Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CC(C)=O)cc1
Yield: 79.2 %

Procedure:
A suspension of 15.0 g of 1-(4-hydroxyphenyl)-2-propanone, 24.6 g of 1-bromopropane and 13.8 g of potassium carbonate in 100 ml of N,N-dimethylformamide was heated for 4 hours at 65°-70° C. After cooling, the reaction mixture was poured into water and extracted with ether. The extract was washed with water, dried and evaporated. The residue was distilled to give 15.2 g of the desired compound as a pale yellow oil, b.p.136°-138° C. (7 mmHg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.Cl.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:14]1[C:13]([CH:11]([OH:12])[C:8]2[N:6]3[N:7]=[C:2]([C:30](=[O:32])[CH3:31])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(C(O)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a flask charged with Pd(PPh3)4 (67 mg, 0.058 mmol) under nitrogen was added a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(5,7-difluoroquinolin-6-yl)methanol (200 mg, 0.56 mmol) in DMF (10 mL). The system was purged with nitrogen gas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.21 mL, 0.61 mmol) was added. The temperature was increased to 100° C. and stirred overnight. Then the reaction mixture was cooled to rt, 3N HCl was added and the mixture was stirred for additional 4 h. Water was added and the product was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 132 mg (55%) of the title compound. 1H-NMR (400 MHz, CDCl3). ppm 8.98 (dd, 1H), 8.42 (d, 1H), 8.05 (dd, 1H), 8.00 (s, 1H), 7.77 (dd, 1H), 7.68 (d, 1H), 7.48 (q, 1H), 7.03 (s, 1H), 2.72 (s, 3H). LCMS (method B): [MH]+=355, tR=2.08 min.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][Si:17]([CH3:34])([CH3:33])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH:31]=[O:32])=[CH:28]2)=[N:23]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:31]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:34])([CH3:33])[CH3:16])[N:23]=4)[CH:28]=3)[OH:32])=[CH:3][N:4]=2)[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C=O)ccc2n1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc2n1
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (465 mg, 2.0 mmol) in THF (60 mL) was added dropwise at rt a solution of ethylmagnesium bromide in Et2O (3 M, 1.0 mL). The temperature rose slightly (up to 27° C.) and the RM was stirred 15 min. Then a solution of 2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole-5-carbaldehyde (Stage 150.4, 829 mg, 3.00 mmol) in THF (8 mL) was added dropwise and the RM was then stirred 2 h at rt. The RM was then taken into a solution of NH4Cl and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=95:5->0:100) to afford the title compound as a light brown thick oil (tR 5.35 min (conditions 3), MH+=430).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[BH4-].[Na+].Br.[NH3:16]>>[NH2:16][CH2:1][CH:2]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: N
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Product: NCC(O)c1cccc([N+](=O)[O-])c1

Procedure:
3-Nitroacetophenone is brominated in the α-position, the bromination product is reduced by means of sodium borohydride to the corresponding bromohydride and this is treated with ammonia. There is obtained rac.-α-(aminomethyl)-3-nitrobenzyl alcohol which melts at 107°-108° (softening from 105°) after crystallization from ethyl acetate-ether.
Reaction SMILES: [C:1]([C:4](=[C:10](OCC)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].[O-]CC.[Na+]>C(O)C>[CH3:2][C:1]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:10]([CH3:11])[N:21]=[CH:19][N:20]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(C)=O)=C(C)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
Ethyl 2-acetyl-3-ethoxybut-2-enoate (10.7 g, 0.0537 mol), formamidine acetate (5.6 g, 0.054 mol) and sodium ethoxide (2.7 M in ethanol, 20.0 mL) were mixed in ethanol (30 mL) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was cooled, quenched with water and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with 10%, 50% ethyl acetate/hexane to afford the desired product (7.4 g, 76%) as a yellow oil. MS (EI) 181.1 (M+1). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.97 (s, 1H), 4.44 (q, 2H), 2.56 (s, 6H), 1.42 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[NH3:22]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([NH2:22])(=[O:14])=[O:13]
Reactant: N
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (32a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by a solution of ammonia in dioxan (37.5 ml, 0.5 M). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts are washed with water (2×100 ml) followed by brine (100 ml) and dried (MgSO4). After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate/hexane (1:2) to afford the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: CCOC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.37 g, 50%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.97 mmol) and 4-chlorophthalic anhydride (0.47 g, 2.56 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 1-butylisoquinoline-7-carboxylic acid (79 mg, 0.26 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (1.8 mL) was added HBTU (100 mg, 0.264 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (107 mg, 0.264 mmol) in methylene chloride (1.8 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 93:7 chloroform/methanol) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (103 mg): mp 109-110° C.; ESI MS m/z 546 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C)=O)=[O:14])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].[NH3:21]>>[NH2:21][C:17](=[O:19])[CH2:16][NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][C:1]#[N:2])=[O:14]
Reactant: COC(=O)CNC(=O)c1ccc2[nH]cc(CC#N)c2c1
Reactant: N
Product: N#CCc1c[nH]c2ccc(C(=O)NCC(N)=O)cc12
Reaction time: 8 h

Procedure:
The product of Stage (i) (0.05 g) dissolved in methanolic ammonia (2 ml) was stirred overnight, further 2 ml portions of methanolic ammonia being added after 3.5 h and 5.5 h. The solution was evaporated to dryness and the residual solid triturated with anhydrous ether to present the product as a powder (0.036 g) m.p. 206°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:32]([O:31][C:29]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (160 mg, 0.381 mmol) was dissolved in DCM (20 ml), and DMAP (0.056 g, 0.539 mmol) was added followed by benzyl chloroformate (0.077 ml, 0.539 mmol). The reaction mixture was stirred at RT for 6 hours. Additional benzyl chloroformate (0.077 ml, 0.539 mmol) was added, and stirring was continued at RT overnight. The reaction mixture was diluted with DCM and washed with aqueous saturated NH4Cl solution (20 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The crude was purified by chromatography on silica gel cartridge (DCM:ethyl acetate=8:2) to give 0.120 g of desired compound. A further purification by trituration with ethanol (10 mL) was required to afford (S)-4-(2-(benzyloxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as a white amorphous solid (0.101 g, 0.182 mmol, 47.9% yield, MS/ESI+554.01 [MH]+, [αD]=−6.9, c=0.68, DCM).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4cccc(F)c4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4cccc(F)c4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 205°-207° C.) and piperazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][OH:16].C[O-].[Na+]>O>[CH3:15][O:16][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1cccs1)c1cccnc1Cl
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncccc1C(=O)c1cccs1
Reaction time: 0.5 h

Procedure:
A mixture of 1.64 g of 2-chloro-3-(2-thienylcarbonyl)pyridine, 4.5 ml of a methanol solution of 28% sodium methoxide and 2.0 ml of methanol was heated under stirring for 30 minutes. After cooling as it was, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 1.46 g of the target compound.
Reaction SMILES: [NH2:1][CH:2]([PH:10](=[O:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O>[C:4]1([CH2:3][CH:2]([PH:10](=[O:11])[OH:12])[NH:1][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1-Amino-2-phenylethyl)phosphinic acid (1 g., 5.4 mmole) is suspended in water (25 ml.) at 0° and the pH is adjusted to 9.5 with concentrated sodium hydroxide solution. Benzyl chloroformate (0.9 ml., 1.08 g., 6.3 mmole) is added while the pH is maintained at 9.5 by the addition of sodium hydroxide. After the pH stabilizes, the mixture is stirred for 3 hours at room temperature. The basic solution is washed with ether and then acidified. The white solid precipitate is collected on a frit to give [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-phosphinic acid. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.75.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(-c4nncn4-c4ccncc4)cc3)ccc2c1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol (44 mg) in dimethyl formamide (1 ml) in a 7 ml Teflon capped vial was added cesium carbonate (185 mg) and 2-Chloromethyl-quinoline (37 mg) and the reaction mixture heated on a shaker plate at 60° C. for 18 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated to provide the title compound (45 mg). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.0 Hz, 2H), 8.37 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.61 (t, J=5.8 Hz, 1H), 7.40 (m, 4H), 7.14 (d, J=9.1 Hz, 2H), 5.38 (s, 2H); MS: (M+H m/z=380.2).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])[CH2:22][CH2:21]1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: NC1CC1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)NC4CC4)cc3c2C1
Yield: 41 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopropylamine, 3.5 mg (41%) of the title compound were recovered.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:14]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[C:7]([N:14]1[CH2:21][C:20](=[O:22])[CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.1 12.2 g (122 mmol) of chromium(VI) oxide are added to a mixture, held at 0° C., of 22 ml of pyridine and 50 ml of dichloromethane, and the mixture is stirred at the same temperature for 30 minutes. The solution is allowed to warm to room temperature, and a solution of 5.00 g of cis-Boc-4-hydroxy-D-proline in 80 ml of dichloromethane is added dropwise over the course of 5 minutes. After stirring at room temperature for 1 hour, the solution is filtered, and the filtrate is evaporated. The residue is partitioned between 1N HCl and tert-butyl methyl ether. The organic phase is dried over sodium sulfate, evaporated and recrystallised from diethyl ether/petroleum ether, giving Boc-4-keto-D-proline as a colourless solid; ESI 130. 6.2 742 mg (3.00 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 459 mg (2.00 mmol) of Boc-4-keto-D-proline and 372 mg (2.00 mmol) of 1-(4-aminophenyl)-1H-pyridin-2-one in 25 ml of toluene, and the mixture is stirred at room temperature for 18 hours. 200 ml of tert-butyl methyl ether are added, and the precipitate formed is filtered off. 200 ml of petroleum ether are added to the filtrate, and the resultant precipitate is filtered off, giving tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a brownish solid; ESI 398. 6.3 10 ml of methanol are added to a suspension of 400 mg (1.01 mmol) of tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl-carbamoyl]pyrrolidine-1-carboxylate in 5 ml of 4N HCl in dioxane, and the mixture is stirred at room temperature for one hour. The reaction mixture is evaporated, giving (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenyl-carbamoyl]pyrrolidinium chloride as a brownish solid; ESI 344. 6.4 0.12 ml of triethylamine and 127 mg (0.830 mmol) of 4-chloro-phenyl isocyanate are added to a solution of 250 mg (0.658 mmol) of (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride in 10 ml of dichloromethane. After stirring at room temperature for one hour, the reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent, giving 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide (“A7”) as a colourless solid; ESI 497.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH2:55])=[O:53])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.C(N(CC)CC)C>[C:43]([O:47][C:48](=[O:56])[NH:49][CH2:50][CH2:51][C:52]([NH:54][NH:55][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:53])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in methylene chloride (14.1 mL) were added triethylamine (393 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg), 1-hydroxybenzotriazole.monohydrate (324.6 mg), and tert-butyl(3-hydrazinyl-3-oxopropyl)carbamate (430.8 mg, prepared following a procedure analogous to Reference Example 2), followed by agitating at room temperature overnight. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to afford 347.3 mg of the title compound (yield 53.3%).