Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O.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>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 44%) as white needles. mp: 235-237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+ @ m/z 306.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=1)[CH3:2].[CH3:17][O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([S:30][CH2:31][CH2:32][CH:33]=O)=[CH:24][C:23]=1[CH3:35]>>[CH3:17][O:18][C:19](=[O:36])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([S:30][CH2:31][CH2:32][CH2:33][N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:6][N:5]=2)=[CH:24][C:23]=1[CH3:35]
Reactant: COC(=O)COc1cc(OC)c(SCCC=O)cc1C
Reactant: CCNc1ccc(-c2ccc(F)cc2)cn1
Product: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccc(F)cc2)cn1

Procedure:
Compound 70B and Compound 64A were reacted in a manner analogous to Compound 63C to give the title product. MS m/z 499 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[CH:3]=1.CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:33][C:32]([F:35])([F:34])[S:29]([O:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=2)(=[O:30])=[O:28]
Reactant: Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (prepared using similar method described in Example 1, 500 mg, 1.9 mmol), DIPEA (490 mg, 3.8 mmol) and DMAP (5 mg, 0.02 mmol) in DCM (2 mL) was added Tf2O (1.07 g, 3.8 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 25° C. for 5 hours. The mixture was diluted with H2O extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=5:1) to obtain the product of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (600 mg, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.39 (s, 1H), 7.64 (s, 1H), 7.18˜7.20 (m, 3H), 6.77˜6.82 (m, 1H). MS (M+H)+: 395/397.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:21]([CH3:30])[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>C(O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:21]([CH3:30])[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)c1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
17.5 g (0.1 mol) of 4-benzylpiperidine and then 12 g of sodium carbonate are added to a solution of 21.3 g (0.1 mol) of 2-bromopropiophenone in 100 ml of ethanol, and the mixture is heated under reflux for 2 hours. It is then filtered and the solvent is driven off. An oil remains, which is used as such in the subsequent reduction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a stirred solution of 2,5-difluorophenol (1.0 g, 0.0076 mole) in DMF (20 mL) was added cesium carbonate (12.4 g, 0.038 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 0.076 mole). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (10% ethyl acetate in hexane) to afford 1.5 g (63.0%) of 4-(2,5-Difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 85%. 1H NMR (CDCl3): δ 7.0 (m, 1H), 6.6 (m, 1H), 6.5 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.4 (m, 4H), 2 (m, 2H), 1.9 (m, 2H). 1.5 (s, 9H). A solution of 4-(2,5-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.0047 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 1 hour. Ether was then added, and the resulting precipitate was isolated by filtration and dried to afford 0.65 g (65%) of 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride. LCMS: 214.1 (M+1)+, 100%. 1H NMR (CDCl3): δ 9.2 (bs, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.2 (m, 2), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br.N1C=CN=CC=1>C1COCC1>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1[Mg]Br
Reactant: BrC1CCCCC1
Solvent: c1cnccn1
Solvent: C1CCOC1
Product: Cc1ccccc1C1CCCCC1
Yield: 99 %

Procedure:
Bromocyclohexane (81.7 mg, 0.5 mmol) and a THF solution (0.94 mL, 0.80 M, 0.75 mmol) of 2-methylphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 2-methylphenylmagnesium bromide was added dropwise at 40° C. over 20 minutes. 1H-NMR analysis was conducted using pyrazine (13.2 mg, 0.16 mmol) as an internal standard (yield 99%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC=CC=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=1)#[CH:55]>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42]([C:55]#[C:54][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=2)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Product: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1F

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3,4-difluorobenzene.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)[O:3]C1>CC(C)=O.Cl>[CH3:17][O:16][C:14]1[N:13]=[CH:12][N:11]=[C:10]([N:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH:15]=1
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ncn1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(N2CCC(=O)CC2)ncn1
Yield: 83.4 %

Procedure:
A solution of 1-(6-methoxypyrimidin4-yl)-4-piperidone ethylene ketal (1.38 g, 5.5 mmol) in acetone (25 ml) and 1 N HCl (25 ml) was stirred for 18 hr. The acetone was removed in vacuo and the mixture made basic with saturated sodium carbonate. The mixture was extracted twice with ethyl acetate. The extracts were combined, dried with brine, and concentrated in vacuo to give 1-(6-methoxypyrimidin-4-yl)-4-piperidone as a white powder (0.95 g, 83.5%, mp: 111-114° C.).
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=O.[CH2:30](O)[CH3:31].C(CC(=O)C)(=O)C.C(OCC)(=O)C>Cl.[Cl-].[Na+].O>[CH3:29][O:28][C:20]1[CH:19]=[CH:18][C:3]2[C:2]([C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:1][CH:30]([CH3:31])[N:6]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH:4]=2
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1N
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)=O
Product: CCCCCOc1c(OC)ccc2c1=NC(C)N(CCc1ccc([N+](=O)[O-])cc1)C=2

Procedure:
2-Amino-4-methoxy-N-[2-(4-nitrophenyl)ethyl]-3-pentyloxydenzamide (200 mg, 0.498 mmol) obtained in Example 2-46, ethanol (3 ml) and acetyl acetone (0.13 ml, 1.25 mmol) were mixed, and one drop of concentrated hydrochloric acid was added to this solution. The mixture was refluxed under heating for 2.5 hours, and ethyl acetate (30 ml) and saturated brine (30 ml) were added to separate the organic layer. This organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give a crude product of 7-methoxy-2-methyl-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-3H quinazolin A one.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:15]=[CH2:16])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(I)c(Cl)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc2c(cc1Cl)N(C(C)=O)CC2

Procedure:
1-Acetyl-6-chloro-5-iodoindoline (D60) (0.19 g, 0.6 mmol) was treated with vinyl tributyltin as in the method developed by Stille (A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109, 5478) to give the title compound (0.13 g) as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[NH:3]C2[C:9]([CH:10]=1)=[CH:8][CH:7]=CN=2.[H-].[Na+].CI.[CH3:15][N:16]([CH:18]=O)[CH3:17]>>[Cl:1][C:2]1[N:3]=[C:15]2[N:16]([CH3:17])[CH:18]=[CH:7][C:8]2=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1ccc2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6 chloro-7-aza indole (1.00 g, 6.55 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (0.524 g, 13.11 mmol) and the mixture was stirred at 0° C. for 20 min. Methyl iodide (0.512 mL, 8.19 mmol) was added at 0° C. and the mixture was warmed to room temperature and stirred for 2 h. The reaction was stopped, quenched with water and extracted with ethyl acetate. The organic layer was washed with water. It was then dried over sodium sulfate and concentrated in vacuo to give 1.01 g of the desires product as a brown color oil. ESI-MS: m/z 167.0 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[N:26]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1nc(C(=O)O)co1
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Yield: 36 %

Procedure:
(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (521 mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40 mmol). The product was purified by Flash-chromatography. Yield 36.0%. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.61 (s, 3H), 3.75-3.98 (m, 2H), 4.59-4.71 (m, 1H), 6.62 (d, 1H), 7.45-7.53 (m, 2H), 7.71 (d, 1H), 7.86 (dd, 1H), 7.98 (d, 1H), 8.32 (s, 1H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1C=CC=CC=1)=O.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]([NH:2][CH3:1])[CH3:10])[CH:16]=[CH:17][CH:18]=1
Reactant: CN
Reactant: COc1cccc(C(=O)c2ccccc2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Product: CNC(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Titanium(IV) isopropoxide (130 ml) was added to a methanolic methylamine solution (125 ml, 8M) followed by the addition of 3-methoxybenzophenone (50 g). The reaction mixture was stirred at room temperature for 5 hours, after which sodium borohydride (12 g) was carefully added at 0-5° C. The mixture was stirred at room temperature for 2 hours, after which water (60 ml) was added. The inorganic precipitate was filtered off and the filtrate concentrated to dryness. The residue was partitioned between ethyl acetate (400 ml) and aqueous hydrochloric acid (2M, 400 ml). The aqueous phase was made alkaline (pH 11-12) and extracted with dichloromethane (2×300 ml). The organic phase was dried and concentrated to dryness, leaving 1-(3-methoxyphenyl)-N-methylethylamine (43.4 g) as a viscous oil.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:18]([O:25][CH2:26][CH2:27][C@H:28]1[CH2:40][C:39]2[C:38]3[C:37](Cl)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][C@H:28]1[CH2:40][C:39]2[C:38]3[C:37]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:6][CH2:5]4)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CCc2sc3ncnc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 62 mg, 1.55 mmol, 30.00 equiv) was treated with tert-butyl trans-N-(4-hydroxycyclohexyl)carbamate (157 mg, 0.73 mmol, 1.40 equiv) in 8 mL of freshly distilled THF for 30 min in a water/ice bath under nitrogen. Then a solution of (12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (200 mg, 0.52 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(4-[[(12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (200 mg, 68%) as a yellow oil.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=1.N1C=CC(C=O)=CC=1.O1CCCC1>C1(C)C=CC=CC=1.O.O1CCCC1>[OH:23][CH:22]([C:19]1[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[C:2]([O:3][CH3:4])[C:1]=1[O:9][CH3:10]
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 0 °C
Yield: 65.4 %

Procedure:
A suitable reactor, maintained under an inert atmosphere is charged with veratrole (36 kg, 261 mol) and about 240 kg tetrahydrofuran. n-Butyllithium (63 kg, 242 mol, 24.6% in n-hexane) is added maintaining the temperature at about 0° C. The addition line is flushed with about 5 kg tetrahydrofuran. The reaction mixture is held at about 0° C. for at least 1 hour, then heated to about 25° C. and maintained there for about 3 hours. In a second suitable vessel, 4-pyridinecarboxaldehyde (9) (20 kg, 187 mol) is mixed with about 90 kg of tetrahydrofuran. The 4-pyridinecarboxaldehyde/tetrahydrofuran solution is added to the lithiated veratrole slurry at a rate to maintain the temperature at about −10° C. The reaction mixture is maintained at about −15° C. for at least 1 hour, then warmed to about 0° C. over about a 1 hour period. Water (about 100 kg) is added to the reaction mixture while maintaining the temperature at about 10° C. Toluene (about 160 kg) is added and the phases are separated. The organic phase is washed with about 50 kg of water and the phases are separated. The concentration of product in the organic phase is adjusted to about 20 wt % by atmospheric distillation. The optimum tetrahydrofuran range is about 10 to 20 wt % as determined by GC analysis. The solution is cooled to less than about −15° C., and 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine is collected by filtration. The wet cake is washed with about 20 kg of cold toluene to give the title compound (10) (30 kg, 70% yield).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(=O)([O-])O.[Na+].[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O.COCCOC.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>[CH:26]1([C:32]2[C:33]3[S:48][C:47]([C:49]([O:51][CH3:52])=[O:50])=[CH:46][C:34]=3[NH:35][C:36]=2[C:2]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:3]=2[O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Reactant: O=[N+]([O-])c1cccc(Br)c1OCCOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)c(C3CCCCC3)c2s1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a solution of 2-[2-(2-bromo-6-nitrophenoxy)ethoxy]tetrahydropyran (1.29 g, 3.72 mmol) in water (10 ml) and ethylene glycol dimethyl ether (20 ml) were added sodium hydrogen carbonate (1.23 g, 14.8 mmol) and tetrakis(triphenylphosphine)palladium (430 mg, 0.372 mmol). Methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.60 g, 4.10 mmol) obtained in Step 1 was divided in 4 portions and added every 30 min while stirring at 90° C. with heating. After the completion of addition, the mixture was further stirred at 90° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1-3:1) to give methyl 6-cyclohexyl-5-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-thieno[3,2-b]pyrrole-2-carboxylate (863 mg, yield 44%).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:13])([C:10]([OH:12])=O)[CH2:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[N:2].[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:13])([C:10]([N:22]([O:23][CH3:24])[CH3:21])=[O:12])[CH2:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[N:2]
Reactant: Cc1ccc(C2=C(C#N)C(=O)NC(C)(C(=O)O)C2)cc1
Reactant: CNOC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Intermediate 108C (0.25 g, 0.925 mmol) was dissolved in DCM (15 mL) in a 25 mL 1 neck rb flask that was equipped with a magnetic stirrer and an Ar inlet. N,O-Dimethylhydroxylamine (0.062 g, 1.017 mmol), EDC (0.195 g, 1.017 mmol) and N-methylmorpholine (0.112 mL, 1.017 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction solvent was removed under vacuum. The residue was dissolved in EtOAc (10 mL) and washed with water (5 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to a dark solid. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (0089 g, 31%) as a white solid. LCMS Anal. Calc'd for C17H19N3O3 313.3, found [M+H] 314.1. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.69-3.75 (m, 1H), 3.22 (s, 3H), 2.72 (d, J=17.6 Hz, 1H), 2.42 (s, 3H), 1.63 (s, 3H).