Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH2:21][O:20]4)[CH2:16][CH2:15]3)=[O:13])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br>CN(C)C=O>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:12]([N:14]2[CH2:15][CH2:16][C:17]3([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20]3)[CH2:18][CH2:19]2)=[O:13])=[C:7]1[CH3:11]
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc2n1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 0.031 g (0.080 mmol) 1′-[(6-chloro-2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (5) in 1 ml dry N,N-dimethylformamide were added 0.004 g (0.08 mmol) sodium hydride (50% in oil). After stirring for 20 min 0.015 ml (0.08 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added. After stirring for 16 h the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.020 g; 41%) as a white solid. MS m/e (%): 607 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1
Reactant: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate (1.29 g, 4.71 mmol) in DCM (15 mL) was added TFA (7 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product which was diluted with DCM and washed with sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried and concentrated to give the desired product (700 mg, 4.02 mmol, 85% yield) as yellow oil. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH2:11].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH:11][S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: NS(N)(=O)=O
Reactant: NCC1Oc2ccccc2O1
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1Oc2ccccc2O1

Procedure:
C-Benzo[1,3]dioxol-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfamide (3.74 g, 38.9 mmol) were combined in dry dioxane (50 mL) and the solution was heated to reflux overnight. The reaction was concentrated and the residue was chromatographed (2% to 10% acetone in dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:27][C@H:26]([O:28][CH3:29])[C@@H:25]([NH2:30])[CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][C@@H:25]2[C@@H:26]([O:28][CH3:29])[CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCN1C[C@H](OC)[C@@H](N)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCN1C[C@H](NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)[C@@H](OC)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (3S,4S)-1-ethyl-4-methoxypyrrolidin-3-amine (14.4 mg, 0.1 mmol). The title compound was obtained as a solid (7.9 mg, 17% yield). MS m/z: 476.86, 478.86 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[Br:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17]C2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:12][C:13]1[CH:14]=[C:6]2[C:20]([C:19]([CH3:23])([CH3:24])[CH2:18][CH2:17][C:5]2=[O:7])=[CH:21][CH:22]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F1) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:17][CH2:16][C@@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[O:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[C@H]2CCCCO2)c2cccc(Cl)c2)cc1

Procedure:
Into toluene (20 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethanol obtained in 3) above (6.0 g) and triethylamine (4.7 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (4.9 g), and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and the organic layer was further washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (9.1 g, 94.8%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12]C(=O)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CO>[C:5]1([CH:4]=[CH:3][CH:2]=[CH:1][C:11](=[N:17][OH:18])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(=O)C=Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=CC=Cc1ccccc1)=NO
Yield: 60.6 %

Procedure:
In a 250 ml single neck flask was charged 5.28 g (30 mmoles, 1.0 eq.) of 4-(1-naphthyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 of 4-(2-phenylethenyl)-3-buten-2one 2-oxime (E/Z mixture of isomers) as an oil in 60.6% yield.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[F:32])[C:24]([NH:26][O:27][CH3:28])=[O:25]>CN(C)C=O.C(OCC)(=O)C>[F:32][C:31]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:22][C:21]=1[NH:20][C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1cnc(-c2cn3ncnc(Cl)c3c2C(C)C)o1
Reactant: CONC(=O)c1ccc(F)c(N)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CONC(=O)c1ccc(F)c(Nc2ncnn3cc(-c4ncc(C)o4)c(C(C)C)c23)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 47.1 %

Procedure:
To a solution of Example 58 (30 mg, 0.11 mmol) in dimethyl formamide (0.7 mL) at RT was added 3-amino-4-fluoro-N-methoxy-benzamide (30 mg, 0.16 mmol). After stirring at ambient temperature for 19 h, the mixture was dissolved in ethyl acetate and washed with 10% LiCl solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% methanol in chloroform to afford the title compound (22 mg, 48%) as an off-white solid. LC/MS; (M+H)+=425.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([Cl:39])(C)C.CS(C)=O.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][Cl:39])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CCl)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, for preparation see step D, example 16), trimethylsilyl chloride (47 mg, 0.4 mmol) and DMSO (4 mg, 0.06 mmol) was stirred at RT for 10 min. Aq. NaHCO3-solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to yield the title compound which was used in the next step without further purification. LCMS (method A) RtA=1.598 min; [M+H]+=484.0.
Reaction SMILES: [CH3:1][N:2](C)[C:3](C1C=CC(Br)=CN=1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=1>>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:2]([CH3:3])[CH3:1])=[O:19])=[CH:16][N:15]=1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: O=C(O)c1ccc(Br)nc1
Product: CN(C)C(=O)c1ccc(Br)nc1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 6-bromo-nicotinic acid (1.00 g, 4.95 mmol) to give a colorless oil (780 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.53 Hz, 1 H) 7.61-7.71 (m, 1 H) 7.56 (d, J=8.08 Hz, 1 H) 3.08 (d, J=41.68 Hz, 6 H); LCMS for C8H9BrN2O m/z 229.00 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[N:6]([C:13](=[O:23])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C@H:7]2[CH3:12].[CH2:33](OB(C=C)OCCCC)[CH2:34]CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Si:26]([O:25][CH2:24][C@H:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:33]=[CH2:34])[C@H:7]([CH3:12])[N:6]1[C:13](=[O:23])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:28])[CH3:27]
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(F)cccc1Cl)[C@H]2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Dissolve 1-((1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one (1.8 g, 3.33 mmol) and vinylboronic acid dibutyl ester (1.5 mL, 6.65 mmol) in 1,4-dioxane (22 mL). Add aqueous Na2CO3 solution (11 mL, 2M in water). Degas with nitrogen 10 min Add bis(triphenylphosphine)palladium(II) chloride (467 mg, 0.67 mmol). Heat to 80° C. Stir 2 hours. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-40%) to give the title compound as a white foam (1.54 g, 3.15 mmol). MS (m/z): 488.2 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[BrH:11]>C1(C)C=CC=CC=1>[Br:11][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9]
Reactant: C=CCCCCCC(=O)O
Reactant: Br
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCBr
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 500-ml four-necked flask equipped with hydrogen bromide inlet, thermometer, 7-octenoic acid inlet and oxygen inlet was charged with 10 g of 7-octenoic acid and 50 ml of toluene. After passing air at 20° C. with stirring at a rate of 10 liters per hour for 30 minutes, hydrogen bromide and a solution of 90 g of 7-octenoic acid in 250 ml of toluene were continuously fed with stirring at the rates of 120 ml/hr and 9 l/hr, respectively. After 3 hours of reaction, the reaction mixture was treated in the same manner as described above under (3) (i) to give 139 g (89% yield) of 8-bromocaprylic acid.
Reaction SMILES: CS([O:5][CH:6]1[CH:11]([CH3:12])[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:8][CH:7]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)=O.C(N(CC)CC)C.C[C:38]([O:41]C(OC(OC(C)(C)C)=O)=O)(C)C>N1C=CC=CC=1>[CH3:12][CH:11]1[CH:6]2[CH:7]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:38](=[O:41])[O:5]2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:10]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.2 M) was heated in the microwave at 110° C. for 10 min. The orange reaction was then concentrated under vacuo, the crude was dissolved in ethyl acetate and water, the organic phase was dried with sodium sulfate and concentrated under vacuo. The crude material was dissolved in DCM (0.2 M), triethylamine (1.8 equiv.) was added, followed by Boc2O (1.2 equiv.). The reaction was stirred for 40 min, then concentrated to dryness. The crude material was purified via silica gel column chromatography eluting with hexane and ethyl acetate (1:1) to afford (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate as a white foam in 66% yield. LC/MS=376.0 (M+H), LC: 3.424 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[C:4]([CH:3]=1)[NH2:11]
Reactant: C=C(C)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To 4-fluoro-2-nitro-1-(prop-1-en-2-yl)benzene (0.837 g, 4.62 mmol) in a 250 mL round-bottomed flask equipped with a stir bar and rubber septum was added EtOAc (46.2 ml) followed by palladium on carbon (0.983 g, 0.462 mmol). The reaction was evacuated and purged with hydrogen (balloon) (2×) and stirred under hydrogen at room temperature overnight. The reaction was determined to be complete by TLC (10% EtOAc/Hex). The mixture was filtered through Celite, washed with EtOAc and concentrated. 5-Fluoro-2-isopropylaniline (673 mg, 4.40 mmol, 95%) was obtained as a clear and yellow oil: IR (thin film) 3480 (w), 3390 (w), 2962 (m), 2872 (w), 1622 (m), 1504 (s), 1431 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J=8.5, 6.4 Hz, 1H), 6.45 (td, J=8.5, 2.6 Hz, 1H), 6.37 (dd, J=10.6, 2.6 Hz, 1H), 3.74 (bs, 2H), 2.83 (hept, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 161.75 (d, JCF=241.3 Hz), 144.76 (d, JCF=10.3 Hz), 128.11 (d, JCF=2.8 Hz), 126.53 (d, JCF=9.6 Hz), 105.06 (d, JCF=20.7 Hz), 102.26 (d, JCF=24.2 Hz), 27.27, 22.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[NH2:14][C:15]1[O:19][N:18]=[C:17]([CH3:20])[C:16]=1[CH3:21]>N1C=CC=CC=1>[CH3:20][C:17]1[C:16]([CH3:21])=[C:15]([NH:14][S:10]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:11])[O:19][N:18]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1C
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
2-Methoxycarbonylthiophene-3-sulfonyl chloride (2.50 g, 10.05 mmol) was added to a solution of 5-amino-3,4-dimethylisoxazole(0.98 g, 8.75 mmol) in dry pyridine (5.0 ml). The reaction mixture was stirred at room temperature for 16 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was washed with 1 N HCl (2×50 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue, which, after purification by column chromatography over silica gel (1:1 hexanes/ethyl acetate as eluent), yielded 2.20 g (65%) of a brown solid. Further purification was achieved by recrystallization from ethyl acetate/hexanes, giving the pure product as a white solid, m.p. 113-116° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:38])[CH3:37]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in DCM (1.5 mL) was added triethylamine (42 uL, 0.31 mmol) and acetyl chloride (71 uL, 0.31 mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, then diluted with water and ethyl acetate. The organic layer was concentrated and purified by prep HPLC (low pH) to give an off-white solid (5.7 mg, 0.013 mmol, 9% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>O1CCCC1.[Zn]>[OH:7][C:4]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCOCC1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCOCC1
Yield: 69.3 %

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (5.5 g, 51.6 mmol), a zinc powder (4.05 g, 61.9 mmol) and a small amount of iodine in tetrahydrofuran (60 ml) was added dropwise ethyl bromoacetate (6.28 ml, 56.7 mmol) under a nitrogen atmosphere. After heating under reflux for 6 hrs., 10% sulfuric acid (50 ml) was carefully added under ice-cooling and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (6.73 g, 69%) as a colorless oil.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)[CH:12]=[O:13])(C(C)(C)C)(C)C.[F-].[K+].I[CH2:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)[CH:12]=[O:13])[CH3:24]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCI
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CC)cc(C=O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 118C (244 mg, 0.87 mmol) in DMF (2.0 mL) was added potassium fluoride (100 mg) and iodoethane (0.13 mL). The mixture was stirred at rt overnight. It was diluted with EtOAc and the organic extracts were washed with brine and dried. The crude product was purified by column chromatography to give 118D (158 mg, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J=7.69 Hz, 3H) 1.46 (t, J=7.03 Hz, 3H) 2.62 (q, J=7.47 Hz, 2H) 4.13 (q, J=7.03 Hz, 2H) 7.02 (dd, J=7.91, 2.20 Hz, 1H) 7.22 (dd, J=5.27, 2.20 Hz, 1H) 10.35 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reactant: OCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-[4′-(3-methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl alcohol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>C(Cl)Cl>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:3]
Reactant: COC(=O)c1cc(F)cc(CBr)c1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc(CN(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of 2.0M dimethylamine in THF (3.24 mL, 6.48 mmol) was added methylene chloride (2 mL) and methyl 3-(bromomethyl)-5-fluorobenzoate (0.200 g, 0.810 mmol from Step 2). The reaction was heated in a sealed reaction vessel in an oil bath held at 60° C. for 2 hours. Solvent and excess reagent were removed in vacuo and the residue was subjected to flash chromatography, eluting with a gradient from 0-20% MeOH in DCM containing some NH4OH (50 mg, 29%). 1H NMR (300 MHz, CDCl3): δ 7.80-7.77 (m, 1H), 7.62 (ddd, 1H), 7.29 (ddd, 1H), 3.90 (s, 3H), 3.53 (s, 2H), 2.29 (s, 6H); 19F NMR (282 MHz, CDCl3): δ−113.10 (t, 1F); LCMS (M+H)+: 212.1.