CC2)C)OC1>>[OH:27][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16][C@@H:17]([OH:28])[CH2:18]1
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 0.1 %

Procedure:
The procedure of Example 25 was repeated except that 3.9 mg (0.010 mole) of 20-(1,3-dioxolan-2-yl)pregna-5,7-diene-1α,3β-diol was used in lieu of 4.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol to give 2.7 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C(O)C.C[O-].[Na+].Br[CH2:18][C:19]([OH:21])=[O:20]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C(O)COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-trichlorophenol, 100.7 gm, was added to 250 ml of ethanol. 228.6 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 1 hour. Afterwards, 69.5 gm of bromoacetic acid was added and the system was then heated to reflux. After 18 hours, an additional equivalent of sodium methoxide in methanol (114.3 ml) was added as well as 34.7 gm of bromoacetic acid. The system was continued at reflux for 12 hours. The reaction was then stopped and the solvent removed by stripping. The resulting solid was washed with water and then with ether. Concentrated HCl was next added to the solid precipitate and the system was left standing for 12 hours. Afterwards, the product was filtered, washed with water and air dried. Toluene was then added to the product. The toluene was removed by stripping and any remaining water was azeotroped off with the toluene. 74.4 gm of 2,4,6-trichlorophenoxyacetic acid was recovered.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:21]#[C:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:4][N:3]=1.[CH3:30][CH2:31]CC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:21]=[C:22]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[N:8]([C:9]3([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:19][CH2:31][CH2:30][CH2:20]3)[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC(C)(C)CNC(=O)OC(C)(C)C)OCC
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C1(CNC(=O)OC(C)(C)C)CCCC1

Procedure:
tert-butyl N-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]methyl]carbamate is synthesized by treating tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate with TBAF using similar experimental conditions as described for the synthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 4534 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:21][NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
4-(Chloromethyl)phenylacetic acid (5.0 g, 27.1 mmol) was suspended in dichloromethane (50 ml), and oxalyl chloride (9.2 ml, 0.11 mol) and N,N-dimethylformamide (2 drops) were added. After stirring at room temperature for 1 hr, and the mixture was concentrated under reduced pressure. Dichloromethane (50 ml) and tert-butyl carbazate (4.29 g, 32.5 mmol) were added to the residue, and the mixture was cooled to 0° C. N,N-diisopropylethylamine (14 ml, 81.3 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration. The filtrate was concentrated and added with diethyl ether to recover the secondary crystals. They were dried to give tert-butyl 2-{[4-(chloromethyl)phenyl]acetyl}hydrazinecarboxylate (5.9 g, primary and secondary crystals, total yield 73%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[N:13]([CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[CH:12]=1)[N:7]([CH3:41])[CH2:6][CH2:5]2.Cl.O1CCOCC1>C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)(=[O:23])=[O:22])=[C:19]3[C:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH3:41])=[CH:3][C:2]=3[F:1])=[CH:12]2)[CH2:33]1
Reactant: CN1CCc2cc(F)c(-c3cn(C4CN(C(=O)OC(C)(C)C)C4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCc2cc(F)c(-c3cn(C4CNC4)c4nccc(NS(=O)(=O)c5ccccc5)c34)cc21
Yield: 97.4 %

Procedure:
To a solution of tert-butyl 3-(3-(5-fluoro-1-methylindolin-6-yl)-4-(phenylsulfonamido)-1H-pyrrolo[2,3-b]pyridin-1-yl)azetidine-1-carboxylate (D33) (489 mg, 0.847 mmol) in DCM (8 mL) was added 4M HCl in dioxane (4.23 mL, 16.93 mmol). The final mixture was stirred at RT for 6 hours. The mixture was concentrated in vacuo. The residue was dissolved in MeOH and passed through a SCX cartridge eluting with MeOH followed by 2M ammonia in MeOH to give the title compound (394 mg). LCMS (A): m/z (M+H)+ 478, C25H24FN5O2S requires 477 (acidic).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(F)ccc3F)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,5-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=428.6 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:12](CC2C=CC(C3C=CC=CC=3)=CC=2)[C:5]2=[N:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=[C:4]2[N:3]=1.CC1N(CC2C=CC(C3C=CC=CC=3)=CC=2)C2C(N=1)=NC(C#N)=CC=2>>[CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:12]=1)=[N:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=2
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc(-c2ccccc2)cc1
Agent: Cc1nc2nc(C#N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Product: Cc1nc2nc(C#N)ccc2[nH]1
Yield: 293 %

Procedure:
In the same manner as in the following Preparation Example 14-2, 2-methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (140 mg) and 2-methyl-1-(4-phenylbenzyl)-1H-imidazo[4,5-b]pyridine-5-carbonitrile (113 mg) were respectively obtained as pale-brown crystals and pale-yellow amorphous from 2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (200 mg).
Reaction SMILES: Cl[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[I-].[K+]>CO.[Zn]>[CH3:8][C:6]1([CH3:9])[CH2:5][C:4](=[O:10])[CH:3]=[CH:2][CH2:7]1
Reactant: CC1(C)CC(=O)C=C(Cl)C1
Agent: [I-]
Agent: [K+]
Agent: [Zn]
Solvent: CO
Product: CC1(C)CC=CC(=O)C1
Reaction time: 18 h

Procedure:
Activated zinc dust (15.0 g) was added to a stirred solution of 3-chloro-5,5-dimethylcyclohex-2-enone (9.0 g) and potassium iodide (7.5 g) in methanol (50 ml). After stirring for a period of 18 hours the mixture was filtered and the filtrate concentrated by evaporation under reduced pressure. The residue was mixed with dilute (8% w/v) hydrochloric acid and extracted with diethyl ether (2 × 100 ml). The combined ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was purified by distillation. 5,5-Dimethylcyclohex-2-enone was obtained as a pale yellow oil, b.p. 75° C./17 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:17](F)=[O:18])[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:29])[CH3:28])[N:26]=1.CN1CCOCC1>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:17](=[O:18])[NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:29])[CH3:28])[N:26]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: CC(=O)c1csc(N)n1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1csc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)c2ccccc2)n1
Yield: 99.1 %

Procedure:
Crude ((1S,2S)-1-fluorocarbonyl-2-phenyl-propyl)-carbamic acid tert-butyl ester (2.2 g, ≈6.93 mol), 1-(2-amino-thiazol-4-yl)-ethanone (1.0 g, 7.0 mmol), 4-methyl morpholine (1.56 mL, 14 mmol) and N,N-dimethylaminopyridine (10 mg, 0.082 mmol) were dissolved in tetrahydrofuran (20 mL). The mixture was microwaved at 120° C. for 15 minutes. The solution was diluted with ethyl acetate and washed with 1.5 M aqueous potassium hydrogen sulfate, water and brine. After drying (sodium sulfate), filtration and evaporation of the solvents, [(1S,2S)-1-(4-acetyl-thiazol-2-ylcarbamoyl)-2-phenyl-propyl]-carbamic acid tert-butyl ester (2.8 g, 89%) was obtained as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: CCC(CC)(c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1

Procedure:
The title compound is prepared from 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one and trifluoromethane sulfonyl chloride using a procedure analogoues to Example 17 (45%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.O1CCOC[CH2:14]1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C1COCCO1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
A colorless, homogeneous solution of 2,5-dimethylbenzoic acid (6.3264 g, 42.1 mmol) and 4 N HCl/1,4-dioxane (11.58 mL, 46.3 mmol) was refluxed under nitrogen. After 2.5 hr, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water (40 mL), 1N aq. NaOH (40 mL), water (40 mL) and brine (40 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give the desired product (5.934 g, 34.7 mmol, 82% yield) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]([F:19])([F:28])[F:29])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1ccccc1C(F)(F)F
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2C(F)(F)F)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-trifluoromethyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.10 (br, 1H), 7.90-7.35 (5H), 6.98 (2H), 6.42 (br, 1H), 3.94 (brt, 2H), 3.83 (s, 3H) and 2.95 (t, 2H); MS (ESI) (M+H)+ 388.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([O:28]C)=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1>Br>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([OH:28])=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[CH:6][CH:7]=1
Reactant: COc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Br
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2O)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To aqueous HBr solution (48%, 10 mL) was added 7-(4-chlorophenyl)-2-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (210 mg, 0.41 mmol). The resulting solution was stirred at 85° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the solvent. The remaining liquid was stirred at 0° C., and neutralized to pH 7-8 by careful addition of 1.0 N aqueous NaOH. Yellow precipitate formed, and this was collected by filtration, washed with water (20 mL×2), and dried in a vacuum oven at 45° C. for 16 h to afford 200 mg (93% pure) of the title compound as a yellow solid. The product was purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 18 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The product was dissolved in acetonitrile, frozen and lyophilized to afford 150 mg (74%) of the title compound as a light yellow powder. HPLC/MS: retention time=2.50 min, [M+H]+=498.2.
Reaction SMILES: Cl.O[C:3]1([C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]=[CH2:23])[OH:11])[CH2:5][CH2:4]1.Cl.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH:28]1[C:29]2[C:25](=[C:24]([C:3]3[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([CH2:12][O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH:22]=[CH2:23])[OH:11])[CH2:5][CH:4]=3)[CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: C=CCOc1ccccc1OCC(O)CN1CCC(O)(c2cccc3[nH]ccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccccc1OCC(O)CN1CC=C(c2cccc3[nH]ccc23)CC1
Yield: 93.9 %

Procedure:
A solution of 9.3 g of the free base of Example 10, 300 ml of lN hydrochloric acid and 100 ml of ethanol was refluxed for 3 hours and the mixture was diluted with water and made alkaline. The aqueous phase was saturated with potassium carbonate and was extracted with ethyl acetate. The organic phase was chromatographed over silica gel and eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 7.7 g of 4-(1H-indole-4-yl)-α-[[2-(2-propenyloxy)-phenoxy]-methyl]-1,2,3,6-tetrahydro-1-pyridine ethanol with an Rf=0.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NCC(=O)O)cc12
Yield: 53.3 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide (Example 52) (100 mg, 0.204 mmol) was hydrolysed using potassium hydroxide (5 eq.) in 3 ml water and 3 ml methanol for 12 h at room temperature. The solid precitated was filtered and washed with ethanol to obtain the product as pale yellow solid (50 mg). mp: >260° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:6][CH2:7][C:8]([CH3:19])([CH3:18])[C:9]23[CH2:15][CH:12]([CH2:13][CH2:14]2)[C:11]([CH3:17])([CH3:16])[C:10]=13)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[C:1]([O:4][C:5]12[CH:10]3[C:11]([CH3:17])([CH3:16])[CH:12]4[CH2:15][C:9]3([CH2:14][CH2:13]4)[C:8]([CH3:19])([CH3:18])[CH2:7][CH:6]1[O:28]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OC12OC1CC(C)(C)C13CCC(C1)C(C)(C)C23
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,2,7,7-tetramethyltricyclo[6.2.1.01.6]undecen-5-yl acetates described in Example 1a (2a+2b, 30.0 g, 95% pure, 0.11 mol) and MCPBA (36.5 g, 77% pure, 0.16 mol) in methylene chloride (300 ml) was stirred at room temperature (r. t.) for 24 h. An additional portion of MCPBA (10.0 g, 0.045 mol), added after 17 h, was necessary to complete the reaction. The reaction mixture was washed with aqueous sodium hydroxide solution and then water to pH 7 and negative peroxide test (KI paper), concentrated in vacuo and purified by flash chromatography (MTBE/hexane 1:9) to give a 61+37% mixture of 2,2,8,8-tetramethyl-5-oxatetracyclo[7.2.1.01.7.04.6]dodec-6-yl acetate (3) and the isomeric 2,2,8,8-tetramethyl-6-oxatetracyclo[7.2.1.01.7.05.7]dodec-5-yl acetate (14.8 g, 30+18% yield, pale yellow waxy solid). This mixture was used in the next steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(CCNS(=O)(=O)c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc(CCNS(=O)(=O)c2cccc(Cl)c2)cc1

Procedure:
A mixture of 5.0 g. (11.8 mmole) of the product obtained according to (d), 18 ml. 2N aqueous sodium hydroxide solution and 20 ml. methanol is stirred for 3 hours at 50° C. The methanol is then distilled off in a vacuum and the aqueous solution is extracted with diethyl ether. Subsequently, it is acidified with 6N hydrochloric acid and the precipitated acid is filtered off with suction, washed with water and dried over potassium hydroxide. Yield 4.6 g. (quantitative); m.p. 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10](=[O:23])[N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH:44](=O)[CH2:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10](=[O:23])[N:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][N:20]([CH2:44][CH2:45][CH3:46])[CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 52 mg (0.08 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-(4-piperidin-4-ylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzimidazol-2-one (Example 128) in 3 ml of THF was mixed with 5.32 mg (0.09 mmol) of propionaldehyde and 70 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.17 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 8-11% methanol in dichloromethane). Yield: 33.2 mg (60%) of colorless solid