Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14]C(C)(C)C)=[O:13])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]([CH3:19])([CH3:20])[C:12]([OH:14])=[O:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-allyloxycarbonylphenoxy)-2-methylpropionate (11.59 g, 36.19 mmol) was dissolved in dichloromethane (20 mL). Subsequently, trifluoroacetic acid (40 mL) was added at room temperature, and the mixture was stirred for three hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the concentrate. The resultant mixture was concentrated again under reduced pressure. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby a yellow oil was obtained (8.30 g, 31.41 mmol, 86.7%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[CH3:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:19]1=[O:23]
Reactant: CC1CCNC1=O
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: CC1CCN(Cc2ccc(C#Cc3ccccc3)cn2)C1=O

Procedure:
The title compound, light yellow oil, MS: m/e=291.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and rac-3-methyl-pyrrolidin-2-one.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC>[CH3:1][NH:2][C:3](=[O:17])[C:4]([CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]
Reactant: CNC(=O)C(CCCN(C)C)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)C(CCCN(C)C)(c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methyl-5-dimethylamino-2-phenylpentanamide (5.0 g, 0.023 mol) dissolved in 50 ml THF was added 18.1 ml of a 2.5M solution of n-BuLi in n-hexane with ice-cooling under N2. After stirring at 0° C. for 30 min, benzaldehyde (2.4 g, 0.023 mol) dissolved in 10 ml THF was added dropwise to the foregoing solution. The reaction mixture was stirred for 5 min at 0° C. and then poured into ice-cold HCl. The resulting solution was washed with Et2O, basified by adding dilute NaOH while stirring in the cold, and extracted with CHCl3. The CHCl3 extract were combined, dried (Na2SO4), and evaporated Chromatography of the post-evaporation residue afforded the desired compound as a mixture of diastereoisomers as an oil. Dissolution in EtOH, acidification with HCl, followed by addition of Et2O gave the hydrochloride salt as a colorless solid. [Anal. Calc'd for C21H28N2O2.HCl.1/4EtOH: C, 66.17; H, 7.93; N, 7.18; Cl, 9.08. Found: C, 65.82; H, 8.02; N, 7.04; Cl 10.27.]
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20](O)=[O:21])[C:14]1=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[OH:21][CH2:20][CH2:19][C:15]1[C:14](=[O:23])[N:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:3][O:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Under argon, 37.7 g (109 mmol) of {1-[2-(methoxymethyl)-4-nitrophenyl]-2-oxo-1,2-dihydropyridin-3-yl}acetic acid in 310 ml of tetrahydrofuran were introduced as initial charge at RT, and 53.3 g (327 mmol) of borane-diethylaniline complex were added, at first carefully then, after the considerable foaming has abated, rapidly. The reaction mixture was stirred overnight at RT, diluted with 500 ml of ethyl acetate and admixed with 1N hydrochloric acid (1.55 l), at first carefully (considerable foam formation), then rapidly. The reaction mixture was after-stirred for 30 min, the organic phase was separated off and the aqueous phase was extracted again with 500 ml of ethyl acetate. The combined organic phases were washed twice with in each case 500 ml of 1N hydrochloric acid, washed once with 200 ml of 1N sodium hydroxide solution, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was chromatographically purified firstly over 500 g of silica gel (0.04-0.06 mm) with methanol:dichloromethane 5:95 then 1:9 and again over 500 g of silica gel (0.04-0.06 mm) with acetone:dichloromethane 3:7. 14.2 g (43%) of the desired product were obtained here.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)([C:6]#[N:7])[CH2:3]1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:5][C:4]([C:6]#[N:7])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(c2ccccn2)CC(O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CC(C#N)(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a solution of 3-hydroxy-1-(pyridin-2-yl)cyclobutanecarbonitrile (WO 2007/060484)(10.996 g, 63.1 mmol) in dry DCM (100 mL) and pyridine (20.59 mL, 252 mmol), was added (with stirring and cooling in an ice water bath) methane sulfonyl chloride (4.88 mL, 63.1 mmol). The mixture was stirred at RT for 25 hours. The solvent was removed at reduced pressure, and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with aqueous NaHCO3 and was concentrated at reduced pressure. The residue was eluted through a short pad of silica gel (eluent 30%-50% EtOAc/hexane). The solvent was removed, and the resulting oil was crystallized from toluene on dilution with hexane to afford the title compound as a 3:1 mixture of geometrical isomers (assessed by NMR).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26])[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=C(Cl)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(=O)C1CC1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 6 eq KOt-Bu in THF at room temperature was added 6 eq 2-acetylamino-malonic acid diethyl ester and after 5 min 1 eq cyclopropane-carbonylchloride. After 15 min, the mixture was concentrated and partitioned between EtOAc and H2O. The organic layer was concentrated to give the desired product in 60% yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]([F:39])([F:38])[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][C:26]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:21][N:20]=1.O>CN1CCCC1=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:21]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:27]2[C:19]([C:18]([F:17])([F:39])[F:38])=[N:20]1)[C:6]#[N:7]
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Cc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 120 °C
Reaction time: 60 h
Yield: 11 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.052 g) and cesium carbonate (0.150 g) were added to a solution of compound (1d) (0.092 g) in 1-methyl-2-pyrrolidone (hereinafter referred to as NMP) (1.0 mL), followed by stirring at 120° C. for 60 hr. Water was added to the reaction solution, and the precipitate was collected by filtration and was washed by sprinkling water to obtain 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (11%). According to Example 1(7), compound (82) (64%) was prepared as a white solid using 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)=[CH:8][CH:7]=1)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>>[NH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 99.7 %

Procedure:
A solution of 4-(5-acetylaminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (4.76 g) in 1N-hydrochloric acid (51.1 ml) was refluxed for 8 hours with stirring. The solution was made basic to pH 10 with an aqueous potassium carbonate. The resulting precipitate was collected by filtration and washed with water to afford 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (4.03 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]O)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:59]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][Br:59])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCO)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Yield: 63 %

Procedure:
The crude product from Example 72C and triphenylphosphine (0.730 g, 2.78 mmoles) in anhydrous DMF (5 mL) at 0° C. were treated with N-bromosuccinimide (0.396 g, 2.24 mmoles). Reaction mixed at 0° C. for 30 minutes. Reaction diluted with ethyl acetate, washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate:hexanes) to provide the title compound (0.214 g, 63%). MS (ESI+) m/z 609 (M+H)+.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CN(C)CCCNC(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCCNC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (292 mg, 0.75 mmol) 5 was added to a solution of compound 4 (200 mg, 0.65 mmol), DIPEA (0.39 mL, 2.25 mmol), and ethanol (5 mL). The reaction mixture was stirred at 65° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (80:18:2 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 6 (190 mg, 56%) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.65 (m, 6H), 2.15 (s, 6H), 2.32 (m, 2H), 2.64 (m, 2H), 3.27 (m, 8H), 4.49 (s, 2H), 6.89 (d, 2H), 7.15 (d, 2H). m/z (ESI) 520.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][OH:27]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2([CH3:1])[O:27][CH2:26][CH2:25][CH2:24][O:3]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCCO1
Temperature: 25 °C

Procedure:
A mixture of 4-nitroacetophenone (1.65 g, 10.0 mmol), p-toluenesulfonic acid (172 mg, 1.00 mmol) and 1,3-propanediol (2.3 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Recrystallisation from ether and hexane afforded 2-(4-nitrophenyl)-2-methyl-1,3-dioxane (26) as a pale yellow crystals (1.60 g, 72%; yield based from the first crop of crystals). 1H nmr (300 MHz, CDCl3) 1.52 (s, 3H, CH3), 2.08-2.22 (m, 2H, OCH2CH2CH2O), 3.65-3.80 (m, 2H, OCH2), 3.88-4.00 (m, 2H, OCH2), 7.63 (d, J=8.9 Hz, 2H, 2×ArH), 8.26 (d, J=8.9 Hz, 2H, 2×ArH).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4]1.Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:3]2[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]2)[CH:22]=1
Reactant: ClCc1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2cccnc2)n1
Temperature: 50 °C
Yield: 62 %

Procedure:
NaH (0.9 g., 60% suspension in liquid paraffin) is dissolved in DMF (10 ml) and 2-(1H-pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added at 0° C. To this solution is added 3-chloromethyl-pyridine (10.1 mmol) and the mixture is heated to 50° C. for 16 hours. The solvent is removed in vacuo. The residue is dissolved in ethanol (100 ml) and hydrazinium-hydroxide (30 ml) is added and the reaction is heated to 120° C. for 9 days. The solvent is removed in vacuo. 1-Pyridine-3-ylmethyl-1H-pyrazole-3-ylamine is obtained after column chromatography as colorless oil in a yield of 62%; LC-MS (method B): 0.39 min, 175.15 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-butoxybenzaldehyde (1.64 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol to give 3.0 g (85%) of a pale yellow powder. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (d, 2H), 7.0 (d, 2H), 4.05 (t, 2H), 4.0 (s×2, 9H), 1.8 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). Mass Spectrum m/e (M+1) 370.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)C)c1

Procedure:
4-(2-Methoxycarbonylvinyl)-2,6-diisopropylphenol (Example 1, 350 mg) was dissolved in a solution of ethyl acetate (10 mL) and methanol (10 mL) and hydrogenated at 35 psi over palladium on carbon (Pd/C) for 24 hours. The resulting mixture was filtered and the filtrate was concentrated to provide the title compound; 1H-NMR (CDCl3) δ=1.27 (d, 12H, CH(CH2)2), 2.60 (t, 2H, CH2), 2.87 (t, 2H, CH2), 3.13 (m, 2H, CH(CH3)2), 3.68(S, 3H, OCH3), 6.87 (S, 2H, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].OO>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH:13]([OH:23])[CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CC[C@H]1NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-N1,N2-Bis(tert-butoxycarbonyl)-4-cyclohexene-1,2-diamine (6.1 g) was dissolved in absolute tetrahydrofuran (40 ml), and borane-dimethyl sulfide complex (2.22 ml) was added by a syringe under ice cooling. The mixture was stirred for 16 hours while gradually heating the mixture to room temperature as it is. Ice was added to the reaction mixture, and a 1N aqueous solution of sodium hydroxide and 30% aqueous hydrogen peroxide (50 ml) were added to stir the mixture at room temperature for 2 hours as it is. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→2:1) to obtain the title compound (6.1 g) as a colorless oil.
Reaction SMILES: [N:1]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])=[CH:17][CH:16]=3)[C:11]2=[O:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])=[CH:17][CH:16]=3)[C:11]2=[O:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1[C@@H](N2CCc3ccccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C1[C@@H](n2ccc3ccccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 50 °C

Procedure:
A suspension of (S)-4-(3-(indolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)-benzenesulfonamide (10 mg, 0.023 mmol) and activated MnO2 (20 mg, 0.23 mmol) in CH2Cl2 (1.0 mL) was heated to 50° C. for 20 h. After cooling to RT, the reaction mixture was filtered through a syringe filter, concentrated and dissolved in DMSO/MeOH (1:1, 0.8 mL). Purification via reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave (S)-4-(3-(1H-Indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=2.1 Hz, 2H), 7.82 (d, J=3.0 Hz, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.19 (d, J=3.3 Hz, 1H), 7.08-7.03 (m, 1H), 7.01-6.94 (m, 2H), 6.62 (d, J=4.7 Hz, 1H), 6.44 (d, J=3.2 Hz, 1H), 5.51 (dd, J=8.9, 10.9 Hz, 1H), 4.02-3.98 (m, 2H), 2.72-2.68 (m, 1H), 2.49-2.40 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=439.2; tR=2.99 min.
Reaction SMILES: OC[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:24]
Reactant: CN(OCCOCCCO)C(=O)OC(C)(C)C
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)OCCOCCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxypropoxy)ethoxy(methyl)carbamate (152 mg, 0.646 mmol) and monomethyl adipate (104 mg, 0.646 mmol) in CH2Cl2 (4 mL) were added DCC (146 mg, 0.711 mmol) and DMAP (16 mg, 0.129 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered. The solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography using 27% EtOAc/hexanes as eluent. The desired product was obtained as colorless oil (152 mg, 0.403 mmol, 62%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.41 (s, 9H), 1.56-1.60 (m, 4H), 2.25-2.27 (m, 4H), 3.03 (s, 3H), 3.58 (s, 3H), 3.59-3.63 (m, 4H), 3.91-3.94 (m, 2H), 4.14-4.16 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:7][N:8]1[CH:12]=[C:11]([I:13])[CH:10]=[N:9]1)[C:3](OC)=[O:4].[NH3:14]>>[OH:1][CH:2]([CH2:7][N:8]1[CH:12]=[C:11]([I:13])[CH:10]=[N:9]1)[C:3]([NH2:14])=[O:4]
Reactant: COC(=O)C(O)Cn1cc(I)cn1
Reactant: N
Product: NC(=O)C(O)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanoate (4 g, 13 mmol) and ammonia (saturated in methanol, 100 mL) in a sealed tube was stirred at 60° C. for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propanamide. MS ESI calc'd. for C6H9IN3O2 [M+H]+ 282. found 282. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.50 (s, 1H), 4.53-4.49 (m, 1H), 4.36-4.29 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[C:11](=[O:19])[NH:10][C:9]2[CH:20]=[CH:21][CH:22]=[N:23][C:8]1=2)=[O:6].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:25]>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11](=[O:19])[NH:10][C:9]3[CH:20]=[CH:21][CH:22]=[N:23][C:8]=3[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])[CH2:32][CH2:33]3)=[O:6])[C:13]=2[CH:14]=1
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2cc(Cl)ccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Solvent: CN(C)C=O
Product: CCN(CC)CCCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 19 %

Procedure:
Prepared analogously to Example 109 from 11-[[[2-bromo-ethyl]amino]carbonyl]-9-chloro-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine, but using dimethylformamide instead of acetonitrile, in a yield of 19% of theory. Colourless crystals, m.p. 157° C.