Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5](OC)=[O:6].[CH2:11]1COC[CH2:12]1.C([Mg]Br)C>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)C.O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]1([OH:6])[CH2:12][CH2:11]1
Reactant: COC(=O)CC(OC)OC
Reactant: C1CCOC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: COC(CC1(O)CC1)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 1.0 L RBF containing methyl 3,3-dimethoxypropanoate (17.6500 g, 119 mmol) was added THF (150 ml) and diethyl ether (150 ml), and the mixture was allowed to stir at 0° C. for 15 min. At this time, tetra-isopropoxy titanium (6.98 ml, 23.8 mmol) was added in one portion before the dropwise addition of ethylmagnesium bromide (99.3 ml, 298 mmol) via syringe. The reaction was allowed to warm to 23° C. and stir for 14 hours before being re-chilled to 0° C. After 5 min at this temp, water (15 ml) was added and a solid formed. Diethyl ether (200 ml) was added and the quenched reaction was stirred for 10 min before filtering through a plug of magnesium sulfate. The filtrate was dried with additional magnesium sulfate, filtered and concentrated to give a colorless oil. The crude material was used directly in the next reaction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]1([C:20]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=3[OH:33])[N:23]=[C:22]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:35]=3[OH:41])[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:42].[K+]>COCCOCCOC>[C:14]1([C:20]2[N:21]=[C:22]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:36][C:35]=3[OH:41])[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:42])=[CH:28][C:27]=3[OH:33])[N:25]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCCCCCCCCCCBr
Reactant: [OH-]
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: [K+]
Solvent: COCCOCCOC
Product: OCCCCCCCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
Under nitrogen, 32.4 g (128 mmol) of 11-bromo-1-undecanol are added at 80° C. to a solution of 20.0 g (54 mmol) of 2-phenyl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine, 6.6 g (109 mmol) of potassium hydroxide and 150 ml of diglyme. The mixture is heated at 100° C. for 14 hours and filtered while hot, and the filtrate is cooled to 0° C. The solid which crystallizes therefrom is filtered off, pressed and dried for 24 hours under reduced pressure (60 mmHg, 60° C.), giving 27.6 g (72% yield) of 2-phenyl-4,6-bis[2-hydroxy-4-(11-hydroxyundecyloxy)phenyl]-1,3,5-triazine as a pale yellow solid of melting point 126°-135° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:16]=[C:17]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:18]=[CH:19][CH:20]=1.CO>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]I>[O:22]1[CH:23]=[CH:24][O:25][CH:21]1[C:17]1[CH:16]=[C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1C(=O)N(c2cccc(C3OC=CO3)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Isatin (3.2 g, 0.0218 mol) was dissolved in anhydrous DMF (75 ml) and cooled in an ice-bath under a nitrogen atmosphere. To this cold solution, sodium hydride (0.575 g, 0.0239 mol) was added and the reaction was stirred at 0° C. for 1.5 hours. This solution was then treated with 2-(3-bromophenyl)-1,3-dioxolane (5 g, 1 equivalent) followed by CuI (8.3 g, 2 equivalents). The resulting suspension was heated in an oil-bath under nitrogen at 130-140° C. for 16 hours. It was then cooled to room temperature and diluted with an equal volume of chloroform. This suspension was filtered and the filtrate was concentrated under reduced pressure. A viscous brown oil was recovered which was suspended in xylenes (150 ml) wand evaporated to dryness. The residue was used as such for the next reaction. TLC (5% methanol in chloroform) showed clean conversion; Rf (product)=0.86.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:6][C:7]([OH:9])=O.[NH2:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:5]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:6][C:7]([NH:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1)=[O:9]
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
Using thionyl chloride, N-palmitoyl-Gly was converted to the acid chloride in toluene at room temperature, then reacted with L-histidine using triethylamine as the base. However, only a trace amount of N-palmitoyl-Gly-His formed.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:31][CH2:30][C:17]3([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1>C(O)C>[ClH:4].[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]2[CH2:31][CH2:30][C:17]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:11]1
Reactant: CC(=O)Cl
Reactant: CN1CCN(C(=O)C2CCC3(CC2)CCN(C(=O)OC(C)(C)C)CC3)CC1
Solvent: CCO
Product: CN1CCN(C(=O)C2CCC3(CCNCC3)CC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethanol (3 ml) and acetyl chloride (0.24 ml, 3.43 mmol) were added to tert-butyl 9-(4-methylpiperazine-1-carbonyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.26 g, 0.685 mmol) and the mixture was stirred at room temperature for 12 h. When the reaction was complete, the solvent was removed in vacuo. Yield: 0.22 g (101%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]([C:6]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:12])[CH3:13])(=[O:24])=[O:23]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3-hydroxypropyl)methylcarbamate (551 mg, 2.92 mmol) was dissolved in dichloromethane (15 mL), triethylamine (0.811 mL, 5.83 mmol) and methanesulfonyl chloride (0.337 mL, 4.38 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified by short-path silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=1:1→0:1, v/v) to give crude 3-([tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate as a colorless oily substance. The resulting crude product was dissolved in ethanol (15 mL), N,N-diisopropylethylamine (5.07 mL, 29.2 mmol) and methoxyamine hydrochloride (2.43 g, 29.2 mmol) were added, and the mixture was stirred at 50° C. for 14 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=9:1:0→0:1:0→0:9:1, v/v/v) to give the title compound (362 mg; yield, 19%).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([CH2:22]Cl)=O)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([NH2:26])=[S:25].CN1CCOCC1>CC(C)=O.CCOCC>[CH2:1]([C@H:8]([CH2:19][C:20]1[N:26]=[CH:24][S:25][CH:22]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=S
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)Cc1cscn1
Yield: 75.9 %

Procedure:
The resultant compound from Example 34 (476.8 mg, 1.44 mmol) and thioformamide (176 mg, 2.88 mmol) in acetone (6 ml) were stirred at room temperature for 108 h. N-methylmorpholine (0.16 ml, 1.40 mmol) was added and after 20 min the mixture was diluted with ether, filtered, evaporated, and chromatographed on silica gel with 20% ethyl acetate in hexane to afford 369 mg (76%) of an oil. 1H NMR (CDCl3) δ8.70 (d,1H), 7.05-7.35 (m,10H), 6.90 (d,1H), 5.00 (d,1H), 4.95 (d,1H), 3.28-3.35 (m,1H), 3.19 (dd,1H), 2.95-3.10 (m,2H), 2.88 (dd,1H).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)([CH3:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[OH:23]>>[OH:23][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[C:9]1[CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)(O)c1ccc(C(C)(C)O)cc1
Reactant: Cc1ccc(O)c(C)c1
Product: Cc1cc(C)c(O)c(-c2cc(C(C)C)ccc2C(C)C)c1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of 1164 g (6 mols) of α,α'-dihydroxy-p-diisopropyl benzene in 5490 g (45 mols) of 2,4-dimethyl phenol is added dropwise with stirring over a period of 9 to 10 hours at 150° C in a nitrogen atmosphere to a solution of 1830 g (15 mols) of 2,4-dimethyl phenol. At the same time, about 200 to 210 g of water distilled over. The reaction mixture is stirred for 15 minutes, the catalyst is neutralised with 6.5 g of soda and freed from 2,4-dimethyl phenol under reduced pressure up to a sump temperature of 140° C/12 Torr. This leaves a light, crystallising residue of 2230 g (93% of the theoretical). The recrystallisation of 100 g from 150 ml of tetrachloroethane gives α,α'-bis-(2-hydroxy-3,5-dimethyl phenyl-p-diisopropyl benzene in a yield of 80% (melting point 179° C).
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)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)[C:36](=[O:41])[CH2:37]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1c1ccccn1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(c4ccccn4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-(pyridin-2-yl)piperazin-2-one dihydrochloride salt (109 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.0 min (conditions 4), MH+=486).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([OH:19])=[O:18])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])#[CH:2].ClCCl.Cl.CN(C)CCCN=C=NCC.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36].[CH3:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>CN(C)C1C=CN=CC=1>[CH2:39]([O:38][C:35]([CH2:36][C:43]1[CH:42]=[CH:41][C:46]([O:18][C:17]([C:5]2[CH:6]=[C:7]3[C:12](=[C:3]([C:1]#[CH:2])[CH:4]=2)[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]3([CH3:15])[CH3:16])=[O:19])=[CH:45][CH:44]=1)=[O:37])[CH3:40]
Reactant: CCOC(C)=O
Reactant: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Reactant: CCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#Cc1cc(C(=O)Oc2ccc(CC(=O)OCC)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following General Procedure D and using 8-ethynyl-2,2,4,4-tetramethyl chroman-6-carboxylic acid (Compound 26, 0.45 g, 1.75 mmol), anhydrous dichloromethane (20 mL), ethyl-4-hydroxy phenyl acetate (Compound 15, 0.38 g, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 g, 2.62 mmol) and 4-(dimethylamino)pyridine (0.43 g, 3.5 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound was obtained as white solid (0.536 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1(B(O)O)C=CC=CC=1.[CH3:22][C:23]([CH3:27])=[CH:24][CH:25]=O.C1(O)C=CC=CC=1>C(O)(=O)C.C1(C)C=CC=C(C)C=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:23]([CH3:27])([CH3:22])[CH:24]=[CH:25]2
Reactant: CC(C)=CC=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: OB(O)c1ccccc1
Solvent: Oc1ccccc1
Solvent: Cc1cccc(C)c1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2c(c1)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
175.6 g methyl-4-hydroxyphenylacetate and 128.9 g phenylboronic acid were added to 3.5 l m-xylene. 88.9 g 3-methylbut-2-enal, and 130 ml of glacial acetic acid were added to this mixture. The mixture was heated to 140° C. in a Dean-Stark apparatus under a nitrogen atmosphere until approximately 70% of the phenol had reacted (approximately 48-72 hours). Then the reaction mixture was allowed to cool to room temperature, the mixture was filtered, and the solvent was evaporated at reduced pressure. The remaining residue was dissolved in a 1:1 mixture of tetrahydrofuran (THF) and a 25%-strength aqueous ammonia solution (v/v) and stirred for 2 hours. The THF was largely evaporated off at reduced pressure and ethyl acetate was added. The organic phase was separated, washed in succession with an aqueous 1 N NaOH and a saturated aqueous common salt solution and finally dried over sodium sulfate. The solvent was largely evaporated at reduced pressure, and the remaining residue was chromatographed on silica gel (mobile phase: n-hexane/EA 15:1 to 10:1 v/v). Drying of the product fractions in an oil pump vacuum yielded 106 g methyl-(2,2-dimethyl-2H-chromen-6-yl)acetate as pale yellow oil, which was used without further characterization for the subsequent reaction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[N:10]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN=[N+]=[N-]
Yield: 96.2 %

Procedure:
Ethyl 4-bromobutanoate (17.11 g, 87.7 mmol) and NaN3 (28.50 g, 438.5 mmol) was dissolved in 70 mL DMF and reacted at 77° C. for 30 hours. 250 mL of 4:1 EtOAc/hexanes was added, and was washed twice with 250 mL saturated aqueous sodium bicarbonate, and once with 200 mL water. Organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 4-azidobutanoate 6 (13.26 g, 96%). Ethyl 4-azidobutanoate 6 (6.18 g, 39.29 mmol) was then saponified using excess KOH in 12:10 methanol/water at 0° C. for 5 minutes and then ambient temperature for 11 hours, followed by acid workup to yield 4-Azidobutanoic acid 7 (4.69 g, 92%). 1H NMR (400 MHz, cdcl3) δ 1.71-1.98 (2H, m), 2.45 (2H, t, J=7.2 Hz), 3.35 (2H, t, J=6.7 Hz), 11.21 (1H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](Cl)=[O:30]>>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29]([CH:25]4[CH2:26][CH2:27][CH2:28][O:24]4)=[O:30])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)C1CCCO1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C1CCCO1
Yield: 33.2 %

Procedure:
As described for Example 8, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine is reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to give a glass which is crystallized from ethyl acetate to give 0.22 g of crystals, m.p. 208-214° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCN(C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.27 ml; 1.92 mmol; 4 eq) and 1-methyl-piperidin-4-ylamine (0.11 ml; 0.96 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 40 minutes. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (185 mg; 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl.C(N(CC)CC)C>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2-Nitrobenzyl alcohol (1 g, 6.5 mmol) was dissolved in 40 ml of dry DCM and 1.36 ml of triethylamine. p-toluenesulfonyl chloride (1.24 g, 6.5 mmol) was added and the solution was stirred for 2 hours before quenching with water. The organic layer was separated and washed with 1 N HCl (1×50 ml), water (1×50 ml), 2 N NaOH (1×50 ml), water (1×50 ml) and brine (1×50 ml). The organic layer was dried over anhydrous Na2 SO4 and concentrated under reduced pressure to give a dull white solid, which was further purified by flash chromatography (silica gel, dichloromethane/ethanol=9.5:0.5) to give 2-nitrobenzyl tosylate, 22 (1.57 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.08-7.99 (dd, J=9.21 & 8.04 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.72-7.62 (m, 3H), 7.50 (d, J=8.85 Hz, 1H) 7.33 (d, J=8.43 Hz, 2H), 4.93 (s, 2H), 2.42 (s, 3H). 13C-NMR (60 MHz, CDCl3) δ 149.33, 146.12, 137.71, 135.27, 134.11, 133.09, 132.69, 132.57, 128.12, 123.89, 42.72, 20.64. MS (ESI): m/z 329.9 [(M+Na)]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([N:12](CC)CC)C.C[Si](C#N)(C)C>C(#N)C.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O>[Br:1][C:2]1[C:3]([C:10]#[N:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: N#Cc1ncc(Br)cc1Br
Reaction time: 16 h
Yield: 73.2 %

Procedure:
3,5-dibromopyridine 1-oxide (25.09g, 0.099 mol) was dissolved in acetonitrile (200 mL) and triethylamine (28 mL, 0.198 mol) and trimethylsilylcyanide (40 mL, 0.297 mol) were added. The reaction was stirred 16 hours and then diluted with dichloromethane, aqueous sodium carbonate, water, and then filtered through Celite eluting with dichloromethane. The mixture was extracted with dichloromethane and purified by silica gel chromatography (3:2 hexanes:ethyl acetate gradient elution) to afford 3,5-dibromo-2-pyridinecarbonitrile (18.98 g, 73% yield) as a tan solid. 1H NMR (CDCl3) δ 8.68 (d, J=2 Hz, 1 H), 8.20 (d, J=2 Hz, 1 H); MS m/z 262 M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:5]([CH3:18])[S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Yield: 64.4 %

Procedure:
A mixture of 0.97 g (3.9 mmol) of N-tert-butyl-6-chloropyridine-3-sulfonamide, 2.43 mL (39 mmol) of methyl iodide and 5.4 g (39 mmol) of K2CO3 in 40 mL of acetone is refluxed for 12 hours. The reaction medium is filtered at room temperature, and the filtrate is concentrated under reduced pressure. The residue obtained is purified on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 20% EtOAc, to give 0.66 g of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide in the form of a yellow solid.