Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)([CH2:12][CH2:13]1)[CH2:10][O:9]2)(=O)=O.[C-:29]#[N:30].[Na+]>CS(C)=O.C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([C:11]23[CH2:12][CH2:13][C:8]([CH2:7][CH2:6][C:29]#[N:30])([CH2:15][CH2:14]2)[O:9][CH2:10]3)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 110A compound (100 mg, 0.25 mmol) and NaCN (61 mg, 1.2 mmol) in DMSO (3 mL) was stirred at 80° C. overnight. The mixture was cooled to rt, diluted with DCM, washed with 1N aq HCl, dried (MgSO4), and concentrated in vacuo. The crude was chromatographed (SiO2; continuous gradient of hexanes/EtOAc from 100:0 to 50:50) to afford the title compound (62 mg, 75% yield) as a colorless oil. LCMS [M+H]+=334.3. 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.31-7.25 (m, J=7.9, 7.9 Hz, 1H), 7.14-7.09 (m, 1H), 7.00 (dd, J=8.6, 1.1 Hz, 3H), 6.96 (t, J=2.0 Hz, 1H), 6.84 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.96 (s, 2H), 2.47-2.41 (m, 2H), 2.12-2.03 (m, 2H), 2.00-1.89 (m, 4H), 1.84-1.78 (m, 2H), 1.74-1.64 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1O
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCCCCCc1ccccc1

Procedure:
A solution of 10 g (80.56 mmol) of 2-hydroxybenzyl alcohol in 200 ml of dry acetonitrile is mixed with 27.45 g (120.83 mmol) of (5-bromopentyl)benzene and 12.25 g (88.61 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 18.7 g (81% of theory) of a colorless solid are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32]([O:33][CH2:34][CH3:35])=[O:36])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CCOC(=O)Nc1ccc2[nH]ccc2c1
Product: CCOC(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and ethyl 1H-indol-5-ylcarbamate (intermediate-52) (6.0 g, 35%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=1.O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:15][CH:16]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
tetrahydro-2H-pyran-4-ol (850 mg, 8.32 mmol) was dissolved in DMF (10 mL), cooled to 0° C., NaH (500 mg, 10.4 mmol) was added and stirred for 45 minutes at room temperature, then 5-bromo-2-chloropyridine (2 g, 10.4 mmol) was added and the mixture was stirred overnight at 60° C. The mixture was poured into water, extracted by EA, the organic layer was washed by brine, dried over Na2SO4, concentrated and purified by flash chromatography, gave 1.7 g white solid. MS: (m/z): 258 (M−H)+, 260 (M+H)+
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]#[CH:27])[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:27]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: ON=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of Example 2, 1.72 g, 10.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (3.00 g, 10.0 mmol) and triethylamine (1.70 mL, 12.0 mmol) in dichloromethane (40 mL). The solution was heated at reflux under a nitrogen atmosphere for 3.5 hours and additional N-hydroxybenzenecarboximidoyl chloride (0.1 g) was added. The solution was heated at reflux for one hour more, then was allowed to cool to room temperature and was diluted with dichloromethane. The solution was transferred to a separatory funnel and was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 4:1 to 3:2 hexanes/ethyl acetate) to provide pure 4-chloro-2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=C(Cl)[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1
Reactant: O=CNc1ccc(Cl)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
N-(4-Chloro-phenyl)-formamide (766 mg, 4.93 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (60% in mineral oil, 240 mg, 5.91 mmol) was added and the mixture was stirred for 30 min. 2,6-Dichloro-9-methyl-9H-purine (1.0 g, 4.93 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours, cooled to room temperature and poured into water. The resulting precipitate was collected by filtration, washed with water and dried to give (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (1.2 g, 4.08 mmol, 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:7]=1)(=[O:26])=[O:25]
Reactant: NS(=O)(=O)c1cccc(CCCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzenesulfonamide (458 mg) in dry THF (10 ml) was treated with triethylamine (0.307 ml) and the resultant solution cooled to 0° C. Methanesulfonyl chloride (0.17 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was partitioned between 1M HClaq and EtOAc. The aqueous phase was washed with EtOAc. The combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound LCMS RT=2.67 min.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C)C1C=CN=CC=1.C(C(C)=O)C(C)C>[N:10]([CH2:2][CH:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[N+:11]=[N-:12]
Reactant: COC(=O)CC(O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)CC(O)CN=[N+]=[N-]
Reaction time: 11 h
Yield: 104.7 %

Procedure:
To a mixture of methyl 4-chloro-3-hydroxybutyrate (5 g, 33 mmol), and methyl isobutyl ketone (40 ml) are added sodium azide (2.3 g, 36 mmol) and 4-dimethylaminopyridine (403 mg, 3.3 mmol) and the mixture was refluxed under stirring for 11 hours. After cooling the salt was filtered off and the solvent was distilled off under vacuo and there was obtained methyl 4-azido-3-hydroxybutyrate (5.5 g) as a crude product. And followed by the same procedure as in example 1, there was obtained 4-hydroxy-2-pyrrolidone (2.3 g, 23 mmol, yield:70%). When the above reaction was carried out in the absence of 4-dimethylaminopyridine, it took more than 120 hours to detect the disappearance of the starting materials on gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([F:17])=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:17])=[C:6]([F:16])[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(F)c(F)c1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.22 (s, 9H), 7.31 (d, 2H, J=8.4 Hz), 7.40-7.47 (m, 3H), 7.55 (d, 2H, J=8.4 Hz), 7.59 (m, 1H), 8.69 (b, 1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z 431.0 (M++1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:22][CH2:23]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Example 39) following General Procedure B-3 was reacted with 2-aminopyridine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 123. (400 MHz, CDCl3): 0.91-0.94 (2H, m, CH2), 1.10-1.12 (2H, m, CH2), 2.20 (1H, m, CH), 2.58-2.60 (4H, m, CH2), 3.29-3.31 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.94-3.97 (4H, m, CH2), 4.55 (1H, b, NH2), 6.47 (1H, d (J=0.62), ar), 7.22 (1H, s, ar), 8.38 (1H, dd (J=8.89, 2.27), ar), 9.08 (1H, dd (J=2.20, 0.49), ar). (M+H)+ 516.37
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]([OH:24])[CH2:25][N:29]3[CH2:30][CH2:31][CH2:32][CH:27]([OH:26])[CH2:28]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1
Reactant: OC1CCCNC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(O)CN2CCCC(O)C2)CC1

Procedure:
In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and 3-hydroxypiperidine gave the title compound as yellow oil. MS: 484.2 (MH+, 2Cl).
Reaction SMILES: O.O.[Na+:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>[OH-].[Na+].C(O)C>[Na+:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:4][C:5]2[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 22 °C
Yield: 73.6 %

Procedure:
To a stirred solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22° C.), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4.95 g of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyloxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.06-7.12 (m, 4 H), 5.12 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([NH:14][CH3:15])=[O:13])[CH:11]=1)[C:5](OC)=[O:6].C(O)C.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1cc(Cl)cc(CO)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
(Step 1) To a mixed solution of methyl 3-chloro-5-[(methylamino)carbonyl]benzoate (2.5 g) in tetrahydrofuran:ethanol=10:1 (110 ml) was added lithium tetrahydroborate (0.36 g) at room temperature. After stirring at 60° C. for 4 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate) to give 3-chloro-5-(hydroxymethyl)-N-methylbenzamide (1.2 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.Br[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][O:14]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2cn[nH]c12
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccnc2cn(CC3CCCO3)nc12
Yield: 64 %

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.204 mmol), 2-(bromomethyl)tetrahydrofuran (33.7 mg, 0.204 mmol) and cesium carbonate (133 mg, 0.408 mmol) in DMF (1.0 mL) were heated in a microwave 80° C. for 15 minutes. The reaction was cooled, poured into water (10 mL) and extract with ethyl acetate (5 mL). The organics were dried over sodium sulfate, filtered and concentrated to provide 7-iodo-2-((tetrahydrofuran-2-yl)methyl)-2H-pyrazolo[4,3-b]pyridine (43 mg) which was used as is without further purification. MS [M+H] found 330.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=[O:46])[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31]([CH:44]([OH:46])[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)O)c2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
tert-Butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (20 mg, 0.0282 mmol) was dissolved in MeOH (0.2 mL) and sodium borohydride (1.43 mg, 0.0378 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The organic layer was separated and purified by reverse phase prep HPLC to give the title compound (15 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 0.71 (3H, t, J=5 Hz), 1.02 (3H, m), 1.45-1.47 (2H, m), 1.54 (2H, m), 1.74 (2H, m), 2.85 (1H, m), 3.09-3.18 (3H, m), 3.28 (1H, m), 3.49 (2H, m), 3.72-3.81 (4H, m), 3.97 (1H, m), 4.29 (1H, m), 4.41-4.44 (1H, m), 4.75 (1H, m), 4.90 (1H, m), 6.71 (1H, m), 6.81-6.82 (3H, m), 6.89 (2H, m), 7.22 (1H, m), 7.49-7.52 (2H, m), 7.76 (1H, m). HPLC retention time: 2.223 min (method A). MS (ESI) (M+H)+ 712.57.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.ClCCl>CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH2:3][CH3:4]
Reactant: CCC(C)=O
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: ClCCl
Product: C=C(CC)N1CCOCC1
Reaction time: 20 h
Yield: 52.3 %

Procedure:
To a solution of 2-butanone (6.2 ml, 69 mmol) and morpholine (18.1 ml, 208 mmol) in n-pentane (400 ml) was added dropwise 1 M titanium tetrachloride solution in dichloromethane (38.1 ml, 38.1 mmol) at 0-5° C. The cooling bath was removed and the mixture was stirred for 20 h. The precipitate was removed by filtration and washed with two 100-ml portions of diethyl ether. The filtrate was concentrated in vacuo. The residue was distilled over a vigreux column in a Kugelrohr oven (1 mbar, 40-70° C.) to give the title compound (5.1 g, 52%) as colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[CH3:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>CO>[ClH:1].[CH3:10][CH:11]1[CH2:16][CH2:15][C:14]2([S:8][CH2:7][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[NH:6]2)[CH2:13][CH2:12]1
Reactant: CC1CCC(=O)CC1
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CSC2(CCC(C)CC2)N1

Procedure:
34.3 g of L-cysteine methyl ester hydrochloride and 15.4 ml of 4-methylcyclohexanone are suspended in 70 ml of methanol and the suspension is refluxed for 3 hours. The suspension is concentrated to dryness under reduced pressure and the residue is recrystallized from isopropanol/methanol to give 25 g of colorless crystals of melting point 180° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]([C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:37]1[CH:36]=[CH:35][C:34]([N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:42][CH:41]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:39][CH:38]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (83.3 mg) was reacted with N-(4-methoxybenzyl)-N-(4-bromophenyl)pyrimidin-2-amine (102.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-methoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (102.4 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1→1/3) and thin layer chromatography (silica gel, mobile phasae: cyclohexane/ethyl acetate=1/5) were used for purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:36][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dimethyl sulphoxide and 60 mg of cyclopentanamine. After chromatography on a column of silica, eluting with a mixture of diethyl ether/ethyl acetate (gradient from 100/0 to 0/100 by volume), 33 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclopentylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-chlorophenylboronic acid. The title compound was obtained in 71% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).