Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19]Cl.[CH3:21][C:22]1([CH3:28])[O:27][CH2:26][CH2:25][NH:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][N:24]1[CH2:25][CH2:26][O:27][C:22]([CH3:28])([CH3:21])[CH2:23]1
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(CCl)c(C)n1
Reactant: CC1(C)CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCc1cccc(CC)c1-c1cc(Cl)c(CN2CCOC(C)(C)C2)c(C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-3-chloromethyl-6-(2,6-diethyl-phenyl)-2-methyl-pyridine (310 mg, 1.0 mmol), 2,2-dimethyl-morpholine (150 mg, 1.3 mmol) and K2CO3 (417 mg, 3 mmol) in CH3CN (10 mL) is stirred at room temperature for 16 hours. EtOAc (20 mL) and water (20 ml) are added to the mixture. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=2[CH3:16])=[C:5]([CH3:19])[C:4]=1[CH:20]([CH3:22])[CH3:21].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:16])=[C:5]([CH3:19])[C:4]=1[CH:20]([CH3:22])[CH3:21]
Reactant: COc1ccc(Cc2ccc(OC)c(C(C)C)c2C)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)ccc1Cc1ccc(O)c(C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a stirring solution of 4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)-3-methyl-anisole (0.8 g, 2.68 mmol) in CH2Cl2 (10 mL) at −20° C. was added BBr3 (10.7 mL, 1M in CH2Cl2). The reaction mixture was stirred at room temperature for 16 hrs. Ice was add and the mixture was diluted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1) to afford 4-(4′-hydroxy-2′-methyl-3′-iso-propylbenzyl)-3-methylphenol as a yellow solid (0.54 g, 75%): 1H NMR (200 MHz, DMSO-d6): δ 9.03 (s, 1 H), 8.84 (s, 1 H), 6.41-6.60 (m, 5 H), 3.65 (s, 2 H), 3.33 (m, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H), 1.27 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf=0.31.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:29])[C@H:5]1[CH2:9][CH2:8][N:7](CC(C2(O)CCCCC2)C2C=CC=C(C(F)(F)F)C=2)[CH2:6]1.Cl.Cl.N[C@H]1CCN([CH2:38][CH:39]([C:50]2([OH:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)C1>>[ClH:1].[ClH:1].[CH3:3][N:4]([CH3:29])[C@H:5]1[CH2:9][CH2:8][N:7]([CH:51]2[CH2:52][CH2:53][CH2:54][CH2:55][C:50]2([CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:49])[F:48])[CH:41]=2)[CH3:38])[OH:56])[CH2:6]1
Reactant: N[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CN(C)[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CC(c1cccc(C(F)(F)F)c1)C1(O)CCCCC1N1CC[C@H](N(C)C)C1

Procedure:
In an analogous manner to Example 36, 1-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from, 1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol (See Example 221). MS (ES) m/z 385.1; HRMS: calcd for C21H31F3N2O+H, 385.24667; found (ESI, [M+H]+), 385.2454.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:45][CH2:46][CH3:47])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[N+:41]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:45][CH2:46][CH3:47])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[NH2:41])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (688 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][N:10]=[C:11]([OH:21])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:25])=[N-]>CO>[C:1]1([NH:7][C:8](=[O:22])[NH:9][N:10]=[C:11]([O:21][CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:18](=[O:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=[N+]=[N-]
Reactant: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1ccccc1
Solvent: CO
Product: COC(=NNC(=O)Nc1ccccc1)c1cccnc1C(C)=O

Procedure:
A suspension of 2-acetylnicotinic acid 4-phenylsemicarbazone (compound 1) (0.50 g) in 20 ml of methanol is treated with diazomethane until the yellow color of the solution persists. The solvent is removed in vacuo to give methyl 2-acetylnicotinate 4-phenylsemicarbazone, m.p. 177°-178° (compound 53, Table C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14]#[C:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)[OH:23]>>[CH2:18]([N:17]([CH2:20][CH3:21])[CH2:16][CH2:15][C:14](=[O:23])[CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14](=[O:23])[CH:15]=[CH2:16])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CC#CCCCc1cc(OC)cc(OC)c1
Product: C=CC(=O)CCCc1cc(OC)cc(OC)c1
Product: CCN(CC)CCC(=O)CCCc1cc(OC)cc(OC)c1

Procedure:
Proceed exactly as described for the preparation of the 3,4-dimethoxy compound above, using 6-(3,5-dimethoxyphenyl)-1-diethylaminohex-2-yne (8.5 g.), mercuric sulphate (0.45 g), and 10% sulphuric acid (25 cc) to obtain 1-diethylamino-6-(3,5-dimethoxyphenyl)hexan-3-one and 6-(3,5-dimethoxyphenyl)hex-1-en-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][N:20]=[N+]=[N-])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N:51]=[C:52]=S)[CH:46]=1.O>O1CCOCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:23][C:52]([NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([Cl:44])[CH:46]=4)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CN=[N+]=[N-])cc2)CC1
Reactant: S=C=Nc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
To a solution of {4-[4-(2-azidoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (154 mg, 0967 mmol) in 1,4-dioxane (5 mL) is added triphenylphosphine (122 mg, 0.967 mmol) and 1-chloro-3-isothiocyanatobenzene (0.051 mL, 0.389 mmol). The reaction mixture is then heated at 90° C. for 30 min. Water (10 mL) is added and EtOAc (20 mL) is used to extract. The organic phase is washed with brine (1×15 mL), dried with MgSO4, and concentrated to give the title compound (109 mg) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.20 Hz, 3H) 1.12-1.19 (m, 2H) 1.43-1.52 (m, 2H) 1.81 (d, J=10.61 Hz, 4H) 1.73-1.84 (m, 1H) 2.23 (d, J=6.82 Hz, 2H) 4.07 (q, J=7.07 Hz, 2H) 6.99 (ddd, J=7.83, 2.02, 0.76 Hz, 1H) 7.28-7.36 (m, 3H) 7.41 (s, 1H) 7.47-7.53 (m, 3H) 7.85 (t, J=2.02 Hz, 1H) 10.52 (s, 1H); (M+H)+439.2.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.Cl.[NH:9]1[CH:13]=[C:12]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][C:24](C4C=NC=CC=4)=[CH:25][C:20]=3[CH2:19][N:18](C(=O)C(F)(F)F)[CH:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:16]2)[N:11]=[CH:10]1.C[CH2:46][N:47](C(C)C)C(C)C>C(Cl)Cl>[ClH:5].[NH:9]1[CH:13]=[C:12]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][C:24]([C:46]#[N:47])=[CH:25][C:20]=3[CH2:19][N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[C@H:17]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:16]2)[N:11]=[CH:10]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
Methylsulfonylchloride (0.031 ml, 0.39 mmol) was added dropwise to a solution of Compound B (0.070 g, 0.27 mmol) and DIEA (0.14 ml, 0.80 mmol) in methylene chloride (2 ml) at −78° C. The mixture was allowed to warm slowly to room temperature and was stirred at rt for 16 h. The mixture was quenched with 10% NaHCO3 (10 ml) and the solution was extracted with methylene chloride (3×10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1 methylene chloride/iPrOH) to afford Compound C (0.064 g, 85%) as a solid. MS (M+H)+ 343.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Yield: 69.1 %

Procedure:
A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), (4-aminophenyl)(morpholino)-methanone (408 mg, 1.98 mmol) and CSA (356 mg, 1.53 mmol) in iPrOH (30 mL) was stirred at 90° C. overnight. The solvent was evaporated. The residue was dissolved in DCM (30 mL). A NaHCO3 solution (10 mL) was added to adjust to pH=8. The organic layer was separated and dried over Na2SO4. The drying agent was removed by filtration and the resultant solution was concentrated in vacuo. The residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:1) to give the desired product as a yellow solid (500 mg, 69% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:2]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: O=C(Cc1ccccc1)c1ccoc1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccoc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 110 °C
Yield: 11 %

Procedure:
A mixture of 1-(furan-3-yl)-2-phenylethanone (Intermediate 22) (692 mg, 3.72 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (942 mg, 4.46 mmol), and urea (669.6 mg, 11.16 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.2 mL), and the reaction mixture was refluxed (110° C.) for thirteen hours. TLC (eluting with EtOAc) showed that the most of the starting materials were consumed. The reaction mixture was concentrated, and purified by column chromatography and preparative HPLC to afford Compound 50 as a yellow solid (173 mg, yield: 11.0%). 1H NMR (DMSO-d6 400 MHz TMS): δ10.26 (s, 1H), 8.478 (s, 1H), 6.981-7.708 (m, 10H), 5.766 (s, 1H), 5.141 (d, J=2.4 Hz, 1H), 3.918-4.061 (m, 2H), 1.304 (t, J=6.8 Hz, 3H); MS (ESI): m/z 422.1[M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:21])([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:18][C:17]([F:19])([F:20])[CH2:16][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:21])[CH2:13][OH:14]
Reactant: CC(CC(F)(F)F)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO)(CC(F)(F)F)NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-4,4,4-trifluoro-2-methylbutanoic acid (1.6 g, 5.2 mmol) in THF (17 ml) was cooled to 0° C. and triethylamine (910 ul, 6.5 mmol) was added, then ethyl chloroformate (624 ul, 6.5 mmol) dropwise over 40 min. A solution of sodium borohydride (491 mg, 13 mmol) in H2O (2.6 ml) was added dropwise over 2 h. The reaction was quenched by the addition of 1 M HCl, stirred for 5 min, and then extracted with EtOAc. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried on Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (15% to 100% EtOAc in hexanes) to afford the title compound as a clear oil (838 mg). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.33-2.45 (m, 1H), 2.93-3.03 (m, 1H), 3.62 (br s, 1H), 3.65-3.76 (m, 2H), 5.07-5.10 (m, 3H), 7.28-7.39 (m, 5H). LRMS (ESI/APCI): 292 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.C[N:38]([CH:40]=O)[CH3:39].[CH2:42]1[CH2:46][O:45][CH2:44][CH2:43]1>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([NH:24][C:23]4[CH:44]=[CH:43][C:42]([C@H:46]([OH:45])[C:39]5[CH:3]=[CH:2][CH:1]=[CH:40][N:38]=5)=[CH:21][CH:22]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3S(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.50 g) in THF (10 ml) were added thionyl chloride (0.12 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, a solution of the residue in THF (20 ml) was added dropwise at 0° C. to a solution of (S)-(+)-(4-aminophenyl)(2-pyridyl)methanol (0.24 g) and triethylamine (0.6 ml) in THF (5 ml), and the mixture was stirred for 18 hours at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 93) (542.7 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][CH2:12][C:11](=O)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29])=[CH:23][CH:22]=1>O1CCOCC1.CCOC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][C:11]([NH:29][CH2:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)([CH3:31])[CH3:30])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: O=C1CNC(c2cccc(Cl)c2)=NN1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(CNc1cnc(-c2cccc(Cl)c2)nn1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
To a solution of 3-(3-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (6.0 g, 29 mmol) dissolved in dioxane (75 mL) was added MnO2 (10 g, 120 mmol). The mixture was stirred at 90° C. for 18 h. After filtering through diatomaceous earth and rinsing with hot dioxane, the combined organics were evaporated to dryness in vacuo. The crude residue (⅓ was used) was dissolved in POCl3 (10 mL, 108 mmol) and heated to 70° C. for 2.5 h. The mixture was allowed to cool to rt and evaporated to dryness in vacuo. The residue was dissolved in EtOAc/ether (1:1) and washed with 1 M NaOH. The organic phase was evaporated to dryness and dissolved in NMP (5.0 mL) in a microwave vial. Potassium carbonate (1.0 g) was added followed by (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.0 g, 12 mmol), and the mixture was heated in a microwave reactor to 165° C. for 20 min. The solution was diluted with EtOAc and washed with saturated NaCl (4×), dried over Na2SO4, and evaporated to dryness. Purification using silica gel chromatography (0-35% EtOAc/hexanes) gave the desired product (430 mg) as an orange film.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19].ClC(Cl)(Cl)C(O)=O>CC(C)=O>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19]
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=C(NO)N1CCOCC1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(N1CCOCC1)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 96 h

Procedure:
1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 ml of acetone were treated with 630 mg (4.3 mmol) of N-hydroxymorpholino-carboxamide and a trace of trichloroacetic acid and stored at -25° C. After 4 days the crystals were drawn off by suction and recrystallized from acetone.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=1>CO.O>[Cl:11][C:9]1[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=[C:5]([O:2][CH3:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Sodium methoxide (28% solution in methanol, 47.0 g, 244 mmol) was added dropwise to a stirred solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (48.3 g, 232 mmol) in methanol (600 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water, concentrated, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.9 g, 58.5 mmol, 25%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.[OH-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Temperature: 92.5 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (3.00 g), malonic acid (1.99 g) and bis(2-methoxyethyl) ether (9 mL) was added dropwise piperidine (1.89 mL) over about 10 min. The mixture was stirred at 90-95° C. for 1 hr. and further at 105-110° C. for 4 hrs. After cooling to 25° C., toluene (12 mL) and 1N aqueous sodium hydroxide solution (15 mL) were added and the mixture was stirred. The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide solution (6 mL). The aqueous layers were combined and washed with toluene. The layers were adjusted to pH 3.5-4.0 with 2N hydrochloric acid at 20-30° C. and water (9 mL) was added dropwise. After stirring at 25° C. for 1 hr., the precipitated crystals were collected by filtration and washed with 20% ethanol to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (3.24 g, yield 90%).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:15][CH3:16].C(O)(=O)C.[O-]S([O-])(=O)=O.[Mg+2]>CO.CCOC(C)=O>[CH3:16][NH:15][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CNC(C)=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl acetoacetate (57.6 g, 300 mmol) in MeOH (50 mL) in a 350 mL pressure vessel was added H2NMe (150 mL of a 2M solution in MeOH, 300 mmol) and acetic acid (2 mL). The capped vessel was placed in an oil bath at 70° C. and the reaction mixture was stirred for 16 hours. After the mixture had cooled to room temperature, the solvent was evaporated in vacuo leaving a yellow emulsion, which was dissolved in EtOAc (500 mL) and MgSO4 was added to remove water. The drying agent was filtered off, and the solvent evaporated in vacuo to give benzyl 3-(Methylamino)but-2-enoate as a viscous yellow oil in quantitative yield 60 g which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. The reaction mixture was then partitioned between water and ethyl acetate, and the two layers were separated. The aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give 7.15 g (90%) 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).