Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 99 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylate (0.09 g, 0.24 mmol) and 1 N aqueous sodium hydroxide solution (1.5 mL, 1.5 mmol) in ethanol (3 mL) was stirred at reflux for 1 h, and then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless solid in 99% yield (0.08 g): 1H NMR (300 MHz, DMSO-d6) δ 12.33 (br s, 1H), 7.29 (dd, J=8.8, 7.2 Hz, 2H), 6.99-6.93 (m, 3H), 6.28 (s, 1 H), 4.13 (t, J=5.3 Hz, 2H), 3.87-3.79 (m, 2H), 3.72-3.64 (m, 2H), 3.58 (t, J=5.3 Hz, 2 H), 2.39 (s, 3H): MS (ES+) m/z 347.3 (M+1).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][PH:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:12][C:13]#[N:14].[Na+]>C(#N)C>[C:1]1([CH:7]=[CH:8][PH:9]([N:14]=[C:13]=[O:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[PH](Cl)C=Cc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C=N[PH](=O)C=Cc1ccccc1
Reaction time: 23 h
Yield: 76.3 %

Procedure:
106 g (0.57 mol) of phenylvinylphosphinic acid chloride were dissolved in 150 ml of acetonitrile and stirred with 38 g (0.59 mol) of sodium cyanate at a temperature of 30° C. After 23 hours, the precipitate was filtered off by suction and washed with acetonitrile; the filtrate was concentrated and the residue distilled at a temperature of 107°-110° C. and at a pressure of 33 Pa. 84 g of phenylvinylphosphinic acid isocyanate (77% of theory) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]2[O:13][CH2:14][CH2:15][O:16][C:6]=2[CH:5]=1>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([NH2:10])=[CH:8][C:7]2[O:13][CH2:14][CH2:15][O:16][C:6]=2[CH:5]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1N)OCCO2
Reaction time: 4 h

Procedure:
A mixture of 6.0 g. of 6-nitro-3,4-ethylenedioxybenzoic acid methyl ester, 150 mg. of 5% palladium on charcoal and 20 mls. of glacial acetic acid is hydrogenated under an initial hydrogen pressure of 30-40 p.s.i. and without external heating. After four hours, the reaction mixture is filtered diluted with 80 ml. of ice water, stirred for up to one half hour and the resulting precipitate filtered off, water washed and dried to obtain 6-amino-3,4-ethylenedioxybenzoic acid methyl ester, m.p. 73°-77°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:3][CH:2]=1.O.O.O.[F:17][C:18]([F:26])([F:25])[C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].C(#N)C>C1C=CC=CC=1>[F:17][C:18]([F:26])([F:25])[C:19]([C:11]1[S:10][C:9]([NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:13][CH:12]=1)([OH:20])[C:21]([F:24])([F:23])[F:22]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: c1cc(CNc2nccs2)ccn1
Solvent: O
Solvent: CC#N
Solvent: c1ccccc1
Product: OC(c1cnc(NCc2ccncc2)s1)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C

Procedure:
Molecular sieves powder (4A) (1 g) was added to a mixture of crude intermediate N-(pyridin-4-ylmethyl)-1,3-thiazol-2-amine prepared above (2.5 g 13 mmol) and hexafluoroacetone trihydrate (4 g, 18.1 mmol) in benzene (3 ml). The mixture was heated at 80° C. for 24 h. Acetonitrile was added and mixture was filtered. Solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with a 95:5 mixture of CHCl3 and CH3OH, to afford the title compound as an orange solid (1.1 g). 1H NMR (DMSO-d6) δ 4.3 (d, 2H), 7.10 (s, 1H), 7.42 (d, 2H); 7.78 (d, 2H), 8.45 (brs, 1H), 8.82 (brs, 1H); ESIMS: m/z 356 (M−H).
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=O)=[CH:14][CH:15]=3)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:35][N:36]1[C:40]([CH2:41][NH2:42])=[CH:39][C:38]([CH3:43])=[N:37]1>>[CH3:35][N:36]1[C:40]([CH2:41][NH:42][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:13]2[CH:12]=[C:11]3[C:16]([C:8]([CH:7]=[N:6][N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)=[N:9][N:10]3[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])=[CH:15][CH:14]=2)=[CH:39][C:38]([CH3:43])=[N:37]1
Reactant: Cc1cc(CN)n(C)n1
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)O)cc21
Product: Cc1cc(CNC(=O)c2ccccc2Nc2ccc3c(C=Nn4cccc4)nn(COCC[Si](C)(C)C)c3c2)n(C)n1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using 2-[3-(Pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid and C-(2,5-Dimethyl-2H-pyrazol-3-yl)-methylamine. 1H NMR (CDCl3) δ 9.56 (1H, s), 8.68 (1H, s), 8.30 (1H, d, J=8.7 Hz), 7.49 (1H, d, J=8.3 Hz), 7.43 (1H, dd, J=7.9, 1.5 Hz), 7.36–7.31 (2H, m), 7.23 (2H, t, J=2.6 Hz), 7.17 (1H, dd, J=8.7, 1.9 Hz), 6.83 (1H, t, J=7.2 Hz), 6.32 (1H, bt), 6.29 (2H, t, J=2.3 Hz), 6.01 (1H, s), 5.67 (2H, s), 4.61 (2H, d, J=5.6 Hz), 3.60 (3H, s), 3.58 (2H, t, J=8.3 Hz), 2.22 (3H, s), 0.90 (2H, t, J=8.7 Hz), 0.06 (9H, s).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[N:24](CC[Si](C)(C)C)[S:23]3(=[O:35])=[O:34])=[C:18]([O:36]CC3C=CC=CC=3)[CH:17]=2)[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:44]1([CH2:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:34])=[O:35])=[C:18]([OH:36])[CH:17]=2)[C:12]([NH:54][CH2:53][CH2:52][CH2:51][CH2:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S1(=O)=O
Reactant: NCCCCc1ccccc1
Product: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from (S)-2-benzenesulfonylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid and 4-phenylbutylamine analogous to Example 210, steps C and D: (M−1)−=585. HPLC retention time: 1.27 min. (Method A).
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:19])=[C:16]([CH2:17][OH:18])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:20][CH2:21][CH2:22][OH:23])[C@H:6]([O:24]C(=O)C(C)(C)C)[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>NC(O)C>[OH:18][CH2:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:20][CH2:21][CH2:22][OH:23])[C@H:6]([OH:24])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:19]
Reactant: CC(=O)N1c2c(ccn3c(CO)c(C)nc23)[C@@H](OCCO)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: CC(N)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2c3c(ccn2c1CO)[C@@H](OCCO)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 0.17 g (0.30 mmol) (7R,8R,9R)-10-acetyl-3-hydroxymethyl-7-(2-hydroxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 0.30 g (2.10 mmol) potassium carbonate in aminoethanol is stirred at 90° C. for 2 h. The reaction is quenched by adding the mixture directly of silica gel for purification by column chromatography (dichloromethane/methanol: 13/1/1) to give 0.02 g (0.06 mmol/19%) of the title compound as a armorph solid. 1H-NMR (200 MHz,[D6] DMSO): δ=2.29 (s, 1H), 3.30-3.44 (m, 2H), 3.46-3.65 (m, 2H), 4.01 (q, 1H), 4.47 (t, 2H), 4.70 (d, 2H), 6.79 (d, 1H), 7.20-7.43 (m, 5H), 7.63 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1OC(=O)Cc1cccs1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1OC(=O)Cc1cccs1
Yield: 75 %

Procedure:
1.86 parts of 3-thiolacetoxy-dihydrothiophene-4-carboxylic acid methyl ester are reacted with 1.76 parts by volume of sulfuryl chloride in 25 parts by volume of chloroform in the course of one hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.4 parts (75% of theory) of 3-thiolacetoxy-thiophene-4-carboxylic acid methyl ester of melting point 92°-95° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[CH2:9](Br)[CH:10]=C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8])[CH:9]=[CH2:10]
Reactant: CN1CCC[C@H]1CO
Reactant: C=CCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-methyl-2-pyrrolidinemethanol (5.10 g, 50 mmol, Aldrich Chemical Co.) was dissolved in 50 mL of CHCl3, then 5.25 mL of allyl bromide and 8.34 mL of triethylamine were added. The reaction mixture was stirred at room temperature for 2 hours, then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel to give 6.3 g of the title product. MS (DCI/NH3) m/e: 142 (M+H)+. 1H NMR (CDCI3, 300 MHz) δ: 6.05-5.90 (m, 1H), 5.33-5.17 (m, 2H), 3.77-3.68 (m, 1H), 3.58-3.47 (m, 2H), 3.32-3.20 (m, 1H), 3.16-3.05 (m, 1H), 2.90-2.78 (m, 1H), 2.53-2.40 (m, 1H), 2.02-1.73 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([N:17]=O)[C:12](=[O:13])[N:11]([CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.CN(C)N>CN(C)C=O>[CH2:19]([N:11]1[C:12](=[O:13])[C:14]2[NH:17][C:32]([C:30]3[CH:29]=[CH:28][C:27]4[O:22][CH2:23][CH2:24][O:25][C:26]=4[CH:31]=3)=[N:16][C:15]=2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10])[CH2:20][CH3:21]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Agent: CN(C)N
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3ccc4c(c3)OCCO4)nc2n(Cc2ccccc2)c1=O
Yield: 23.9 %

Procedure:
2.9 g (0.01 mol) of 1-benzyl-3-propyl-5-nitroso-6-aminouracil are added to 60 ml of dimethylformamide together with 2.3 g (0.014 mol) of 1,4-benzodioxan-6-aldehyde, then 0.5 g (0.014 mol) of 1,1-dimethylhydrazine are added and the mixture is refluxed for 8 hours. After working up in the usual way, the crystalline residue is triturated with ethanol and filtered under suction. 1.0 g of the title compound is obtained in the form of yellow crystals, m.p. 290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[C:22]([CH3:25])([CH3:24])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])([CH3:24])[C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCC2=C1C(C)(C)C=C2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1C2=C(C=CC2(C)C)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7,7-trimethyl-2,3,4,7-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.N1C=CC=CC=1>>[OH:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]2[C:9]=1[CH:17]=[CH:16][C:15]([CH3:19])([CH3:14])[O:10]2
Reactant: CC(C)=CC=O
Reactant: O=Cc1cc([N+](=O)[O-])c(O)cc1O
Solvent: c1ccncc1
Product: CC1(C)C=Cc2c(O)c(C=O)cc([N+](=O)[O-])c2O1
Reaction time: 18 h

Procedure:
A solution of 2,4-dihydroxy-5-nitro-benzaldehyde (10.61 g, 58 mmol) in Me2CO (6 mL) is added during a 5.5 h period to a stirring solution of 3-methyl-but-2-enal (4.00 g, 29 mmol) in pyridine (2.29 g, 2.34 mL, 29 mmol) at 120° C. After completion of addition heating is continued for an additional 18 h. The Me2CO is evaporated and the pyridine is removed by azeotrope distillation with toluene to afford a crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to afford 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:36]=3)[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:36]=3)[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:37])[C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14]([NH:37][CH2:26][C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of 14 g of the compound obtained in Step 4.4, 7.46 g of veratrylamine, 19.99 g of HBTU and 13.1 g of DIEA in 300 ml of DMF is stirred for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is taken up in DCM. The resulting solution is washed twice with saturated aqueous NaHCO3 solution. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (90/10, v/v) to (40/60, v/v) to give 16 g of the expected product.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]([CH:36]4[CH2:38][CH2:37]4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33][CH:34]=C)[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:7][CH2:6]1)[CH:2]=C.[BH4-].[Na+]>C(Cl)Cl.O>[C:47]([O:46][C@@H:40]([C:12]1[C:13]([CH3:39])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH2:2][CH2:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[CH2:22][N:21]([CH:36]2[CH2:37][CH2:38]2)[CH2:20]3)[CH2:10][CH2:9]1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])([CH3:50])([CH3:49])[CH3:48]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN(Cc4ccc(C)cc4O[C@@H](C)CC=C)C4CC4)nn23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)ccc1CN(C1CC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((cyclopropyl(4-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.128 mmol) and Grubb's II catalyst (10.89 mg, 0.013 mmol) in DCM (80 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (4.85 mg, 0.128 mmol) was added and the reaction was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOac/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-[(20S)-11-cyclopropyl-4,16,20,26-tetramethyl-19,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetate (90 mg, 0.107 mmol, 83% yield) as a white solid. LCMS (M+1)=676.4.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])=[CH2:20].[H-].[Na+]>C1(C)C=CC=CC=1>[F:16][C:14]([F:17])([F:15])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=1)[C:3]([CH:23]1[CH2:24][CH2:25][N:21]([CH:19]=[CH2:20])[C:22]1=[O:26])=[O:18]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CN1CCC(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Reaction time: 12 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)-benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil. A solution of 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodium hydride (60% suspension in mineral oil—0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 hrs, then it was partitioned between saturated ammonium chloride solution and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (1.6 g) as a beige oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])\[CH3:32])\[CH3:27].O>C(COC)OC>[CH2:24]([CH:3]([P:4](=[O:13])([O:9][CH:10]([CH3:11])[CH3:12])[O:5][CH:6]([CH3:8])[CH3:7])[P:14](=[O:23])([O:15][CH:16]([CH3:18])[CH3:17])[O:19][CH:20]([CH3:22])[CH3:21])/[CH:25]=[C:26](/[CH2:28][CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:37])[CH3:38])\[CH3:32])\[CH3:27]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Oily sodium hydride (60%, 0.24 g) was added to a solution of tetraisopropyl methylenebisphosphonate (3.44 g) in dimethoxyethane (25 ml). The mixture was stirred at room temperature for 1 hour. Then, a solution of (E,E)-farnesyl bromide (1.43 g) in dimethoxyethane (5 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The oily residue was subjected to column chromatography on silica gel. Tetraisopropyl (E,E)-farnesylmethylenebisphosphonate (1.67 g, 60.9%) was obtained as an oil from the fractions obtained by elution with ethyl acetate-chloroform (1:1, v/v).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]=1[CH3:33])=O>>[CH3:28][C:26]1[NH:27][C:23](/[CH:21]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)=[C:24]([CH3:33])[C:25]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)O

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid to give the titled compound.
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]=1)[CH2:19]2.Cl.C(N)CN.[OH-].[Na+]>CO.O>[NH2:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH2:19][C@:3]1([C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]1=[O:1])[CH2:26]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: NCCN
Solvent: O
Product: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(R)-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)carbamate from Step C (13.4 g, 27.8 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (1.9 mL, 27.8 mmol) and 10 N sodium hydroxide (6 mL, 60 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (1 L). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (35 mL) to give the title compound. MS: m/z=252 (M+1).