Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][NH:17][C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:37]I>O1CCCC1>[CH3:37][N:17]([CH2:16][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19]
Reactant: CCOP(=O)(CCCCc1ccccc1)CNC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCCc1ccccc1)CN(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[[[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester (2.43 g., 5 mmole) in dry tetrahydrofuran (15 ml.) is treated with 50% sodium hydride oil dispersion (0.24 g., 5 mmole) and stirred at room temperature for one hour. The mixture is then treated with methyl iodide (0.34 ml., 5.5 mmole) and stirred at room temperature for an additional 3 hours. The mixture is then partitioned between ethyl acetate--5% potassium bisulfate. The organic phase is washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4) and evaporated. The residue is purified by flash chromatograhy on silica eluting with acetone/dichloromethane (2:3) to give 1-[[methyl[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccncc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Yield: 60.1 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (10.0 g, 37.2 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 44.7 mmol), and Cs2CO3 (36.27 g, 111.6 mmol) in toluene (100 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(ll) (2.7 g, 3.7 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h and monitored by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexanes on 230-400 mesh silica gel to afford 4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (8.3 g, 60.2%) as a light orange color solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.2 (d, 2H), 7.85 (d, 2H), 7.6 (d, 4H), 7.4 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (97.5%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38](Cl)=[O:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:38]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][N:32]=4)=[O:39])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.40 M with anhydrous dichloromethane, then delivered to an 8 mL vial via pipette (0.2 mmol). To the amine solution was added base (0.4 M triethylamine in dichloromethane, 0.20 mmol). Pyrazine-2-carbonyl chloride was diluted to 0.40 M with dichloromethane, and added at rt (0.2 mmol). The reaction was shaken overnight at rt, then evaluated by MS. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). Pyrazine-2-carboxylic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 88% purity @ 254 nm, LCMS (APCI): 445 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)/[C:29](=[N:33]/[OH:34])/[CH2:28][CH2:27][CH2:26]2)=[CH2:22].[CH3:35][C:36]1([C:39]2[O:43][N:42]=[C:41]([C:44](OC)=O)[C:40]=2[C:48]([F:51])([F:50])[F:49])[CH2:38][CH2:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:35][C:36]1([C:39]2[O:43][N:42]=[C:41]([C:44]3[O:34][N:33]=[C:29]4[C:30]5[C:25]([CH2:26][CH2:27][C:28]=34)=[CH:24][C:23]([CH:21]=[CH2:22])=[CH:32][CH:31]=5)[C:40]=2[C:48]([F:51])([F:49])[F:50])[CH2:38][CH2:37]1
Reactant: COC(=O)c1noc(C2(C)CC2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2(C)CC2)c1C(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
A fresh solution of lithium diisopropylamide was made by adding n-butyllithium (0.855 mL, 2.14 mmol) to a stirred mixture of diisopropylamine (0.299 mL, 2.14 mmol) in THF (10 mL) at 0° C. After stirring for 30 min., the lithium diisopropylamide solution was added to a solution of (E)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.200 g, 1.068 mmol) in THF (25 mL) at 0° C. over 10 min., during which time the reaction mixture became orange in color. The reaction mixture was stirred for an additional 20 min., and then methyl 5-(1-methylcyclopropyl)-4-(trifluoromethyl)isoxazole-3-carboxylate (Preparation 4E, 0.177 g, 0.712 mmol) in THF (1 mL) was added. The resulting reaction mixture was stirred for 30 min. at 0° C., quenched with 1N aqueous hydrochloric acid (10 mL), and concentrated under reduced pressure. The crude residue was dissolved in toluene (10 mL), p-toluenesulfonic acid monohydrate (0.271 g, 1.424 mmol) was added, and the mixture was heated at 110° C. for 45 min. The reaction mixture was concentrated using methanol to azeotrope off the toluene solvent. The crude residue was taken up in ethyl acetate (25 mL), stirred, and filtered. The filtrate was concentrated to give 0.442 g of the crude product which was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane. Fractions containing the product were combined and concentrated to give 3-(5-(1-methylcyclopropyl)-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.043 g, 16%) as a yellow solid. The product had an HPLC ret. time=4.35 min. (condition B); LC/MS M+1=387.12; 1H NMR (500 MHz, CDCl3) δ ppm 0.79-0.93 (m, 2H), 1.02-1.16 (m, 2H), 1.42 (s, 3H), 2.75-3.12 (m, 4H), 5.26 (dd, J=11.37 Hz, 1H), 5.79 (dd, J=17.48 Hz, 1H), 6.44-6.89 (m, 1H), 7.29 (s, 1H), 7.43 (m, 1H), and 7.88 (d, J=8.05 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:46])[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:45])[C@@H:12]([NH:14][C:15](=[O:44])[C@@H:16]([NH:20][C:21](=[O:43])[C:22]([CH3:42])([CH3:41])/[CH:23]=[CH:24]/[C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][C:31]([C@H:35]([O:37]C(=O)C)[CH3:36])=[N:32]3)=[CH:27][CH:26]=2)[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[OH:37][C@@H:35]([C:31]1[CH:30]=[CH:29][C:28]2[C:33](=[CH:34][C:25](/[CH:24]=[CH:23]/[C:22]([CH3:42])([CH3:41])[C:21]([NH:20][C@@H:16]([CH:17]([CH3:19])[CH3:18])[C:15]([NH:14][C@@H:12]([CH3:13])[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C:5]([CH3:46])([C:3]([OH:4])=[O:2])[NH:6]3)=[O:45])=[O:44])=[O:43])=[CH:26][CH:27]=2)[N:32]=1)[CH3:36]
Reactant: COC(=O)C1(C)CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)C(C)(C)/C=C/c2ccc3ccc([C@@H](C)OC(C)=O)nc3c2)C(C)C)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@@H](C)C(=O)N1CCCC(C)(C(=O)O)N1
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of 1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-3-methyl-hexahydro-pyridazine-3-carboxylic acid methyl ester (790 mg, 1.24 mmol) in tetrahydrofuran/water (60 mL, 5:1) at 0° C. was added lithium hydroxide monohydrate (380 mg, 9.04 mmol). After stirring at 0° C. for 5 h, the reaction was quenched with hydrochloric acid (1 M, 12 mL). The volatiles were removed in vacuo and residual acetic acid and methanol were azeotroped off with toluene (3×). The residue was partitioned between ethyl acetate and water. After separation of the layers, the aqueous phase was extracted with ethyl acetate (4×) and dichloromethane (5×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (668 mg, 93%) as a pale yellow solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 582 [M+H], Tr=1.54 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6]/[N:7]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(OC)c(CCN)c1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: COc1ccc(OC)c(CC/N=C/c2ccccc2)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Under an argon atmosphere, a solution of 2,5-dimethoxyphenethylamine (3.175 g) in benzene (4 mL) was added with stirring to a suspension of benzaldehyde (1.86 g) and magnesium sulfate (3.89 g) in benzene (10 mL). An exothermic reaction took place, followed by further stirring overnight. After the reaction was complete, the reaction liquid was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(2,5-dimethoxyphenyl)-N-[(1E)-phenylmethylene]ethanamine (4.72 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[C:15]=3[F:22])[N:12]=[N:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[CH:35]=2)O1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:35]=2)=[CH:3][C:4]=1[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[C:15]=2[F:22])[N:12]=[N:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: Cc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)c(F)c1F
Temperature: 70 °C

Procedure:
A round-bottom flask was charged with 5-bromo-3-(1-(2,3-difluoro-4-methylphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1073, 3.672 g, 10 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1098, 4.150 g, 11.00 mmol) and DME (100 mL) was bubbled with nitrogen gas for 20 min. A 1.2 M aqueous solution of sodium bicarbonate (25.00 mL, 30.00 mmol) was added and nitrogen flow was continued for another 40 min before addition of PdCl2(dppf)2 (731.7 mg, 1.000 mmol). The suspension was heated at 70° C. for 15 hours, filtered though a layer of diatomaceous earth, and the filtrate washed with brine. The volatiles were removed by vacuum evaporation to afford a residue that was purified by silica gel chromatography, eluting with 20-100% EtOAc/hexanes, to produce tert-butyl 4-(4-(6-amino-5-(1-(2,3-difluoro-4-methylphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid (Compound 1102, 4.0 g, 74%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][C:8](C)(C)[CH2:7][CH:6]2[C:16]([O:18][CH3:19])=[O:17])#[N:2].[OH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:28]([O:27][C:25]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:33][CH:32]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: COC(=O)C1CC(C)(C)Oc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (from Example 3, Step E) (700 mg, 2.98 mmol), tert-butyl 4-hydroxybenzoate (578 mg, 2.98 mmol) and K2CO3 (494 mg, 3.57 mmol) were diluted with N-methylpyrrolidone (6 mL) and bubbled with argon for 10 minutes. The reaction was heated to 110° C. and stirred for 5 hours. The reaction was loaded directly onto a Biotage 40M cartridge and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (400 mg, 32.8% yield).
Reaction SMILES: OC([C:5]1[N:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1)(C)C.[Cl:22]C1C=CC(B(O)O)=CN=1>>[Cl:22][C:5]1[N:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Reactant: OB(O)c1ccc(Cl)nc1
Product: NC(=O)c1cc(-c2ccc(Cl)nc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (2.0 g, 7.97 mmol) and 2-chloro-5-pyridine boronic acid (1.25 g, 7.97 mmol) according to the general procedure described in Intermediate 10 Step 5.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:9]=[C:8]([C:10](OC)=[O:11])[CH:7]=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc(OC(F)F)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cccc(OC(F)F)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of methyl 6-(difluoromethoxy)picolinate (4.310 g; 21.21 mmol) in anh. toluene (120 ml) was treated dropwise with a solution of 1 M DIBAH in toluene (63.60 ml; 63.60 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 1.5 h. The obtained mixture was treated successively with water (55 ml), 1 M aq. NaOH (12 ml), and aq. sat. NaHCO3 (100 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording (6-(difluoromethoxy)pyridin-2-yl)methanol as a yellow oil (3.310 g; 89%). LC-MS (conditions D): tR=0.76 min.; no ionisation.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C@@H:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C@@H:14]3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CCCOc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A 0° C. solution of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (257 mg, 0.80 mmol) in trifluoroacetic acid (4 mL) was treated with a solution of sodium cyanoborohydride (269 mg 4.28 mmol) in methanol (2 mL). The reaction was allowed to slowly warm to room temperature over 1.6 hours then diluted with water and concentrated in vacuo to remove the majority of acid. The residue was made basic with 15% NaOH, extracted twice with CH2Cl2 dried over MgSO4 and concentrated in vacuo and passed through a column of silica gel with 1:19 methanol/chloroform with 1% NH4OH to give 104 mg (40%) of a brown oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.32-7.30 (m, 1 H), 7.25 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.11-7.07 (m, 1 H), 7.02-6.96 (m, 2 H), 6.65-6.59 (m, 1 H), 4.24-4.21 (m, 1 H), 3.97-3.84 (m, 2 H), 3.73 (dt, J=9.7 Hz, 3.3 Hz, 1 H), 3.13-3.08 (m, 1 H), 2.80-2.76 (m, 1 H), 2.73-2.67 (m, 1 H), 2.47-2.41 (m, 1 H), 2.06-2.04 (m, 1 H), 1.95-1.92 (m, 1 H), 1.75-1.70 (m, 2 H), 1.59-1.55 (m, 1 H), 1.37-1.34 (m, 1 H) 0.95 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C21H26N2O+H1: 323.2123 found 323.2116.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@H:19]([CH:20]=[C:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[C@H:18]1[C:29]([OH:31])=[O:30].[C:33]([C@@H:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)#[N:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][C:17]1([CH3:16])[C@H:19]([CH:20]=[C:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[C@H:18]1[C:29]([O:31][C@H:35]([C:33]#[N:34])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:37]=1)=[O:30]
Reactant: CCOC(=O)C(C)=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)=C=C[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
A mixture of 1.3 g of dicyclohexylcarbodiimide and 30 mg of 4-dimethylamino-pyridine in 15 ml of dichloromethane were added to a solution of 1.5 g of the product of Step E, 1.42 g of (S)α-cyano-3-phenoxy-benzyl alcohol and 30 ml of dichloromethane and the mixture was stirred at 20° C. for 18 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 4-1 hexane-ethyl acetate mixture yielded 1.16 g of (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(3-ethoxycarbonyl-1,2-butadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+35° (chloroform).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:12]2[C:8]([S:9][CH:10]=[CH:11]2)=[CH:7][N:6]=1)=[O:2].C([Li])CCC.CCCCCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH:1]([NH:3][CH2:4][C:5]1[N:12]2[C:8]([S:9][C:10]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11]2)=[CH:7][N:6]=1)=[O:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=CNCc1ncc2sccn12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(CNC=O)ncc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9 06 mg of 5-formylaminomethyl imidazo[5,1-b]-thiazole in a mixed solvent of 30 ml of THF and 6 ml of HMPA was cooled to −78° C. under the atmosphere of argon, and 10.9 ml of a 1.6 N solution of n-butyl lithium/n-hexane was added dropwise at an internal temperature of −70-−65° C. After the reaction mixture was stirred at the same temperature for 1 hour, 1.63 ml of tri-n-butylstannyl chloride was added, and the mixture was further stirred at the same temperature for 1 hour and for 2 hours during which the temperature was raised up to 0° C. 100 ml of a semi-saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with 100 ml of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give the title compound in an amount of 1.59 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2-fluoro-6-methoxybenzene boronic acid according to the general procedure B. Obtained as a yellow solid (0.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:6]2[CH3:21].O.O.[Sn](Cl)Cl.O.N>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:21])[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4]3)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc([N+](=O)[O-])cc3)c2n1C
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc(N)cc3)c2n1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of 4.10 g (10.9 mmol) of ethyl 4-chloro-1-methyl-7-(4-nitrophenoxy)-2-indolecarboxylate, 12.34 g (54.7 mmol) of tin (II) chloride dihydrate and 150 ml of ethanol was stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature, 28% ammonia water was added to render alkaline and the mixture was extracted with ethyl acetate. Insoluble matters were filtered off. The filtrate was washed with 5% sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2.70 g of ethyl 7-(4-aminophenoxy)-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH2:21]([C:23]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]#[N:32])[CH:26]=[CH:25][N:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH2:32])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:26]=[CH:25][N:24]=1)[CH3:22]
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: CCc1cc(/C=C/C#N)ccn1
Product: CCc1cc(-c2cc(N)n3nc(-c4ccco4)nc3c2)ccn1

Procedure:
The title compound, mp. 184-186° C. and MS m/e (%): 305 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(2-ethyl-pyridin-4-yl)-acrylonitrile.