Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]1([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]#[N:27].[ClH:28]>CC(C)=O>[ClH:28].[C:2]1([CH:12]2[CH2:17][CH2:16][N:15]([CH2:25][C:26]#[N:27])[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Reactant: N#CCBr
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: N#CCN1CCC(c2cccc3ccccc23)CC1
Yield: 91.83 %

Procedure:
5 g of the compound from Example 3, 7.088 g of potassium carbonate and 2.259 g of bromoacetonitrile in 200 ml of acetone are stirred for 10 hours under reflux and a stream of nitrogen. After filtering and evaporation of the filtrate, the residue obtained is treated with an ethanolic solution of hydrogen chloride to give 4.5 g of the expected hydrochloride.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH3:22])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:23]1(B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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:23]1([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH3:22])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CCOc1ccccc1CCNc1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccccc1CCNc1ccc2ncc(C3=CCCC3)n2n1
Temperature: 150 °C
Yield: 68.9 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-[2-(2-ethoxy-phenyl)-ethyl]-amine (90 mg, 0.25 mmol), 2-cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (97 mg, 0.5 mmol), K2CO3 (104 mg, 0.75 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.8 mg, 0.013 mmol) in MeCN/water (2.8 ml/0.7 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was concentrated. The residue was subjected to ISCO. The product was further purified by preparative to give the titled compound (60 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][N:52]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:49]5[CH2:54][CH2:53][N:52]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 0 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (1.00 g, 2.2 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.80 g, 2.2 mmol), p-toluenesulfonic acid (0.99 g, 5.2 mmol) and iPrOH (20 mL) was heated in the microwave at 175° C. for 20 min. LCMS indicated the reaction had proceeded to completion and the reaction mixture was concentrated onto silica gel. Flash chromatography afforded the title compound (1.1 μg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (bs, 1H), 8.45 (s, 1H), 8.33-8.31 (m, 1H), 8.19 (d, J=5.2 Hz, 1H), 8.07-8.03 (m, 1H), 7.83-7.80 (m, 1H), 7.74-7.71 (m, 1H), 7.60 (at, J=7.7 Hz, 1H), 7.48-7.35 (m, 3H), 7.23-7.17 (m, 2H), 7.01-6.95 (m, 1H), 6.67 (d, J=2.5 Hz, 1H), 6.50-6.44 (m, 2H), 3.79 (s, 3H), 3.76-3.70 (m, 2H), 3.11-3.06 (m, 4H), 2.85 (s, 3H), 2.71-2.63 (m, 2H), 2.62-2.57 (m, 4H), 2.46-2.36 (m, 2H), 1.87-1.79 (m, 2H), 1.60-1.47 (m, 2H). MS (ES+, m/z) 794 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH3:37])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CCO>[OH:1][C:2]1([CH3:37])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3CCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-(8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate (step 1) (10 mg, 0.020 mmol) in EtOH (1 ml) was added 2M NaOH (aq) (0.040 ml, 0.080 mmol). The reaction mixture was stirred at RT overnight under an atmosphere of nitrogen. A further portion of 2M NaOH (aq) (0.040 ml, 0.080 mmol) was added and stirring continued overnight. The resulting mixture was treated with 2M HCl (aq) to adjust the pH to pH5. The organic solvent was removed under reduced pressure and the mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×10 ml). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with iso-hexane/EtOAc to afford the titled compound;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[CH:16]([C:20]2[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=2)[C:25](O)=[O:26])[S:15]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([CH:16]3[S:15][C:14](=[O:13])[NH:18][C:17]3=[O:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Yield: 53.3 %

Procedure:
To a solution of 4-trifluoromethylbenzylamine (71.9 g) in DMF (1 L) were added 5-(2,4-dioxothiazolidin-5-yl)-2-methoxybenzoic acid (98.7 g), diethyl cyanophosphate (94.7 g) and triethylamine (63 ml) under cooling with ice and stirring, and the mixture was stirred for 15 minutes as it was. Thereafter, it was stirred for 7 hours at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate and, after washing with water, dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was dissolved into ethanol. After treating with activated charcoal, this was filtered through celite and water was added to the filtrate. The crystals deposited were collected by filtration and dried to obtain 83.6 g (53%) of aimed compound as colorless powder. Melting point: 168.0~169.0° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7](CC(N3CCOCC3)=S)[CH:8]=[CH:9][C:2]1=2.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:20][C:19]([OH:22])=[O:21])[CH:8]=[CH:9][C:2]1=2
Reactant: S=C(Cc1ccc2c(c1)CCS2)N1CCOCC1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCS2
Temperature: 100 °C
Yield: 41 %

Procedure:
In a round bottom flask with a reflux condenser was placed 2-(2,3-dihydro-benzo[b]thiophen-5-yl)-1-morpholin-4-yl-ethanethione (1.85 g, 6.62 mmol) and to it was added acetic acid (7.7 mL), concentrated sulfuric acid (1.1 mL) and water (2 mL). The reaction mixture was then heated at 100° C. for 4 h. After this time the solution was added to water (40 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified using reverse phase HPLC to afford (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid (525 mg, 41%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)ccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of methyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.35 g) in tetrahydrofuran (30 mL)-ethanol (5 mL) was gradually added sodium borohydride 1 (65 mg) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.30 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][N:15](CC3C=CC(OC)=CC=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.FC(F)(F)C(O)=O.[Na]>O>[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
100 mg (0.16 mmol) of 1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea were dissolved with 5 ml of trifluoroacetic acid and the solution stirred at 70° C. for 6 hours. The mixture was then poured into icy water, neutralized with aqueous sodium hydrogenocarbonate and extracted with ethylacetate. The organic layer was dried over sodium sulphate and evaporated to dryness. The residue was purified by flash-chromatography on a silica gel column (dichloromethane-methanol, from 1% to 10%), giving 63 mg (90%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Br[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:30][CH2:31][O:32][CH3:33])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: COCCBr
Product: COCCOc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available 1-bromo-2-methoxyethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 454.25 g/mol.
Reaction SMILES: [C:1]([C:11]1[O:17][CH:16]2[CH:13]([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[N:12]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Al]>O1CCCC1>[C:1]([CH:11]1[O:17][CH:16]2[CH:13]([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:24])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2N=C(C(=O)OCc3ccccc3)OC21
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)C2NC(C(=O)OCc3ccccc3)OC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of 5.00 g of methyl α-(3-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 100 ml of tetrahydrofuran containing 5% water is added aluminium amalgam prepared from 4 g of aluminium and 0.5 g of mercuric chloride, and the mixture stirred at room temperature for 1.5 hours. The reaction mixture is dried on magnesium sulfate and concentrated under reduced pressure to yield 4.92 g of methyl α-(3ξ-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in 98.4% yield.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[C:39]#[N:40])=[CH:26][C:25]2=[O:41])[C:17]([O:19]C(C)(C)C)=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+]>>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH:16]([N:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[C:39]#[N:40])=[CH:26][C:25]2=[O:41])[C:17]([OH:19])=[O:18])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [Li+]
Agent: [OH-]
Product: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
479 mg (797 μmol) of tert-butyl 3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoate (mixture of two racemic diastereomers) were reacted with 4 ml of aqueous lithium hydroxide solution (1N) according to General Method 6B, giving the title compound. Yield: 400 mg (80% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14][CH3:15])=[CH:9][CH:8]=2)=O.P(Cl)(Cl)(Cl)=O.O.[NH2:31][NH2:32]>C(O)C>[C:19]1([S:16]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14][CH3:15])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]2[O:2][CH:1]=[N:31][N:32]=2)(=[O:18])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc2cc(SC)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NN
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CSc1ccc2c(c1)cc(-c1nnco1)n2S(=O)(=O)c1ccccc1

Procedure:
To a solution of 1-benzenesulfonyl-5-methylthio-1H-indole-2-carboxylic acid methyl ester (370 mg) in ethanol (12 ml), hydrazine monohydrate (0.55 ml) was added at 15 to 30° C. and the mixture was heated under reflux for 13 hours. Further, to the mixture was added hydrazine monohydrate (0.55 ml) and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure. To the resulting residue was added water, and the insolubles were filtered off and washed with water and ether. To the filtered crude product was added formic acid (9 ml) and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate and the insolubles were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 330 mg of the crude product of 1-benzenesulfonyl-5-methylthio-1H-indole-2-carboxylic acid-N′-formylhydrazide. A mixture solution of 509 mg of the crude product thus obtained and phosphorus oxychloride (15 ml) was stirred at 15 to 30° C. for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 265 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]NC(=O)CCC(N)=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 75 °C
Yield: 63.1 %

Procedure:
To a solution of 5-Bromo-2-methyl-benzothiazole (1.0 g, 4.385 mmol) in 0014 (15 mL) is added N-bromosuccinamide (1.1 g, 6.140 mmol) and azobisisobutyronitrile (0.029 g, 0.175 mmol) at room temperature reaction. The reaction mixture is heated to 75° C. for 16 hours. Reaction mixture is cooled to room temperature, filtered and the solvent evaporated in vacuo to give the crude material, which is then purified by flash chromatography using 3.5% ethyl acetate in hexane as an eluent to afford the title compound (0.85 g). 1H NMR (400 MHz, DMSO-d6) δ: 5.12 (s, 2H), 7.68-7.71 (dd, J1=1.92 Hz, J2=8.76 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.43 (d, J=1.92 Hz, 1H). LC-MS (m/z): [M+H]=308.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([O:15]CC)=[O:14].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN2CCCCC2C(=O)O)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (3.0 g) and 1N NaOH (21.6 ml) in ethanol (31.6 ml) was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and evaporated in vacuo. The residue was extracted with methylene chloride and the extract was evaporated in vacuo to afford 1-(3-methoxybenzyl)-2-piperidinecarboxylic acid (2.64 g) as an amorphous powder. (+) APCI-MS (m/z): 250 (M+ +1) mp: 186.0-187.3° C. IR (Film): 1600, 1265 cm-1NMR (CDCl3, δ): 1.3-1.85 (6H, m), 2.2-2.3 (1H, m), 2.86-2.93 (1H, m), 3.09 (1H, dd, J=7.6, 4.3 Hz), 3.52 (1H, d, J=13.4 Hz), 3.74 (3H, s), 3.87 (1H, d, J=13.4 Hz), 6.81-6.93 (3H, m), 7.24 (1H, d, J=8.0 Hz)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:24]#N)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:8][CH2:7]2)[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:4][NH:3]1.C[Mg]Br>C1COCC1>[CH3:24][C:12]1([N:9]2[CH2:8][CH2:7][C:6]3([N:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:4][NH:3][C:2]3=[O:1])[CH2:11][CH2:10]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCC1c1ccccc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCC1c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 20 mg (0.048 mmol) 1-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)-2-phenyl-cyclohexane-carbonitrile in 1.5 ml dry THF under argon at 0° C. were added 0.03 ml (0.096 mmol) methyl magnesium bromide (3M solution in THF) and the resulting mixture heated to reflux for 3.5 h. The reaction mixture was cooled to ambient temperature, quenched by the addition of water and the product extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate: 10 mg 8-(1-methyl-2-phenyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as colorless solid; MS (ISP): 404.6 MH+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC([Mg]Cl)C.[O:15]=[C:16]1[CH2:19][O:18][CH2:17]1.[NH4+].[Cl-]>C1COCC1>[OH:15][C:16]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][O:18][CH2:17]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)COC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-iodobenzonitrile (5.0 g, 21.8 mmol) in dry THF (100 mL) was added 2-propyl magnesium chloride (2M solution in diethyl ether, 11 mL, 21.8 mmol) dropwise at −40° C. After stirring for 1.5 h at this temperature, the reaction mixture was cooled to −78° C. before it was canulated to a solution of 3-oxooxetane (80% in dichloromethane, 2.95 g, 32.7 mmol; preparation described in: G. Wuitschik et al., Angew. Chem. Int. Ed. Engl. 45 (46), 7736-7739 (2006)) in dry THF (100 mL) which was likewise cooled to −78° C. After the slow addition of the Grignard reagent was completed, the reaction mixture was stirred at −78° C. for additional 10 minutes, then at 0° C. for 2 h, and finally at rt for 30 minutes. A few mL saturated aqueous NH4Cl were added and then most of the solvent was evaporated. The residue was partitioned between water and ethyl acetate (200 mL each). After separation, the aqueous layer was extracted using ethyl acetate. The combined organic layers were successively washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was crystallized from cyclohexane/ethyl acetate 10:1. The title compound was obtained in pure form (2.42 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, 2H), 7.80 (d. 2H), 6.63 (s, 1H), 4.79 (d, 2H), 4.65 (d, 2H); DCI(NH3)-MS m/z 193 (M+NH4)+; HPLC RT (Method I) 3.09 min.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: OCCc1ccc2c(n1)NCCC2
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Cl)Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.16 g, 0.9 mmol) and Polymer bound PPh3(0.3 g, 0.9 mmol) in dry THF (6 mL) was added ethyl [2,2-dichloro-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, the reaction mixture was filtered through Celite to remove the polymer and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (01 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 0.12 g (36%) of desired product. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=8 Hz), 7.26 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.77 (d, 1H, J=7.6 Hz), 4.32 (t, 2H, J=6 Hz), 3.53 (t, 2H, J=5.6 Hz), 3.19 (t, 2H, J=6 Hz), 2.87-2.59 (m, 5 H), 2.32-2.26 (m, 1H), 2.01-1.95 (m, 2 H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.