Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:23][C:24]1[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([C:27]5[CH:26]=[N:25][C:24]([Cl:23])=[CH:29][N:28]=5)[CH2:20][CH2:21]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCNCC1
Reactant: Clc1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
A flask was charged with (S)-3-(1H-indazol-5-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one (0.120 g, 0.400 mmol), 2,5-dichloropyrazine (0.0655 g, 0.439 mmol), DIEA (d 0.742) (0.0696 mL, 0.400 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using preparative TLC with 10% methanol in ethyl acetate to provide (S)-3-(1H-indazol-5-yloxy)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.0047 g, 0.0114 mmol, 2.85% yield). Mass spectrum (apci) m/z=413.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH:3]=1.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>>[CH3:1][C:2]1[O:16][C:5]2=[CH:6][C:7]3[CH:8]([C:17]([O:18][CH2:19][CH3:20])=[O:21])[C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)OCC
Reactant: CCN1C(=O)Cc2cc3oc(C)cc3cc21
Product: CCOC(=O)C1C(=O)N(CC)c2cc3cc(C)oc3cc21
Yield: 85 %

Procedure:
Starting with 1.5 g. (6.98 mmoles) of 2-methyl-5-ethyl-6-oxo-6,7-dihydro-furo[2,3-f]indole and 2.47 g. (20.9 mmoles) of diethyl carbonate, and following the procedure of Preparation C, 1.7 g. (85% yield) of the desired intermediate was obtained, m.p. 82°-90° C.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5]CC)=O.C(O)(=O)C.Cl.Cl.[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([F:33])[C:27]([CH2:28][NH:29][NH2:30])=[C:26]([F:34])[CH:25]=1)[CH3:22]>O1CCOCC1>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([F:34])[C:27]([CH2:28][N:29]2[C:3]([OH:5])=[C:2]([CH3:1])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:30]2)=[C:31]([F:33])[CH:32]=1)[CH3:22]
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: CCOc1cc(F)c(CNN)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4.65 g of diethyl 2-methyl-3-oxobutanedioate (23.0 mmol, 1.00 eq.) were dissolved in 100 mL of dry dioxane under argon atmosphere. 2.1 mL of glacial acetic acid and 6.32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred for 16 hours at 90° C. bath temperature. The reaction mixture was evaporated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried in vacuo at 40° C. The filtrate was concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate-gradient with hexane 0-100%). The filter cake and the received purified compound of the flash chromatography were stirred together in ethyl acetate, filtered off and provided 3.95 g (11.3 mmol, 49%) of the analytically pure target compound.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[C:39](=[O:40])[NH:38][N:37]=[CH:36]2)[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:38]2[C:39](=[O:40])[N:35]([C:27]3[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=3)[CH:36]=[N:37]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CCOc3ccc(F)cc3)c2=O)nc1C
Yield: 48 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(2-bromoethoxy)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 6.93-6.84 (m, 2H), 6.81-6.75 (m, 2H), 4.32-4.15 (m, 6H), 2.62 (s, 3H), 1.31 (t, J=7.1 Hz, 3H); MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[C:16](Cl)(=O)C>>[Cl-:7].[CH3:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[CH:16]=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1Cl
Reactant: C1CCNCC1
Reactant: CC(=O)Cl
Product: Cc1ccccc1C=[N+]1CCCCC1
Product: [Cl-]

Procedure:
The reaction of 8.5 g (0.100 mol) piperidine and 7.0 g (0.050 mol) 2-chlorobenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 3.9 g (0.050 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 7.1 g (corresponding to 58% of the yield calculated by theory) 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH2:19]([C@H:27]1[CH2:32]N[CH2:30][CH2:29][NH:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:32]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 42.3 %

Procedure:
By using a similar method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.47 g, 5.69 mmol) and (S)-2-phenethyl-piperazine (1.08 g, 5.69 mmol) to give 1.04 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=432 (M+1); Analysis for C25H29N5S: calcd: C, 69.57; H, 6.77; N, 16.22; found: C, 69.40; H, 6.90; N, 15.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[C:28]([O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29].C([BH3-])#N.[Na+]>ClCCl>[C:28]([O:32][C:33](=[O:41])[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([NH:16][C:10]3[S:11][C:12]([C:13](=[O:14])[NH2:15])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH2:37][CH2:36]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a mixture of 0.6 g (1.5 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b) and 0.328 g (1.6 mmole) of piperidin-4-yl-carbamic acid tert-butyl ester in 15 mL of dichloromethane was added 0.477 g (2.3 mmole) of sodium cyanoborohydride. The mixture was stirred for 3 hours, then quenched by the addition of 25 ml, of water. The mixture was extracted three times with 50 mL of ethyl acetate. The combined ethyl acetate layers were washed once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-80:20) to give 0.7 g of (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (VI.12a).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][C:24](OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCCC1.C(O)C.C(Cl)(Cl)[Cl:40]>>[ClH:40].[O:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]1[NH:23][CH3:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 12 from LiAlH4 (250 mg, 6.5 mmol), (±) cis-1-phenoxy-2-tert-butoxycarbonylaminoindane (425 mg, 1.3 mmol) and tetrahydrofuran (30 ml). After a reaction time of 2 h the reaction was worked up as previously described and subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a colourless oil (290 mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. >215° C. dec. (from methanol-diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])C#N.[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:29]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:28]([OH:26])=[O:30]
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1

Procedure:
To a suspension of 3-chloro-4-(5H,11H-pyrrolo-[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzonitrile (90.72 g) in ethanol was added 10 N sodium hydroxide (1.02 ml) and the mixture heated under reflux for two hours. The solvent was removed in vacuo, the residue dissolved in water, and made acidic with 2 N hydrochloric acid (4.7 ml). The resulting precipitate was extracted with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. After removing the solvent in vacuo, a foam was triturated with diethyl ether for 18 hours and filtered to give a crude product (0.69 g). The crude product was purified by treatment with activated charcoal in methanol. Crystallization from methanol/ether afforded the title compound as a purified solid (0.29 g), m.p. 198-199° C.; MS (EI), m/z: 366 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)#[CH:23].C(N(C(C)C)CC)(C)C>O1CCOCC1.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1[C:23]#[C:22][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1ccc(C#Cc2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (50 mg, 0.120 mmol), 2-(4-ethynylphenyl)propan-2-ol (28.2 mg, 0.176 mmol), Pd(Ph3P)4 (13.58 mg, 0.012 mmol), copper(I) iodide (2.237 mg, 0.012 mmol) and diisopropylethylamine (0.062 ml, 0.360 mmol) in dioxane (2 ml) was charged in a reaction tube. Then the tube was sealed and N2 was bubbled through for 5 min. The mixture was heated at 80 C for 2 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS m/e=458.35 (M+H)+ (Rt 1.70/4.0 min); 1H NMR δ (ppm) (CD3OD): 7.83 (s, 1H), 7.58-7.54 (m, 4H), 5.13 (septet, 1H, J=5 Hz)), 4.34 (ddd 1H, J=12, 5, 2 Hz), 3.89 (dd, 1H, J=12, 2 Hz), 3.64 (dd, 1H, J=12, 6 Hz)), 3.61 (dd, 1H, J=12, 5 Hz), 3.37 (t, 1H, J=11 Hz), 3.19-3.15 (m, 1H), 2.77-2.73 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz), 1.55 (s, 6H).
Reaction SMILES: OC1C=C(O)C=CC=1[CH:9]([C:16]([CH:18]([C:25]1[CH:30]=[CH:29]C(O)=CC=1O)C1C=CC=CC=1)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=[O:36].N1CCOCC1.[CH2:44]([O:46][CH:47]([O-])[O-])[CH3:45]>C(Cl)(Cl)Cl>[OH:36][C:29]1[CH:45]=[C:44]2[C:18]([C:16](=[O:17])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:47][O:46]2)=[CH:25][CH:30]=1
Reactant: CCOC([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Solvent: ClC(Cl)Cl
Solvent: C1COCCN1
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A mixture of 100 kg (438.5 mole) of 2,4-dihydroxy-phenyl-benzyl-ketone, 38 kg of dimethyl-formamide, 5.2 kg of morpholine and 75 kg (506 mole) of ethyl-orthoformate is stirred at 80°-90° C., while within one hour crystallization is initiated. 360 kg of chloroform are added to the suspension after 7 hours at 60° C. After cooling the crystalline substance is centrifuged, covered with chloroform, filtered and dried. 94.5 kg of 7-hydroxy-isoflavone are obtained, 7-ethoxy-isoflavone content: 0.1% by weight, yield: 90.5%.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:25][SH:26].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:6]2[C:7](=[O:8])[CH:2]([S:26][CH3:25])[CH2:3][O:4][C:5]=2[CH:12]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reactant: CS
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In 50 ml of methylene chloride were dissolved 2.06 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one and 480 mg- of methylmercaptan. Thereto was added 2.02 g of triethylamine at 0°-5° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was introduced into 30 ml of water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 50 : 1 mixture of toluene and ethyl acetate) to obtain 900 mg (yield: 47.4%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][O:6][C:7]1[CH:41]=[CH:40][C:10]([CH2:11][S:12][C@@H:13]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C@H:15]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:32])[CH2:14]2)=[CH:9][CH:8]=1.[N+:42]([C:45]1[CH:58]=[CH:57][C:48]([CH2:49][O:50][C:51]([NH:53][C:54](=N)[CH3:55])=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:12][C@@H:13]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C@H:15]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][N:36]([C:54](=[N:53][C:51]([O:50][CH2:49][C:48]4[CH:57]=[CH:58][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=4)=[O:52])[CH3:55])[CH2:35][CH2:34]3)=[O:32])[CH2:14]2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 14.5 %

Procedure:
25 ml of methylene chloride were added to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (i) above] in 25 ml of methanol, which was being heated under reflux, and then 904 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine were added to the resulting mixture. The reaction mixture was heated under reflux for a further 5 hours, after which it was worked up and purified by the same procedure as described in Preparation 1(iii), to give 415 mg of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:30]([S:31]([NH:1][C:2]1[C:3](=[O:16])[N:4]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 3-amino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.12 g, 5.0 mmol), and N-methylmorpholine (1.5 mL, 10.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (950 mg, 5.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4 and filtered and the filtrate was concentrated to give a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) to give the title compound as a white solid (1.8 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.42 (br s, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (m, 5H), 6.92 (d, J=7.0 Hz, 1H), 6.14 (t, J=7.2 Hz, 1H), 4.58 (s, 2H), 4.34 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (44.1 mg, 0.203 mmol) in DCM (2 mL) was added DMAP (41.4 mg, 0.339 mmol) and DCC (41.9 mg, 0.203 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give (S)-2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (110 mg, 82%).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I:9][CH2:10][C@H:11]1[NH:14][C:13](=[O:15])[CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[Si:5]([N:14]1[C@H:11]([CH2:10][I:9])[CH2:12][C:13]1=[O:15])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](CI)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
t-butyldimethylchlorosilane (7.51 g, 49.8 mmol) is added in one portion to an ice-cold, stirring solution of (4S)-4-iodomethyl-azetidin-2-one (10.0 g, 47.4 mmol) and triethylamine (5.04 g, 49.8 mmol) in anhydrous dimethylformamide (100 ml). A voluminous white precipitate forms almost immediately. The reaction mixture is stirred at 0°-5° for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed wih 2.5N hydrochloride acid (50 ml), water (3×50 ml), and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to provide (4S)-1-(t-butyldimethylsilyl)-4-iodomethyl-azetidin-2-one (15.1 g) as a white solid. Recrystallization from petroleum ether-ethyl ether gives the product as colorless plates, mp 71°-72°; n.m.r. (CDCl3), δ3.8 (m, 1), δ2.6-3.6 (2 overlapping d of AB, 4) δ1.0 (S, 9), δ0.3 (S, 6), δ0.25 (S, 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[NH:40]([C:44]1[S:45][CH:46]=[C:47]([CH2:49][S:50][CH2:51][CH2:52][NH2:53])[N:48]=1)[C:41]([NH2:43])=[NH:42]>>[NH:40]([C:44]1[S:45][CH:46]=[C:47]([CH2:49][S:50][CH2:51][CH2:52][NH:53][C:28]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:25])=[O:29])[N:48]=1)[C:41]([NH2:43])=[NH:42]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=O)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.74 g (2.0 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=628 ([M+H]+, 4), 121 (100); IR (KBr): 1597 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 60° C. (ethanol/ether).