Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(Cl)(Cl)Cl>[OH:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: NCCCN(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: OCCN(CCO)CCCNc1ccnc2ccccc12

Procedure:
A mixture of 5.0 g. of 4-chloroquinoline, 7.2 g. of bis(2-hydroxyethyl)aminopropylamine, 3.0 g. of sodium carbonate and 25 ml. of isopropanol is heated in a pressure vessel at 150° C. for 17 hours. The resulting mixture is diluted with chloroform, filtered and purified by filtering over silica gel to obtain an oil of 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C@@H:11]2[C@@H:18]3[C@@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C@@H:11]2[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: O=C(Nc1cccc(F)c1)[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1cccc(F)c1)[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
The title compound was prepared by combining (3aS,4S,6aS)—N-(3-fluorophenyl)octahydrocyclopenta[c]pyrrole-4-carboxamide (98 mg, 0.395 mmol) from Example 55, 2-bromo-6-(trifluoromethyl)pyridine (125 mg, 0.553 mmol), and triethylamine (0.165 mL, 1.184 mmol) in ethanol (0.2 mL). The reaction mixture was heated at 80° C. for 72 hours. The reaction was quenched with water (1 mL) and the resulting brown oil was purified using a 12 g silica gel cartridge eluting with 1-100% ethyl acetate/hexanes over 20 minutes to give a solid. The solid was recrystallized from ethyl acetate/heptane (10%) to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 11.06 (s, 1H), 8.21 (dt, J=11.7, 2.2, 1H), 7.60-7.59 (m, 1H), 7.54-7.47 (m, 1H), 7.30 (td, J=8.2, 6.8, 1H), 6.98 (d, J=7.3, 1H), 6.91 (tdd, J=8.6, 2.6, 0.6, 1H), 6.41 (d, J=8.6, 1H), 3.46 (dd, J=10.3, 7.6, 3H), 3.23-3.14 (m, 1H), 3.06 (dd, J=10.8, 5.7, 1H), 2.90-2.72 (m, 2H), 2.22-2.12 (m, 1H), 2.12-1.95 (m, 2H), 1.39 (dtd, J=10.4, 8.0, 5.4, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:32])[C:24]2[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=2)[CH3:20])=[CH:14][CH:13]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([N:21]2[C:3](=[O:4])[CH2:2][O:32][CH:23]([C:24]3[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=3)[CH2:22]2)[CH3:20])=[CH:16][CH:17]=1)([O:7][CH3:6])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(C)C)n2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(C)C)n3)OCC2=O)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
0.60 ml (7.89 mmol) of chloroacetyl chloride is added dropwise to a stirred solution of 3.10 g (7.89 mmol) of N-[2-(4-methoxycarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)-ethanamine and 1.10 ml (7.89 mmol) of triethylamine in 20 ml of chloroform at 25° C. internal temperature. After the mixture has stood overnight at 20° C., it is concentrated in vacuo, and the resudue is dissolved in 30 ml of anhydrous dimethyl formamide. To this is added 0.888 g (15.78 mmol) of a 55% dispersion of sodium hydride in oil, during which brief foaming is observed. The mixture is stirred at 20° C. for 3 hours, concentrated in vacuo, and the residue is partitioned between water and ether. The ether solution is dried, filtered and concentrated in vacuo, and the oily residue is purified on silica gel (toluene/acetone =4:1).
Reaction SMILES: [S:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]1[N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH2:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24].[Cl:25]N1C(=O)CCC1=O>O1CCCC1>[S:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]1[N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][Cl:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(N3C=CC=CS3)c2c1
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=CCl)c3ccccc3)cc2n1N1C=CC=CS1

Procedure:
A solution of 500 mg. of 1-(thiazin-2-yl)-2-amino-6-(α-methylenebenzyl)benzimidazole in 50 ml. of tetrahydrofuran containing 250 mg. of N-chlorosuccinimide was stirred at room temperature for sixteen hours. The reaction mixture was filtered, and the filtrate was diluted with water and then concentrated to a volume of about 25 ml. The precipitate which formed was collected by filtration, dried, and identified as 140 mg. of 1-(thiazin-2-yl)-2-amino-6-(α-chloromethylenebenzyl)benzimidazole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>CN(C=O)C.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C1CSCCN1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCSCC3)n2n1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 99 mg, 0.287 mmol) and thiomorpholine (91 mg, 0.861 mmol) in DMF (1.11 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with methanol and then purified by preparatory HPLC (35-60% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (26.9 mg, 39%). Melting point (229.1-229.2° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H), 2.38 (s, 3H), 2.75-2.90 (m, 4H), 4.02 (dt, J=4.67, 2.46 Hz, 4H), 6.16 (s, 1H), 7.35 (s, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.99 (d, J=8.34 Hz, 2H), 10.86 (s, 1H); ESI-MS: m/z 412.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: CC(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: CC(C)C(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (200 mg, 1.069 mmol), isobutyric acid (0.159 mL, 1.711 mmol), BOP-reagent (757 mg, 1.711 mmol) and diisopropylethylamine (0.747 mL, 4.28 mmol) in DMF (6 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)isobutyramide (230 mg, 0.894 mmol, 84% yield) as an orange oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.42 (s, 2H), 2.53 (dt, J=13.8, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 6H). MS (ES+) m/z: 257.0, 259.0 (M+H); LC retention time: 1.200 min (analytical HPLC Method O).
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[H-].[Na+].[CH3:19]I.[Cl-].[NH4+]>CO.O1CCCC1>[CH:1]([C:4]1[C:12]([CH2:13][O:14][CH3:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1c(C(C)C)nn2ccccc12
Yield: 55.3 %

Procedure:
To a cold solution of 2.0 g of 2-isopropyl-3-formylpyrazolo[1,5-a]pyridine in 60 ml of methanol were added in small portions 2.0 g of sodium borohydride under cooling and stirring. The mixture was heated to reflux for 2 hours and after cooling, concentrated in vacuo. Water was added to the residue and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to give an oily residue, weighing 2.2 g. The residue in 5 ml of dry tetrahydrofuran was added to a suspension of 1.53 g of sodium hydride (55% oil suspension) in 10 ml of dry tetrahydrofuran under stirring and cooling. The mixture was stirred at room temperature for 5 minutes and then at reflux temperature for 15 minutes. After cooled under ice-water, 5.0 g of methyl iodide were added to the mixture. The mixture was stirred at toom temperature for an hour, followed by addition of aqueous 20% ammonium chloride, and extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was subjected to silica gel column chromatography, eluted with dichloromethane, to give 1.2 g (55%) of the desired compound as pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2ccc(F)cn2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1c(Br)c(CO)nc2ccc(F)cn12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A heterogeneous mixture of (3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (7.7539 g, 24.61 mmol), HCl (6.972 mL, 83.67 mmol), and 1,4-dioxane (70.31 mL) was heated under stirring at 70° C. After 4 h, the mixture was cooled to rt and the mixture was concd under reduced pressure. The residue was diluted with water (100 mL) and treated with 28% ammonium hydroxide (10 mL) until pH neutral. The precipitate was filtered, washed with water (300 mL), and dried under high vacuum overnight to give 3-bromo-7-fluoro-2-(hydroxyl-methyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1 H, ddd, J=4.9, 2.8, 0.7 Hz), 8.17 (1 H, ddd, J=9.8, 7.1, 2.8 Hz), 7.88 (1 H, ddd, J=9.8, 5.4, 0.7 Hz), 5.35 (1 H, br. s.), 4.60 (2 H, s); Mass Spectrum (ESI) m/e=273.0 [M+1 (79Br)] and 274.9 [M+1 (81Br)].
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N+:14]([O-])=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]3[C@@H:25]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:26][C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>>[C:42]([O:45][C@@H:16]1[C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]3[C@@H:25]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:26][C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[C:11]=3[C:10]=2[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:18][C:17]1([CH3:20])[CH3:19])(=[O:44])[CH3:43]
Reactant: CC(C)c1c2c(c3c([n+]1[O-])CC(C)(C)C[C@@H]3O[Si](C)(C)C(C)(C)C)C1(CCCC1)O[C@@H]2c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O[C@@H]1c2nc(C(C)C)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: 130 °C

Procedure:
250 mg (3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]5′-oxide and 3 ml acetic acid anhydride are mixed and heated for 2 hours at 130° C. Excess acetic acid anhydride is removed in vacuo and the residue is diluted with diethylether. After washing with saturated aqueous sodium bicarbonate the organic phase is dried with sodium sulphate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (hexane/ethylacetate 95:5).
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Ni]>[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Yield: 50.3 %

Procedure:
Dissolved 4-[10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (0.39 g, 1.2 mmol) in 50 mL of absolute ethanol, and added a teaspoon of Raney nickel paste. Hydrogenated on a Paar shaker at 17 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to a solid. Recrystallized crude product from hexane to give 0.20 g (50% yield) of 4-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(Cl)nc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Temperature: 65 °C
Yield: 56 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate (X-1) (0.25 g, 1.22 mmol) and phenol (0.15 g, 1.61 mmol) in acetone (3 mL) was added K2CO3 (0.25 g, 1.81 mmol). The mixture was heated for 18 h at 65° C. Additional K2CO3 (0.25 g) was added and the mixture was continued to heat at 70° C. for 24 h. Upon cooling, water was added (10 mL). The mixture was extracted with Et2O. The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a white solid (0.18 g, 56%). 1H NMR (CDCl3) δ 7.44 (m, 2H), 7.33-7.27 (m, 3H), 4.26 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][OH:26])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=[O:26])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(CO)cc34)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C=O)cc34)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.8 %

Procedure:
In a round-bottomed flask, 2-(5-hydroxymethyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (crude from Step 2, 476 mg, 0.625 mmol) was dissolved in dichloromethane (3.2 ml) and Dess-Martin periodinane (292 mg, 0.688 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h then quenched with 10 ml of a 1:1 mixture of 10% aqueous Na2S2O3 and saturated aqueous NaHCO3 and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO3 then the aqueous layers were back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/Hexanes (gradient: 0-60% EtOAc) to afford 218 mg (71%) of 2-(5-formyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.25 (s, 1H), 8.97 (dd, J=1.4, 0.9 Hz, 1H), 8.41 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 8.07 (dd, J=8.8, 1.5 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 5.75 (s, 2H), 4.42-4.53 (m, 1H), 4.26 (s, 3H), 3.56-3.64 (m, 2H), 1.41 (d, J=6.6 Hz, 6H), 0.92-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:29])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:17]2[CH:16]=[C:15]3[C:20]([C:12](=[CH:11][C:10]4[NH:9][CH:8]=[C:7]([CH3:33])[C:6]=4[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:29])[NH:14]3)=[CH:19][CH:18]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(C)c2CCC(=O)O)c1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
4-(2-Carboxyethyl)-5-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (413 mg) suspended in ethylene glycol (5 mL) was held in ealed tube in a pre-heated oil bath at 200° C. for 2½ hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (4 pellets) was added. It was then stirred at 100° C. for 2 more hours. The reaction mixture was cooled, poured into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water and dried in a vacuum oven overnight. The crude solid was purified on a silica gel column using 33:66:1 ethyl acetate:hexanes:glacial acetic acid as eluent to give 75 mg (20%) of 3-{2-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4-methyl-1H-pyrrol-3-yl}-propionic acid as an orange-red solid.
Reaction SMILES: [N+](=C1CCCCCCCC1C1CCCCCCCC1)=[N-].[CH2:21]([O:23][C:24]([CH2:26][C:27]([CH3:33])([CH3:32])[CH:28](Br)[C:29]#[N:30])=[O:25])[CH3:22]>O>[CH2:21]([O:23][C:24]([CH:26]1[C:27]([CH3:33])([CH3:32])[CH:28]1[C:29]#[N:30])=[O:25])[CH3:22]
Reactant: CCOC(=O)CC(C)(C)C(Br)C#N
Agent: [N-]=[N+]=C1CCCCCCCC1C1CCCCCCCC1
Solvent: O
Product: CCOC(=O)C1C(C#N)C1(C)C
Temperature: 20 °C
Yield: 74.8 %

Procedure:
14.8 g (0.12 mol) of diazobicyclononane were added dropwise to a solution of 24.8 g (0.1 mol) of 3-bromo-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester in 100 ml of alcohol at 20° C. The mixture was then warmed to 50°-60° C. for 3 hours and cooled to 20° C., and 200 ml of water were added to the reaction mixture. The mixture was extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride extracts were washed twice with 50 ml of 5% strength hydrochloric acid each time and twice with 50 ml of water each time, dried over sodium sulphate and concentrated. The residue was fractionated. 12.5 g (75% of theory) of 2-cyano-3,3-dimethyl-cyclopropane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 62°-64° C./1 mm Hg.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C12BC(CCC1)CCC2.FC(F)(F)S(O[C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][C@H:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]2)=[CH:27][CH:26]=1)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.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.O.O1CCOCC1>[C:39]([O:38][C:36]([NH:35][C@H:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:27]=2)[CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: C=CCCC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)CCCCc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Yield: 45.8 %

Procedure:
Ethyl 4-pentenoate (317 mg) was dissolved in tetrahydrofuran (5 ml), and 9-borabicyclo[3.3.1]nonane (302 mg) was added to the solution. After reaction for 15 hours at room temperature with stirring, 1,4-dioxane (9 ml), (S)-2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl trifluoromethanesulfonate (890 mg), tetrakis(triphenylphosphine)palladium (0) (65 mg) and potassium phosphate (716 mg) were added to the reaction mixture, followed by reaction for 15 hours at 85° C. with stirring. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo. Purification by medium pressure liquid column chromatography on silica gel (eluent: dichloromethane) and sequential recrystallization from hexane of the residue gave ethyl (S)-5-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]valerate (387 mg) having a melting point of 65-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)sc1C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.15 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.13 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (1.05 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.