Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](F)[C:3]=1[C:4]([OH:6])=[O:5].[OH-:13].[Na+]>CN1CCCC1=O>[F:11][C:9]1[CH:8]=[C:7]([OH:13])[C:3](=[C:2]([F:1])[CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1c(O)cc(F)cc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
1.76 g (0.01 mole) of 2,4,6-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. Then, the same post-treatment as in Example 2 was conducted to obtain 1.47 g of 4,6-difluorosalicylic acid. The isolated yield was 84.3% relative to the 2,4,6-trifluorobenzoic acid used.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]=[CH:4][CH:5]=[O:6].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH3:1][CH:2]([CH3:7])[C@@H:3]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:8])[CH:10]=1)[CH2:4][CH:5]=[O:6]
Reactant: Cn1ccc2ccccc21
Reactant: CC(C)C=CC=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 74.1 %

Procedure:
Prepared according to the general procedure from 4-methyl-2-pentenal (175 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −50° C. for 32 h to provide, after silica gel chromatography (10:90 EtOAc/hexanes), the title compound as a colorless oil (85 mg, 74% yield, 93% ee). IR (film) 3052, 2958, 2870, 2834, 2716, 1723, 1609, 1546, 1482, 1469, 1423, 1373, 1328, 1246, 1160, 1138, 1015, 743 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.61 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.63 (dt, J=0.9, 8.1 Hz, 1H, ArH), 7.33-7.22 (m, 2H, ArH), 7.13 (ddd, J=1.5, 6.9, 8.1 Hz, 1H, ArH), 6.82 (s, 1H, NCH), 3.75 (s, 3H, NCH3), 3.40 (dt, J=6.6, 7.8 Hz, 1H, ArCH), 2.81 (d, J=2.4 Hz, 1H, CH2CO); 2.79 (d, J=2.4 Hz, 1H, CH2CO); 2.10 (ddd, J=6.6, 13.2, 19.8 Hz, 1H, CH(CH3)2, 0.96 (d, J=2.1, 3H, CH(CH3)2, 0.94 (d, J=2.1 Hz, 3H, CH(CH3)2; 13C NMR (75 MHz, CDCl3) δ 203.4, 137.0, 127.6, 126.7, 121.6, 119.4, 118.8, 115.6, 109.3, 46.1, 38.0, 32.9, 32.9, 20.6, 20.4; HRMS (CI) exact mass calcd for (C15H19NO) requires m/z 229.1467, found m/z 229.1465. [α]D=+15.8 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (4% ethanol/hexanes, 1 mL/min); R isomer tr=13.4 min and S isomer tr=16.7 min.
Reaction SMILES: C[O:2][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=O.[CH3:11][N:12]([CH3:18])[C:13]([N:15]([CH3:17])[CH3:16])=[NH:14]>O1CCCC1>[CH3:11][N:12]([CH3:18])[C:13](=[N:14][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=[O:2])[N:15]([CH3:17])[CH3:16]
Reactant: COC(=O)P(=O)(OC)OC
Reactant: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=O)N=C(N(C)C)N(C)C

Procedure:
A solution of 54 parts of dimethyl methoxycarbonylphosphonate and 38 parts of 1,1,3,3-tetramethylguanidine in 1000 parts of anhydrous tetrahydrofuran was refluxed for one hour. The solvent was removed under reduced pressure to yield 77 parts of dimethyl 1,1-bis(dimethylamino)-methyleneaminocarbonylphosphonate, nD27 = 1.4855.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12])(=[O:8])=[O:7])[CH3:2]>C(O)C.[Pd]>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([OH:13])=[O:12])(=[O:8])=[O:7])[CH3:29]
Reactant: CCN(CC)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)O

Procedure:
The title compound of Step 16 (167 mg, 0.4 mmol) is debenzylated in ethanol with 5psi H2 at room temperature for 1.5 hours using 4% Pd/C catalyst. After filtering, the solvent is stripped off to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C.O>[CH:15]([N:10]1[C:11](=[O:12])[C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:8]1=[O:9])([CH3:20])[CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4-nitrophthalimide (2.0 g, 10.41 mmol), triphenylphosphine (11.45 mmol, 2.99 g) and iso-propanol (11.45 mmol, 0.73 ml) in anhydrous THF (40 ml) was added diisopropylazodicarboxylate (2.37 g, 11.45 mmol) and the reaction stirred for 16 hrs at room temperature. Water and ethyl acetate were added and the organic phase separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The crude residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound as a pale yellow solid (1.27 g, 52%). HPLC retention time 4.60 min. Mass spectrum (ES+) m/z 235 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH2:3]1.P(Cl)(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][C:5]1[C:4]2[CH2:3][C:2]([CH3:13])([CH3:1])[CH2:11][CH2:10][C:9]=2[N:8]=[CH:7][N:6]=1
Reactant: CC1(C)CCc2nc[nH]c(=O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2ncnc(Cl)c2C1
Yield: 75 %

Procedure:
To 6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6.41 g, 36 mmol) in chloroform (10 mL) added phosphorus oxychloride (10 mL) and refluxed for 2 hours. The mixture was concentrated to an oil, then diluted with ethyl acetate (80 mL) and washed with saturated sodium carbonate (50 mL) and brine (25 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated, then the residue purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to give 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (5.3 g, 75% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.72 (s, 1H), 2.52 (t, 2H), 2.14 (s, 2H), 1.48 (t 2H), 0.93 (s, 6H); MS (EI) for C10H13ClN2: 197 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[N:30]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: Cl
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1ccc(-c2ccc(C(=O)N3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 4A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH3:17][CH:18]([NH2:20])[CH3:19]>ClCCl>[CH:18]([NH:20][CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1)([CH3:19])[CH3:17]
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Reactant: CC(C)N
Solvent: ClCCl
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CNC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 151b (500 mg, 2.04 mmol), propan-2-amine (180 mg, 3.06 mmol), and dichloromethane (20 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford 151c (400 mg, 74%) as a yellow solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 271.1
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:26][CH3:27])=[C:19](/[F:25])\[C:20](OCC)=[O:21])=[CH:6][C:7]2[C:8]([CH2:16][CH3:17])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:26][CH3:27])=[C:19](/[F:25])\[CH2:20][OH:21])=[CH:6][C:7]2[C:8]([CH2:16][CH3:17])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(CC)=CCC2(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(3-ethoxy-8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-enoate (Compound A-42, 42 mg, 0.11 mmol) in toluene (2 mL) and diisobutylaluminum hydride (1.0 M in hexane, 0.48 mL, 0.48 mmol) were reacted to give the title compound after purification by flash chromatography (silica gel, 2.5% ethyl acetate in hexanes).
Reaction SMILES: N.C1N2CN3CN(C2)C[N:3]1C3.Br[CH:13]([F:35])[C:14]([NH:16][C:17]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=O)=[O:15].NC1C=CC([N+]([O-])=O)=CC=1C(C1C=CC=CC=1F)=O.BrC(F)C(Br)=O>C(O)C>[F:35][CH:13]1[N:3]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:17]=2[NH:16][C:14]1=[O:15]
Reactant: O=C(c1ccccc1F)c1cc([N+](=O)[O-])ccc1NC(=O)C(F)Br
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Agent: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: O=C(Br)C(F)Br
Solvent: CCO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2F)=NC1F

Procedure:
NH3 is passed into a refluxing solution of 1.48 g. of hexamethylenetetramine in 30 ml. of ethanol; 3.83 g. of 2-(α-bromo-α-fluoroacetamido)-5-nitro-2'-fluorobenzophenone, obtainable from 2-amino-5-nitro-2'-fluorobenzophenone and α-bromo-α-fluoroacetyl bromide, are added over 2 hours. The mixture is then heated under reflux for 3 hours more and is evaporated. The resulting 2-(α-amino-α-fluoroacetamido)-5-nitro-2'-fluorobenzophenone is treated with 15 ml. of toluene and 20 mg. of p-tolunesulfonic acid and is heated under reflux for 1 hour. Working up in the customary manner gives 3-fluoro-5-o-fluorophenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[C:21](O)=[O:22].C[O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[Li+].[OH-]>CN(C=O)C.C1COCC1.O.CO>[CH3:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[C:4]=2[C:3]=1[C:21]([NH:35][C@H:33]([C:30]1[CH:31]=[CH:32][C:27]([C:26]([OH:25])=[O:36])=[CH:28][CH:29]=1)[CH3:34])=[O:22]
Reactant: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
A mixture of 0.043 g of 2-methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.060 g of (S)-4-(1-amino-ethyl)-benzoic acid methyl ester, 0.040 g of HOBT-hydrate, 0.054 g of ethyl-dimethylaminopropyl-carbodiimide hydrochloride (EDCI) and 0.060 ml of N-methylmorpholine in 2 ml of DMF was stirred at room temperature for 18 h. The reaction was then quenched with 1 ml of water and 2 ml of saturated NaHCO3 solution. The resulting mixture extracted with 15 ml of EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude methyl ester which was dissolved in 2 ml THF, 2 mL MeOH and 0.5 mL water and treated with 0.5 mL of 1M LiOH solution. After stirring for 24 h at room temperature, the reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The residue was diluted with 2 mL of water and treated with 0.3 mL of AcOH with vigorous stirring. After stirring for 2 h, the solid was collected by filtration and air-dried to give 0.029 g of the title compound as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH:18]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:17]34)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH:18]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23][CH:17]34)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(N)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
17 mg (0.05 mmol) of cesium carbonate were added to a solution of 43 mg (0.1 mmol) of tert butyl 1-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo-[3,4-b]pyrrole-5-carboxylate in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 12 μl (0.10 mmol) of benzoyl chloride were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 10 mg (20%) of the desired compound were obtained.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[C:27]([CH3:29])([CH3:28])[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.O>[C:1]([N:23]1[CH2:24][CH:25]2[C:27]([CH3:29])([CH3:28])[CH:21]([CH2:20][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:26]2)[CH2:22]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)C2CNCC1CN(Cc1ccccc1)C2
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)C2CN(Cc3ccccc3)CC1CN(C(=O)C=Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
3.9 g cinnamic acid chloride were dissolved in 20 ml dichloromethane, and to this solution a solution of 5.5 g 3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane in 10 ml dichloromethane was added with ice cooling. Subsequently the reaction mixture was stirred for 3 hours at room temperature. Then, for working up, the solvent was distilled off and the residue containing the 7-cinnamyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane which had formed was dissolved in water. To remove non-basic fractions, extraction was carried out using ethyl acetate. Then the aqueous phase was made alkaline with dilute sodium hydroxide solution, and the reaction product was extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate, filtered, and the solvent was distilled off. 5 g 7-cinnamoyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were obtained as a residue.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[C:5]([Cl:21])=[CH:4][C:3]=1[OH:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25]>CS(C)=O>[Cl:21][C:5]1[C:6]2[O:10][CH:9]=[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[C:2](=[O:25])[C:3](=[O:22])[CH:4]=1
Reactant: COc1ccc(C(=O)c2coc3c(Cl)cc(O)c(Cl)c23)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 10e (100 mg, 0.29 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (253 mg, 0.59 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice-water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-03 (50 mg, 53%) as an orange solid. TLC Rf=0.5 (petroleum ether-EtOAc, 6:4); 1H NMR (CDCl3) δ 7.90-7.84 (m, 3H), 6.95 (d, J=8.6 Hz, 2H), 6.53 (s, 1H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: ClCCl.Br[C:5]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[C:11]2[C:7](=[CH:8][N:9](CC3C=CC(OC)=CC=3)[N:10]=2)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S([N:42]2[C:46]3=[CH:47][N:48]=[C:49]([N:51]=CN(C)C)[CH:50]=[C:45]3[C:44](Br)=[CH:43]2)(=O)=O)C=CC=CC=1.C([SiH](C(C)C)C(C)C)(C)C.[OH-].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:51][C:49]1[CH:50]=[C:45]2[C:44]([C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=3)[NH:10][N:9]=[CH:8]4)=[CH:43][NH:42][C:46]2=[CH:47][N:48]=1
Reactant: COC(=O)c1cc(Br)cc2cn(Cc3ccc(OC)cc3)nc12
Reactant: CN(C)C=Nc1cc2c(Br)cn(S(=O)(=O)c3ccccc3)c2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Nc1cc2c(-c3cc(C(=O)O)c4[nH]ncc4c3)c[nH]c2cn1
Temperature: 90 °C
Yield: 93.8 %

Procedure:
[1,1′-Bis(diphenylphosphino)-ferrocene)dichloropalladium(II) 1:1 complex with dichloromethane (408 mg, 0.50 mmol) was added to a mixture of methyl 5-bromo-1-(4-methoxy-benzyl)-1H-indazole-7-carboxylate ester and methyl 5-bromo-2-(4-methoxy-benzyl)-2H-indazole-7-carboxylate (Preparations #11 and 12, 1:1, 3.99 g, 9.45 mmol), cesium carbonate (9.75 g, 30.0 mmol) and N′-(1-benzenesulfonyl-3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)-N,N-dimethyl-formamidine (Preparation #10, 3.85 g, 9.45 mmol) in 1,2-dimethoxyethane (100 mL) and water (25 mL) under an atmosphere of N2. The reaction mixture was heated at about 90° C. for about 4 hours. The reaction was cooled to ambient temperature and the layers separated. The organic layer was filtered through a silica gel pad, eluting with 5% MeOH/EtOAc and the filtrate was concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (50 mL) containing triisopropylsilane (2.05 ml, 10.0 mmol) and the mixture was heated in a sealed tube at about 100° C. for about 30 minutes then cooled to ambient temperature and concentrate under reduced pressure. The residue was triturated with ether (100 mL) and the resulting solid was collected by filtration. The solid was then dissolved in methanol (75 mL), treated with aqueous sodium hydroxide (2N, 50 ml, 100 mmol) and heated at reflux for about 6 hours. The reaction was filtered hot, then cooled and acidified with acetic acid to about pH 5.5. The product was filtered off, washed with water (2×10 mL) and dried to yield 5-(5-amino-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indazole-7-carboxylic acid (2.60 g, 78%) as the acetate salt. The acetate salt was dissolved in methanol (300 mL) and aqueous HCl (2N, 25 mL) was added. The mixture was concentrated and dried to yield 5-(5-amino-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indazole-7-carboxylic acid monohydrochloride (2.35 g, 75%) as a pale yellow solid. RP HPLC (Table 1, Method e) Rt=1.31, m/z: (MH)+ 294.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=1>>[C:31]([C:29]1[N:30]=[C:26]([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[S:27][CH:28]=1)#[N:32]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: N#Cc1csc(CN)n1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2nc(C#N)cs2)cn1
Yield: 68 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 2-aminomethyl-thiazole-4-carbonitrile instead of aminomethyl-isoxazolidin-3-one to the title compound (SiO2, heptane:ethyl acetate=90:10 to 40:60, 188 mg, 68%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH:22]=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17][CH2:22][CH2:21][Cl:20])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Reactant: O=CCCl
Solvent: ClCCl
Product: ClCCN[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of (trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropanamine (4.2 g, 13.24 mmol) in DCM (42 mL) 4° A molecular sieves was added followed by chloroacetaldehyde (1.0 g, 13.24 mmol), stirred at RT for 1 h. After completion of reaction, monitored by TLC, the reaction mixture was cooled to −10° C. and Na(CN)BH3 (0.99 mg, 15.88 mmol) was added and stirred at RT for 2 h. After completion, the reaction mixture was quenched with NH4Cl (5%) and filtered through a pad of celite. The filtrate was extracted with DCM (2×150 mL) combined extracts were washed with water (50 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography by using EtOAc: Pet ether to get (trans)-2-(4-(4-bromobenzyloxy)phenyl)-N-(2-chloroethyl)cyclopropanamine (4 g, 80%)
Reaction SMILES: [Mg].[CH3:2]I.[CH:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][C:5]2=[O:11].[Cl-].[NH4+]>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH2:6][CH:7]2[CH2:10][CH:4]1[CH2:9][CH2:8]2
Reactant: CI
Reactant: O=C1CC2CCC1C2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CC2CCC1C2
Temperature: 25 °C
Yield: 97 %

Procedure:
A Grignard reagent was prepared from 96 g (4.0M) of magnesium flakes and 553.0 g (3.9M) of methyl iodide in 600 ml of absolute diethyl ether under a nitrogen gas stream in the conventional manner. 225.0 g (2.05M) of norbornanone (I) (manufactured by Aldrich Chemical Co., Inc.) was added dropwise thereto at room temperature and the resulting mixture was stirred at room temperature over night. The reaction mixture was poured into 800 ml of a saturated aqueous solution of ammonium chloride. The organic phase was collected and dried over anhydrous magnesium sulfate. After evaporation of the ether, the residue was distilled under reduced pressure to give 250.1 g (theoretical yield: 97%) of the aimed compound (II) as a colorless oily material. b.p.: 75° C./18 mmHg.