Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[NH:33][N:32]=[C:31]([CH2:34][C:35](O)=[O:36])[N:30]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:31]1[N:30]=[C:29]([CH3:28])[NH:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2, Compound 90) (100 mg, 0.273 mmol), in CH2Cl2:DMF (1:1, 3 mL), then treated with (5-methyl-1H[1,2,4]triazol-3-yl)-acetic acid (50.0 mg, 0.355 mmol), followed by the addition of diisopropylethylamine μL, 0.819 mmol) and HATU (135 mg, 0.355 mmol). (100 The reaction stirred at room temperature for 8 h. The solution was washed with a saturated aqueous solution of NaHCO3 (10 mL) followed by brine (10 mL). The organic portion was dried over MgSO4, filtered and evaporated to an oil which was purified by silica gel flash chromatography with 5% then 10% MeOH/EtOAc as eluant to afford product as a colorless solid (86 mg, 65%). 1H NMR (CDCl3) 1.50-1.65 (m, 4H), 1.70-2.00 (m, 6H), 2.42 (s, 3H), 2.46 (s, 2H), 2.61-2.99 (m, 2H), 3.21-3.51 (m, 3H), 3.72-3.99 (m, 4H), 4.62-4.79 (m, 1H), 6.38-6.60 (m, 2H), 6.70-6.82 (m, 1H), 7.20-7.39 (m, 5H). 13C NMR 44.8 (CH2), 53.5 (CH2), 54.8 (CH), 55.3 (CH2), 56.6 (CH2), 63.2 (CH2), 105.4 (CH), 127.1 (CH), 128.2 (CH), 129.0 (CH), 130.0 (CH), 138.0, 139.8 (CH). LC/MS (Method B) 3.32 min, [M+1]+ 490.2.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20].CN(C=O)C>O>[CH2:1]([N:5]([CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(C)Br
Reactant: CCCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C)N(CCCC)c1ccccc1
Temperature: 130 °C
Reaction time: 86 h
Yield: 60 %

Procedure:
A mixture of N-butylaniline (7.45 parts) anhydrous potassium carbonate (7.5 parts), 2-bromoheptane (13.5 parts) and DMF (25 parts) was stirred at 130° C. for 86 hours. The reaction mixture was poured into water, saturated with salt and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated to leave N-butyl-N-(1-methylhexyl)aniline (11.8 parts, approximately 60% strength). This material had acetic anhydride (10 parts) added to it prior to further use.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[CH2:10]([N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Oc1ccncc1
Reactant: CCCCCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCn1ccc(=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (2.04 g) in N,N-dimethylformamide (50 ml) was added 4-hydroxypyridine (5 g) at room temperature. Octyl bromide (9.08 ml) was added thereto. The mixture was stirred for 2 hours at 50° C. The reaction mixture was added to a mixture of brine (100 ml), trtrahydrofuran (100 ml) and ethyl acetate (100 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-octyl-4-pyridone (14.7 g).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([CH3:44])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:43])[CH2:39][CH2:40][CH2:41]Cl)[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)[CH3:44])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NC(=O)CCCCl)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N3CCCC3=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound (0.2 g) obtained in step 1 in DMF (5.6 mL) was added sodium hydride (0.017 g) at 0° C., and the mixture was stirred at room temperature for 6 hr. To the mixture was added sodium hydride (0.017 g), and the mixture was stirred at room temperature for 12 hr, and sodium hydride (0.017 g) was further added. The mixture was stirred at room temperature for 6 hr, diluted with water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→10% methanol/ethyl acetate) to give the title compound (0.14 g, 76%) as a white powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9](F)[CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[CH:22][C:23]([N:26]3CCOC[CH2:27]3)=[N:24][CH:25]=2)O1.[CH3:33][O:34]C1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>CCCCCCC.CCOC(C)=O>[CH3:33][O:34][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH3:27])=[N:24][CH:25]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Fc1ccc2nc(Br)sc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
2-Bromo-6-fluoro-1,3-benzothiazole (100 mg, 0.43 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (150 mg, 0.52 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine. Flash chromatography (Heptane/EtOAc 1:1) furnished the title compound (126 mg) as an off-white solid. 1H NMR δ 8.79 (d, 1 H) 8.15 (dd, 1 H) 8.05-7.97 (m, 2 H) 7.40-7.34 (m, 1 H) 6.99 (d, 1 H) 3.73-3.69 (m, 4 H) 3.64-3.60 (m, 4 H); MS m/z (M+H) 316.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (14 mg, 0.04 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (14 mg, 0.12 mmol). Methyl iodide (0.03 mL, 0.08 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 10 mg (70%) of the title compound as a white solid. mp 59°-60°. FDMS: m/e=350.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)=[O:4].S(Cl)([Cl:18])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:18])=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC(F)F)n(C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1nn(C)c(OC(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.1 g (10 mmole) 3-Methoxycarbonyl-5-difluoromethoxy-1-methylpyrazole, dissolved in 30 ml methylene chloride, was treated with 1.35 g (10 mmole) sulfuryl chloride and stirred for 10 minutes at room temperature. It was then concentrated and recrystallised from diisopropyl ether/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([NH:33][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:4]=3)=[O:10])=[CH:19][CH:18]=2)=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: Nc1ccc(N)nc1
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,5-diaminopyridine via Procedure G. The prodcut was purified on reverse phase HPLC to yield N1-(6-aminopyridin-3-yl)-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]=2SC)=[CH:10][CH:9]=1.[NH2:35][CH:36]([CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:37]>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]=2[NH:35][CH:36]([CH3:37])[CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:10][CH:9]=1
Reactant: CSc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CCN(CC)CCCC(C)N
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCN(CC)CCCC(C)Nc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.47 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(methylthio)imidazolium tetrafluoroborate are suspended in 50 ml of absolute acetonitrile, whereupon the suspension is treated with 7.8 g of absolute 2-amino-5-(diethylamino)pentane. The mixture is stirred at room temperature under an argon atmosphere for about 24 hours. The insoluble constituents are removed by filtration and the filtrate is treated with 450 ml of diethyl ether. The pale yellow precipitate obtained is removed by filtration under suction, washed three times with diethyl ether and recrystallized from methanol/diethyl ether. There is obtained pale yellow 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[[4-(diethylamino)-1-methylbutyl]amino]imidazolium tetrafluoroborate of melting point 187°-191° (decomposition).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35](O)=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Temperature: 70 °C

Procedure:
1-{4′-[4-(6-benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (sodium salt; 0.050 g, 0.083 mmol), carbonyldiimidazole (0.0676 g, 0.417 mmol), MeSO2NH2 (0.0789 g, 0.83 mmol) and DBU (0.0248 mL, 0.166 mmol) were combined in THF (1 mL) and the mixture was heated to 70° C. in a capped vial for 25 hours. The mixture was purified by preparative HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6]CC)=[O:4].[I-].[Na+:14]>O1CCCC1>[CH3:1][O:2][C:3]([P:5](=[O:6])([OH:12])[OH:9])=[O:4].[CH2:10]([Na:14])[CH3:11]
Reactant: CCOP(=O)(OCC)C(=O)OC
Reactant: [Na+]
Agent: [I-]
Solvent: C1CCOC1
Product: CC[Na]
Product: COC(=O)P(=O)(O)O

Procedure:
A solution of 5.9 parts of diethyl methoxycarbonylphosphonate and 4.5 parts of sodium iodide was stirred at room temperature in 50 parts of tetrahydrofuran for 60 hours. The resulting mixture was filtered to give 3.5 parts of the desired ethyl sodium methoxycarbonylphosphonate, m.p. 123° d.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.C(C1CN([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C1)=O>C1COCC1>[C:49]([O:48][C:46]([N:16]1[CH2:15][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)=[C:2]3[Cl:1])[OH:13])[CH2:19]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 76.3 %

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 47: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5M in hexanes, 1.08 mL, 2.69 mmol)) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 min, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 min, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 min at which time the mixture was quenched with NH4Cl solution. The contents were diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a yellow foam. The crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc) to give the title compound (950 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.6, 1.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.99 (dd, J=8.0, 3.3 Hz, 1H), 4.35 (s, 2H), 4.05 (bs, 2H), 3.82 (t, J=8.7 Hz, 1H), 3.74-3.67 (m, 1H), 2.99-2.90 (m, 1H), 2.20-2.15 (m, 1H), 1.41 (s, 9H). MS (ESI): mass calcd. for C27H28ClF3N2O4: 536.98, m/z found 537.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH3:4].[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: N
Yield: 96.1 %
Yield: 2 %

Procedure:
A mixture of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 96, 350 mg, 0.71 mmol), iron (236 mg, 4.23 mmol) and NH4Cl (28.3 mg, 0.53 mmol) in ethanol (15 mL) and water (5 mL) were heated at reflux for 1.5 h. The mixture was then cooled and concentrated in vacuo. The residue was triturated in 10% CH3OH in CH2Cl2 (15 mL) for 0.25 h and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (15 mL) and then filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 5% CH3OH in CH2Cl2 and then 2-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (159 mg, 48%) as a yellow foam; 1H NMR: 2.18 (6H, s), 2.38 (2H, t), 2.66 (3H, s), 2.91 (2H, t), 3.68 (3H, s), 4.54 (2H, s), 6.77 (1H, s), 6.99-7.10 (2H, m), 7.12-7.22 (1H, m), 7.46 (1H, d), 8.25 (1H, s), 8.30-8.40 (2H, m), 8.49 (1H, d), 11.85 (1H, s); m/z: ES+ MH+ 466.6.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CO.[Si:10]([O:27][C@@H:28]([CH2:32][CH2:33][S:34][CH3:35])[C:29]([OH:31])=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Si:10]([O:27][C@@H:28]([CH2:32][CH2:33][S:34][CH3:35])[C:29]([O:31][CH3:1])=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CSCC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Sodium thiomethoxide (0.187 g, 2.67 mmol) was added to (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (CAS no. 220351-82-6: Klar, U.; Schwede, W.; Skuballa, W.; Buchmann, B.; Schirner, M. Ger. Offen. 1999 DE 19735575 A1) (0.826 g, 2.43 mmol) in DMF (2 mL) at 0° C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was neutralised with 2M HCl and diluted with ethyl acetate. The organic layer was extracted with water (3×100 mL), the organic layer was dried (MgSO4) and evaporated to afford (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 16.98%) which was used without further purification. A solution of trimethylsilyldiazomethane (2M solution in ether, 0.412 ml, 0.82 mmol) was added dropwise to a stirred solution of methyl alcohol (0.167 ml, 4.12 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 0.41 mmol) in toluene (0.174 ml) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with acetic acid (0.071 ml, 1.24 mmol) and stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (0.120 g, 72.4%). 1H NMR (400 MHz, CDCl3) δ 1.09 (9H, s), 1.94-2.05 (5H, m), 2.48-2.60 (2H, m), 3.47 (3H, s), 4.33-4.36 (1H, m), 7.34-7.45 (6H, m), 7.62-7.67 (4H, m); m/z (ES+) (M-Ph)-=325; HPLC tR=3.63 min
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH2:20](N)[CH:21]=[CH2:22].C(O[CH2:28][CH3:29])(=O)C>CO>[CH2:20]([N:8]1[C:3]([CH2:2][OH:1])=[CH:4][C:5](=[O:19])[C:6]([O:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:29]2[CH:28]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:7]1)[CH:21]=[CH2:22]
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Reactant: C=CCN
Reactant: CCOC(C)=O
Solvent: CO
Product: C=CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 14 h

Procedure:
To a suspension of 1.542 g of 6-hydroxymethyl-3-(p- methoxybenzyl)oxy-4-pyridone in methanol is 5.710 g of allylamine at room temperature, and the mixture is stirred for 14 hours. After condensing at reduced pressure, 20 ml of ethyl acetate is added to the residue to perform crystallization. After the mixture is left standing at 4° C. for 4 hours, the crystal is collected by filtration, washed with a small amount of ethyl acetate and dried under reduced pressure to give 1.050 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][C@@H:21]([OH:24])[CH2:22][NH2:23])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][C@@H:21]([OH:24])[CH2:22][NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1ccc([N+](=O)[O-])c(NC[C@H](O)CNC(=O)OC(C)(C)C)n1
Yield: 86 %

Procedure:
Starting from 2-chloro-6-methoxy-3-nitropyridine (5.4 g; commercial) and ((S)-3-amino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (5.3 g, 1 eq.; prepared according to Adv. Synth. Catal. 2004, 346, 1195) and proceeding in analogy to Example 17, step 17.i, the title compound was obtained as a yellow solid (8.20 g; 86% yield).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([C@@H:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2=[O:25])[N:7]=1)=O.[CH2:26](O)C.[CH:29]([NH2:32])([CH3:31])[CH3:30].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH:29]([NH:32][CH2:1][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([C@@H:14]([C@@H:22]([CH3:24])[CH2:23][CH3:26])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2=[O:25])[N:7]=1)([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: CCO
Reactant: CC(C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(C=O)n2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(CNC(C)C)n2)C1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of Example 273D (65 mg) in toluene:ethanol (0.7 mL, 1:1) was treated with isopropylamine (0.14 mL, 10 equivalents), stirred at 70° C. in a capped vial for 2 hrs. The mixture was cooled to 25° C. and NaBH4 (19 mg, 3 equivalents) was added and the mixture was stirred at 25° C. for 3 days. The solvents were evaporated, and the residue was partitioned between ethyl acetate and saturated NaHCO3, the organic layer was separated and washed with brine, dried over MgSO4, filtered and evaporated to give 59 mg of the title compound.