Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].O>CC(C)=O>[Cl:14][CH2:15][CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: ClCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 43.2 %

Procedure:
17.9 g (107 mmol) of carbazole and 500 ml of acetone as solvent were placed in a 1000 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 22.0 g (93.7 mmol)of 2-chloroethyl-p-toluene sulfonate, 12.5 g of sodium hydroxide and 9.2 ml of water. The resultant product was heated to 60° C. in a silicone oil bath, and subjected to the reaction for 20 hours. After the reaction was completed, the product was cooled to the ambient temperature. The precipitated solid was subjected to suction filtration with a glass filter. The resultant liquid was concentrated in an evaporator and dried under vacuum to obtain a brown solid, which was recrystallized in the presence of ligroin to obtain 9.3 g of a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.C(#N)C.[O:21]([C:23]#[N:24])[Na].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:23]([NH2:24])=[O:21])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#CO[Na]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC#N
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
10-methoxy-5H-dibenz(b,f)azepine (29.9 g, 0.134 mol) was added to 300 ml acetonitrile in a three-neck flask (500 ml) equipped with a mechanical stirring apparatus. The mixture was stirred at room temperature for 15 minutes, and then NaOCN (18 g, 0.277 mol) was added, followed by pyridinium p-toluenesulfonate (75 g, 0.3 mol). The mixture was stirred at room temperature for about 4 hours, at which time TLC indicated that the reaction was complete (disappearance of 10-methoxy-5H-dibenz(b,f)azepine). 30 ml water was added, and the mixture stirred for 15 minutes. The solids were filtered and the filtrate was concentrated under vacuum. The semi-solid residue was triturated with acetone to provide a creamy solid, which was dried at 80° C. to provide 18 g (0.068 mol, 50% yield) of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide (10-methoxycarbamazepine).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:57]([C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])=[CH:61][CH:60]=1)#[N:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:62]2[CH:63]=[CH:64][C:59]([C:57]#[N:58])=[CH:60][CH:61]=2)[C:66]1=[O:73])=[O:71]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 3.4 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.434 mmol), PyBOP (0.340 g; 0.651 mmol), N,N-diisopropylethylamine (0.224 mL; 1.30 mmol) and 1-(4-cyanophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.434 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified preparative HPLC (method 1) to yield 0.006 g (3%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24](Br)[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(#N)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of ester 112 (3.0 g, 7.07 mmol) and bis(triphenylphosphine)palladium (II) acetate (0.42 g, 0.57 mmol) was dissolved in a mixed solvent system of acetonitrile (80 mL) and TEA (120 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (2 mL, 14.14 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 112 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). Conditions for TLC were EtOAc. A white solid 113 (2.60 g, 83.3%) was obtained. mp 160-162° C.; IR (KBr, cm−1) 3365, 2925, 1706, 1616, 1553, 1498; 1H NMR (CDCl3) δ 7.89 (s, 1 H), 7.73 (dd, J=1.73 Hz, 1 H), 7.51-7.36 (m, 7 H), 6.66 (q, J=7.30, 1 H), 4.45-4.30 (m, 2 H), 1.40 (t, J=7.11, 3 H), 1.25 (d, J=7.38 Hz, 3 H), 0.15 (s, 9 H). MS (EI) m/e (relative intensity) 441 (M+, 15), 369 (25), 323 (55), 295 (100), 267 (15).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:16]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH2:31]([O:30][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:18]=1)[CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 113 mg (86%). HPLC-MS: m/z: 484.9 (M+H)+; Rt: 1.70 min. δH (400 MHz; CDCl3) 1.03 (d, 6H), 2.04-2.12 (m, 1H), 2.24 (s, 3H), 2.90-3.30 (m, 2H), 3.40-3.70 (m, 2H), 3.71 (d, 2H), 3.74 (s, 2H), 3.95-4.05 (m, 4H), 4.17 (s, 2H), 4.69 (s, 2H), 6.14 (m, 1H), 6.53 (d, 1H), 6.77 (dd, 1H), 6.81 (m, 1H), 6.89 (m, 1H), 7.23 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH2:6][S:7][CH3:8].I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH2:6][S:7]([CH3:8])=[O:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CCS(C)=O)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Sulfide 59 (5.40 g, 18.2 mmol) was dissolved in methanol (60 mL). This was cooled in ice and a solution of sodium metaperiodate (4.08 g, 1.05 equiv) in water (25 mL) was added dropwise over 10 mins. This was stirred in ice for 1 h and then at rt for a further 2 h. The resultant white precipitate was removed by filtration under vacuum, the residue washed with methanol and the filtrate concentrated in vacuo. The resultant colourless oil was partitioned between DCM and water. The aqueous phase was extracted twice more with DCM, methanol added to the combined organic extracts to obtain an homogenous solution and this was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil, 5.69 g, 100%. This was obtained as a 1:1 mixture of diastereoisomers.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49](OS(C(F)(F)F)(=O)=O)=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([O:17][C@@H:18]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[C@@H:22]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[O:21][C@@:19]1([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:48][CH:47]=2)[CH:39]=1)[OH:20])(=[O:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(C#C[Si](C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C

Procedure:
Under argon, 17.3 mg copper iodide, 31.9 mg bis-(triphenylphosphine)-palladium dichloride, 0.22 ml triethylamine and finally 0.19 ml trimethylsilylacetylene are added to a solution of 0.30 g 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulfonyloxy)-benzyl]-4-methyl-benzene in 1.5 ml of dimethylformamide. The flask is tightly sealed and stirred at 90° C. over night. After 4 h additional 20 mg bis-(triphenylphosphine)-palladium dichloride and 0.2 ml trimethylsilylacetylene are added, and the mixture is further stirred at 90° C. for 4 h. After cooling the reaction mixture to room temperature, the solvent is removed and the residue purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1->1:2).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[I:41]N1C(=O)CCC1=O>CC#N.C(Cl)Cl>[I:41][C:3]1[CH:4]=[C:5]([C:19]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 78.8 %

Procedure:
To a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (200 mg, 0.43 mmol) in MeCN (1.5 ml) at room temperature and under argon was added trifluoromethanesulfonic acid (1 ml) followed by N-iodosuccinimide (97 mg, 0.43 mmol). After 45 min, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, with aqueous NaS2O4 and water, dried (Na2SO4), and evaporated to give the title compound (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19](Cl)(=[O:21])=[O:20])=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:28][CH:25]([CH3:27])[CH3:26])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(S(=O)(=O)Cl)n2Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl chloride (115 mg, 0.295 mmol, intermediate 64) in DCM (5 mL) was added isopropylamine (17.4 mg, 0.59 mmol) followed by TEA (60 mg, 0.59 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (50:1) to give 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (59 mg, 48.6% yield) as yellow syrup. LCMS retention time 1.436 min; LCMS MH+ 412.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]1([CH2:10][C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.O.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:5]1([CH2:10][C:11]([C:18]2[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add aluminum trichloride (2.719 g, 20.4 mmol) in three portions to a solution of cyclopentylacetyl chloride (2 g, 13.6 mmol) in anhydrous toluene (30 mL) at 0° C. Stir the solution at room temperature overnight. Cool to 0° C., add water and extract the aqueous phase with EtOAc. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as an oil (2.5 g, 91%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH:29]=[O:30])=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCn1c(-c2ccccc2)nc(C(OC)OC)c1C=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous THF under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 min. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60–7.56 (m, 2H), 7.51–7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73–1.63 (m, 2H), 1.28–1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[C:23]1([N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]1([N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCCC=C(c1ccc(N)cc1)c1cccnc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CCCC=C(c1ccc(NC(=O)N(c2ccccc2)c2ccccc2)cc1)c1cccnc1

Procedure:
A mixture of 2.4 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 2.1 g of N,N-diphenyl-carbamoylchloride is stirred in 25 ml of pyridine for 18 hours at ambient temperature. The solvent is eliminated and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried and evaporated down. The residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution for 30 minutes at 50° C. The reaction solution is diluted with water and extracted with ethyl acetate. Then the aqueous phase is neutralised by the addition of citric acid, the precipitate formed is suction filtered and recrystallised from ethyl acetate/isopropanol.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:21])=[N-]>CCOCC>[CH3:21][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Solvent: CCOCC
Product: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(N-Boc-piperidine-4-yl)-propionic acid (4.0 g, 15.6 mmol) in ether (100 mL) was added a solution of diazomethane in ether (0.2 M, 100 ml) in portions until the solution became lightly yellow. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated to give 3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (4.2 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][N:9]([CH3:13])[C:10]=1[CH2:11]O)=[O:5])[CH3:2].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:11][C:10]1[N:9]([CH3:13])[N:8]=[C:7]([CH3:14])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(C)nn(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nn(C)c1CCl

Procedure:
This material was combined with the product of a second reaction (5.0 g of 4-ethoxycarbonyl-5-(1-hydroxymethyl)-1,3-dimethylpyrazole and 1.93 ml thionyl chloride), dissolved in dichloromethane, washed with brine, dried (MgSO4) and concentrated to give 10.7 g of a solid, mp. 81°-83° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1([F:19])[CH2:18][NH:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][C:15]([F:19])([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(F)(F)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), 3,3-difluoroazetidine hydrochloride (0.364 g, 2.80 mmol) and 4 Å molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.67 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give the title compound as a colourless oil (0.33 g, 57%). 1H NMR (300 MHz, CDCl3): δ 4.02-3.69 (m, 4 H), 3.65 (t, J=12.15 Hz, 4 H), 3.55-3.48 (m, 1 H), 1.43 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:12][S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].CC([O-])(C)C.[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[CH2:12][S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: -20 °C

Procedure:
A stirred solution of 4-fluoro-nitrobenzene (1 equiv.) and chloromethyl-1-naphthylsulfone (1 equiv.) in dry THF under nitrogen at −78° C., was treated with 1.0 M KOt-Bu (2.2 equiv., 1.0 M in THF), warmed to −20° C. over 1 h period, quenched with acetic acid and treated sequentially with water, saturated aqueous NaHCO3 and extracted with ether. The combined extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed (Silica gel, 1:1 and 1:0 ethyl acetate:hexanes as eluent) to give 1-(5-fluoro-2-nitrobenzyl-sulfonyl)naphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:36]>CCOC(C)=O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:6][CH:7]=2)=[CH:39][CH:40]=1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: COc1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)Oc4ccc(OC)cc4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indole-3-carbonitrile (530 mg, 1.58 mmol) in EtOAc (10 mL) is added 2M aqueous K2CO3 (556 uL, 5.9 mmol) and 4-methoxyphenyl chloroformate over a period of 5 min. The reaction mixture is stirred further for 3 h at room temperature. The reaction mixture is diluted with EtOAc (20 mL) and then washed with water (5 mL). The solvents are removed under reduced pressure and the residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (761 mg, 98%).