Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(CC)CC.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:39]([NH:13][C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=C=NCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(2-thiophene-2-yl)thiazol-4-yl)ethan-amine hydrobromide salt, 8, and Et3N (0.42 mL, 3 mmol) in 10 mL DCM is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Yield: 99.1 %

Procedure:
The product from Example 18a (0.30 gm, 1 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.27 gm, 100%) as an amber oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([N:19]=[C:20]=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: Nc1ccc(F)c(O)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)c(O)c2)no1
Temperature: 70 °C

Procedure:
A mixture of 5-amino-2-fluorophenol (1.3 g, 10.2 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (1.7 g, 10.2 mmol) in toluene (60 mL) was heated at 70° C. overnight. The solid was filtered and dried under vacuum to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-fluoro-3-hydroxyphenyl)urea as solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH3:3]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)C=Cc1ccc(CN(C)C)s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN(C)C)s1
Reaction time: 5.5 h
Yield: 97.9 %

Procedure:
A solution of ethyl 3-(5-dimethylaminomethyl-2-thienyl)acrylate (30.30 g) in ethanol (175 ml) was hydrogenated (initial press. 344 kPa) over a total of 8.5 hr at a temperature of between 55°-60° C. in the presence of 10% palladium on charcoal catalyst (ca. 10 g) used in two portions. The first portion was added to the reaction mixture initially and the second after 5.5 hrs. The catalyst was filtered off over diatomecous earth and washed with ethanol. The filtrate was evaporated at reduced pressure to give ethyl 3-(5-dimethylaminomethyl-2-thienyl)-propionate (29.91 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.Cl[C:11]1C(Cl)=CC=[CH:14][C:12]=1[NH2:13]>>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]2[C:3]=1[CH2:11][CH:12]([NH2:13])[CH2:14]2
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Nc1cccc(F)c1Cl
Product: NC1Cc2ccc(F)c(Cl)c2C1

Procedure:
Substituting 2-chloro-3-fluoroaniline as a starting material for 2,3-dichloroaniline and following the procedure of Example 1 yields 4-chloro-5-fluoro-2-indanamine.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:38][N:3]1[CH2:4][CH:5]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[CH:18]=2)=[O:12])[CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NCC2=CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride (30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.47 mmol, 0.1 g) was added and stirred at room temperature for 2 h. The reaction was diluted with DCM (5 mL), and the DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM -6% (NH3 in MeOH, 2M) in DCM to provide 6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1-methyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide, which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and solid was dried under high vacuum (38 mg). LCMS: m/z 464.1 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.38 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 5.71 (1H, s), 4.40-4.50 (1H, m), 4.11 (2H, s) 3.88 (1H, d), 3.55-3.70 (2H, m), 3.17-3.28 (3H, m), 2.94 (3H, s), 2.52-2.66 (1H, m), 2.44 (1H, d), 1.97-2.10 (2H, m),1.75-1.88 (2H, m), 1.25-1.70 (10H, m), 0.84 (3H, t).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].CN(C1C=CC=CN=1)C.[C:16]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17].C(N(CC)CC)C>ClCCl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]#[N:17])[CH:19]=1)(=[O:26])=[O:25]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of bromopropylamine hydrogen bromide (0.219 g, 1 mmol) in dichloromethane (2 ml) is treated with a solution of dimethylaminopyridine (0.004 g) in dichloromethane (0.5 ml) followed by a solution of 3-cyano-benzenesulfonyl chloride (0.2 g, 1.0 mmol) in dichloromethane (0.5 ml). Triethylamine (0.3 ml, 2.16 mmol) is added and the reaction mixture stirred at ambient temperature for 2 hours, then quenched with water and saturated aqueous NaHCO3, and extracted into dichloromethane. The organic phase is washed with aqueous 1M HCl solution and brine, dried over MgSO4 and evaporated to afford crude N-(3-bromopropyl)-3-cyano-benzenesulfonamide. (13C NMR, 100 MHz, CDCl3, 30.2, 32.6, 41.9, 114.3, 117.5, 130.7, 130.9, 131.1, 136.3, 142.1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:47])[CH:10]([C:12]1[CH:46]=[CH:45][CH:44]=[CH:43][C:13]=1[CH2:14][CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[N:28][CH:29]=2)[N:17]=1)[CH3:11]>C(Cl)Cl>[Cl:22][C:21]1[C:16]([CH2:15][CH2:14][C:13]2[CH:43]=[CH:44][CH:45]=[CH:46][C:12]=2[CH:10]([CH3:11])[C:9]([NH2:8])=[O:47])=[N:17][C:18]([NH:23][C:24]2[CH:29]=[N:28][C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[N:19][CH:20]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
TFA (0.71 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-chloropyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A31 (34 mg, 0.06 mmol) in DCM (7 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo before the addition of 2.0 M NaOH solution (2 mL) and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4 and the solvent removed under reduced pressure to give the title compound 37 (23 mg, 82%). LCMS-C: rt 6.02 min; m/z 465.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)[C:17](O)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:52][OH:53]>ClCCl.C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:22][CH:21]=2)[C:17]([NH:52][OH:53])=[O:18])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: NO
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NO)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a 0° solution of ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid (1.58 g, 3.35 mmol) and DMF (0.52 ml, 6.69 mmol) in dichloromethane (29 ml) was added oxalyl chloride (3.35 ml of 2M in CH2Cl2; 6.69 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 2 h, then cooled again. A THF (2 ml) solution of triethylamine (1.87 ml 13.38 mmol) and hydroxylamine (2.05 mL of 50% hydroxylamine in water, 33.5 mmol) was added in one portion. The reaction was stirred at room temperature overnight. After removing the solvent, the oily residue was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. Preparative TLC chromatography eluting with dichloromethane:methanol (8:2) provided 0.33 g of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetamide. mp 70° C. This compound (0.28 g, 0.57 mmol) was dissolved in dichloromethane (3 ml) and methanol (2 ml) cooled in ice bath. Then 1M hydrogen chloride in ethyl ether (0.86 ml, 0.86 mmol) was dropped in. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1.5 h, and then concentrated to obtain 0.27 g of the hydrochloride salt. mp 68-70° C. Electrospray Mass Spec 488.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1>>[Br:19][C:20]1[N:21]=[C:22]([C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: Brc1cccc(Br)n1
Product: N#Cc1ccc(F)cc1-c1cccc(Br)n1

Procedure:
4-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (synthesised as in Example 24) was coupled with 2,6-dibromopyridine as described in Example 27 to give 2-(6-bromopyridin-2-yl)-4-fluorobenzonitrile as a white solid: δH (360 MHz, d6-DMSO) 7.55-7.60 (1H, m), 7.67-7.84 (2H, m), 7.89-8.02 (2H, m), 8.12 (1H, dd, J 9 and 6).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[CH2:16]([NH:23][S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][S:24](/[C:27](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:28]#[N:29])(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C(C)C)c1O

Procedure:
The titled compound was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and N-benzyl cyanomethylsulfonamide under the similar conditions as described for EXAMPLE 12 (part B).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH:23][CH2:24][C:25]([NH:27][NH2:28])=O>C(O)CCC>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:9][CH2:10][C:11]3[N:12]([C:25]([CH2:24][OH:23])=[N:27][N:28]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NC(=S)CN=C2c1ccccc1F
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)-n1c(CO)nnc1CN=C2c1ccccc1F

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-8-nitro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol is heated to reflux with hydroxyacetic acid hydrazide to give 9-nitro-1-(hydroxymethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:36]([F:39])([F:38])[F:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:36]([F:37])([F:38])[F:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(C#Cc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(CCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
A solution of [4-({3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}ethynyl)-phenyl]acetic acid (50 mg, 0.09 mmol), in ethyl acetate:acetic acid (8:1, 4.0 mL) is treated with Pd/C (10%) (3 mg) and placed on a PARR hydrogenator under 40 psi H2 The reaction filtered through celite and concentrated in vacuo. After chromatography (ethyl acetate:hexane, 33:70) the title saturated compound is obtained, 40 mg (80%). MS (ES) m/z 524.1.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[C:19]([CH3:20])=[N:18]1
Reactant: C1CCNC1
Reactant: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c2c1N(C(=O)CN1CCCC1)c1ccccc1NC2=O
Yield: 92 %

Procedure:
2.0 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 0.55 g of pyrrolidine, 0.85 g of ground sodium carbonate and 15 ml of absolute ethanol are heated at the boil for 2 hours; the hot solution is then filtered and concentrated in vacuo. The thus-obtained residue is dissolved in ethylene chloride, and the resulting organic solution is washed at pH 7 with water and concentrated to yield 2.05 g of 1,3-dimethyl-4-(pyrrolidinoacetyl)-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 114° to 116° C. (from toluene).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[S:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[S:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h

Procedure:
To a solution of #32 (321 mg, 0.881 mmol, 1 eq.) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #39 (484 mg, ≦0.769 mmol, 0.9 eq.), HATU (353 mg, 0.881 mmol, 1 eq.) and diisopropylethylamine (463 μL, 2.64 mmol, 3 eq.). After stirring for 18 hours, the mixture was diluted with dichloromethane, washed with water and with brine, dried over magnesium sulfate, filtered, and concentrated onto silica in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #43 (574 mg, 68% over two steps) as a white solid. LC-MS: m/z 956.6 [M+H+], retention time=4.49 minutes; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.80 (d, J=7.5 Hz, 2H), 7.64-7.72 (m, 2H), 7.16-7.35 (m, 7H), [5.43 (dd, J=11, 4.5 Hz) and 5.58 (dd, J=11.5, 4 Hz), total 1H], 3.72 and 3.75 (2 s, total 3H), 3.34 and 3.35 (2 s, total 3H), 3.26 and 3.29 (2 s, total 3H), 3.05 and 3.11 (2 br s, total 3H), 1.39 and 1.40 (2 s, total 3H), [1.24 (d, J=6.7 Hz) and 1.29 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:34]=[CH:33][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23](CCCCCC)[C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:2]([NH:26][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:7]3[CH:33]=[CH:34][C:4]([CH2:3][CH2:2][NH:1][CH2:63][C@H:61]([OH:62])[CH2:60][O:59][C:56]4[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=4)=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[O:16])=[CH:18][CH:19]=1)=[O:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCN(C(N)=O)c1ccc(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Product: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 61.5 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl)carbonyl)phenyl]-N-hexylurea (0.394 g, 0.846 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.308 g, 0.761 mmol) according to Procedure G to give the title compound (0.232 g, 0.26 mmol).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate [Example 1, step a] (2.3 g) in a mixture of dichloromethane (40 mL) and trifluoroacetic acid (10 mL) was allowed to stand at 20° C. for 30 minutes. Toluene (50 mL) was added and the solvents were evaporated, then this process was repeated with further toluene (50 mL). The residue was triturated with ether. The gum was then dissolved in acetonitrile and the solvent evaporated to afford the subtitled compound. Yield 1.64 g.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]([O:29][CH3:30])[C@H:25]([O:27][CH3:28])[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reaction time: 8 h
Yield: 89.4 %

Procedure:
708 mg of N-iodosuccinimide was added little by little to a mixture of 783 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridine and 7.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 995 mg of the target compound.
Reaction SMILES: O=C1O[N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][CH:16]([C:18]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[O:19])[O:15][C:14]3=[O:33])=[CH:9][CH:8]=2)[NH:3]1.C(OCC)(=O)C>CO.[Ni]>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:17][CH:16]([C:18]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[O:19])[O:15][C:14]2=[O:33])=[CH:11][CH:12]=1)(=[NH:3])[NH2:5]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(-c4noc(=O)[nH]4)cc3)C(=O)O2)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1

Procedure:
1.37 g of tert-butyl 1-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonyl}piperidine-4-carboxylate are dissolved in 50 ml of methanol and hydrogenated over Raney nickel. The reaction mixture is, subsequently filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate, with heating, and the product, after cooling, is filtered off with suction. Tert-butyl 1-[3-(4-amidinophenyl)-2-oxo-5-oxazolidinylcarbonyl}piperid-4-yl-carboxylate is obtained, m.p. 160°.