Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[N:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.C([N:35]([CH:38]([CH3:40])C)[CH2:36]C)(C)C.C(CN)[OH:42]>C(Cl)Cl>[OH:42][CH:40]1[CH2:36][N:35]([CH:2]2[C:10]3[C:5](=[C:6]([C:11]4[S:15][C:14]([C:16]5[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=5)[C:21]#[N:22])=[N:13][CH:12]=4)[CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH2:38]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O)s2)cc1C#N
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4N3CC(O)C3)s2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Prepared using General Procedure 20: To a stirred solution of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile (20 mg, 0.05 mmol) in DCM (1 mL) was added thionyl chloride (12.6 mg, 0.106 mmol) at 0° C. The reaction was stirred at room temperature for 3 h. The solvent was evaporated and the crude chloride re-dissolved in dimethyl acetamide (1 mL). Diisopropyl ethylamine (20.5 mg, 0.16 mmol) and ethanolamine (9.7 mg, 0.16 mmol) were added and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was quenched with water (200 uL) and purified by preparative HPLC to afford 11 mg (46%) of 5-(5-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 208. LCMS-ESI (m/z) calculated for C25H25N3O2S: 431.1; found 432.1 [M+H]+, tR=6.48 min (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C[CH2:13][N:14](C(C)C)[CH:15](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reaction time: 0.08 h

Procedure:
To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200 ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min, dimethylamine (0.75 g) was added dropwise. This was stirred overnight. The reaction was added to water and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) afforded the title compound (320 mg). Rf=0.56 (1:1 cyclohexane:EtOAc)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41]C(O)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH:31]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC4CCOCC4)cc3C)c2cc1OC
Yield: 81.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, tetrahydro-2H-4-pyranol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 84%).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=2)[N:5]=1)(=O)[NH2:2].[ClH:34].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:34].[C:31]([C:28]1[CH:29]=[CH:30][C:25]([N:6]2[C:7](=[O:24])[CH:8]=[C:9]([O:10][CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:4]([C:1]#[N:2])=[N:5]2)=[CH:26][C:27]=1[F:33])#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C(N)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (example 34) (22 mg, 0.050 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 19 mg (100%) of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 340 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl.CO>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.39, FD-MS: M+ =580.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.FC(F)(F)C(O)=O.[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:41][CH2:42][CH:43]([CH2:46][NH:47][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:44][CH2:45]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: NCC1CCN(C(N)=NC(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NCC2CCN(C(N)=NC(=O)OCc3ccccc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
97 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and 124.3 mg of [Amino-(4-aminomethyl-piperidin-1-yl)-methylene]-carbamic acid benzyl ester trifluoroacetic acid salt were dissolved in 5 ml of DMF. After cooling to 0° C. 136 mg of HATU and 106 mg of NEM were added. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column) (gradient acetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to 0:100). The fractions containing the product were evaporated and lyophilized.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.Cl>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Yield: 0 %

Procedure:
Pyridine-3-sulfonic acid (3.00 g, 18.8 mmol) and PCl5 (4.79 g, 23.0 mmol) were mixed in POCl3 (6 mL). The reaction was stirred and refluxed at 120° C. over night (15 h). Cooled to rt., diluted with CHCl3 (20 mL) and saturated with HCl (g). This gave a white precipitation, which was filtered off, washed with CHCl3 and dried under reduced pressure to give the title compound (3.36 μg, 83%) as a white powder.
Reaction SMILES: [NH:1]([S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1)=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])=[O:4].C([O-])(=[O:45])C.[Ca+2].C([O-])(=O)C>>[NH:1]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=1)(=[O:35])=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:18]([OH:45])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])=[O:4].[N+:25]([C:24]1[CH:28]=[CH:29][C:21]([NH2:20])=[CH:22][CH:23]=1)([O-:27])=[O:26]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ca+2]
Product: Cc1ccc(S(=O)(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Product: Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.07 h

Procedure:
After precisely 4 minutes, 150 μl. of starting reagent, consisting of 1.1 mmole/litre Chromozym® TH (Tos-Gly-ProArg-pNA) and 100 mmole/litre calcium acetate, are added thereto and at 405 nm there is determined in a photometer the time until a definite amount of substrate is reacted by newly formed thrombin to give Tos-Gly-Pro-Arg and p-nitroaniline (pNA). The amount of reacted substrate, which is measured, is defined by a threshold extinction value (for example ΔE=0.2).
Reaction SMILES: N1[CH2:6][CH2:5][O:4]CC1.[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(NCC)C>>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:15]2[CH2:16][CH2:17][CH2:6][C:5](=[O:4])[CH:14]=2)[CH:8]=1
Reactant: C1CCNC1
Reactant: C1COCCN1
Reactant: C1CCNCC1
Solvent: CCNCC
Product: O=C1C=C(c2cccnc2)CCC1

Procedure:
Following the procedure described in Example A-2 but using in place of morpholine a molar equivalent quantity of piperidine, pyrrolidine or diethylamine, there is obtained the same final product, 3-(3-pyridinyl)-2-cyclohexen-1-one; however, the following respective intermediates are first produced: 1-(3-pyridinyl)-1-(piperidino)ethylene, 1-(3-pyridinyl)-1-(pyrrolidino)ethylene or 1-(3-pyridinyl)-1-(diethylamino)ethylene and 1-(3-pyridinyl)-3-(piperidino)-1,3-cyclohexadiene, 1-(3-pyridinyl)-3-(pyrrolidino)-1,3-cyclohexadiene or 1-(3-pyridinyl)-3-(diethylamino)-1,3-cyclohexadiene.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:67]([O:71][C:72](=[O:80])[CH2:73][CH2:74][C@@H:75]([C:77]([OH:79])=[O:78])[NH2:76])([CH3:70])([CH3:69])[CH3:68].Cl>CN(C=O)C.O>[C:67]([O:71][C:72](=[O:80])[CH2:73][CH2:74][CH:75]([NH:76][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[O:24])[CH:21]=[CH:22][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[C:77]([OH:79])=[O:78])([CH3:70])([CH3:68])[CH3:69]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150 mg, 0.33 mmol) in 10 ml of anhydrous DMF were added HATU (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl ester (102 mg, 0.50 mmol). The mixture was heated at 60° C. for 30 minutes, cooled to room temperature, and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid as white solid. Yield: 185 mg, 87%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.N1C=CC=CC=1>[F:31][C:18]([F:17])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A portion of the raw N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (100 mg, 0.45 mmol) was dissolved in CH2Cl2/pyridine 9/1 (20 ml) and 4-(trifluoromethoxy)benzenesulfonyl chloride (100 μl, 0.58 mmol) was added dropwise. After stirring at room temperature over night, the reaction mixture was concentrated and the purification of the residue by chromatography on silica gel (CH2Cl2:CH3OH, 97:3) gave the title compound (94 mg, 47% for steps 31.4 and 31.5) as a gum.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1.O>C(O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1)[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CBr)cc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C)C(=O)OCC
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
Diethyl malonate (183 mg, 1.14 mmol) was dissolved in ethanol (2 mL). Thereafter, sodium ethoxide (78.0 mg, 1.15 mmol) and an ethanol (2 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(bromomethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (390 mg, 0.76 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (300 mg, 67%) in the form of a colorless amorphous product.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[ClH:5].NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[ClH:5].[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=2)=[CH:22][N:1]=1
Reactant: N=C(N)N
Reactant: COc1ccc(CC(C#N)=CNc2ccccc2)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)c2ccccc12

Procedure:
To 65 mL of ethanolic guanidine solution prepared from 3.42 g (35.8 mmol) of guanidine hydrochloride and 2.00 g (37.0 mmol) of sodium methoxide was added 9.00 g (28.6 mmol) of 3-anilino-2-(4-methoxy-1-naphthylmethyl)acrylonitrile. The solution was heated under reflux for 1.5 hr, and then 60 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 108° by distillation of the ethanol, after which it was heated at this temperature for 2.5 hr. The hot mixture was filtered, and the precipitate (7.04 g, 87% of crude product) recrystallized from 30% ethanol in the presence of hydrochloric acid, to give the title compound; mp 312°-314° dec. Anal. Calcd for C16H16N4O.HCl: C, 60.66; H, 5.41; N, 17.69; Cl, 11.19. Found: C, 60.67; H, 5.45; N, 17.70; Cl, 11.19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH:5]=1.[CH3:23][N:24](C=O)C>C(OC)(C)(C)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:23]#[N:24])[CH:16]=2)[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(OC)c(OCCc2cccc(C#N)c2)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A flask was charged with zinc cyanide (129 mg, 1.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.0547 mmol). Under an atmosphere of argon, a solution of the compound of step 1 (400 mg, 1.10 mmol) in DMF (1.9 ml) was added to the mixture. After stirring at 150° C. for 1 h and cooling, the mixture was diluted with methyl tert-butyl ether and filtered over celite. The filtrate was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to give 275 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH3:15])[C:6]=1[CH3:26].CO.[OH-].[Li+]>C1COCC1>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]2[CH3:26])[CH3:15])=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: COC(=O)Cc1c(C)n(C(C)c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1C(C)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[1-(4-methanesulfonyl-phenyl)-ethyl]-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-acetic acid methyl ester (Enantiomer A) (22 mg, 0.05 mmol) in THF (0.5 ml) and methanol (0.5 ml) is treated with 2M lithium hydroxide (0.2 ml) and stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the crude is dissolved in water (10 ml) and acidified to pH1 using concentrated HCl. The mixture is then extracted with ethyl acetate (2×10 ml) and the organic portions are washed with brine, dried (MgS04) and concentrated in vacuo to yield the titled product as a colourless glassy solid. (MH+373) The enantiomer of the titled compound (Enantiomer 2) is prepared analogously using the procedure described above by replacing Enantiomer A with Enantiomer B. (MH+373)
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1>C(O)C>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1)=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CCC(=O)N(C)C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N(C)C(=O)CC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14 g of ethyl acrylate in 45 ml of ethanol are added dropwise to 23.8 of the amine obtained in Stage C of Example 1 dissolved in 45 ml of ethanol. The mixture is stirred at room temperature for 3 hours, evaporated, and the residual oil is distilled in a Kugelrohr (bulb tube) at 120° C. and 0.09 mm Hg.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:10]=[CH:9]2)C=CC=CC=1.Cl>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:10]=[CH:9]1
Reactant: C(#CCCC1CCCCC1)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCO
Product: C(#CCCC1CCCCC1)CCc1c[nH]cn1
Temperature: 90 °C
Yield: 105.1 %

Procedure:
1-[1-Triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-3-hexyne (0.30 gram, 0.64 mmol) was dissolved in ethanol (10 ml). 2N HCl (20 ml) was added, and the mixture heated at 90° C. for 1 hour. The reaction mixture was cooled, filtered, and the filtrate neutralized with 10% NaOH solution and then partitioned between chloroform and water. The chloroform layer was separated, dried over Na2SO4, filtered and evaporated in vacuo to obtain the crude oil. The crude product was purified using column chromatography using MeOH/CHCl3, 10:90 to afford 155 mgs of 1-[1H-imidazol-4-yl]-6-cyclohexyl-3-hexyne (23).