Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)=[O:4].[CH3:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14]
Reactant: COC(=O)c1ccnnc1
Reactant: COP(C)(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccnnc1)OC
Yield: 28.8 %

Procedure:
To a solution of methylpyridazine-4-carboxylate (1.00 g, 6.95 mmol) and dimethyl methylphosphonate (889 mg, 6.95 mmol) in THF (20 ml) was added a 2 M solution of lithium diisopropylamide (2 M in THF/heptane/ethylbenzene; 7.3 ml, 14.6 mmol) between −5° C. and 0° C. Then after 5 min the reaction mixture was carefully quenched with 4 M aq. hydrochloric acid solution to adjust the pH to ca. 6 and diluted with dichloromethane. The aqueous layer was separated and extracted 2 times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient ethyl acetate to ethyl acetate/methanol 9:1) afforded the title compound (460 mg, 29%). Dark red oil; MS: 231.1 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:24]=1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3cccnc3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cncc(CC[C@H]2CNCCN2)c1
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-3-yl-ethyl)-piperazine (1.6 g, 4.31 mmol) in ethanol (30 mL). Add ammonium formate (1.63 g, 25.8 mmol) and palladium (240 mg, 5 wt. % on carbon) and heat to reflux. After 3 hours 30 minutes, add additional ammonium formate (1.63 g, 25.8 mmol). After 3 hours, filter the palladium on carbon and concentrate the filtrate. Slurry the residue in water and methylene chloride, basify with 5N NaOH, and extract with methylene chloride and chloroform-isopropanol (3:1 mixture). Dry the extracts over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–15%) as the eluent to give (261 mg, 32%) of the title compound: mp 104–110° C.; mass spectrum (ion spray): m/z=192 (M+1). 1H NMR (DMSO-d6, D2O): δ8.42 (d, 1H), 8.38 (dd, 1H), 7.63 (dt, 1H), 7.31 (dd, 1H), 2.38–2.83 (m, 8H), 2.18 (dd, 1H), 1.50 (dd, 2H).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:20][C:19]=2[CH2:28][CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:20][C:19]=2[CH2:28][CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C(CC)CC)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(C(CC)CC)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 38.8 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[2-ethyl-5-(1-ethylpropyl)thiophen-3-yl]methoxy}benzoic acid (212 mg) synthesized in Example 73 (5) and ethyl 3-(methylamino)propanoate (80.4 mg) to give the title compound (99.2 mg, 39%).
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].ClC1C=CC(C)=CC=1[N+]([O-])=O>>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:17]
Reactant: [S-]c1ccccc1
Reactant: CCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: CCc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Sodium thiophenolate was reacted with 1-Chloro-4-ethyl-2-nitro-benzene according to the procedure from Example 5H substituting 1-Chloro-4-ethyl-2-nitro-benzene for 4-chloro-3-nitrotoluene to provide 4-Ethyl-2-nitro-1-phenylsulfanyl-benzene which was reduced according to the procedure from Example 5I to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=1)[C:41]([NH:43][CH3:44])=[O:42]>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=2)[C:41]([NH:43][CH3:44])=[O:42])[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CNC(=O)c1cc(Br)cnc1OC
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: CNC(=O)c1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cnc1OC
Yield: 66 %

Procedure:
The title compound was synthesized as described for Intermediate I-28 in 66% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman -3-amine and 5-bromo-2-methoxy-N-methylnicotinamide; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (q, 1 H), 8.29 (d, 1 H), 8.06 (d, 1 H), 7.24-7.32 (m, 8 H), 7.11-7.21 (m, 3 H), 6.71-6.82 (m, 2 H), 4.26-4.38 (m, 1 H), 4.04 (s, 3 H), 4.01-4.11 (m, 1 H), 3.57-3.73 (m, 4 H), 2.87-3.09 (m, 2 H), 2.84 (d, 3 H), 2.46-2.54 (m, 1 H, obscured by DMSO); MS (ESI) m/z 494[M+H+].
Reaction SMILES: CS(O[C@@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:8]([C:9](=[O:26])[CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:25])[CH2:7]1)(=O)=O.[K+].[C:28]([O-:31])(=[S:30])[CH3:29]>CN(C=O)C>[C:28]([S:30][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:8]([C:9](=[O:26])[CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:25])[CH2:7]1)(=[O:31])[CH3:29]
Reactant: CC([O-])=S
Reactant: C[C@]12CC[C@@H](OS(C)(=O)=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 70 °C
Yield: 55 %

Procedure:
To a solution of 3α-methanesulfonyloxyandrostane-6,17-dione (2.00 g) in dry DMF (25 mL), thioacetic acid potassium salt (1.20 g) was added. The mixture was heated to 70° C. for 3 h. After cooling, 5% NaH2PO4 was added and extracted with EtOAc (3×). The organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 8/2) to give 3β-acetylthioandrostane-6,17-dione in 55% yield as a yellow solid. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.50 (1H, m), 3.10 (3H, s), 2.50-0.90 (20H, m), 0.88 (3H, s), 0.77 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([OH:13])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(O)N1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A solution of 13.0 g (45.6 mmol) of 44 in 150 ml of anhydrous THF was added dropwise with 100 ml of DIBAL-H (1 M/hexane, 100 mmol, 2.2 eq.) at −78° C. over a period of 30 min, and after completed addition the solution was stirred for two more hours. Thereafter, excess reagent was destroyed by adding 7 ml of isopropanol (evolution of hydrogen). This was added with 200 ml of K—Na tartrate solution (1.77 M), followed by slow thawing to RT overnight. The batch was subsequently transferred into a separating funnel and diluted with 300 ml of MTBE and 100 ml of water. After phase separation, the aqueous phase was extracted with 2×100 ml of MTBE, and the combined organic phases were subsequently dried over MgSO4. Following filtration over a short silica gel column, the solvent was removed under vacuum to obtain 12.2 g of α-hydroxycarbamate 207 (42.3 mmol, 93%) as a colorless oil that was reacted without further purification. An analytical sample was obtained by column chromatography over silica gel (EE/CH 1:2).
Reaction SMILES: [CH2:1]([O:5][PH:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]=[O:20]>>[CH2:12]([O:11][CH2:10][CH2:9][CH2:8][P:6]([CH2:19][OH:20])(=[O:7])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCO[PH](=O)CCCOCc1ccccc1
Reactant: C=O
Product: CCCCOP(=O)(CO)CCCOCc1ccccc1

Procedure:
The title compound was prepared from 3-benzyloxypropylphosphinic acid n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[C:15](O)=[O:16])=[O:11])[CH2:5][CH2:4]1)[CH3:2].CC1CCC(NC([C@@H]2C[C@H]2C(O)=O)=O)CC1>>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][OH:16])=[O:11])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1CCC(NC(=O)[C@@H]2C[C@H]2C(=O)O)CC1
Agent: CC1CCC(NC(=O)[C@@H]2C[C@H]2C(=O)O)CC1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1

Procedure:
Follow the procedure of Example 11c, and substitute trans-2-(4-ethyl-cyclohexylcarbamoyl)-cyclopropanecarboxylic acid (Example 13b) for trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropane carboxylic acid therein to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COCc1ccccc1

Procedure:
The title compound was prepared from 2.06 g (7.06 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Example 2, Step A) and benzyl chloromethyl ether essentially following the procedure outlined in Example 2, Step B. Purification by flash chromatography (silica gel, 5 to 10% ethyl acetate/hexane gradient) gave the title compound as a white foam. LC/MS 357 (M+1-tBu).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].C(OC([N:28]1[C:36]2[C:31](=[CH:32][C:33]([P:37]([O:41]C)([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=2)[C:30](I)=[N:29]1)=O)(C)(C)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.CN(C)C=O>[CH3:40][O:39][P:37]([C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[NH:28][N:29]=[C:30]2[C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)(=[O:38])[OH:41]
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(O)c1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
44.8 mg (0.25 eq; 0.039 mmol) of tetrakis(triphenylphosphine)palladium(0), 65.3 mg (2 eq; 0.310 mmol) of 1-boc-pyrrole-2-boronic acid, 3 ml of dimethylformamide and 150 μl of saturated sodium bicarbonate solution are added to 70 mg (1 eq; 0.155 mmol) of 5-(dimethoxyphosphoryl)-3-iodo-indazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 4.10 mg of ([3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]-phosphonic acid monomethyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a solution of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.55 g) and triethylamine (0.7 ml) in chloroform (15 ml) was dropwise added p-methoxybenzoyl chloride (0.85 g) at ambient temperature with stirring, which was continued for 20 minutes. The reaction mixture was washed successively with aqueous sodium bicarbonate and water. The organic layer was separated, dried and evaporated in vacuo. The resultant oily product was subjected to column chromatography on silica gel eluting with ethyl acetate. The fractions containing the desired compound were combined and evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and hexane to give 1-[3-(4-methoxybenzoylamino)propyl]-4-benzhydrylpiperazine (1.1 g) as white crystals. mp: 126°-128° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])([O-:8])=[O:7].[H-].[Na+].C(Cl)Cl>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:18]([CH2:19][CH2:20][CH3:21])[S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7])(=[O:16])=[O:17]
Reactant: BrCCCBr
Reactant: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
1,3-Dibromopropane (8.5 mL, 82.0 mmol, 10 eq.) was added to a solution of compound 49 (2.0 g, 8.2 mmol) in DMF (20 mL). Then NaH (0.6 g, 15.0 mmol) was added in portions. The temperature rose to 50-60° C. The mixture was stirred at this temperature for 20 min (TLC monitoring, eluent: CH2Cl2). Then the mixture was carefully poured into ice. The product was extracted with ethyl acetate, and the extract was evaporated. The residue was washed from 1,3-dibromopropane with hexane. The resulting product was dissolved in CH2Cl2 and purified on a short thick column with silica gel, eluent: hexane-CH2Cl2100:0→0:100. Compound 50 (1.87 g, 62%) was isolated as rapidly crystallizable oil.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=O)[CH2:10][C:4]2=[N:3][N:2]=1.B.CSC.CO>O1CCCC1>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: O=C1Cc2nncn2-c2ccccc2N1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)NCCc1nncn1-2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]-triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1(C(O)=O)[C:10]([OH:12])=[O:11].Cl.CCOCC>CN1C(=O)CCC1.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)C1Cc2ccccc2C1
Temperature: 20 °C
Yield: 35.1 %

Procedure:
A solution of indane-2,2-dicarboxylic acid (17 g, Baeyer and Perkin, Ber. 1884, 17, 122) in NMP (200 ml) was heated to 150° C. for 1 hour. After cooling to 20° C. the solution was poured in water (300 ml) and concentrated hydrochloric acid was added to pH=1. Conventional work up with ether gave the title product (4.7 g). Mp 132-33° C. (from ether).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: ClCc1ccc2ccccc2c1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc3ccccc3c2)cc1

Procedure:
5,6-dichloro2-(4-formylphenyl)-1-(2-naphtylmethyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-chloromethylnaphthalene by following General Procedure 3.
Reaction SMILES: B(O)O.[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[N:24][CH:25]=1>>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:20]2[CH:25]=[N:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH3:18])[CH:13]=1)(=[O:10])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1cncc(Br)c1
Reactant: Cc1cccc(S(=O)(=O)NC(C)(C)C)c1
Agent: OBO
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1-c1cncc(F)c1
Yield: 56.5 %

Procedure:
This compound was prepared analogous to Example 52, starting from N-tert-butyl-3-methyl-benzenesulfonamide boronic acid (0.5 g, 1.84 mmol) and 5-bromo-3-fluoropyridine (357 mg, 2.03 mmol, 1.1 equiv.) After purification on silica-gel with n-heptane/ethyl acetate, 335 mg of the title compound were obtained as a light yellow solid MS (ES): m/e 321.1 (M−H)
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([OH:8])[CH2:6][NH2:7])[CH3:2].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1C=CC=CC=1>[C:10]1([CH:9]2[NH:7][CH2:6][CH:5]([CH2:4][S:3][CH2:1][CH3:2])[O:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CCSCC(O)CN
Solvent: c1ccccc1
Solvent: O
Product: CCSCC1CNC(c2ccccc2)O1
Temperature: 25 °C

Procedure:
Thirteen and five tenths (13.5) grams of 2-hydroxy-3-aminopropyl ethyl sulfide and 10.6 grams of benzaldehyde were combined in 100 milliliters of benzene and refluxed under a modified Dean-Stark apparatus until about 2 milliliters of water had been azetropically removed. The mixture was cooled to room temperature and the volume adjusted to 89.2 milliliters (4 milliliters=1 gram). Aliquots of this mixture were used in subsequent reactions.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Nc1ccc(B(O)O)cn1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.1 g) was reacted with 2-aminopyridine-5-boronic acid, pinacol ester via General Procedure A to yield 40.3 mg 122 following reverse phase HPLC purification. MS (Q1) 464.3 (M)+
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: CC(C)=O
Reactant: OCC[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OC[C@@H](CCO)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 72.3 %

Procedure:
A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture, triethylamine was added and the mixture was concentrated. The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient). Desired fractions were concentrated to obtain the title compound (29.9 g, 72.3% yield) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)=O.[NH2:16][C:17](=[S:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCO>[F:13][C:12]([F:15])([F:14])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:23][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Yield: 57.7 %

Procedure:
A solution of 2-bromo-1-(4-(trifluoromethoxy)phenyl)ethanone (20.0 g, 71 mmol) and ethyl 2-amino-2-thioxoacetate (9.466 g, 71 mmol) in absolute EtOH (200 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium carbonate (100 mL) and extracted with EtOAc (4×80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, to give the title compound as a white solid (13 g, 57%). MS (ES+) C13H10F3NO3S requires: 317. found: 318 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc(=O)oc2ccccc12)c1ccccc1
Temperature: 0 °C
Yield: 62.8 %

Procedure:
To a solution of 4-hydroxycoumarin (1.62 g, 10 mmol) in acetone (60 ml) were added 2-bromoacetophenone (1.99 g, 10 mmol) and potassium carbonate (5.53 g, 40 mmol). The mixture was refluxed for 3 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 4-(2-Oxo-2-phenylethoxy)-2H-1-benzopyran-2-one (2a) (1.76 g, 62.9%) as a needle crystal. mp: 183°-184° C.; IR(KBr) νmax : 1721, 1703, 1626; UV(CHCl3) λmax (log ε): 306 (3.79), 253 (4.28); 1H-NMR (CDCl3): δ5.50 (s, 2H, OCH2), 5.61 (s, 1H, 3-H), 7.26-7.35 (m, 2H, 6- and 8-H), 7.50-7.71 (m, 4H, 5-, 7-H and aromatic H), 7.94-8.02 (m, 3H, aromatic H). Anal. Calcd for C17H12O4 : C, 72.85; H, 4.32. Found: C, 72.85; H, 4.72.