Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:29]#[C:28][C:26]([OH:30])([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)[CH3:27])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(O)c1cnccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)c3cnccn3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a DMF/Et3N mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.792 g of (±)-2-pyrazin-2-ylbut-3-yn-2-ol (5.34 mmol), 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:12][C@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.22 g, 0.2 mol), 1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (40.06 g, 0.2 mol) and sodium tri(acetoxy)borohydride (85 g, 0.4 mol) in 1,2-DCE (1 L) was stirred at room temperature over-weekend. The reaction mixture was treated portion-wise with NaHCO3 solution (400 mL) over a period of ˜2 h. After a further 30 minutes, the organic layer was separated, washed with brine, dried and concentrated to give a viscous pale yellow oil. Purification by column chromatography eluting with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow crystalline solid (61.1 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=O)(C)(C)C.O>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH:23]=2)=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(C2=CCNCC2)nc1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated with thionyl chloride (3 g) for 24 hours, and the concentrated reaction solution was purified by preparative HPLC. The product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+) was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[N:25]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cnn(C)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 58.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g, 2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d, J=6.8, 6H). MS (ES+): 475 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[NH2:37]>COCCO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:37][C:36]4[CH:38]=[C:39]([O:43][CH3:44])[C:40]([O:41][CH3:42])=[C:34]([O:33][CH3:32])[CH:35]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3ccc(-c4ccc(S(C)(=O)=O)cc4)n3n2)cc(OC)c1OC
Temperature: 180 °C
Yield: 14.4 %

Procedure:
2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125 mg, 0.000373 mol), N,N-Diisopropylethylamine (0.0974 mL, 0.000559 mol) and 3,4,5-Trimethoxyaniline (81.9 mg, 0.000447 mol) were dissolved in 2-Methoxyethanol (2.2 mL) and the reaction was heated at 180° C. under 300 W microwave conditions until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 24.45 mg of [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine as a lyophilated powder. (M+H)=455.14. 1H NMR (400 MHz, CDCl3) δ 9.11 (m, 1H), 8.73 (s, 1H), 8.34 (d, 2H, J=8.59 Hz), 8.05 (d, 2H, J=8.34 Hz), 7.23 (m, 1H), 7.18 (d, 1H, J=5.05 Hz), 6.87 (s, 2H), 3.86 (s, 3H), 3.77 (s, 6H), 3.25 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:13]#[N:14].O.[C-]#N.[Na+]>CN(C=O)C>[C:13]([C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: O=c1[nH]oc2cccc(Br)c12
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc2o[nH]c(=O)c12
Temperature: 165 °C
Reaction time: 6.5 h
Yield: 51.6 %

Procedure:
To a solution of 4-bromo-1,2-benzoxazolinone (5.0 g, 23 mmol) in DMF (11 mL) was added copper (I) cyanide (3.6 g, 39 mmol) and the reaction heated at 165° C. After 6.5 h, the reaction mixture was cooled to rt and water (20 mL) and sodium cyanide (3.6 g) were added and the reaction heated at 100° C. After 12 h, the reaction mixture was extracted with ethyl acetate and the combined organic layers were filtered through a scrub pad of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.9 g (51%) of 4-cyano-1,2-benzoxazolinone as a brown solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 7.8 (s, 1H), 7.6 (d, 1H), 7.2 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[C:32]([CH3:36])=[N:31]1.FC(F)(F)C(O)=O>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[C:32]([CH3:36])=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CCNCC3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (504.1 mg, 1.214 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine hydrochloride (381.0 mg, 2.581 mmol) in n-BuOH (10 mL) was added trifluoroacetic acid (678.1 mg, 5.947 mmol). The mixture was stirred at 100° C. overnight, then quenched with water (30 mL), and adjusted to pH=9 with solid NaHCO3, and then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (271 mg, 45.57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14].[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1.Cl>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=C(C(=O)OC)c1ccc(Cl)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(CC(C)(C)[N+](=O)[O-])c1ccc(Cl)c(F)c1
Yield: 106.7 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)acrylate (1.00 g, 4.66 mmol) and 2-nitropropane (502 uL, 5.59 mmol) were dissolved in MeCN (16 mL) and treated with DBU (835 uL, 5.59 mmol) at room temperature. The mixture was allowed to stir over the weekend to completion. The mixture was poured into 1M HCl solution and extracted with ethyl acetate (2×). The combined organic portions were washed with water (1×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to yield methyl 2-(4-chloro-3-fluorophenyl)-4-methyl-4-nitropentanoate (1.51 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].Cl[C:21]([O:23][CH3:24])=[O:22].C([O:27]CC)C>C(OCC)(=O)C>[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].[CH3:24][O:23][C:21](=[O:27])[O-:22]
Reactant: COC(=O)Cl
Reactant: CCOCC
Agent: Cc1ccc2ccccc2c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[O-]
Reaction time: 1 h

Procedure:
2.64 g (26 mmole) of triethylamine were added to a stirred solution of 3.16 g (20 mmole) of 2-methyl-1-naphthol in 25 mL of ethyl acetate, while the solution was maintained in an ice bath. Then 2.36 g (25 mmole) methyl chloroformate were added portionwise to the solution. The reaction mixture was stirred for one hour and then 100 mL diethylether was added. The reaction mixture was filtered over a Celite pad and the filtrate concentrated to give 3.65 g (85% yield) of an oil which was crystallized in hexane. The resulting crystals had a melting point of 54-55° C. The following 1HNMR was obtained: (300 MHz, DMSO-d6) δ2.30 (s, 3H), 3.89 (s, 3H), 7.44 (d, 1H, J=8 Hz), 7.48-7.58 (m, 2H), 7.78 (t, 2H, J=9 Hz), 7.95 (d, 1H, J=8 Hz). The mass spectrum showed a molecular ion at m/z 216.
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][N:14]1[C:15]2[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][C:11]=2[C:12]2[CH2:21][CH:20]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:19][C:13]1=2
Reactant: CN(C)CC1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC1Cc2c(n(C)c3ccc(O)cc23)C1

Procedure:
In a 500 ml Parr hydrogenation bottle was suspended 0.5 g of 10% Pd/C in 50 ml of ethyl alcohol. To this was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-N,N,4-trimethylcyclopent[b]indole-2-methanamine (2.3 g, 0.007 mole) in 200 ml of ethyl alcohol. After shaking at 50° C. under 50 psi hydrogen for two hours, the mixture was cooled and filtered, and the filtrate concentrated to a tan solid, 1.5 g, m.p. 110° C.
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-].[Cl-].[Cl-].C1([Zr+3:26])C=CC=C1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]1([Zr:26])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Zr+3]C1C=CC=C1
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [Zr]c1cccc2c1C=C1C2=Nc2ccccc21
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum. Yield of complex 10: 16.5 g. The 1H NMR spectrum is consistent with the proposed structure:
Reaction SMILES: ClP([N:5]=[C:6]=[O:7])(Cl)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[C:13](=[N:31]/[O:32][CH3:33])/[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15]>CC(C)=O>[CH3:33][O:32]/[N:31]=[C:13](\[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:6]([NH2:5])=[O:7])[CH2:22][S:23][C@H:18]12)=[O:15])/[C:9]1[O:8][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=NP(=O)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
The process of Example 3 was repeated, using dichlorophosphinyl isocyanate (1.46 ml) and a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetone (50 ml) cooled to 4°, but the reaction mixture was heated at 45° for 2 hours and then kept at 20° overnight, to give the title compound (2.40 g, 56.7%); purity by HPLC 95.6% and by TLC 94.5%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([F:30])[C:27]=1[CH:28]=[O:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[F:30][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[C:27]=1[CH:28]=[O:29]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: O=Cc1c(F)cncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(-c3cncc(F)c3C=O)cc21
Temperature: 100 °C
Yield: 34.5 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (138 mg, 0.5 mmol), 3-Bromo-5-fluoro-pyridine-4-carbaldehyde (102 mg, 0.5 mmol), Na2CO3 (2 M in water, 0.75 mL, 1.5 mmol) and PdCl2(PPh3)2 (17 mg, 0.03 mmol) in DMF (3 mL) was heated at 100° C. for 4 hrs. After concentration, the residue was diluted with DCM and saturated NH4Cl solution. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-1.5%) and afforded the title compound (47 mg, 35%). 1H NMR (400.3 MHz, CDCl3): δ 3.45 (s, 3H), 6.96 (d, J=1.7 Hz, 1H), 7.08 (dd, J=8, 1.7 Hz, 1H), 7.32 (d, J=8 Hz, 1H) 8.59 (s, 1H), 8.68 (d, J=1.3 Hz, 1H), 10.07 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([C:15]#[N:16])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(C2CC2)c1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ncccc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.47 g of 3-cyclopropylpyridine-1-oxide [121-1] was dissolved in 15 mL of chloroform, and 1.89 mL of trimethylsilyl cyanide was added thereto. Subsequently, a solution prepared by dissolving 1.3 mL of dimethylcarbamoyl chloride in 5 mL of chloroform was added dropwise over 30 minutes, and was stirred overnight at room temperature. Thereto, 10 mL of 10% aqueous solution of potassium carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure, to obtain a residue. The residue was purified by silica gel column chromatography, and 680 mg of 3-cyclopropylpyridine-2-carbonitrile [121-2] was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][CH2:33][CH2:34][OH:35].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:35][CH2:34][CH2:33][CH2:32][C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=2)[N:5]=[C:4]([NH:12][CH2:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: OCCCc1ccc2ccccc2n1
Reactant: Cc1nc(C)c(CNc2nc(S(C)(=O)=O)nc(Cl)c2C)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CNc2nc(OCCCc3ccc4ccccc4n3)nc(Cl)c2C)s1
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-methylsulfonyl-pyrimidin-4-amine F5 (51 mg, 0.15 mmol) and 3-(quinolin-2-yl)propan-1-ol G6 (25 mg, 0.13 mmol) in 3 mL of THF was added LiHMDS (200 μL of a 1M solution in THF, 0.20 mmol). After stirring for 2 hours, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was partitioned between a saturated solution of NaHCO3 and EtOAc, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by silica gel flash column chromatography (EtOAc/hexanes gradient) to provide 17 mg (28%) of G7 as an off-white solid. 1H NMR δ (400 MHz, CDCl3): 8.1-8.0 (2H, m), 7.75 (1H, m), 7.65 (1H, m), 7.5 (1H, m), 7.35 (1H, m), 4.9 (1H, m), 4.7 (2H, d), 4.4 (2H, t), 3.15 (2H, t), 2.6 (3H, s), 2.35 (5H, m), 2.0 (3H, s). HRMS (ES) calculated M+H for C23H24ClN5OS: 454.1463. Found. 454.1455.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]([CH3:48])[O:28][C@H:26]1[OH:27])(=[O:3])[CH3:2].[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]#[N:52].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]([O:27][C@@H:26]1[O:28][C@@H:29]([CH3:48])[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:25]1[O:24][C@@H:6]1[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])=[NH:52]
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The hemiacetal 320 (541 mg, 0.80 mmol) was dissolved in CH2Cl2 (20 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.810 mL, 8 mmol), then DBU (10 μL, 80 μmol) were added. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 1:1 cyclohexane-EtOAc and 0.2% of Et3N to give 307 (560 mg, 86%) as a colourless foam; [α]D+2° (c 1, CHCl3). 1H NMR: δ 8.56 (s, 1H, NH), 7.50-7.20 (m, 10H, Ph), 6.29 (d, 1H, J1,2=1.3 Hz, H-1A), 5.50 (d, 1H, J2,NH=8.3 Hz, NHD), 5.17 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.09 (dd, 1H, J4,5=9.5 Hz, H-4D), 4.85-4.60 (m, 4H, CH2Ph), 4.68 (d, 1H, J1,2=8.0 Hz, H-1D), 4.22-4.10 (m, 2H, J5,6=5.0, J6a,6b=12.2 Hz, H-6aD, 6bD), 4.00 (m, 1H, H-2D), 3.99 (dd, 1H, J2,3=3.5 Hz, H-2A), 3.90 (dq, 1H, J4,5=9.6, J5,6=6.2 Hz, H-5A), 3.89 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.62 (m, 1H, H-5D), 3.50 (dd, 1H, H-4A), 2.02, 2.00, 1.98 (3s, 9H, OAc), 1.65 (s, 3H, NHAc), 1.32 (d, 3H, H-6A); 13C NMR: δ 171.2, 171.0, 170.4, 169.6 (C═O), 160.5 (C═NH), 138.2-128.0 (Ph), 103.3 (C-1D), 97.3 (C-1A), 91.4 (CCl3), 80.3 (C-4A), 79.9 (C-3A), 77.5 (C-2A), 76.0, 73.8 (2C, CH2Ph), 73.1 (C-3D), 72.2 (C-5D), 71.1 (C-5A), 68.8 (C-4D), 62.5 (C-6D), 54.8 (C-2D), 23.3 (NHAc), 21.4, 21.1, 21.0 (3C, OAc), 18.4 (C-6A) Anal. Calcd for C36H43Cl3N2O13: C, 52.85; H, 5.30; N, 3.42. Found: C, 52.85; H, 5.22; N, 3.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([B:24]([OH:29])[OH:25])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cc(I)ccc2Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(B(O)O)ccc2Cl)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 145 g (387 mmol) of 2-[(4-methoxybenzyl)oxy]-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF, placed under argon and stirred at −50° C., are added dropwise 220 mL (440 mmol) of a 2N solution of iPrMgCl in THF, while maintaining the temperature between −40 and −50° C. The reaction mixture is allowed to warm to −10° C. and stirring is continued for 1 hour. 94 mL (406 mmol) of triisopropyl borate are then added and the reaction mixture is then allowed to warm slowly to 0° C. After stirring for 2 hours, the mixture is treated with 500 mL of aqueous 5N HCl solution and then extracted with ether (2×600 mL). The organic phase is washed with 2×1 L of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue obtained is solidified in 300 mL of pentane, filtered off on a sinter funnel and washed with 200 mL of pentane. 96 g of [3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid are thus obtained in the form of a white solid.