Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35]>>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C@@H:24]([CH:27]3[CH2:29][CH2:28]3)[CH2:25][NH:37][S:34](=[O:36])(=[O:35])[N:33]([CH3:38])[CH3:32])[C:5](=[O:30])[C@@:4]([CH3:31])([CH2:1][CH:2]=[CH2:3])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)S(N)(=O)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)N(C)C)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A) and N,N-dimethylsulfamide (TCI America, Portland, Oreg.) following a procedure similar to the one described in Example 202, Step C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:11][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(=O)O)c(F)c2)cn1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 4-bromo-2-fluorobenzoic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and 10 molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) δ 13.30 (br s, 1H), 8.59 (d, 1H), 8.11 (dd, 1H), 7.90 (t, 1H), 7.68-7.57 (m, 2H), 6.91 (d, 1H), 3.88 (s, 3H). ESI MS (M+1)+: 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:11][Si](C(C)(C)C)(C)C)=[CH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.CS(N)(=O)=[O:21].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[C@H:9]([OH:21])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC=C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 28 h
Yield: 86.2 %

Procedure:
Z-1-(3-Chlorophenyl-tert-butyldimethylsilyloxy-1-propene (12.0 g, 44 mmol) was added to a well-stirred mixture of AD-mix-P (80 g) and CH3SO2NH2 (4.2 g, 44 mmol) in tert-butyl alcohol/water mixture (220 mL/220 mL) maintained at 0° C. The reaction mixture was stirred at 0° C. for 28 hours. Solid sodium sulfite (40 g) was added. The mixture was stirred for an additional 45 minutes and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with NaHCO3 and brine, and evaporated. The residue was passed through a silica gel column to give the desired product (7.0 g). 1H NMR (CDCl3): δ 1.45 (d, 3H), 5.15 (q, 1H), 7.2-7.9 (m, 4H).
Reaction SMILES: [N:1]1([N:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[C:14]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C(=Nn2cncn2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc(C(Nn2cncn2)c2ccccc2)cc1

Procedure:
Added to a solution of 2.0 g (8.1 mmol) of N-(1H-1,2,4-triazol-1-yl)-benzophenoneimine in 20 mL of ethanol was 0.45 g (12.1 mmol) sodium borohydride at room temperature. After stirring 41/2 h, aqueous ammonium chloride was added and the mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. Product can be purified by crystallization from n-butylchloride; yield 1.7 g (84%); mp 142°-145° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].CN(C)C=O.[CH2:41]([NH2:46])[CH2:42][CH2:43][CH2:44][CH3:45]>O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23]([NH:46][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:24])[N:17]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCCCCN
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Yield: 74.4 %

Procedure:
0.65 g (1.1 mmol) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate, 12 ml of dimethylformamide and 1 ml (8.8 mmol) of pentylamine are heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 0.35 g (76%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}propanoate is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:13])[C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid (4.68 g, 24.1 mmol) in dichloromethane (50 mL) at 0° C. is treated with oxalyl chloride (11.5 mL, 132 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at 0° C. for 5 minutes and then at room temperature for 1.5 hours. The mixture is concentrated to dryness and subsequently co-evaporated from benzene. The resulting acid chloride is diluted with dichloromethane (50 mL), cooled to 0° C., and anhydrous ethanol (15.0 mL, 256 mmol) is added dropwise. The resulting solution is stirred at room temperature for 4.5 hours, then poured into saturated NaHCO3 and extracted with chloroform. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5.37 g). 1H NMR (CDCl3): δ 7.67–7.55 (m, 1H), 4.42 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Ni]>[NH2:19][C:18]1[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
Raney Ni (1 g) was added to a solution of methyl 2-(bis-(tert-butoxycarbonyl)amino)-3-nitrobenzoate 12 (6 g, 27.5 mmol) in THF. The reaction mixture was hydrogenated under balloon pressure for 4 h. The catalyst was removed by filtration and the solvent evaporated to give 13 (4.4 g, 80% yield).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([C:32]([NH2:34])=O)[CH:27]=1.C(N(CC)CC)C.O>ClCCl.CCCCCC>[O:24]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:14])[N:16]1[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([C:32]#[N:34])[CH:27]=1
Reactant: Cn1nc(C(N)=O)cc1CN1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cn1nc(C#N)cc1CN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
A solution of trifluoroacetic anhydride (0.996 mL, 7.05 mmol) in dichloromethane (15 mL) was added slowly to a 0° C. solution of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxamide (1.67 g, 5.87 mmol) and triethylamine (1.78 g, 17.6 mmol) in dichloromethane (15 mL). The resulting solution was stirred for 30 minutes, and water (50 mL) was added. The work-up procedure described in Part D of Example 64 was followed. Hexane (100 mL) was added to the resulting off-white solid, which was isolated by filtration and washed with hexane. The resulting light-brown solid was purified by chromatography using a HORIZON HPFC system (40M cartridge, eluting with 1% to 10% CMA in chloroform) to provide 1.57 g of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[CH:9]2)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][CH:14]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CCOC(=O)c1ccc2ncncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of quinazoline-6-carboxylic acid ethyl ester (79 mg, 0.391 mmol) in ethanol (4 mL) was added an aqueous solution of 1N sodium hydroxide (4 mL), and the solution was stirred for 1 hour at room temperature. 1N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and the solution was evaporated in vacuo. Ethanol was added to the residue, and the organic layer was concentrated. The residue was dissolved in an ethyl acetate-tetrahydrofuran mixture solvent, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and quinazoline-6-carboxylic acid (15 mg, 0.086 mmol, 22%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH3:13])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCC(Oc1ccccc1)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 57.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.64 g of 2-phenoxybutyric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C1COCC1.[BH4-].[Na+].CO>C(O)(C)(C)C.C(O)(=O)C>[Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)(C)O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
To a suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (2.0 g, 0.004 mol) in t-butanol (15.0 mL and THF (5.0 mL) was added NaBH4 (0.18 g, 0.0047 mol) and the mixture was stirred at room temperature for 16 h under argon atmosphere. It was cooled, added MeOH (5.0 mL) and acetic acid (1.0 mL) and concentrated to dryness. The residue was triturated with water and filtered. It was washed with water, dried in vacuo and purified by flash chromatography (1% MeOH in EtOAc to afford the title compound (0.75 g, 41%) as a pale yellow powder: 1H NMR (CD3OD/400 MHz) δ 8.58 (d. 1H, J=1.6 Hz), 8.56 (d, 1H, J=1.6 Hz), 7.6 (m, 1H), 7.01 (m, 2H), 6.52 (s, 1H), 5.46 (s, 2H), 5.29 (s, 2H), 4.71 (s, 2H), and 2.54 (s, 3H); 19F NMR (CD3OD/400 MHz) δ −111.70 (m), and −116.06 (m); ES-HRMS m/z 452-0394 (M+H C19H17N3O3BrF2 requires 452.0416).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]([CH3:19])[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN(C)CC(C)(C)CO
Product: CN(C)CC(C)(C)COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and 3-(dimethylamino)-2,2-dimethylpropan-1-ol, reacted in an analogous manner to the preparation of intermediate 68. UPLC-MS 3: Rt=0.40 min; MS m/z [M+H]+ 249.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:2]C.C1C[O:24]CC1>O.[Os](=O)(=O)(=O)=O>[O:24]=[CH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC=Cc1ccc(OC)cc1CCC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COc1ccc(CC=O)c(CCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of tert-butyl 3-(2-propeny-5-methoxyphenyl)propionate (7.2 g, 26 mmol) in THF (60 mL) and H2O (30 mL) were added NaO4 (9.8 g, 46 nmmol) and 4% osmium tetroxide (1 mL). After stirring at RT, the mixture was filtered and the filtrate was diluted with ether. The combined extracts were dried and evaporated to give the crude product which was flash chromatographed to give the titled compound (3.0 g; 43% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([Cl:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Product: CC(C)(COCc1ccccc1)C(=O)Cl

Procedure:
The obtained carboxylic acid (3.0 g) was reacted with 4 ml of thionyl chloride, and 3-benzyloxy-2,2-dimethylpropionyl chloride was obtained quantitatively as an oily material.
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(CC)CC>CO.[Fe]>[Cl:3][C:4]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1Cl
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A mixture of concentrated hydrochloric acid (1.0 mL), water (50 mL) and iron powder (5.58 g, 100 mmol) was stirred at 65° C. for 15 min. The aqueous layer of the mixture was poured out, and a solution of 2-chloro-N,N-dihexyl-4-nitroaniline (3.41 g, 10 mmol) in MeOH (100 mL) was added to the above processed iron powder. The mixture was acidified to pH 3 with hydrochloric acid and stirred at 65° C. for 45 min. The mixture was then cooled to rt, adjusted to pH 10 with Et3N and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in 150 mL of DCM. The solution was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (3.00 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16]>C(#N)C>[C:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 10.0 g (57.8 mmol) of 4-bromophenol in 100 mL of acetonitrile was added 9.6 g (69.5 mmol) of potassium carbonate. A white slurry was obtained to which was added 8.6 mL (121.0 mmol) of acetyl chloride and the resultant reaction mixture was stirred at ambient temperature for 17.5 hours. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a clear, nearly colorless oil.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])=[O:19]>>[N:1]1([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[O:19])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: O=C(CCl)N1CCNCC1=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(CC(=O)N2CCNCC2=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 364.6 %

Procedure:
Thymine (630.6 mg, 5 mmol) and K2CO3 (1.38 g, 10 mmol) were combined in a 50 mL round bottom flask and azeotroped with benzene (3×10 mL). The mixture was suspended in anhydrous DMF (15 mL) under argon and allowed to stir at room temperature for 4 hours. Solid chloroacetyl piperazinone (1.37 mmol, 1.4 eq) as prepared was added, and the reaction mixture was stirred for an additional 3-4 hours. The crude reaction mixture was filtered, concentrated and precipitated by treatment with EtOAc (30 mL). The solid was washed extensively with EtOAc and dried in a dessicator under vacuum to afford 1.33g of N-(thymin-1-ylacetyl)-piperazinone (100% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13](=[O:12])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)P(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
134 parts of 2-methylbenzoyl-diphenylphosphine oxide are prepared from 77 parts of 2-methyl-benzoyl chloride and 108 parts of methoxydiphenylphosphine by a method similar to that described for compound XI. Yield 84% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[OH:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[OH:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.77 g (38.50 mmol) of 2-hydroxy-5-nitrobenzoyl chloride dissolved in 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization in dioxane/H2O. This yields 0.99 g (67%) of 4-[2-(2-hydroxy-5-nitrobenzoylamino)benzoylamino]butanoic acid as a cream-coloured solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][C:15]#[N:16].[H][H]>CO.[Ni]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: N#CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Yield: 93.4 %

Procedure:
A mixture of (±)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propanenitrile (0.069 mol) in methanol (250 ml) was hydrogenated with Raney nickel (5 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst was filtered off and the filtrate was evaporated, yielding 20 g (94% crude residue) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N-(phenylmethyl)-1,3-propanediamine (interm. 4-c).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Reactant: C1CNCCNC1
Product: Clc1ccc(OCCOc2nccnc2N2CCCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and homopiperazine (287 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (69%) of the title product. HRMS m/z calcd for C17H2IClN4O2(M)+ 348.1353, found 348.1353. Anal. (C17H21ClN4O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11])=[CH:4][CH:3]=1.C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.C(OCC)(=O)C>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-(6-Bromopyridin-3-yl)-2-(tert-butoxycarbonylamino)propanoic acid (1.72 g), N-ethylmorpholine (1.261 mL) and TBTU (2.4 g) were combined in DMF (5 mL) and the solution was stirred, at room temperature for 0.5 h then it was cooled to 0° C. Aqueous 880 ammonia (0.827 mL) was added and the mixture was allowed to reach RT overnight. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the sub-title compound (1.5 g).