Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]CC.CN(C)C=O.Cl.[CH3:18][CH:19]([CH3:23])[C:20](=[NH:22])[NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:18][CH:19]([C:20]1[NH:22][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:21]=1)[CH3:23]
Reactant: CC(C)C(=N)N
Reactant: CCOC1=C(Br)C(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 50 °C

Procedure:
To 2-bromo-3-(ethyloxy)-2-cyclohexen-1-one (160 g) was added N,N-Dimethylformamide (1000 mL) followed by 2-methylpropanimidamide hydrochloride (107 g) and potassium carbonate (151 g). The suspension was then stirred at 50° C. under nitrogen. After 2.75 hr the mixture was filtered and as much DMF as possible was evaporated off under high vacuum. The residue was partitioned between ethyl acetate (400 ml) and a minimum of aq lithium chloride (120 ml). The aqueous layer was extracted well with ethyl acetate (3×200 ml). The combined organics were washed with brine, filtered to give a small amount of a white solid and the filtrate dried (MgSO4), filtered and evaporated, including high vacuum. This was stirred with TBME (350 ml) then filtered to give a white solid, 16.27 gm. The filtrate from this was evaporated and weighed; this partly solidified overnight. Ether and cyclohexane were added to try and precipitate out more product but the solid was oily. The solution was decanted off and gave a golden oil on evaporation, 77 gm. The oily solid was evaporated: 38 gm, dissolved in DCM and purified by column chromatography (silica cartridge), eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Fractions were evaporated and the resulting solid slurried in ether and collected by filtration: This gave a white solid, 4.0 gm. No solid came out from the aqueous phase overnight. So it was extracted with more ethyl acetate and DCM. The organics were dried and evaporated and gave 69 gm of a beige slurry that was stirred with diethyl ether and filtered to give a white solid, 11.3 gm. The filtrate was combined with aqueous extraction solvents from a previous experiment and purified by column chromatography (silica), eluting with 0-100% ethyl acetate in dichloromethane. All product came through in fractions 1 & 2 so they were combined and washed with aq LiCl, dried and re-evaporated to a beige slurry, 46.4 gm, that was stirred in ether and filtered to give a white solid, 5.85 gm. Because all the batches were of the same purity, they were combined: This gave the title compound, a white solid, 37.42 gm.
Reaction SMILES: [CH2:1]([C:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:46])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][OH:26])[C:5]1=[O:46])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To an ice-cooled solution of 1.30 g (1.90 mmol) of(5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (Example 121, Step K) in THF (55 mL) was added 11.37 mL (11.37 mmol) of a 1 M solution of TBAF in THF. The orange solution was warmed to room temperature and stirred for 3.75 h. The reaction was partitioned between 1 M HCl and EtOAc (2×), and then the combined organic layers were washed with water (2×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% MeOH/DCM, gradient elution) provided the title compound as a light yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C[N:20](C=O)C>>[NH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)[C:7]([CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])=[CH:8]1
Reactant: CN(C)C=O
Reactant: CC(C)(O)CCc1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Product: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (8.1 g, 204 mmol, 60% in mineral oil) in DMF (100 mL) at 0° C. is treated with 4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (3 g, 13.6 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (7.7 g, 68 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by filtration through a short plug of silica gel to afford 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol, which is used in the next step without further purification. MS: 237 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 7.22 (m, 1H), 6.98 (m, 2H), 4.71 (s, NH2, 2H), 2.75 (m, 2H), 1.86 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)CC>[CH:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:13]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[CH:3]=[C:4]([CH3:15])[C:5]=2[CH3:14])[CH2:12][CH2:11]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Br)cc(C(=O)NC2CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Solvent: O
Product: COC/C=C/c1cc(C)c(C)c(C(=O)NC2CC2)c1
Temperature: 100 °C

Procedure:
5-Bromo-N-cyclopropyl-2,3-dimethylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.1 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting biphasic suspension was heated at 100° C. for 18 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.Cl[C:14]1[C:15](=[O:28])[NH:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[C:14]2[C:15](=[O:28])[NH:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: COc1ccc2c(c1)NCCC2
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(OC)cc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (1.34 g, 8.21 mmol) in NMP (5 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.1 g, 4.61 mmol). The resulting solution was stirred for 1 h at 150° C. in an oil bath and then diluted with water (300 ml). The solids were collected by filtration to afford methyl 3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a red solid (844 mg, 28%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]=[C:13]4[N:20]([CH2:23][C:24]5[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=5)[CH:21]=[CH:22][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]=[C:13]4[N:20]([CH2:23][C:24]5[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=5)[CH:21]=[CH:22][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)CCCO3)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)CCCO3)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (4-(chroman-6-yl)-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (967 mg, 2.300 mmol) in dichloromethane (DCM) (24 mL) was treated with PCC (644 mg, 2.99 mmol) and the mixture was stirred at ambient temperature for 90 minutes. The mixture was diluted with dichloromethane, filtered over Celite™ and the filtrate was concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford the desired product as a pale yellow foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.11 (s, 1 H), 7.22 (dd, J=2.1, 8.4 Hz, 1 H), 7.16-7.04 (m, 4 H), 7.04-6.97 (m, 1 H), 6.93 (d, J=8.4 Hz, 1 H), 6.44 (d, J=3.5 Hz, 1 H), 5.47 (s, 2 H), 4.37-4.20 (m, 2 H), 2.95 (s, 3 H), 2.86 (t, J=6.4 Hz, 2 H), 2.20-1.96 (m, 2 H); LC/MS (m/z) ES+=419 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:12]=[CH:11][N:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
1.05 g of sodium hydride (60% oil suspension) was suspended in 24 ml of tetrahydrofuran. 8 ml of tetrahydrofuran solution of 1.42 g of 2-butyn-1-ol was added dropwise at room temperature therein slowly, and the mixture was stirred for 20 minutes. Into the mixture was added dropwise 8 ml of tetrahydrofuran solution of 3 g of 4,6-dichloropyrimidine at 0° C. slowly, and stirred for 4 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with chloroform three times. The organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 3.16 g of 4-chloro-6-(2-butynyloxy)pyrimidine.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH:1]1([N:5]([CH3:31])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)NC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)N(C)C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-benzamide (1.67 grams, 4.51 mmol) in N,N-dimethylformamide (50 mL) at 0° C. under nitrogen was added NaH (60% dispersion in mineral oil, 0.27 grams, 11 mmol). After stirring 30 minutes at 0° C., iodomethane (3.2 g, 23 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours, poured into water (450 mL), and extracted with ethyl acetate (3 times 75 mL). The combined organic extracts were washed with water (5 times 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexane to 40% ethyl acetate in hexane) to afford the title compound (1.65 grams) as an off white foam. 1H NMR (400 MHz, CDCl3) δ7.96 (s, 2H), 6.80-6.52 (m, 3H, 2 rotomers observed), 5.04, 4.02-3.98 (m, m, 1H, 2 rotomers observed), 3.74, 3.67 (s,s, 3H, 2 rotomers observed), 3.02, 2.75 (s,s, 3H, 2 rotomers observed), 2.25-1.94 (m, 9H, 2 rotomers observed), 1.75-1.41 (m, 3H, 2 rotomers observed). MS (APCI+) Calc: 384.0, Found: 385.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][CH:21]([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]1)[CH2:22][CH:21]2[OH:23]
Reactant: C=CC(=O)OC
Reactant: OC1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(O)CC1(CCN(Cc3ccccc3)CC1)O2

Procedure:
1′-Benzyl-6-bromo-4-hydroxy-spiro[chromane-2,4′-piperidine] (3.0 g, 7.7 mmol, Intermediate 3) was treated with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, giving (E)-3-{1′-benzyl-4-hydroxy-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (3.1 g). The crude intermediate was dissolved in THF (20 ml) under N2 and p-TsOH (0.15 g, 0.79 mmol) was added. The mixture was heated to reflux. After 16 h, the mixture was poured into water and a 10% NaOH solution was added until reaching a neutral pH value. The solution was extracted with DCM, dried over Na2SO4, filtered and evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH (90/10) and then hexane/AcOEt (70/30) as eluent to give (E)-3-{1′-benzyl-spiro[chromene-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:4].O=[CH:15][CH:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:17]#[N:18]>C(O)(=O)C>[C:17](/[C:16](/[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:15]\[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:18]
Reactant: N#CC(C=O)c1cccnc1
Reactant: CCOC(=O)CCNCC(=O)OC
Solvent: CC(=O)O
Product: CCOC(=O)CCN(/C=C(\C#N)c1cccnc1)CC(=O)OC
Temperature: 80 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To an acetic acid (30 mL) solution of ethyl 3-{[(methoxycarbonyl)methyl]amino}propanate (6.720 g) was added a crude product of 3-oxo-2-(3-pyridyl)propanenitrile (7.826 g), and the mixture was stirred at 80° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and sodium carbonate was added thereto for neutralization, followed by extracting the solution with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate, which was then filtered for separation. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/3), to obtain the title compound (7.521 g, yield 83%). The ESI/MS data of the compound are given below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Reactant: c1cn[nH]c1
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1cccn1

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) was treated with pyrazole using essentially the conditions of Example 5. Crude product was chromatographed on a S g silica Mega Bond Elut® column, eluting with a gradient from 0–25% ethyl acetate in dichloromethane. Relevant fractions were combined to give the desired product (37 mg). MS ESP): 329 (MH+) for C16H13FN4O3
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:11]Br>O>[Br:11][CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)CC
Solvent: O
Product: CCOC(=O)C(Br)C(=O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a 0° C. solution of ethyl 3-oxopentanoate (5.0 mL, 34.7 mmol) in water (30 mL) was added bromine (1.8 mL, 35.0 mmol) via syringe pump addition (0.5 h). The mixture was stirred at 0° C. for 0.5 hour. The solution was extracted with EtOAc (2×35 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 2-bromo-3-oxopentanoate (7.3 g, 94% yield). The product was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[CH2:3][N:4]([CH3:14])[C:5](=[O:13])[O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].C([O-])(O)=O.[Na+]>CC#N>[CH3:14][N:4]([CH2:3][C@@H:2]([NH:1][C:23](=[O:24])[O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[CH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[C:5]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:13]
Reactant: CN(C[C@@H](N)C[C@H]1CCCOC1)C(=O)OCC[Si](C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C[C@H](C[C@H]1CCCOC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (0.7350 g, 2.32 mmol, 1.0 equiv, ˜7% diastereomeric impurities) in CH3CN (50 mL) was treated with 4-nitrophenyl chloroformate (0.4950 g, 2.45 mmol, 1.05 equiv) and 0.600 g (7.14 mmol, 3 equiv) of NaHCO3. The reaction was stirred at rt for 3 hr. The mixture was filtered using Celite® 545. The filtrate was evaporated under reduced pressure to afford 1.1647 g (100%) of (4-nitrophenyl) (S)-1-(N-methyl-N-(trimethylsilylethoxycarbonyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate, which was used in the next step without further purification. MS ESI +ve m/z 504 (M+Na).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[SiH:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9]>N1C=CC=CC=1C1C(C2C=CC=CN=2)=CC=CN=1.C[Si](C[Fe]C[Si](C)(C)C)(C)C.C1(C)C=CC=CC=1>[Si:7]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: CC[SiH](CC)CC
Reactant: C=CCCCC
Agent: C[Si](C)(C)C[Fe]C[Si](C)(C)C
Agent: c1ccc(-c2cccnc2-c2ccccn2)nc1
Solvent: Cc1ccccc1
Product: CCCCC=C[Si](CC)(CC)CC
Reaction time: 4 h
Yield: 5 %

Procedure:
A stock solution containing 5 mg of bis[(trimethylsilyl)methyl]iron(II) terpyridine and 0.60 g of toluene was charged into a scintillation vial in a nitrogen filled drybox. The toluene was removed in vacuo followed by addition of 0.114 g (1.4 mmol) of 1-hexene. To the same vial, 0.105 g (0.90 mmol) of Et3SiH was added. The vial was sealed with a small amount Krytox grease and electrical tape, removed from the drybox and placed in a 95° C. oil bath. The concentration of the iron complex was less than 0.1 mol % relative to the silane, and the reaction time was 4 hours to achieve greater than 90% conversion to (CH3CH2)3Si—(CH2)5—CH3. Less than 5% each of (CH3CH2)3Si—CH═CH—(CH2)3—CH3 and (CH3CH2)2(H)Si—(CH2)5—CH3 were formed.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:5]3[N:16]=[CH:15][S:14][C:6]=3[NH:7][C:8](=[O:13])[C:9]=2[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]2[C:5]3[N:16]=[CH:15][S:14][C:6]=3[NH:7][C:8](=[O:13])[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2c(=O)[nH]c3scnc3c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c2scnc2c2c(O)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a suspension of 9-methoxy-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.048 g, 0.21 mmol) and CH2Cl2 (2 ml) was added boron tribromide (1.05 ml of 1M sol. in CH2Cl2, 1.05 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated, methanol (2 ml) was added, the resulting mixture stirred for 1 hour and then evaporated. The resulting solid was purified by flash chromatography on SiO2 gel to yield the title compound (0.042 g, a 90% yield) as a solid. m.p.>250° C.; 1H NMR (400 MHz, DMSO) δ 7.28 (d, 1H, Ar), 7.47 (t, 1H, Ar), 7.75 (d, 1H, Ar), 9.06 (s, 1H, 2-CH), 10.36 (s, 1H, OH), 12.41 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.Cl.N>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:16]=[CH:17]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(C2=NNC(=O)CS2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CSC(c2ccc(-n3ccc(=O)cc3)cc2)=NN1

Procedure:
A stirred mixture of 2-(4-aminophenyl)-4H,6H-1,3,4-thiadiazin-5-one (1.0 g), 4H-pyran-4-one (0.51 g), water (20 ml) and concentrated hydrochloric acid (0.42 ml), was heated under reflux for 3 hours. The warm solution was neutralised with concentrated aqueous ammonia and cooled to give a solid, 1.33 g. Recrystallisation from methanol gave the title compound, 0.89 g, m.p. 289°-291° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH2:18])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])([CH3:12])[CH3:14]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Product: CC(C)(C)c1ccc(C(C)(C)C)c(NC(=O)c2cc(Cl)ccc2O)c1
Yield: 75.7 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.