Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[C:31][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(C#CC(C)(C)C)cnc1O2
Temperature: 90 °C

Procedure:
3-Bromo-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (104186-10-peak 1) (500 mg, 1.381 mmol), tetrakis(triphenylphosphine)palladium (160 mg, 0.138 mmol), copper(i) iodide (52.6 mg, 0.276 mmol) were combined, and to the mixture was added DMF (6903 μL, 1.381 mmol), 3,3-dimethylbut-1-yne (340 mg, 4.14 mmol) and DIPA (4837 μL, 34.5 mmol). The reaction was flushed with argon, sealed and heated at 90° C. for 2 hours. The reaction mixture was diluted with water (100 mL) and poured into a separatory funnel containing EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide the desired product contaminated with triphenylphosphine. The yellow solid was suspended in 25 mL of ether, resulting in the formation of a fine white precipitate. Decanted ether and washed the solid with 10 mL of ether. Dried under reduced pressure to provide 3-(3,3-dimethylbut-1-ynyl)-7-methoxy-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](=[O:15])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sccc1OCc1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1sccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 3-(benzyloxy)-N-methoxy-N-methyl-2-thiophenecarboxamide (3.47 g, 12.50 mmol) in THF (50 mL) was added a solution of methyl-magnesium bromide in THF (1 M, 35 mL). After being stirred at 0° C. for 1 hr, the reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water, and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate/CH2Cl2=3/1/1) followed by recrystallization from n-hexane/ethyl acetate to give 1-[3-(benzyloxy)-2-thienyl]ethanone as a white solid (2.592 g, yield; 89%). [Starting Compound 2A]
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ccnc(C=O)c2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(c2ccnc(CO)c2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridine-2-carbaldehyde (1100 mg, 5.69 mmol) was dissolved in MeOH (15 mL). NaBH4 (278 mg, 7.05 mmol) was added portionwise at 0° C. and the reaction mixture was stirred at rt for 1 h. Water was added and the mixture extracted with EA (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.41 min; [M+H]+=196.51.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:32]([O:34]C)=[O:33])[CH2:21][C:22]3[CH:30]=[C:29]([CH3:31])[C:25]4[NH:26][CH:27]=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:32]([OH:34])=[O:33])[CH2:21][C:22]3[CH:30]=[C:29]([CH3:31])[C:25]4[NH:26][CH:27]=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]cnc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 96 mg (4.0 mmol) LiOH in 5 mL water was added dropwise to a solution of 910 mg (1.8 mmol) (R)-1-methoxycarbonyl-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 12 mL THF and the reaction solution was stirred overnight at RT. The residue was combined with 1 mL 4 M HCl and evaporated to dryness i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][N:15]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=4)=[O:24])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@@H]23)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2CC[C@@H](Oc3ccc(Cl)cn3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 100F (120 mg, 0.473 mmol) and 3-(trifluoromethyl)benzoyl chloride (118 mg, 0.568 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.3 mL, 2.18 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound 1H NMR (400 MHz, pyridine-4.90° C.) δ ppm 1.66-1.79 (m, 1 H), 2.18-2.44 (m, 4 H), 2.85-2.90 (m, 1 H), 2.92-3.13 (m, 3 H), 4.19 (br. s, 1 H), 4.58 (br. s, 1 H), 5.10-5.16 (m, 1 H), 6.64 (d, 1H, J=8 Hz), 7.40-7.50 (m, 2 H), 7.63-7.69 (m, 2 H), 7.87 (s, 1 H), 7.96 (s, 1 H); MS (DCI) m/z 426 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH:14]1[C:20](=[O:21])[N:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:1]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0° C.) of 2-methyl-malonic acid mono-tert-butyl ester (1.01 g, 5.79 mmol) and 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one (1.15 g, 4.83 mmol) in THF (8 ml) was added hydroxybenzotriazole (652 mg, 4.83 mmol), diisopropylethylamine (624 mg, 4.83 mmol)and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (925 mg, 4.83 mmol), and the mixture was stirred overnight at r.t. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=395.3 (M+H+), (920 mg, 48%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH2:83][CH2:82][C:81]2=[O:86])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:88].[Na+].[Na+].[Na+].[Na+].[CH3:93][C:94]1([CH3:177])[C:102]2[C:101]3[CH:103]=[C:104]([S:111]([O-:114])(=[O:113])=[O:112])[CH:105]=[C:106](S([O-])(=O)=O)[C:100]=3[CH:99]=[CH:98][C:97]=2[N:96]([CH2:115][CH2:116][CH2:117][CH2:118][S:119]([O-:122])(=[O:121])=[O:120])/[C:95]/1=[CH:123]/[CH:124]=[C:125](\[C:159]1[CH:164]=[CH:163][CH:162]=[C:161]([CH2:165][CH2:166][C:167](ON2C(=O)CCC2=O)=[O:168])[CH:160]=1)/[CH:126]=[CH:127]/[C:128]1[C:136]([CH3:138])([CH3:137])[C:135]2[C:134]3[CH:139]=[C:140](S([O-])(=O)=O)[CH:141]=[C:142]([S:143]([O-:146])(=[O:145])=[O:144])[C:133]=3[CH:132]=[CH:131][C:130]=2[N+:129]=1[CH2:151][CH2:152][CH2:153][CH2:154][S:155]([O-:158])(=[O:157])=[O:156].[Na+].[Na+].[Na+].[Na+].[Na+]>>[CH3:137][C:136]1([CH3:138])[C:135]2[C:134]3[CH:139]=[C:140]([S:111]([O-:114])(=[O:113])=[O:112])[CH:141]=[C:142]([S:143]([O-:146])(=[O:144])=[O:145])[C:133]=3[CH:132]=[CH:131][C:130]=2[N:129]([CH2:151][CH2:152][CH2:153][CH2:154][S:155]([O-:158])(=[O:156])=[O:157])/[C:128]/1=[CH:127]/[CH:126]=[C:125](\[C:159]1[CH:164]=[CH:163][CH:162]=[C:161]([CH2:165][CH2:166][C:167]([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH:83]=[CH:82][C:81]2=[O:86])=[O:168])[CH:160]=1)/[CH:124]=[CH:123]/[C:95]1[C:94]([CH3:93])([CH3:177])[C:102]2[C:101]3[CH:103]=[C:104]([S:111]([O-:114])(=[O:113])=[O:112])[CH:105]=[C:106]([S:119]([O-:122])(=[O:121])=[O:120])[C:100]=3[CH:99]=[CH:98][C:97]=2[N+:96]=1[CH2:115][CH2:116][CH2:117][CH2:118][S:119]([O-:122])(=[O:120])=[O:121].[Na+:88].[Na+:88].[Na+:88].[Na+:88].[Na+:88]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)NCCN3C(=O)C=CC3=O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 22 is prepared analogously to compound 21 (Example 27), except that compound 11 is used as a starting material.
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[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:40]=[CH:39][NH:38][N:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[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[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:37]4[C:36]([CH3:35])=[CH:40][CH:39]=[N:38]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc[nH]n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CCl)cc2)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of [5-({[1-(4-Chloromethyl-benzyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (200 mg, 0.412 mmol), 3-methylpyrazole (33.9 mg, 0.412 mmol) and cesium carbonate (269 mg, 0.825 mmol) in 2 mL of DMF was stirred at 80° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 μm 30×100 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min, then ACN/water (0.1% TFA) 5195-100/0 over 15 min). LCMS (Method A) RtA=1.527; [M+H]+=531.1.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1)(=[O:4])=[O:3].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:21])=[O:13])=[CH:11][C:6]=2[O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: NS(=O)(=O)O
Reactant: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A mixture of 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol) and sulfamic acid (0.223 g, 2.299 mmol) in acetic acid (8 ml) was cooled to 0° C., and a solution of sodium chlorite (0.378 g, 4.18 mmol) in water (3 ml) was added. The resulting yellow mixture was allowed to warm to RT and stirred for 2 hours. Additional sulfamic acid (0.081 g, 0.836 mmol) and sodium chlorite (0.133 g, 1.463 mmol) in water (2 ml) were added over 1 hour. The reaction mixture was diluted with water (15 ml), and the precipitate was collected by filtration, washed with water and dried to obtain 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.521 g, 1.820 mmol, 87% yield, MS/ESI+ 286.9 [MH]+). This product was employed in the next step without purification.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[C:10]#[CH:11])[CH3:7].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:6]([O:8][CH:9]([O:12][CH2:13][CH3:14])[C:10]#[C:11][C:20]([C:19]1[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=1)=[O:21])[CH3:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C#CC(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)c1cc(OC)c(OC)c(OC)c1)OCC
Reaction time: 0.5 h

Procedure:
43.6 ml of n-butyllithium solution (1.6M in hexane) are added at -78° to a solution of 10 ml (69.8 mmol) of 3,3-diethoxy-1-propyne in 210 ml of absolute tetrahydrofuran. The mixture was stirred at -78° for 30 minutes and treated at -40° with 13.70 g (69.8 mmol) of 3,4,5-trimethoxybenzaldehyde in 60 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 1 hour and treated with 100 ml of saturated ammonium chloride solution and 150 ml of ether. The aqueous phase was extracted twice with ether. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was dissolved in 100 ml of methylene chloride and added dropwise at 0° to a suspension of 176.8 g of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at 0° for 20 minutes, filtered over magnesium sulphate and evaporated. The residue was crystallized from iso-octane at 0° and there is obtained 4,4-diethoxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one of melting point 52°-54°.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].CN(C1C=CC=CN=1)C>ClCCl.Cl>[CH3:14][C:13]1[C:2]([NH:1][C:22](=[O:25])[CH:23]=[CH2:24])=[C:3]([CH:10]=[CH:11][CH:12]=1)[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1c(C)cccc1C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of the title compound of Step B (0.93 g, 4.8 mmol) in dichloromethane (10 mL) was added triethylamine (0.876 mL, 6.2 mmol) and the mixture was cooled to 0° C. Acryloyl chloride (0.433 mL, 5.3 mmol) was then added and the mixture was warmed to ambient temperature and stirred overnight. Dimethylaminopyridine (1.0 g, 7.7 mmol) was then added followed by acryloyl chloride (0.475 mL, 5.8 mmol). The mixture was stirred at ambient temperature for 0.5 h before being diluted with 1N HCl and extracted twice with dichloromethane. The organic extracts were dried (MgSO4) and concentrated to give the product of Step C (0.62 g) as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH2:11](Br)[CH3:12]>O1CCCC1>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCBr
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with ethyl bromide yielding para-ethoxyphenol. The para-ethoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-ethoxytosyloxybenzene. The para-ethoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-ethoxy-3-iodo-1-tosyloxybenzene. The 4-ethoxy-3-iodo-1-tosyloxybenzene is extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-ethoxy-3-iodophenol. The 4-ethoxy-3-iodophenol can be extracted and exposed to resin-bound triphenyphosphine (PPh3) in a solution of azopyridine and methanol (CH3OH) in a salt bath at 0° C., yielding 4-ethoxy-3-iodomethoxybenzene. The 4-ethoxy-3-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-methoxy-4-iodo-5-ethoxybenzaldehyde. The 2-methoxy-4-iodo-5-ethoxybenzaldehyde can be extracted and half of the yield can be added to tri-iso-propylsilylacetylene (TIPS-acetylene) in an amine solvent such as triethylamine, diethylamine, piperidine, or di-iso-propylethylamine. This mixture can be passed over a palladium (Pd) catalyst bed, yielding 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyl)benzaldehyde.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2([CH3:21])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]3=[O:14])[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:23].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[CH2:15]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:23])[CH:3]=2)[CH3:21])[C:12]1=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=N[O-]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
6-(3-Aminophenyl)-3-hexyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 84, 1.0 g, 3.5 mmol) was dissolved in aqueous hydrochloric acid (2.5 M, 3.5 ml) and cooled to 0° C. Sodium nitrite (0.25 g, 3.6 mmol) dissolved in water (I ml) was added to the reaction mixture and stirred for 30 min. The reaction mixture was neutralised with solid sodium carbonate and then diluted with water (5 ml). The reaction mixture was heated to 60° C. for 1 h during which time a dark brown oil formed on top of the aqueous layer. The product was extracted with dichloromethane (50 ml), and the organic extracts were dried (Na2SO4) and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (20 g) eluting with ethyl acetate:hexane (1:1) to give the title compound (0.34 g, 34%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].C[Sn](C)(C)[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]2)=[CH:19][C:18]=1[F:34]>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][C:29](=[O:33])[C:30]([NH2:32])=[O:31])[O:25][CH2:24]4)=[CH:19][C:18]=3[F:34])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1nc(-c2ccc(Br)cc2)oc1C
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Product: Cc1nc(-c2ccc(-c3ccc(N4CO[C@@H](CC(=O)C(N)=O)C4)cc3F)cc2)oc1C

Procedure:
The same procedure as in Example 1 was conducted, except for adding 4-(4,5-dimethyloxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>>[CH2:1]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: BrCc1ccccc1
Product: CN(CCO)Cc1ccccc1

Procedure:
The title compound was prepared from benzyl bromide (4 g) and 2-(methylamino)ethanol (18.6 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:14](O)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>O>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])(=[O:12])[CH3:11]
Reactant: COc1ccc(N)c(O)c1C(C)=O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(NC(C)=O)c(O)c1C(C)=O
Temperature: 60 °C

Procedure:
1-(3-Amino-2-hydroxy-6-methoxy-phenyl)ethanone (12.9 g) was added to a mixture of acetic acid (3 mls) and water (20 mls) and heated to 60° C. Acetic anhydride (9.5 mls) was then added and the whole heated on a steam bath for thirty minutes. The reaction mixture was poured into water and extracted into ether, which was dried using magnesium sulphate, and after filtration the volatiles were removed in vacuo, affording a golden brown solid which was triturated with chloroform and dried under reduced pressure, yielding 3.7 g of the sub title compound, mp 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:26][C:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])=[O:33])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 3,5-dimethyl-isoxazole-4-carbonyl chloride (43 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 12.4 mg of the title compound.