Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].C(OC([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=O)(C)(C)C>O1CCOCC1.O.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>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9]([C:30]3[CH:29]=[N:28][N:27]([CH:24]4[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]4)[CH:31]=3)=[C:4]2[C:3]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2c(Cl)c(Cl)oc12
Temperature: 100 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (300.0 mg, 0.9121 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (516 mg, 1.37 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was degassed and refilled with argon (3×). The reaction was heated at 100° C. for 20 h using a Biotage Initiator microwave reactor. The reaction was concentrated in vacuo to give a solid which was purified by flash chromatography (30 to 60% EtOAc:hexanes), which afforded the desired intermediate. 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 4.80 (br s, 2H), 4.32 (m, 3H), 2.99 (m, 2H), 2.18 (m, 2H), 1.97 (m, 2H), 1.47 (s, 9H); MS (ESI): 452.00 [M+H]+; HPLC tR=3.14 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.Br[CH2:20][C:21]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:22]=1[O:23][CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([N:8]([CH2:20][C:21]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: COc1ccc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(CBr)c1
Reactant: CC(=O)Nc1cc(F)ccc1Oc1ccccc1
Product: COc1ccc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 56 %

Procedure:
The general procedure C was applied to N-(5-Fluoro-2-phenoxy-phenyl)-acetamide and 9b. The desired compound 9c was obtained in 56% yield (3.27 g; 5.61 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13]=2[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
{(S)-1-[6-Fluoro-1-(4-fluorophenyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.8 g, 2.14 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) added. The reaction mixture was stirred at RT for 1 h. The resultant mixture was concentrated in vacuo to afford a dark green gum. This was dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 (20 mL) for 10 minutes. The layers were separated and the organic fraction dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10% MeOH in DCM) to afford the title compound (0.33 g, 57%). LCMS (Method C): RT 1.86 min [M+H]+ 274.2
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CCN(CC)CC>C(O)C>[CH:11]([N:8]1[C:6]2[N:7]=[CH:2][CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)ccnc21

Procedure:
To a 100 mL round bottom flask was charged 10% Pd/C(degussa) (0.213 g, 0.100 mmol), under N2 followed by addition of ca. 5 mL EtOH. The slurry was stirred followed by addition of 6-chloro-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.48 g, 2.003 mmol) and ethanol (22 mL). Next added Et3N (0.837 mL, 6.01 mmol) and stirred for 5 min under nitrogen. The contents were then stirred under an atmosphere of hydrogen (1 atm) for 6 h at RT. The vessel was then flushed with nitrogen and the contents diluted with DCM (10 mL) and a small amount of celite. The contents were stirred for 10 min., filtered through analytical grade celite and washed with 10% MeOH/DCM, EtOH, then DCM. The filtrate was concentrated in vacuo to a residue and dried on hi-vacuum overnight. The solid was treated with water and adjusted to pH 3 with 1M HCl. The contents were filtered, air-dried and then dried in hi-vacuum oven at 45° C. for 18 h. The title compound was collected as 0.326 g (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.82 Hz, 6 H) 5.28 (quin, J=6.69 Hz, 1 H) 7.70 (d, J=4.55 Hz, 1 H) 8.39 (s, 1 H) 8.73 (d, J=4.55 Hz, 1 H) 13.91 (br. s., 1 H). LCMS(ES) [M+H]+ 205.9
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H:4]([O:59]C(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.C(O)(=O)C.[Cl:67]CCl>C(OCC)(=O)C>[C:4]([Cl:67])(=[O:59])[C:3]1[CH:15]=[CH:14][CH:18]=[CH:19][CH:2]=1
Reactant: ClCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccccc1

Procedure:
Before the C-4 sidechain can be added to the C-7 Cbz protected paclitaxel analog (9), the analog (9) must undergo protection of the 2-OH. The protection step is carried out by treating the reaction mixture containing analog (9) with an acid, preferably acetic acid to neutralize the reaction mixture. The dichloromethane in the neutralized reaction mixture is exchanged for ethyl acetate or other ester or amide organic solvent, and the resulting solution of 9 is treated with a strong base, preferably Li t-butoxide, and a benzoyl protecting agent, preferably benzoyl chloride, to form the 2-benzoyl (Bz) 7-hydroxy protected paclitaxel (10).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16](P(OCC)(OCC)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH:42]=O)[CH:35]=1.CCOC(C)=O>C1COCC1>[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH:42]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:10][CH:11]=2)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:35]=1
Reactant: CCOP(=O)(OCC)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Reactant: O=CCCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=CCCc2cccc(-c3ccccc3)c2)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A solution of tert-butyl 3-{6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}-2-(diethoxyphosphoryl)propanoate (1.058 g, 2.31 mmol) in dry THF (4 mL) was added to a solution of sodium hydride (0.111 g, 60% in mineral oil, 2.77 mmol) in dry TBF (3 mL) at 0° C. and the mixture was stirred at 0° C. for 60 min. To this mixture a solution of 3-(1,1′-biphenyl-3-yl)propanal (0.582 g, 2.77 mmol) in dry TBF (3 mL) was added, and the reaction mixture was allowed to attain room temperature over 22 h. EtOAc was then added, and the organic phase was washed with saturated aqueous NH4Cl and water, dried (Na2SO4) and concentrated. Flash chromatography (toluene/EtOAc, 15:1) of the residue gave tert-butyl 5-(1,1′-biphenyl-3-yl)-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)pent-2-enoate (1.105 g, 93%) as a mixture of E/Z-isomers.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH:8]1([C:11]([NH:13][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([OH:17])=O)=[O:12])[CH2:10][CH2:9]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH:8]1([C:11]([NH:13][CH:14]([C:15](=[O:17])[CH3:1])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(NC(=O)C1CC1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(NC(=O)C1CC1)C(C)=O
Temperature: 90 °C
Yield: 70 %

Procedure:
DMAP (5 g, 0.041 mol) and acetic anhydride (306 g, 3 mol) were added to a suspension of 2-[(cyclopropylcarbonyl)amino]-4-ethoxy-4-oxobutanoic acid (Preparation 85, 229 g, 1 mol) in freshly-distilled pyridine (1.5 L). The reaction was heated at 90° C. for 2 hours before concentrating in vacuo at 60° C., azeotroping with toluene. The residue was purified by silica gel column chromatography eluting with 2% methanol in chloroform to afford the title compound (70%) that was taken directly on to the next step.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH2:13][CH2:14][N:15]([O:17][CH3:18])[CH3:16])[NH:10][CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8](=[O:19])[CH2:9][N:10]([C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:11]([CH2:13][CH2:14][N:15]([O:17][CH3:18])[CH3:16])[CH2:12]2)=[CH:20][CH:21]=1
Reactant: CC(C)N=C=O
Reactant: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)CN1
Solvent: ClCCl
Product: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)CN1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-fluorobenzyl)-5-{2-[methoxy(methyl)amino]ethyl}piperazine-2-one (784 mg, 2.65 mmol) in anhydrous CH2Cl2 (13 mL) was treated with isopropyl isocyanate (391 μL, 3.98 mmol) and stirred under inert atmosphere at ambient temperature for 18 h. The solvent was removed in vacuo, and the resulting oil was purified by silica gel chromatography (EtOAc to 5% MeOH/EtOAc to 10% MeOH/EtOAc) to afford the title urea as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:14][C:15](=O)[CH2:16][CH3:17])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH4+].[OH-]>>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][C:12](=[O:13])[N:14]=[C:15]2[CH2:16][CH3:17]
Reactant: CCC(=O)NC(=O)Nc1ccc(OC)c(OC)c1
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nc(=O)[nH]c2cc(OC)c(OC)cc12
Reaction time: 3.5 h
Yield: 24.6 %

Procedure:
A suspension of N-(3,4-dimethoxyphenyl)-N'-propionylurea (32.45 g, 128 mM) in polyphosphoric acid (375.12 g, 1109 mM) is heated at 130°-135° C. under nitrogen with vigorous stirring for 3.5 hours. The mixture is then poured onto 500 g ice-H2O and stirred. The solution is brought to pH 5.5 with concentrated NH4OH and allowed to stand at room temperature overnight. A brown precipitate forms. The resulting solid is filtered and dried to yield 7.40 g of a white solid. This filtrate is extracted with CHCl3 (5×250 ml), the organic extract is dried (MgSO4) and the solvent removed in vacuo to give a tan solid. The solid is triturated with acetone and filtered to give a tan solid (4.98 g). A sample is slurried in water and redried for additional purification, m.p. 263°-265° C. δTMSTFA 7.50 (s, 1H, 5--H), 7.23 (s, 1H, 8--H), 4.30 (s, 3H, 6 or 7--OCH3) 4.17 (s, 3H, 6 or 7--OCH3), 3.50 (q, 2H, J=8.0 Hz, CH2CH3), 1.70 (t, 3H, J=8.0 Hz, CH2CH3).
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1)=[O:12])=[O:8].Cl.C1COCC1.C(Cl)[Cl:40]>O1CCOCC1>[ClH:40].[NH2:20][C@@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:11](=[O:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:28]=[CH:29][CH:30]=[C:4]([C:3]([F:32])([F:31])[F:2])[CH:5]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 20 h

Procedure:
tert-Butyl cis-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate hydrochloride salt (350 mg, 0.79 mmol, 1 eq) was dissolved in dioxane (5 mL) at room temperature then 4N HCl (1.97 mL, 7.9 mmol, 10 eq) was added. Stirred for 20 hours. The reaction was stripped 4 times from 1:1 THF/methylene chloride (20 mL) to give N-(2-(cis-4-amino-cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide hydrochloride (300 mg) as a white amorphous solid. MS found: (M+H)+=344.32.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].C(O)(=O)[CH2:8][CH2:9][C:10](O)=[O:11]>>[CH3:4][C@H:2]1[O:3][C:10](=[O:11])[C@H:9]([CH3:8])[O:6][C:1]1=[O:5]
Reactant: CC(O)C(=O)O
Reactant: O=C(O)CCC(=O)O
Product: C[C@@H]1OC(=O)[C@@H](C)OC1=O

Procedure:
Succinic anhydride is often a significant component of the intermediate-boiling impurities. Succinic anhydride can be separated from meso-lactide by washing the meso-lactide stream with a weakly basic aqueous phase. A suitable pH of the washing solution is in the range of from about 7.2 to about 11. This is believed to hydrolyze the succinic anhydride to form succinic acid. Some of the lactide may also be hydrolyzed to form mainly linear oligomers and possibly some lactic acid. The succinic acid is much more soluble in the basic aqueous phase than in the lactide phase, and will partition to the aqueous phase. The aqueous and organic phases are then separated to form a washed meso-lactide stream having a reduced level of succinic anhydride and perhaps other intermediate-boiling impurities. The washed meso-lactide stream can be recycled as described before.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24]>>[CH3:34][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24]
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCCN(C)C
Yield: 28.2 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (67 mg, 0.32 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylaminopropyl)amide (81 mg) to give 40 mg (28%) of the title compound as an orange solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4](F)=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7]>C(#N)C>[NH2:1][C:4]1[C:3]([Cl:2])=[CH:10][CH:9]=[C:8]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: N#Cc1c(F)ccc(Cl)c1F
Solvent: CC#N
Product: N#Cc1c(F)ccc(Cl)c1N
Temperature: 60 °C

Procedure:
Aqueous ammonia (d 0.880, 2 ml) was added to a solution of 3-chloro-2,6-difluorobenzonitrile (1.93 g, 11.1 mmol) in acetonitrile (10 ml), and the mixture heated to 60° C. for 16 h. The resulting brown solution was evaporated and purified by flash chromatography eluting with 5% ethyl acetate/hexane, increasing the gradient to 20% ethyl acetate/hexane, to furnish a white solid (410 mg), MS (+EI) 173/171 (M+); 1H NMR (CDCl3) 7.39 (1H, dd, J5.7, 9.0 Hz), 6.46 (1H, t, J8.7 Hz), 4.95 (2H, br. s).
Reaction SMILES: Br.C(O[C:7]([NH:9][NH:10][CH:11]1[CH2:21][CH2:20][C:14]2([NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)=O)(C)(C)C.[Br:22][CH:23](C=O)[CH:24]=O.[OH-].[Na+]>O.CC(O)=O>[Br:22][C:23]1[CH:7]=[N:9][N:10]([CH:11]2[CH2:12][CH2:13][C:14]3([NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)[CH2:20][CH2:21]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)NNC1CCC2(CCC(=O)N2)CC1
Reactant: O=CC(Br)C=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC2(CCC(n3cc(Br)cn3)CC2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrobromic acid (1.04 mL of a 48 wt % solution in water; 9.18 mmol; 2.0 eq.) was added to a solution of N′-(2-Oxo-1-aza-spiro[4.5]dec-8-yl)-hydrazinecarboxylic acid tert-butyl ester (1.30 g; 4.59 mmol; 1.0 eq.) and 2-Bromo-malonaldehyde (865 mg; 5.51 mmol; 1.2 eq.) in AcOH (13 mL). The reaction mixture was stirred at RT for 2 hour. It was then basified to pH 5 by addition of a 5N NaOH solution and extracted with DCM (three times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as the pure cis-isomer (1.0 g, 94%).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=1
Reactant: CCC(C)c1cc(N)c(OC)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)c1cc(N)c(OC)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.46 g of 5-sec-butyl-2-methoxy-1,3-diamino-benzene are dissolved in 20 ml dichloromethane, combined with 1.21 ml of pyridine and cooled to 0° C. 600 μl of methanesulphonic acid chloride are added, the mixture is allowed to come up to ambient temperature and stirred for 2 hours. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20 to 20:80).
Reaction SMILES: [I:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([N:29]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([N:29]([CH2:30][C:31]([OH:33])=[O:32])[CH2:38][C:39]([OH:41])=[O:40])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(Cc2ccc(I)cc2)Cc2nccn2CC(=O)N(CC(=O)O)CC(=O)O)cc1
Yield: 104.8 %

Procedure:
A solution of di-tert-butyl 2,2′-((2-(2-(((4-iodobenzyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (28.8 mg, 0.0369 mmol) in DCM (0.50 mL) and TFA (0.5 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (19) as a white solid (25.9 mg, 78.2%). 1H NMR (400 MHz, DMSO-d6) 7.70-7.66 (m, 4H), 7.57 (s, 1H), 7.55 (s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.28 (s, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.26 (s, 2H), 4.34 (s, 2H), 4.06 (s, 2H), 3.91 (s, 2H), 3.69 (s, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H); MS (ESI), 670.1 (M+H)−.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[CH:10]([C:16]([F:19])([F:18])[F:17])[C:11](OCCl)=O>>[F:8][C:9]([F:21])([F:20])[C:10]([C:16]([F:19])([F:18])[F:17])=[CH2:11]
Reactant: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Yield: 71.9 %

Procedure:
In a four necked 100 ml flask equipped with a condenser, a dropping funnel and a thermometer, triethylamine (20.0 g, 198 mmol) was charged and warmed to 60° C. Monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (4.88 g, 20 mmol) was dropwise added thereto while stirring. The reaction was continued at the same temperature as above for 2.5 hours while stirring. The gas evolved from a top of the condenser was washed with an alkaline solution, dried with alumina and cooled. The resultant liquid was distilled to give 2-trifluoromethyl3,3,3-trifluoropropene (2.36 g). Yield, 72 %.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.[Br:21][CH2:22][CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][N:25]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: NCCCBr
Reactant: COC(=O)Nc1ccccc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccccc1C=NCCCBr
Reaction time: 24 h
Yield: 94.3 %

Procedure:
Methyl 2-formylphenylcarbamate (7, 2.5 g, 14 mmol) and magnesium sulfate (5 g) were added to a solution of 3-bromopropylamine hydrochloride (3.68 g, 16.8 mmol) and triethylamine in chloroform (30 mL) and mixture was stirred for 24 h. The mixture was filtered and the residue was washed with chloroform (2×30 mL). The combined filtrates were washed with water (2×30 mL), brine (30 mL), dried with sodium sulfate, and concentrated to afford 21 as a yellow oil (3.95 g, 94.5%). IR (film) 1730, 1638 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J=8.4 Hz, 1 H), 8.30 (s, 1 H), 7.35 (t, J=7.7 Hz, 2 H), 7.26 (d, J=7.7 Hz, 1 H), 7.00 (t, J=7.4 Hz, 1 H), 3.74 (s, 3 H), 3.69 (t, J=6.3 Hz, 2 H), 3.50 (t, J=6.6 Hz, 2 H), 2.20 (pent, J=6.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 164.74, 154.30, 140.07, 133.00, 131.32, 121.25, 119.79, 117.69, 58.17, 52.87, 33.16, 31.15; ESIMS m/z (rel intensity) 299/301 (MH+, 100/99); EIHRMS m/z M+ calcd. for C12H15BrN2O2, 298.0317; found, 298.0320.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].[CH3:30][O:31][CH2:32]I>CN(C)C=O>[CH3:30][O:31][CH2:32][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1
Reactant: COCI
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 23.1 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.15 g), dimethylformamide (25 ml), and iodomethyl methyl ether (0.50 g), the title compound (0.26 g) was obtained as an amorphous solid, MS, m/z: 399.2(M+H)+, 797.2 (2M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (1.0 g, 7.2 mmol) in methanol (15 mL) was added sulfuric acid (881 μL, 16.53 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with DCM (100 mL), washed with sat. aq NaHCO3 solution. The organic layer was separated and dried with sodium sulfate, filtered and concentrated in vacuo to give methyl 5-hydroxypyridine-2-carboxylate, which was used without further purification. ESI-MS m/z calc. 150.1. Found 154.1 (M+1)+; Retention time: 0.33 minutes (3 min run).