Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[C:30]([C:37]([F:40])([F:39])[F:38])=[N:29]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH:10][S:33]([C:31]1[C:30]([C:37]([F:40])([F:38])[F:39])=[N:29][N:28]([CH3:27])[CH:32]=1)(=[O:35])=[O:34])[CH3:9]
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)c(F)c1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)c(F)c1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:24]=1.C(=O)(O)[O-:40].[Na+:43]>C(COC)OC.O>[Na+:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:25]([C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:40])=[O:12])=[N:8][C:7]=2[CH:24]=1
Reactant: O=C([O-])O
Reactant: COc1cc(S(=O)(=O)c2ccc(OCC(=O)O)cc2)c2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(S(=O)(=O)c2ccc(OCC(=O)[O-])cc2)c2[nH]c(S(=O)(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 85.8 %

Procedure:
To a suspension of the sulfoxide acid (4.47 g, 0.008 mol) in glyme (75 mL) was added a solution of sodium bicarbonate (0.672 g, 0.008 mol) in water (50 mL). The reaction mixture was extracted with ethyl acetate (4×50 mL). The combined organic layers were back extracted with water (2×25 mL). The combined aqueous layers were lyophilized to give 4.1 g (88%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:38][CH:37]=[CH2:36])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: C=CCBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: C=CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 53 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 334.6 mg (0.7 mmol) of Compound 24 was used and allyl bromide was used in place of methyl iodide. As a result, 192.8 mg (yield: 53%) of Compound 5 was obtained as pale yellow crystals.
Reaction SMILES: [C:1]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:15]([N:27]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CCCCCCN1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCN=C1CCCCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 g (0.223 mole) of an enantholactam in 250 ml of benzene is added 34.1 g (0.223 mole) of phosphorous oxychloride over 30 minutes. The mixture is stirred at room temperature for 4 hours after which 41.2 g (0.223 mole) of dodecylamine is added. The reaction mixture is stirred at room temperature for 1 hour and refluxed for 4 hours then allowed to stand overnight. The resulting precipitate is washed with benzene, and the benzene wash is extracted with aqueous 2 N hydrochloric acid and combined with the precipitate. The combined fractions are made alkaline with 2N sodium hydroxide, extracted into ether-methylene chloride, dried and recrystallized from isopropyl alcohol to give 2-dodecyliminooctahydroazocine.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 144 was prepared from diphenylacetyl chloride and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.25–7.12 (m, 12H), 7.09–7.06 (m, 1H), 7.00–6.94 (m, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.60 (s, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.79 (s, 1H), 4.04 (q, 1H, J=6.4 Hz), 3.30 (q, 2H, J=5.8 Hz), 2.91–2.83 (m, 2H), 2.42–2.30 (m, 3H), 1.91 (t, 2H, J=11.4 Hz), 1.74–1.67 (m, 2H), 1.65–1.51 (m, 3H), 1.21 (d, 6H, J=6.2 Hz); ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:38][C:39]1[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])=[CH:51][C:50]2[O:49][C:48]3[C:43](=[CH:44][C:45]([F:67])=[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH:47]=3)[C:42](=[O:68])[C:41]=2[CH:40]=1>C1COCC1.CC1CCCO1.C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:42]2([OH:68])[C:43]3[CH:44]=[C:45]([F:67])[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])=[CH:47][C:48]=3[O:49][C:50]3[C:41]2=[CH:40][C:39]([F:38])=[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])[CH:51]=3)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
The bromide 13 (807 mg, 1.59 mmol) was dissolved in 20 mL THF/2-methyltetrahydrofuran (1:1) and cooled to −105° C. in a liquid N2/diethyl ether bath. After stirring at −105° C. for 10 min, 4.5 mL of tert-butyllithium (1.1 M in pentanes) was added dropwise. Stirring was continued for another 15 min. 2,7-difluoro-3,6-bis-(2-methoxy-ethoxymethoxy)-xanthen-9-one 9 (912 mg, 2.07 mmol) dissolved in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at −105° C. for 30 min, the cooling bath removed, and the reaction solution was then stirred for an additional 15 min. The resulting mixture was added to 150 mL NH4Cl(sat) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 50% EtOAc in hexane (with 0.1% Et3N) to yield 956 mg (69%) of 14 as a orange-red oil. Rf=0.33 (in 50% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 5H), 6.97 (d, 2H, J=6.98 Hz), 6.86 (m, 3H), 6.72 (m, 2H), 5.30 (s, 4H), 5.05 (s, 2H), 4.02 (s, 4H), 3.85 (m, 4H), 3.56 (m, 4H), 3.36 (s, 6H), 1.38 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.8, 149.3, 147.6, 145.6, 145.5, 145.4, 145.2, 140.5, 138.4, 136.9, 128.3, 127.7, 127.5, 119.9, 119.8, 119.3, 118.4, 115.2, 114.9, 113.0, 104.9, 94.5, 81.0, 71.4, 70.6, 69.7, 68.1, 58.9, 54.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −139.0 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (MH+) 868.4, Found 867.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:28]#[N:29].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)CC2=O
Temperature: 75 °C
Yield: 50.2 %

Procedure:
This procedure is based on the literature method.22,23 A solution of 1.03 g (2.88 mmol) of 44, 2.03 g (41.5 mmol) of NaCN in THF (30 mL) with 21 drops of H2O was stirred and heated at 75° C. under reflux for 2 h. The reaction mixture was poured into ice water (300 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with H2O (100 mL), dried over Na2SO4 and concentrated in vacuo giving a brown oil. Purification by flash chromatography on a 3×17 cm column of silica gel using 2:1 hexanes/EtOAc as eluent gave 557 mg (50%) of 45 as a white solid. Data for 45: TLC, T-1, Rf 0.3; 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 3H, H-18), 5.06 (s, 2H, benzylic-H), 6.76 (d, 1H, J=2.7 Hz, H-4), 6.81 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.20 (d, 1H, J=8.6 Hz, H-1), 7.33–7.45 (m, 5H, Ar—H).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]1)=O.C([BH3-])#N.[Na+].O>CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (250 mg, 0.766 mmol) in methanol (20 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (130 mg, 0.766 mmol) and the reaction mixture was heated for 2 minutes to reflux. After cooling to room temperature, sodium cyanoborohydride (96 mg, 1.532 mmol) was added and the reaction mixture was stirred for 1 hour. Water (40 mL) was added. The reaction mixture was concentrated. 50 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, dried over MgSO4, filtered and evaporated. The oil was purified by preperatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier. Fractions were combined and evaporated. The resulting oil was dissolved in 10 ml of methanol and 5 mL of 1 M NaOH was added portion wise. The solution was stirred for 1 hour until no protected product was visible by LC-MS. The solution was concentrated, and injected on preperatory HPLC (2 to 20% AcCN:water with 0.1% formic acid as modifier. Fractions were combined 6 M HCl was added (12 mL) and evaporated. trans-4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylic acid (50 mg, 0.107 mmol, 13.98% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.39 (m, 2H), 7.07-7.29 (m, 3H), 3.67 (d, J=12.63 Hz, 2H), 3.36 (d, J=6.82 Hz, 1H), 3.22 (d, J=6.82 Hz, 2H), 2.98-3.10 (m, 4H), 2.63 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz, 1H), 2.01-2.24 (m, 5H), 1.92-2.03 (m, 2H), 1.90 (dt, 1H), 1.69-1.85 (m, 2H), 1.64 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.51 (qd, J=3.16, 13.01 Hz, 2H), 1.33-1.45 (m, 1H), 1.03-1.25 (m, 2H); LC-MS Rt=0.50 min; MS (ESI): 371.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:21]Br>C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:21][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:13]=1
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ncccc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a room temperature suspension of N-[2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide (˜77 mmoles) in acetic acid (300 mL) was added bromine (12 mL, 228 mmoles) as a solution in 50 mL of acetic acid over a 1 hour period. The heterogenous mixture was stirred at room temperature for 5 hours over which time a thick precipitate formed. The mixture was then poured over ice, diluted with 1N Na2S2O3 (500 mL), and stirred for 1 hour. The solids were filtered, re-suspended in water (2 L), stirred for 1 hour, then filtered and washed with water again. The resulting solids were pumped to dryness at 50° C., re-suspended in HOAc (400 mL), and treated with bromine (4 mL, 76 mmoles) in acetic acid solution (20 mL) over a 20 minute period. The resulting heterogenous mixture was stirred for 5 hours, then quenched and treated as described above. The resulting solids were vacuum dried at 50° C. to afford the title compound (19.1 grams, 72%) as a tan powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:20])[C:4](=[O:13])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C=C(C)Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.91), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (244.5 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.21) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4-dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 152-153° C.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCNCC2)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCN(C3CCOCC3)CC2)cc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
A solution of Compound 143 (0.166 g, 0.44 mmol) in dichloroethane was added with acetic acid (0.176 mL, 3.08 mmol) and tetrahydro-4-pyranone (0.224 mL, 2.42 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.345 g, 1.63 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=7:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 154 (44.2 mg, 0.093 mmol, 44%).
Reaction SMILES: [F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:26][NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CNS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-fluoro-4-aminomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with methane sulfonyl chloride (1.40 mmol) and triethylamine (2.08 mmol) in dichloromethane (10 ml) at a temperature 25° C. for 2 hours followed by purification of the compound using silica gel column chromatography in 75% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.[CH3:13][NH:14][CH3:15]>C1COCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)[CH3:15]
Reactant: CNC
Reactant: CC(=O)c1cc(CCl)ccc1O
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN(C)C)ccc1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
In a solution of 2′-hydroxyacetophenone (10 g, 73.53 mmol) in 12 N HCl (160 mL) at room temperature was mixed with paraformaldehyde (2.43 g, 80.88 mmol) and stirred at 40° C. for 8 hours. The reaction was diluted with water, extracted with CH2Cl2 (3×100 mL), and concentrated using a rotary evaporator to provide 13 g of 5′-chloromethyl-2′-hydroxyacetophenone (98%). To a solution of 5′-chloromethyl-2′-hydroxyacetophenone (4 g, 21.74 mmol) in THF (50 mL) at room temperature was added dimethylamine in THF (13 mL, 26 mmol). The reaction mixture was stirred at 60° C. for 6 hours. It was quenched with water and neutralized with potassium carbonate to pH=8. Extract with CH2Cl2 (3×100 mL) followed by concentration using a rotary evaporator provided 3.86 g of 5′-(N,N-dimethylaminomethy)-2′-hydroxyacetophenone (92%). A solution of 5′-(N,N-dimethylaminomethy)-2′-hydroxyacetophenone (1.4 g, 7.25 mmol) and ethyl isonicotinate (1.1 g, 7.25 mmol) in THF (100 mL) at room temperature was mixed with NaH (1.02 g, 25.375 mmol) and was stirred at reflux for 6 hours. The reaction was quenched with water and extracted with CH2Cl2 (3×100 mL). The volume was reduced using a rotary evaporator to minimal and triturated with hexanes. The solid was collected by filtration to afford 1.85 g of the corresponding diketone (86%). A solution of the above diketone (1.85 g, 26.19 mmol) in HOAc (100 mL) was stirred at reflux for 2 hours. All the solvent was removed using a rotary evaporator to afford a solid residue. It was then re-dissolved in CH2Cl2, diluted with water and neutralized with potassium carbonate to pH=8, extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator The solid residue was purified by column (SiO2, hexanes/EtOAc/MeOH=2:2:1) to afford 1.4 g of the intermediate (80%). A solution of the above intermediate (0.7 g, 2.34 mmol) in CH2Cl2 (20 mL) was mixed with HCl in ether (10 mL, 20 mmol) and stirred at room temperature for 30 min. The solid was collected by filtration and washed with CH2Cl2 and MeOH sequentially to obtain 0.48 g of the 6-((dimethylamino)methyl)-2-(pyridin-4-yl)-4H-chromen-4-one hydrochloride (60%) as an off-white solid.