Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][OH:23])[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate in dry CHCl3, triethylamine (2 eq.) was added and mixture was stirred ten minutes at room temperature. Methanesulfonyl chloride (1.5 eq.) was slowly added and the resulting mixture was aged at room temperature for 1.5 hours to afford tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-{[(methylsulfonyl)oxy]methyl}-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as the main product (monitored by LC-MS). MS (ES) C22H27FN4O8S requires 526. Found: 527 (M+H+). The reaction mixture was concentrated under vacuum at 30° C. and the solvent switched to dry acetonitrile. The insoluble material was filtered off and to the filtrated 5 equivalents of N-benzylmethylamine were added. The mixture was warmed at 110° C. upon microwave irradiation for 30 minutes then stirred at room temperature for further 36 hours. The mixture was concentrated by rotary evaporation and the resulting residue, dissolved in the minimum amount of MeOH, was carefully acidified with some drops of glacial acetic acid applied on cation-exchange resin. The resin was washed with MeOH and the crude product was eluted with 1M ammonia in methanol. The pooled eluants were concentrated to dryness under reduced pressure to get tert-butyl 9-{[benzyl(methyl)amino]methyl}-2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as a brown oil. MS (ES) C29H34FN5O5 requires 551. Found: 552 (M+H+).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[CH2:16]([N:23]1[CH:28]2[CH:29]([C:31]#[N:32])[CH2:30][C:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:25](O)[CH2:26][CH2:27]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH2:16]([N:23]1[C@@H:28]2[C@@H:29]([C:31]#[N:32])[CH2:30][C@@:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:25]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:26][CH2:27]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1CC2(c3ccccc3)C(O)CCC1N2Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
t-Butyldimethylsilyl trifluoromethanesulphonate (23 ml, 76 mmol) was added dropwise to a stirred solution of (1R*,2R*5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 41; 31 g), triethylamine (18 ml, 243 mmol) in dichloromethane (100 ml) at room temperature over 30 minutes. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether (3×100 ml). The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH2:12]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc(Nc2ccc3c(c2)CC(=O)N3)c1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 5-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (20 mg, 0.083 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (31 mg, 0.1 mmol), N,N-diisopropylethylamine (54 mg, 0.42 mmol), EDCI (32 mg, 0.17 mmol) and HOBt (11 mg, 0.083 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[CH:28]=[CH:27][O:26][CH:25]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccoc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 17 mL (16 mmol) of a freshly prepared solution 0.94 M in ethyl ether of 3-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 5.3 g (99% of yield) of 4-(6-fluoro-1-furan-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=2)=[CH:12][CH:11]=1.BrC1N=CC(CC2C3C(=NC=CC=3)N([Si](C(C)C)(C(C)C)C(C)C)C=2)=CC=1>>[CH2:1]([NH:8][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Reactant: NCc1ccccc1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)nc2)c2cccnc21
Product: c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1

Procedure:
Additional compounds were prepared following the protocol of Scheme 6, substituting benzyl amine with a suitable amine in Step 1, and using either 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 6 or 3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 6a, in Step 1. The following compounds were made following this procedure:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40 ml of DMSO 3.7 g of 4-tert.butylbenzene sulfonamide potassium salt was added. The resulting solution was stirred for 20 h at room temperature. Eventually, the mixture was poured onto 400 ml of water and washed twice with 200 ml of diethyl ether. The organic layers were extracted with 200 ml of water. The combinded aqueous layers were acidified with conc. hydrochloric acid. The mixture was cooled to 0° C. and 100 ml of brine was added. The precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.80 min, [M+1]+=448.17, [M−1]−=446.21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([NH:9][CH:10]=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])=[N+:22]=[N-:23]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([N:9]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[N:21]=[N+:22]=[N-:23])[CH:10]=[O:11])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC=O)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N(C=O)C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A stirred solution of (2S)-2-formylamino-propionic acid tert-butyl ester (3.524 g, 20.3 mmol) in anhydrous THF (50 mL) was treated at −78° C. with LDA (20.3 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (20.6 mmol) in anhydrous THF (20 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq. NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq. NH4Cl, dried (MgSO4), filtered and evaporated and residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the sub-title compound as a pale yellow oil (3.437 g, 53%): 1H NMR (400 MHz CDCl3) δ 1.49 (9H, s), 1.60 (3H, d), 5.18 (1H, m), 7.27 (2H, m), 7.40 (1H, d), 7.59 (1H, t), 8.60 (1H, s).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+].O>>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[CH:14]=2)[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C4CCCC4)CC3)ccc2c1
Yield: 62 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 114 mg the desired product as a white solid (90%). ESI-MS: 351 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=7.87 (s, 1 H), 7.81-7.55 (m, 3 H), 7.31-7.21 (m, 1 H), 7.18-7.00 (m, 1 H), 4.98-4.59 (m, 3 H), 4.43-4.27 (m, 0.63 H), 3.57-3.14 (m, 4 H), 2.19-0.84 (m, 17 H)
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:18][C:16]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:17]
Reactant: OCC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)OCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 7.0 g (35.4 mmol) of the alcohol (12) in 50 mL toluene at 0 degrees C., was slowly added 100 mL phosgene in toluene (12.5% phosgene in toluene). The reaction mixture was stirred at 0 degrees C. for 30 minutes and then at room temperature for 2 hours. The excess reagent and solvent was removed under reduced pressure and the crude product was quickly passed through a pad of silica gel (silica gel, CH2Cl2 -Hexane 2:3) to yield 7.8 g (80%) of the chloroformate (13). DCI-NH3 -MS, m/z (relative intensity), 259 (M+, 55); 1H-NMR (CDCl3, 300 MHz) 7.28 (m, 10H), 4.83 (d, 2H, J=7.5 Hz), and 4.45 (t, 1H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@H:34]([CH:38]([CH3:39])[CH3:40])[C:35]([NH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[N:14]1)=[O:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (R,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.007 g, yield: 35%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([NH:45]O)=[NH:44])=[CH:41][CH:40]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]3[N:44]=[C:4]([CH2:3][O:2][CH3:1])[O:6][N:45]=3)=[CH:47][CH:48]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: COCC(=O)O
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a solution of methoxyacetic acid (86 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.46 g (90%) 4-chloro-N-[4-(5-methoxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=505.0 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.[NH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1>>[NH:29]1[CH2:30][CH:27]([NH:26][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:28]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)[nH]c(=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NC3CNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 93-1 in Scheme 44 by using 6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl 3-aminoazetidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 410.1, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1 H), 7.87 (s, 2 H), 7.79 (s, 1 H), 7.62 (brs, 1 H), 7.45 (s, 1 H), 7.34 (d, J=8.4 Hz, 1 H), 7.22 (brs, 1 H), 5.06-4.42 (m, 5 H), 3.85 (brs, 1 H), 3.59 (m, 5 H), 2.32 (s, 3 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Li].Cl[CH2:18][O:19][CH2:20][CH2:21][Cl:22]>O1CCCC1>[Cl:22][CH2:21][CH2:20][O:19][CH2:18][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: ClCCOCCl
Reactant: N#CC1CCOCC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(COCCCl)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carbonitrile (3.80 g, 34.2 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min to a cold (−78° C.) solution of lithium diisopropylamine (37.5 mmol) in tetrahydrofuran (50 ml). After 30 min, a solution of 2-chloroethyl chloromethyl ether (5.00 g, 38.7 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 min and the mixture stirred for 30 min. The cooling bath was then removed and the solution was allowed to warm up to 25° C. then stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic fraction was dried over anhydrous magnesium sulfate and concentrated. Filtration of the residue on silica gel (elution toluene-ethyl acetate 8:2) followed by distillation in vacuo gave 6.33 g (91% yield) of the title nitrile as a clear oil: bp 90-100° C./0.2 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.74 (2H, m, CH2), 1.92 (2H, m, CH2), 3.58 (2H, s, CH2), 3.67 (2H, t, J=5.6 Hz, CH2), 3.74 (2H, dt, J=2.3 Hz and J=12.4 Hz, CH2), 3.83 (2H, t, J=5.6 Hz, CH2), 4.0 (2H, m, OCH2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:18])[CH3:17]
Reactant: O=C(O)c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of 4-piperidin-4-yl)-benzoic acid (102 mg, 0.5 mmol, reference example 109) dissolved in pyridine (2 mL) was added acetic anhydride (255 mg, 2.5 mmol) and the reaction stirred overnight at room temperature. The reaction was concentrated in vacuo and residual pyridine partially removed by azeotroping with dichloromethane/methanol 1:1. The crude product was then washed with dichlormethane and the solvent decanted to yield a white solid residue (61 mg, 49%) 4-(1-acetyl-piperidin-4-yl)-benzoic acid. 1H NMR (CD3OD): δ 7.89 (d, 2H); 7.27 (d, 2H); 4.65 (d, 1H); 4.03 (d, 1H); 3.21 (dt, 2H); 2.68-2.88 (m, 2H); 1.93 (s, 3H); 1.85-2.04 (m, 2H); 1.50-1.75 (m, 3H). MS m/z 248 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:22])[O:21]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c2ccccc2c2cc(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)ccc21

Procedure:
A mixture of 3.43 g (0.01 mole) of 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C above to yield 3-[2,4-bis(dimethylamino)phenyl]-3-(9-ethyl-3-carbazolyl)phthalide (Formula V: R°=R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R8 =CH2CH3) which melted over the range 134°-142° C. A significant infrared absorption maximum appeared at 1753 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed a bordeaux-colored image.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[O-][CH2:26][CH3:27]>C(O)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][C:27]2[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CC[O-]
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (Example 20, Step C) (5.8 g., 0.016 mole) is dissolved in a mixture of dry benzyl alcohol (50 ml) and methylene chloride (40 ml.) containing amberlite IRA 400 (ethoxide) (5-6 g.). The mixture is stirred magnetically at reflux for four hours and then filtered. The filtrate is concentrated in vacuo to give a yellow solid (5.3 g.) which upon trituration with ethanol and washing with ether yields the product.