Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][S:32]([CH2:35][C:36]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:37])(=[O:34])=[O:33]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 88.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), (methylsulfonyl)acetic acid (75 mg, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 377, the title compound (171 mg, 88%) was obtained as a white powder.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH:10]=1
Reactant: NCc1cc(Cl)ccc1N1CCOC1=O
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(Cl)ccc1N1CCOC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
(Step 4) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g), 3-[2-(aminomethyl)-4-chlorophenyl]-1,3-oxazolidin-2-one hydrochloride obtained in Step 3 (0.67 g) and potassium carbonate (0.88 g) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.29 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 107.4 %

Procedure:
A solution of amine 84 (220 mg, 0.4 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.21 mL, 1.2 mmol) followed by methanesulfonyl chloride (0.03 mL, 0.42 mmol) and DMAP (5 mg, 0.04 mmol). After 2.5 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 85 (271 mg, 100%) as a yellow-colored foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.08 (q, J=9.3, 18.9 Hz, 1H), 6.86 (br, 1H), 6.76-6.69 (m, 1H), 6.63-6.58 (m, 1H), 4.73-4.65 (m, 1H), 4.60 (d, J=9.6 Hz, 1H), 4.47 (d, J=6.3 Hz, 1H), 4.33-4.29 (m, 1H), 4.16-4.07 (m, 2H), 4.01-3.96 (m, 1H), 3.68-3.53 (m, 3H), 2.93-2.79 (m, 6H), 2.57-2.50 (m, 1H), 2.12-2.06 (m, 1H), 1.61 (s, 1.5H), 1.49 (s, 7.5H), 1.31 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:13])=[O:22])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(SC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)nc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.4 %

Procedure:
Methyl 2-chloro-6-(methylthio)isonicotinate (Intermediate 83; 290 mg), was dissolved in anhydrous DCM (5 ml). mCPBA (345 mg) was added and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with EtOAc and washed with water, 10% sodium thiosulfate, water, brine and dried over sodium sulfate. The mixture was concentrated in vacuo and purified by flash chromatography eluting with EtOAc:Hexane (7:3) to afford the title compound (129 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])[NH:7][NH:8][CH3:9])=[CH:4][N:3]=1.[CH:13](O)=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:10]=[CH:9][N:8]([CH3:13])[N:7]=2)=[CH:4][N:3]=1
Reactant: CNNC(=N)c1ccc(Cl)nc1
Reactant: O=CO
Product: Cn1cnc(-c2ccc(Cl)nc2)n1

Procedure:
A solution of 6-chloro-N′-methylnicotinimidohydrazide (2BX) (2.4 g, 13 mmol) in Formic Acid (99%, 10 ml) was stirred at reflux temperature for 1 hour. Reaction was cooled and solvent evaporated. The residue was extracted with EtOAc (100 ml) and Aqueous NaHCO3 (50 ml), organic layer was separated, dried over Na2SO4, filtered and solvent evaporated. The residue chromatographed on silica gel eluting with 10% MeOH:CH2Cl2 yielding title product as a solid (1.8 g, 72%) MS (MH, 195)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[OH:20]O.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:16])[F:17])[C:11]([F:12])([F:13])[F:14])=[O:20])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCC(C)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene (4.5 g, 14.9 mmol) in acetic acid (15 mL) at ambient temperature, add with stirring aqueous hydrogen peroxide (15 mL, 30% in water) and stir for 1 h. Dilute the reaction with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (4.125 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:25]O)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[O:9][N:8]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[O:9][N:8]=1
Reactant: COC(=O)C1CNC1
Reactant: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {4-methyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.19 g, 0.51 mmol) that was obtained in Example 12 (12a), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.77 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.5 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:3) as the eluent to afford the title compound (0.20 g) in a yield of 85% as a pale yellowish oily product.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37]C)=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([OH:37])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2N NaOH (aq) (6 eq) was added to a solution of methyl (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.02 M) in MeOH/THF (3/1) and the reaction stirred vigorously at 60° C. for 4 h. The reaction was allowed to cool to RT before reducing the volume of MeOH/THF in vacuo. The residue was partitioned between 1N HCl (aq) and EtOAc, ensuring the aqueous phase was acidic. The aqueous was extracted a second time with EtOAc and the combined organics washed with water, brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification. MS (ES+) m/z 548 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.[N:14]1(O)[CH2:18][CH2:17][CH2:16][CH2:15]1.CC[OH:22]>>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([N:14]2[CH2:18][CH2:17][CH:16]([OH:22])[CH2:15]2)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Reactant: ON1CCCC1
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1N1CCC(O)C1
Temperature: 60 °C

Procedure:
A mixture of 2-(3,5-dibromo-4-nitropyrazol-1-yl)ethanol (3) (6.5 g, 21 mmol) and pyrrolidinol (3.75 g, 42 mmol) in EtOH (130 ml) was heated at 60° C. for 15 hours. The reaction was stopped after 67% conversion (monitoring by TLC and HPLC) by evaporating off the solvent under reduced pressure at 40° C. (rotary evaporator). The liquid obtained was purified by column chromatography (gradient of from 5%/95% EtOAc/hexane to 20%/80% EtOAc/hexane). The yellow solid obtained (3.9 g) was recrystallized from EtOH to give 1-[5-bromo-2-(2-hydroxyethyl)-4-nitro-2H-pyrazol-3-yl]pyrrolidin-3-ol (4) in the form of a yellow solid (3.5 g, 53%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:27]=O.[CH3:31][N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:27][C:21]4[C:20]5[C:24](=[CH:25][CH:26]=[C:18]([C:17]([F:30])([F:29])[F:16])[CH:19]=5)[NH:23][CH:22]=4)[C:37]([C:33]4[N:32]([CH3:31])[CH:36]=[CH:35][CH:34]=4)=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: O=Cc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cn1cccc1C=O
Product: Cn1cccc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(C(F)(F)F)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-(trifluoromethyl)-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-pyrrole-2-carbaldehyde. 497.2 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:46]=2N=N1.CCN(C(C)C)C(C)C.C(N)(CC)(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][CH3:46])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CCC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 0.9 g of the compound obtained in Example 15 Step B, 0.9 g of BOP and 1 ml of DIPEA in 20 ml of DCM is added 1 g of tert-amylamine, and the mixture is left stirring for 3 hours at RT. The reaction mixture is washed with 1N HCl solution, with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with DCM. 0.34 g of the expected product is obtained, mp=164° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:45]([O:44][C:40](=[O:43])[CH:41]=[CH:42][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1)[CH3:46]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
A solution of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (2.6 g, Reference Example 7), tri-o-tolylphosphine (0.37 g), palladium (II) acetate, ethyl acrylate (1.6 mL) and tributylamine (8.01 mL) in dry dimethylformamide (25 mL), under argon, was heated at 155° C. for 3 hours then stood at room temperature overnight. The reaction mixture was evaporated and the resulting black oil was partitioned between ethyl acetate (200 mL) and hydrochloric acid (200 mL, 2M). The organic phase was washed with hydrochloric acid (200 mL, 2M), then with water (100 mL), then with brine (100 mL), then dried over magnesium sulfate and then evaporated. The residual yellow oil was subjected to flash chromatography on silica under gradient elution conditions with a mixture of ethyl acetate and pentane (from 3:97 to 10:90, v/v) to give the title compound. LC-MS: RT=4.05 minutes; no molecular ion observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]3[C:22]([O:25][CH3:26])=[N:23][NH:24][C:18]=3[CH:17]=2)=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CO>C(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]3[C:22]([O:25][CH3:26])=[N:23][NH:24][C:18]=3[CH:17]=2)=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]3[C:22]([O:25][CH3:26])=[N:23][NH:24][C:18]=3[CH:17]=2)=[O:14])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCC(NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccc(F)cc1
Agent: O=C=O
Solvent: CO
Product: COC[C@@H](NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccc(F)cc1
Product: COC[C@H](NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccc(F)cc1

Procedure:
The enantiomers of 1-(1-(4-fluorophenyl)-2-methoxyethyl)-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (40 mg, 0.11 mmol) were separated by SFC (Berger Multigram II SFC, column: Phenomenex Lux 4 2.1×25 cm, 5 uM, mobile phase: 30% to 70% MeOH in CO2(l), flow rate: 70 mL/min, 6.5 min run time). The fractions were collected and the solvent evaporated in vacuo to afford 1-[(1R)-1-(4-fluorophenyl)-2-methoxyethyl]-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea and 1-[(1S)-1-(4-fluorophenyl)-2-methoxyethyl]-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C17H18FN5O3 [M+1]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 7.98 (br s, 1H), 7.47 (s, 1H), 7.36 (dd, J=8.5, 5.5 Hz, 2H), 7.15 (t, J=9.0 Hz, 2H), 4.98-4.92 (m, 1H), 3.96 (s, 3H), 3.55 (d, J=5.0 Hz, 2H), 3.25 (s, 3H) (Example 54). MS ESI calc'd. For C17H18FN5O3 [M+1]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 7.98 (br s, 1H), 7.47 (s, 1H), 7.36 (dd, J=8.5, 5.5 Hz, 2H), 7.15 (t, J=9.0 Hz, 2H), 4.98-4.92 (m, 1H), 3.96 (s, 3H), 3.55 (d, J=5.0 Hz, 2H), 3.25 (s, 3H) (Example 55).
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].C(#N)C.[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]1([C:19]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:21]=[CH:22][CH:23]=2)SCCCS1>CCCCCC>[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]([C:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:21]=[CH:22][CH:23]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCC1(c2cccn2Cc2ccccc2F)SCCCS1
Agent: [Ca+2]
Solvent: CCCCCC
Solvent: CC#N
Product: CN(C)CCC(=O)c1cccn1Cc1ccccc1F

Procedure:
To a solution of 28.1 g of mercuric chloride and 10.3 g of calcium carbonate in 150 ml of aqueous 80% acetonitrile is added under nitrogen a solution of 17.0 of 2-(2-dimethylaminoethyl)-2-[1-(o-fluorobenzyl)-2-pyrryl]-1,3-dithiane in 100 ml of aqueous 80% acetonitrile. The reaction mixture is stirred at reflux for 4 hours, the mixture is permitted to cool and filtered through celite. The filter cake is washed with a hexane-dichloromethane mixture and the washed solution is washed successively with a 5M aqueous ammonium acetate solution and water, dried and filtered. The solvents are evaporated off leaving a dark oil which solidifies upon trituration witn n-hexane to give the solid product of 2-(3-dimethylaminopropionyl)-1-(o-fluorobenzyl)pyrrole.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:31][O:30][C:22]1[C:21]2[C:7]3[C:6]([O:5][CH3:4])=[C:11]([O:12][CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:25]=[C:24]([O:26][CH3:27])[C:23]=1[O:28][CH3:29]
Reactant: COc1cc(CCCCc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)-c1c(cc(OC)c(OC)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6 %

Procedure:
Dissolved in 1.2 ml (0.128 mmol) of dichloromethane were 50 mg (0.128 mmol) of 1,4-bis(3,4,5-trimethoxyphenyl)butane, followed by the addition of 0.12 ml of trifluoroacetic acid and 178 mg (0.39 mmol) of ferric perchlorate. After stirred at room temperature for 40 minutes, the reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with 2N-HCl and then with saturated NaCl. The organic layer was thereafter dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 3 mg of the title compound were obtained as colorless oil (yield: 6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=[CH:5]2.C([Li])CCC.[NH:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:23]=[CH:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:13][O:12][C:8]1[C:7]([O:14][CH3:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:26]([C:24]1[N:23]=[CH:22][NH:21][CH:25]=1)([OH:30])[CH:27]([CH3:29])[CH3:28])=[CH:3]2
Reactant: COc1ccc2cc(Br)ccc2c1OC
Reactant: CC(C)C(=O)c1c[nH]cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
6-Bromo-1,2-dimethoxynaphthalene (2.10 g) was dissolved in THF (30 ml). The solution was cooled to −78° C. To the reaction mixture was added dropwise a solution of n-butyllithium in hexane (1.6M: 6 ml), and the mixture was stirred for 1 h. To the mixture was added a solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.367 g) in THF (10 ml), and the temperature of the mixture was elevated to room temperature. To the reaction mixture were added an aqueous solution of ammonium chloride and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the titled compound (0.459 g) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12](=O)[CH3:13])[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClC(Cl)C>[CH3:9][C:8]1[N:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([CH3:13])=[CH:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C(C)=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-phenylhexane-2,5-dione (0.330 g, 1.735 mmol) in dichloroethane (5 ml) was added triethylamine (0.725 ml, 5.20 mmol), followed by ethyl 2-aminoacetate hydrochloride (0.291 g, 2.082 mmol). The reaction was stirred overnight at room temperature, after which LCMS showed formation of the desired product. The reaction mixture was purified directly on an ISCO automated chromatography system (silica gel) using an EtOAc/hexane gradient. The desired fractions were collected and concentrated in vacuum and the crude mixture was taken directly to the next step without further purification.