Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:26][C:27](Br)=[O:28].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:26][C:27]([NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1)=[O:28]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1Br
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccn2)cc1Br

Procedure:
prepared by reaction of 1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]([NH:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CN(C=O)C>ClCCCl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:21][C:16]([C:17]([F:18])([F:19])[F:20])=[N:15][N:14]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(=O)NNC(=O)C(F)(F)F)oc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc2cc(-c3nnc(C(F)(F)F)o3)oc12
Yield: 17.5 %

Procedure:
To a solution (280 ml) of N′-(7-methoxybenzo(b)furan-2-ylcarbonyl)trifluoroacetohydrazide (14.6 g) in 1,2-dichloroethane were added thionyl chloride (4.2 ml) and DMF (0.1 ml) and the mixture was refluxed under heating for 4.5 hr. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to give the title compound (2.4 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][NH:25][C:26](C3C=CC=CC=3)([C:33]3C=CC=CC=3)[C:27]3C=CC=CC=3)=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:46]>CO.CC(C)=O>[ClH:46].[ClH:46].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][N:25]=[C:26]([CH3:27])[CH3:33])=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCC(O)COc2ccc(NNC(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1OC
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(CCNCC(O)COc2ccc(NN=C(C)C)nn2)cc1OC

Procedure:
A solution of 3-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-6-(2-triphenylmethylhydrazino)pyridazine (330 g) and 37% hydrochloric acid (0.12 liter) in methanol (0.5 liter) and acetone (0.5 liter) was heated at reflux for 3 hours, then the solvent was evaporated under vacuum. The residue was diluted with n-butanol (100 ml), evaporated to dryness and triturated with acetone (1 liter) to afford 235 g of crude product which was dissolved in hot methanol (0.65 liter). The solution was filtered and diluted, while hot, with acetone (1.6 liter).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1([N:17]2[CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.CCOC(C)=O.CCCCCC>CO>[N:17]1([C:7]2([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)[CH2:18][CH2:19][CH2:20]1
Reactant: c1csc(C2(N3CCC3)CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: O=C1CCC(c2cccs2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
50 ml 6N hydrochloric acid were added to a solution of 1-(8-(thiophen-2-yl)-1,4-dioxaspiro[4.5]decan-8-yl)azetidine (10 g) in 100 ml methanol at 0° C. and the reaction mixture was stirred for 1 hour at room temperature. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete the methanol was removed by distillation and the residue was mixed with water (150 ml) and extracted with ethyl acetate (2×100 ml). The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure the residue was taken up in cold water (150 ml) and the solution was stirred for 1 hour and then filtered. The residue that was retained was taken up in ethyl acetate and dried over Na2SO4. Following removal of the solvent under reduced pressure, the desired product (6.5 g, 78%) was obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C(=O)N(C)C)C4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (10.5 mg, 0.097 mmol) was added to a solution of 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (25.8 mg, 0.049 mmol) and triethylamine (20.5 μL, 0.146 mmol) in DCM (500 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (25.8 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.33 (d, J=6.3 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.85-2.89 (m, 2H), 2.90 (s, 6H), 3.04-3.13 (m, 2H), 3.41-3.50 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.27 (s, 2H), 4.35-4.42 (m, 1H), 6.67 (ddd, J=9.0, 2.9, 1.5 Hz, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+487.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[CH:14](=O)[CH2:15][CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: CCC=O
Reactant: O=C1CCCNc2ccc(Br)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCN1CCCC(=O)c2cc(Br)ccc21
Reaction time: 6 h

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (5.0 g), propionaldehyde (15 ml) and acetic acid (4.7 ml) in 1,2-dichloroethane (250 ml) was added sodium triacetoxyborohydride (22.0 g) at room temperature, and the mixture was stirred for 6 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4) to give 7-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (5.89 g) as yellow oil.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([N:16]([CH3:25])[C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(Nc1ccc(-c2cn3ccccc3n2)cc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
0.95 g (3.11 mmol) N-[4-(Imidazo[1,2-a]pyridin-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (educt IV.2.c) is dissolved in 10 mL DMF. 0.14 g (3.73 mmol) NaH (60% in mineral oil) is added. Then 195 μL (3.11 mmol) methyl iodide is added and the mixture is stirred at RT over night. The mixture is poured into water. The precipitate is filtered off and dried in vacuo at 50° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([CH:15](Br)[C:16]([O-:18])=[O:17])C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([OH:18])=[O:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C([O-])C(Br)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methylpiperazine (10.7 g), benzylbromoacetate (24 g), triethylamine (28 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 4 hours. The reaction was concentrated to dryness, taken up in tetrahydrofuran (100 ml), filtered, and the filtrate evaporated to dryness. The residue was taken up in methanol (100 ml), treated with aqueous sodium hydroxide solution (100 ml, 1M) and stirred at reflux for 24 hours. The reaction was concentrated to dryness, diluted with water (100 ml) and then acidified to pH6.0 by addition of concentrated hydrochloric acid. The mixture was evaporated.. A portion of the resulting brown oil (2.0 g) was taken up in water (100 ml), treated with Dowex 50WX8 resin (80 g) and stirred at ambient temperature for 10 minutes. The mixture was filtered and the resin washed with water until the washings were neutral. The resin was then stirred with 2.0M aqueous ammonia (3×100 ml) for 5 minutes and filtered. The combined ammonia washings were concentrated to leave the title compound as a white waxy solid (0.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH3:11])=[CH:7][C:6]=2[CH:13]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)[CH3:11])=[N+:27]=[N-:28]
Reactant: CC(O)c1cc2cc(Br)ccc2o1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc2cc(Br)ccc2o1
Yield: 77.2 %

Procedure:
Using 1-(5-bromo-1-benzofuran-2-yl)ethanol (6.11 g, 25.4 mmol), DMF (50 mL), methanesulfonyl chloride (2.9 mL, 38.0 mmol), triethylamine (7.5 mL, 50.8 mmol) and sodium azide (8.64 g, 127 mmol), an operation in the same manner as in Reference Example 22 was performed to give the title compound 5.22 g as an oil. This was used for the next step without purification.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[CH:28]=[CH:27][C:23]([CH2:24][C:25]#[N:26])=[CH:22][CH:21]=1>CCOCC.C1COCC1>[ClH:1].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1
Reactant: [Cl-]
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl
Product: NCCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Aluminum chloride (0.2 g; 1.5 mmol) is added to a suspension of lithium aluminum hydride (60 mg; 1.5 mmol) in dry ether (6 ml) at 0° C. The reaction is stirred for 10 minutes at 20° C. and cooled to 0° C. A solution of 4-(benzoxazol-2-yl)benzyl cyanide (0.24 g; 1.02 mmol) in dry THF (4 ml) is added dropwise and the reaction is stirred at 20° C. for 2 hours. The reaction is quenched with H2O, diluted with ether and washed vigorously with 2N HCl. The ether is decanted and the aqueous layer is washed with ether. The aqueous phase is neutralized with 15% NaOH and extracted with CH2Cl2. The extracts are concentrated and purified with column chromatography using CH2Cl2 to 20% MeOH/CH2Cl2. The product is acidified with acidic methanol and concentrated to yield 2-[4-(benzoxazol-2-yl)phenyl]- 1-ethanamine hydrochloride (m.p. 250° C. dec.).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:8]1(=[O:9])[N:4]([CH2:3][CH:2]([OH:1])[CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[N+:16]([O-:18])=[O:17])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]

Procedure:
To a solution of N-(2,3-epoxypropyl)phthalimide (commercially available, 20.3 g, 0.1 mol) in ethanol (200 mL), 2-nitroimidazole (11.3 g, 0.1 mol) and potassium carbonate (1.2 g) were added and the reaction mixture was refluxed for 6 hrs. The reaction mixture was cooled and poured into water (700 ml) and the yellow solid formed was filtered and dried. Yield 28.2 g) 89%). It was recrystallized from methanol. mp. 213°-214° C. 1H NMR (DMSO) ε 3.62 (m, 4H, PhthNCH2CHOH), 4.08 (m, 1H, CHOH), 4.32 and 4.63 (m, 2H, CHOHCH2N<), 5.54 (d, 1H, CHOH), 7.15 and 7.68 (s, 2H, imiH), 7.8 (m, 4H, ArH). MS: (M+H)+ =317+Anal. Calcd. for C14H12N4O5 : C, 53.17; H, 3.82; N, 17.71. Found C, 53.11; H, 3.76; N, 17.49.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=1[CH3:30])=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:1]1([CH2:4][O:5][NH:6][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[CH3:30])=[O:9])[CH2:3][CH2:2]1
Reactant: NOCC1CC1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)NOCC3CC3)c(C)n(C)c(=O)c2C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
O-cyclopropylmethyl-hydroxylamine (0.046 g, 0.527 mmol) was added to a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (30:1 methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MS ESI (+) m/z 374 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 6.91 (d,1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). 19F (376 MHz, CD3OD)−132.1 (s, 1F).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]2[N:20]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][C@H:41]([F:45])[C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:21][C:22]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:15]=12)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[ClH:1].[F:45][C@@H:41]1[C:37]2[N:38]=[CH:39][N:40]=[C:35]([N:20]3[C:16]4[C:15](=[C:14]([CH2:13][NH:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH:18][CH:17]=4)[C:22]4([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:21]3)[C:36]=2[C@H:43]([CH3:44])[CH2:42]1
Reactant: CC(C)N(Cc1cccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)C[C@@H]2F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)NCc1cccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4N HCl in dioxane (0.1 mL) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-1-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (12 mg, 0.020 mmol) in DCM (0.3 mL). The reaction mixture was stirred at room temperature overnight. The solvents were evaporated. The crude residue was taken up in MeOH and basified with 7N ammonia in MeOH. After evaporation of the solvent, the residue was purified by column chromatography (4% 7 N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. Removal of the solvents afforded N-((1-((5R,75)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (9 mg, 88%) as a solid. LCMS (APCI+) m/z 410 [M+H]+; Rt=1.55 min.
Reaction SMILES: C([C:3](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]([C@@H:6]([NH:11][C:12](=[O:27])[O:13][CH2:14][C:15]1([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#N.[O:47]=[O+][O-].[NH2:50][C:51]1[CH:55]=[CH:54][NH:53][N:52]=1>ClCCl>[O:47]=[C:3]([NH:50][C:51]1[NH:52][N:53]=[CH:54][CH:55]=1)[C:4]([C@@H:6]([NH:11][C:12](=[O:27])[O:13][CH2:14][C:15]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:17][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:5]
Reactant: CCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1cc[nH]n1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(=O)C(=O)Nc1ccn[nH]1
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A −78° C. solution of 200 mg (0.32 mmol) of [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate in 10 mL of dichloromethane was treated with a stream of ozone for 15 min before being purged with a stream of nitrogen for 5 min. To the reaction was added a solution of 26 mg (0.32 mmol) of 3-aminopyrazole in 1 mL of dichloromethane. The reaction was stirred for 30 min and concentrated under reduced pressure. The residue was dissolved in 5 mL of a 1M solution of silver nitrate in 4:1 tetrahydrofuran:water. The reacton was stirred at room temperature for 18 h and diluted with water. The mixture was extracted with dichloromethane, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with 3.5:6.5 acetone:hexanes to afford 30 mg (21%) of [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 7.65 (s, 1H), 7.42 (s, 1H), 7.22 (t, J=6 Hz, 2H), 7.08 (t, J=9 Hz, 2H), 6.54 (s, 1H), 4.93 (m, 1H), 3.82 (s, 2H), 2.78 (s, 2H), 1.70-1.95 (m, 2H), 1.61 (m, 2H), 1.38 (m, 4H), 0.91 (t, J=7 Hz, 3H). ES-LCMS m/z 467 (M+Na). HRMS C23H29N4O4F1 m/z 467.2071 (M+Na)Cal; 467.2073 (M+Na)Obs.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH:21]O>ClCCl.C[Re](=O)(=O)=O>[C:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]([C:7]2[CH:6]=[CH:5][N+:4]([O-:21])=[CH:3][C:2]=2[CH3:1])[CH:20]=[CH:19][CH:18]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: OO
Reactant: Cc1cnccc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 5 h

Procedure:
tert-Butyl 3-(3-methylpyridin-4-yl)benzoate (0.500 g, 1.86 mmol) was dissolved in a mixture of dichloromethane (0.800 mL) and 30% hydrogen peroxide (0.421 mL). Methyltrioxorhenium (VII) (2.3 mg, 0.92 mmol) was added and the reaction mixture was stirred vigorously for 5 hours. The layers were then separated and the organic layer was treated with sodium sulfite, and then dried over sodium sulfate. The crude product filtered, evaporated to dryness, and used without further purification. ESI-MS m/z calc. 285.1. found 286.1 (M+1)+. Retention time 1.22 minutes.
Reaction SMILES: [CH:1]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Mg]Br)=[CH2:25].[Cl-].[NH4+]>O1CCCC1>[CH:1]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:16]=1[NH:21][CH:25]=[CH:24]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(C(Oc2cccc3cc[nH]c23)c2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
11.95 mmol of the compound obtained in Step A above are dissolved, under an inert atmosphere, in 80 ml of anhydrous tetrahydrofuran. The temperature of the reaction mixture is then lowered to −40° C. and then 41.84 mmol of a 1M solution of vinylmagnesium bromide in tetrahydrofuran are added dropwise to the solution, which is then stirred for 2 hours 50 minutes from −40° C. to 0° C. The reaction mixture is then hydrolysed at 0° C. using 100 ml of a saturated aqueous ammonium chloride solution, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated. Purification by flash chromatography over silica gel (petroleum ether/ethyl acetate: 9/1) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(N)(N)=[O:10].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:10])=[C:4]([CH3:8])[CH:3]=1
Reactant: NC(N)=O
Reactant: Cc1cc(Cl)ccn1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: 0 °C
Yield: 100.5 %

Procedure:
4-Chloro-2-methylpyridine (5.0 g, 39 mmol, 1.0 eq) and hydrogen peroxide-urea adduct (7.37 g, 78.4 mmol, 2.00 eq) were dissolved in THF (196 mL) and cooled to 0° C. Trifluoroacetic anhydride (12 mL, 86.3 mmol, 2.2 eq) was added dropwise over 15 minutes and the reaction was allowed to warm to room temperature. After determination of the completion of the reaction by LCMS (approximately 45 minutes), the reaction was cooled to 0° C. and quenched with a 10% aqueous solution of NaS2O3. The reaction was extracted with EtOAc (3×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 5.63 g (99%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1)=[O:12])[CH:2]=[CH2:3].[CH3:22][Mg]Br>C1COCC1>[CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1)([OH:12])[CH3:22])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CCc1c(Br)cncc1C(=O)c1ccc(C#N)c(F)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCc1c(Br)cncc1C(C)(O)c1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-(4-allyl-5-bromo-pyridine-3-carbonyl)-2-fluoro-benzonitrile (as described above in Step C) (0.39 g, 1.13 mmol) in THF (20 mL) at 0° C. was added methylmagnesium bromide (1.13 mmol, 3M) and the reaction was monitored by TLC. Three more portions (1.13 mmol) of CH3MgBr were added until the reaction was complete. The reaction was quenched with saturated NH4Cl (20 mL), then partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification by chromatography on silica eluting with hexane:ethyl acetate 7:3.