Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.[Br:12]P(Br)Br>CN(C)C=O>[Br:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(C(F)(F)F)no1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (2.5 g, 15 mmol) in dimethylformamide (25 mL) was added drop wise tribromophosphine (4.64 g 17.1 mmol, 1.15 eq) and the mixture was stirred at 0° C. for 15 min and at ambient temperature for 2 h. The reaction mixture was partitioned between 10% sodium bicarbonate and dichloromethane. The phases were separated and the organic phase was washed with water and passed over a plug of silica eluting with dichloromethane. The UV active product fractions were collected and evaporated to yield the title compound as colorless oil (2.04 g 59.3%), MS 229 and 231(M)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:35].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:35])[C:17]=2[N:26]=1
Reactant: [NH4+]
Reactant: ClCc1nc2cnc3ccccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CCl)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (3.8 g of 77% pure material, 14.2 mmol) was added to a stirring solution of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (3.0 g, 9.50 mmol) in dichloromethane (60 mL). After 15.5 hours, ammonium hydroxide (12 mL) and then p-toluenesulfonyl chloride (2.2 g, 11.4 mmol) were added to the stirring solution and the biphasic mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with water (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic fractions dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 3-20% methanol in dichloromethane) to provide 1.6 g of 2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[Na].[CH3:19][OH:20]>>[CH2:19]([O:20][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: CC(Oc1ncn(-c2ccccc2)n1)C(=O)O
Agent: [Na]
Product: CC(Oc1ncn(-c2ccccc2)n1)C(=O)OCc1ccccc1

Procedure:
A 5.5 g portion of the compound of Example 22 was added to 50 ml of methanol containing 0.54 g of sodium, and the mixture was heated briefly to reflux. It was then cooled and the solvent was removed under vacuum. To it was added 75 ml of toluene, 2.6 ml of benzyl chloride and 2.3 g of triethylamine, and the mixture was heated under reflux for 22 hours. It was then cooled, poured over ice-water, and extracted with ethyl acetate. The extract was washed with water and with saturated brine, and was dried with sodium sulfate and phase separation paper. It was then evaporated under vacuum, and the residue was recrystallized from ethanol-water to obtain 2.5 g of the desired product, m.p. 78°-80°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CC(C)CN
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCC(C)C
Yield: 82 %

Procedure:
The compound prepared in Example 3 was reacted with isobutylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (3.08 g, 14 mmol) in DMF (30 mL) at 0-5° C. was added 60% NaH (1.05 g, 26 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 14 mmol) in DMF (20 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.66 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49]([N:28]1[CH2:29][CH:30]2[CH2:31][N:24]([CH2:23][CH2:22][CH2:21][N:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])[CH2:25][CH:26]2[CH2:27]1)(=[O:51])=[O:50]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(S(=O)(=O)c4ccc(F)cc4Cl)CC3C2)c2ccc(C)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 42b (0.016 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105 mmol) in DCM (1 mL) at RT was added 2-chloro-4-fluorobenzenesulfonyl chloride (104, 0.016 g, 0.07 mmol) and the mixture shaken overnight at rt. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford II-296: ms (ES+) m/z 639 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@H:11]([CH2:14][CH3:15])[CH2:12][OH:13])=[N:6][C:7]=1[CH2:8][CH3:9].[C:18](OCC)(=O)C>CCCCCCC>[Br:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][C@@H:11]([CH2:12][O:13][CH3:18])[CH2:14][CH3:15])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: CCc1nc(N[C@H](CC)CO)c(CC)nc1Br
Solvent: CCCCCCC
Product: CCc1nc(N[C@H](CC)COC)c(CC)nc1Br
Yield: 42 %

Procedure:
Following the general procedure of Example 13 Step 3 and making non-critical variations but substituting (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol with (2R)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol (Example 12 Step 2) (353 mg, 1.17 mmol) gave 154 mg (42%) of 5-bromo-3,6-diethyl-N-[(1R)-1-(methoxymethyl)propyl]pyrazin-2-amine as a yellow oil after Biotage MPLC (40 g column, 20% ethyl acetate in heptane).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][C:23]#[N:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1-Benzyloxycarbonyl-3-mesyloxymethylpiperidine (WO 0100207; 8.4 g) was dissolved in DMSO (100 ml) and sodium cyanide (1.6 g) was added. The mixture was heated to 100° C. and stirred continuously under an argon atmosphere for 6 hours. The mixture was cooled and poured into water (200 ml). The product was extracted with EtOAc, washed with ferrous sulphate solution (10% w/w), dried and evaporated in vacuo. TLC (40% EtOAc/petroleum ether (60/80) Rf. 0.54.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[C:17](Cl)(=[O:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:28])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: COC(=O)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (0.137 g, 1.09 mmol) and DIPEA (0.52 mL, 2.98 mmol) in DCM (5 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (0.20 g, 0.992 mmol) in DCM (2 mL) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with water, and the organic layer was separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.213 g, 84% yield) as a white solid. LCMS, [M+Na]+=277.1. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=9.1 Hz, 2H), 7.32 (d, J=9.1 Hz, 2H), 5.62 (br. s, 1H), 4.07 (d, J=5.5 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.88 g, 1.5 mMol) in CH2Cl2 (10 mL) was added Et3N (0.23 mL, 1.6 mMol) and toluoyl chloride (0.21 mL, 1.6 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (5-15% EtOAc/hexane) followed by trituration with pet, ether, filtration and drying under vacuum gave the title compound (0.89 g, 90%) as a white solid: MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1.CCN(CC)CC>C(Cl)Cl>[CH:38]1([S:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]5[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]5)[C:20]5[C:15](=[N:16][CH:17]=[CH:18][N:19]=5)[CH:14]=4)=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCN(S(=O)(=O)C5CC5)CC4)cc3)cc3nccnc23)C1
Yield: 42.6 %

Procedure:
A solution of (S)-tert-butyl 2-((7-(4-(piperazin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (100 mg, 0.20 mmol), cyclopropanesulfonyl chloride (33 mg, 0.24 mmol) and Et3N (41 mg, 0.40 mmol) in 5 mL of DCM at 0° C. was stirred at room temperature for 1 hour. The volatiles were removed in vacuo, and the residues was purified by chromatography with PE/EA (1:2˜1:10) to give 52 mg of title compound.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:19]=[N:20][CH:21]=1.C=O>CO>[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:1])[CH2:25][C@@H:24]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc([C@H]2CNCCN2Cc2cncc(Br)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2cncc(Br)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
Sodium triacetoxyborohydride (1.5 g, 7 mmol) was added to a mixture of (S)-1-(5-bromo-pyridin-3-ylmethyl)-2-(4-fluoro-phenyl)-piperazine (as tris(trifluoroacetate) salt) (820 mg, 1.2 mmol) and formaldehyde (37% aqueous solution, 3 mL, 36.9 mmol) in 20 mL of methanol. The mixture was stirred at ambient temperature overnight, and then the volatiles were removed in vacuo and the residue dissolved in water and the pH was adjusted to 11 by the addition of 10 M sodium hydroxide solution. The product was extracted into dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to leave 431 mg of product. LC/MS: Retention time, 2.15 min; (M+H)=366.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH:15]2[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]2[O:13][CH2:12]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH:15]3[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]3[O:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1COC2C(OCCO)COC12
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCCOC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a suspension of 2,4,5-trichloropyrimidine (0.71 g, 3.88 mmol) in EtOH (20 mL) were added 2-((6-aminohexahydrofuro[3,2-b]furan-3-yl)oxy)ethanol (crude product) and N,N-diethylethanamine (1.10 mL, 7.89 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as brown liquid (0.21 g, 16%, for three steps).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH:8][C:9]1[C:14]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]3[C:27]4[N:28]=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[S:30][C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:13][CH:12]=[C:11]([C:35]([F:38])([F:37])[F:36])[N:10]=1)[CH3:7].[CH3:39][C:40]([CH3:42])=O>>[CH:40]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH:8][C:9]1[C:14]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]3[C:27]4[N:28]=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[S:30][C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:13][CH:12]=[C:11]([C:35]([F:38])([F:36])[F:37])[N:10]=1)[CH3:7])([CH3:42])[CH3:39]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N[C@H](C)[C@H]4CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N[C@H](C)[C@H]4CCCN4C(C)C)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-((R)-1-((R)-Pyrrolidin-2-yl)ethylamino)-6-(trifluoromethyl)pyridin-3-yl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide, Example 12(d), (135 mg, 0.25 mmol) was reacted with acetone (56 μL, 0.75 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 586 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(F)cc1

Procedure:
By employing the procedures set forth in Examples 1 and 3, p-fluorophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide to give ethyl 3-cyano-3-(p-fluorophenyl)-pyruvate. Reaction of the latter under similar conditions with p-fluorophenylacetonitrile results in 2,5-di-(p-fluorophenyl)-3,4-dioxoadiponitrile.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[O:7][CH:8]([CH3:9])[C:4]=2[CH:3]=1.[Cl-].[Li+].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>C1(C)C=CC=CC=1.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>[CH3:9][CH:8]1[C:4]2[CH:3]=[C:2]([CH2:17][CH:16]=[CH2:15])[CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[O:7]1
Reactant: CC1OC(=O)c2ccc(Br)cc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)C(C)OC2=O

Procedure:
5-Bromo-3-methyl-2-benzofuran-1(3H)-one (1.00 g, 4.40 mmol) was dissolved in toluene (30 mL) treated with lithium chloride (0.560 g, 13.2 mmol), Pd(Ph3P)4 (0.254 g, 0.220 mmol), and allyl tributylstannane (1.75 g, 5.29 mmol). The reaction mixture was degassed and stirred at reflux under N2 for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate; the organic layer was washed wtih brine 1×, dried and purified by MPLC eluting with 0-10% ethyl acetate/hexanes. to afford the title compound. 1H NMR (500 MHz, D-DMSO, δ in ppm): 7.75 (d, J=8 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=8 Hz, 1H), 6.00 (m, 1H), 5.66 (q, J=6.5 Hz, 1H), 5.13 (m, 2H), 3.53 (d, J=6.5 Hz, 2H), 1.54 (d, J=7 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6](Cl)(Cl)[CH:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])C(=S)N>>[Cl:5][CH:6]=[CH:7][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[S:13]
Reactant: CCOC(=S)CC(C(N)=S)C(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=S)CC=CCl
Reaction time: 0.5 h

Procedure:
Thionyl chloride (25 ml) is dropwise added to the ester (3) (47.6 g). After 30 minutes at 30° C., the mixture is distilled in vacuo (b.p. 104°-105° C./7 mmHg, Yield: 43 g). To the distillate are added benzene (82 ml) and DBU (42 ml), and the mixture is heated under reflux for 1.5 hours. The reaction mixture is washed with water and distilled in vacuo to give methyl vinylthioacetate (4). Yield: 24.7 g, b.p. 59°-65.5° C.4-5 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A solution of tert-butyl {1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 2, 150 mg, 0.37 mmol) in dioxane (4 mL) was treated at room temperature under vigorous stirring with a solution of HCl in dioxane (4M, 2 mL). After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was extracted three times with dichloromethane (3×50 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 113 mg (100% yield) of the crude product as an oil.
Reaction SMILES: [C:1]1([CH:7]([CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[CH2:32]([O:31][C:29]([N:17]1[CH2:18][CH2:19][O:20][CH:15]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16]1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CC(c2ccccc2)C2CNCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCOC(C(Cc2ccccc2)c2ccccc2)C1
Reaction time: 24 h

Procedure:
To a solution of 2-(1,2-Diphenyl-ethyl)-morpholine (2 g, 7.49 mmol) in dry dichloromethane (15 ml) at 0° C. under nitrogen atmosphere is added neat triethylamine (2.2 ml, 15.5 mmol, 2.07 equiv.) followed by the addition of neat benzyl chloroformate (1.61 ml, 11.23 mmol, 1.5 equiv.). The reaction is left to reach room temperature over 24 hours and then quenched by addition of a saturated bicarbonate (NaHCO3) aqueous solution. The resulting mixture is extracted with dichloromethane and the resulting organic phases are mixed, dried (MgSO4) and concentrated under reduced pressure to give an oil containing the four possible diastereoisomers (2.3 g, 78%). The diastereoisomers are separated using preparative HPLC, followed by each single enantiomer being resolved by preparative chiral HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[Br:17]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Nc1ccc(-c2nc3ccccc3s2)cc1Br
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 79 %

Procedure:
To a solution of 2-(4'-aminophenyl) benzothiazole (0.45 g, 1.99 mmol) in CH2Cl2 (50 ml) was added a solution of bromine (0.32 g, 1.99 mmol) in CH2Cl2 (10 ml) at -5° C. After the reaction mixture had been stirred still at -5° C. for 2 minutes, it was poured into ice-water (400 ml). The resulting mixture was stirred for 40 minutes at room temperature. The organic layer was separated, washed with 10% aqueous sodium thiosulfate (50 ml×2) and water (60 ml×2), dried (MgSO4) and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate-hexane (1:3), to give pale yellow crystals (0.48 g, 79.1%), m.p. 160.0-161.4° C.