Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:13]([CH2:24][O:25][CH3:26])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Li+].[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]([N:13]([CH2:24][O:25][CH3:26])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:3]=1
Reactant: COCN(c1nc(-c2cccc(Br)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCN(c1nc(-c2cccc(-c3ccccc3)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of 0.5 g of N-[4-(3-bromo-phenyl)-thiazol-2-yl]-N-methoxymethyl-4-methyl-benzenesulfonamide in 8 ml of toluene was treated in succession with 0.1 g of anhydrous lithium chloride, 60 mg of tetrakis(triphenylphosphine)-palladium, 0.23 g of phenylboric acid and 2 ml of 2N potassium carbonate solution. The mixture was boiled overnight, cooled and, after the addition of water, extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and concentrated. The residue was chromatographed on 80 g of Kieselgel 60 with ethyl acetate/hexane (1:4) as the eluent. The product-containing fractions were concentrated and yielded 0.29 g of colorless, amorphous N-(4-biphenyl-3-yl-thiazol-2-yl)-N-methoxymethyl-4-methyl-benzenesulfonamide, which was processed without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH2:16][CH3:17])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl.O>[Br:20][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][N:13]=1)[CH2:16][CH3:17]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1ccc(-c2cccc(OC)c2)cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(Br)c1ccc(-c2cccc(OC)c2)cn1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 1-(5-(3-methoxyphenyl)pyridin-2-yl)propan-1-ol (0.45 g, 1.8 mmol) in chloroform (5 mL) was added PBr3 (1.5 g, 5.55 mmol) at 0-5° C., the reaction was maintained at the same temperature for 1 h, and then the reaction was slowly warmed to rt and maintained at this temperature for 1 h. The contents were diluted with water (75 mL) and chloroform (100 mL) and the layers were separated. The organic layer was washed with bicarbonate solution (2×30 mL), dried over sodium sulphate and distilled to get the crude product. The non-polar impurity was removed by pentane washings (2×7 mL) to provide 2-(1-bromopropyl)-5-(3-methoxyphenyl)pyridine (0.45 g, crude). LC-MS m/z calcd for [M+H]+ 306.04. found 306.0.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-nitroaniline (Aldrich) according to the method described in Example 1c. Melting Point: 162-165° C. (diethylether)
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]1=[O:11].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]1=[O:11]
Reactant: O=c1ncc(Cl)cn1CCO
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1ncc(Cl)cn1CCCl
Yield: 52 %

Procedure:
1-(2-Hydroxyethyl)-5-chloropyrimid-2-one (0.001 mol) and phosphorus oxychloride (5 ml) were heated together at 80° C. for 60 min. before the solution was evaporated at reduced pressure. The residue was triturated with chloroform before dissolution in water (4 ml) and neutralisation with sodium bicarbonate. Chloroform extraction and evaporation left a solid which was recrystallised from ethyl acetate, yield 52%, m.p. 167°-168° C. (Found: C, 37.20; H, 3.20; Calc for C6H6Cl2N2O: C, 37.34; H 3.13).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C2(C)CCOCC2)cc1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[N:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:11]1[N:8]2[N:9]=[CH:10][C:5]([C:2]([F:1])([CH3:4])[CH3:3])=[N:6][C:7]2=[N:13][CH:12]=1
Reactant: BrBr
Reactant: CC(C)(F)c1cnn2ccnc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(F)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
To a stirred solution of 3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine (0.6208 g, 3.45 mmol) in acetic acid (15 ml) was added sodium acetate (0.4251 g, 5.18 mmol), then, dropwise over 5 min, a solution of bromine (0.195 ml, 3.78 mmol) in acetic acid (2 ml). The solution was stirred at room temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (300 ml) and ethyl acetate (150 ml). The aqueous layer (pH 7) was further extracted with ethyl acetate (2×150 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) to afford 0.8437 g (95%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 1.82 (6H, d, J 22.1), 7.99 (1H, s), 8.81 (1H, d, J 1.1).
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][O:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.[Li+].[OH-].O.O1CCOCC1>>[C:1]1([C:7]2[C:8]([NH:12][CH:14]([C:13]([OH:18])=[O:17])[CH3:16])=[N:9][O:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nonc1-c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(Nc1nonc1-c1ccccc1)C(=O)O

Procedure:
Following General Procedure II-D and using 4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich), the ethyl ester was prepared. Following General Procedure II-A, Method B (LiOH/H2O/dioxane) and using the ethyl ester, the title compound was prepared.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1.C(OCC)(=O)C.ClCCl>O>[O:11]1[C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)=[N:10]1
Reactant: COc1cccc(-c2noc3ccsc23)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(-c2noc3ccsc23)c1
Temperature: 140 °C
Yield: 39.5 %

Procedure:
Combine and stir under nitrogen at 140° C. a mixture of 3-(3-methoxyphenyl)thieno[2,3-d]isoxazole (8 g, 0.035 mol) and pyridine hydrochloride (80 g, 0.69 mol) for nine hours. TLC (ethyl acetate: dichloromethane) shows the reaction is complete. Cool the reaction mixture to room temperature, and pour into water. Extract the organics into ethyl acetate:ether (50:50), and wash once with HCl (3N), three times with water, dry (MgSO4) and evaporate to yield an oil. Purify the oil by column (silica) chromatography, eluting with 5% ethyl acetate in dichloromethane, to yield a solid. Recrystallize this solid (ether:hexane) to obtain the title compound as an orange/tan solid (3 g, 40% yield), m.p. 114–116° C.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23]([O:27][CH3:28])=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)(C)(C)C.[Cl:30][C:31]1[C:41](C(O)=O)=[CH:40][C:34]2[NH:35][C:36](=[O:39])[CH2:37][S:38][C:33]=2[CH:32]=1>>[CH3:28][O:27][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([C:41]3[C:31]([Cl:30])=[CH:32][C:33]4[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=4[CH:40]=3)=[O:5])[CH2:9][CH2:10]1)=[CH:26]2
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)cc2n1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](OCC)=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.C(OCC)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:10]2[CH:9]=[C:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(Br)cccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cc2c(Br)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
To a solution of 4-bromo-2-ethoxycarbonylbenzo[b]furan (0.5 g) in tetrahydrofuran (5 ml) was slowly added sodium borohydride (0.21 g) at room temperature. After 5 minutes, methanol (0.5 ml) was added thereto dropwise. The reaction mixture was stirred at room temperature for one hour and then ethyl acetate and water were added thereto. The mixture was adjusted to pH 5, and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to afford 4-bromo-2-hydroxymethylbenzofuran (0.36 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(OC(=O)c3ccccc3)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1)#[CH:16]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: COc1cncc(Br)c1
Product: C#Cc1cncc(OC)c1

Procedure:
5-Ethynyl-3-methoxy pyridine was prepared from 5-bromo-3-methoxy pyridine (Frontier) in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C(C(C(O)=O)O)O.[CH3:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:25]2[CH2:26][CH2:27][CH2:28][C@@H:24]2[CH3:23])=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (the product of Example 1C, 820 mg, 3.64 mmol) and (S)-2-methylpyrrolidine tartaric acid salt (1.12 g, 4.73 mmol) in ethanol (30 mL) was treated with sodium cyanoborohydride (345 mg 5.46 mmol). The mixture was stirred at room temperature for two hours. The mixture was basified to pH=10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel eluting with 1% to 2% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.87-0.92(m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m, 1H), 1.39-1.49 (m, 1H), 1.73-1.81 (m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz, 1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCl—NH3) m/z 294 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([O-:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12](O)[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[CH:1]1([CH:7]([CH3:11])[C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C(=O)[O-])C1CCCCC1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)C1CCCCC1
Yield: 95 %

Procedure:
Into a 500 ml round bottom flask equipped with a Soxhlet extractor filled with molecular sieves, 50 g of 2-cyclo-hexylpropionate, 100 g of ethanol, 0.5 g of p-toluene sulfonic acid, and 200 ml of chloroform were charged. The mixture was reacted under refluxing for 40 hours. The reaction mixture was washed with water and distilled under reduced pressure to obtain 56.4 g of ethyl 2-cyclohexylpropionate (yield: 96%, purity: 99.4%). The compound obtained had a fruity (namely aldehyde C-16 and apple-like) odor.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CC(O)=O.[O:16]=[C:17]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C@H:33]([CH2:43][C:44]3[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[C:47]([NH2:54])=[C:46]([Cl:55])[CH:45]=3)[C:34](=[O:42])[N:35]3[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]3)=[O:31])[CH2:26][CH2:25]2)[CH2:22][CH2:21][C:20]2[CH:56]=[CH:57][CH:58]=[CH:59][C:19]=2[NH:18]1.[BH3-]C#N.[Na+]>C1COCC1.CO>[NH2:54][C:47]1[C:48]([C:50]([F:52])([F:53])[F:51])=[CH:49][C:44]([CH2:43][C@@H:33]([O:32][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([N:23]3[CH2:22][CH2:21][C:20]4[CH:56]=[CH:57][CH:58]=[CH:59][C:19]=4[NH:18][C:17]3=[O:16])[CH2:25][CH2:26]2)=[O:31])[C:34]([N:35]2[CH2:36][CH2:37][CH:38]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]3)[CH2:39][CH2:40]2)=[O:42])=[CH:45][C:46]=1[Cl:55]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc1C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
62.9 mg (0.4 mmol) ethyl piperidine-4-carboxylate and 11 μL (0.2 mmol) AcOH were added to a solution of 127 mg (0.2 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 2 mL THF/MeOH (2:1) and the reaction mixture was stirred for 2 h at RT. Then it was cooled to 0° C., combined with 10.6 mg (0.16 mmol) NaBH3CN after 2 h and stirred at 0° C. overnight. The solvent was allowed to evaporate, the residue was taken up in 2 mL DMF and the crude product was purified by HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:2]=1.[OH-].[Na+].O.NN>C(O)COCCO>[C:11]1([CH2:10][CH2:9][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(CCCc2cccnc2)cc1

Procedure:
Heat a mixture of 2-phenylethyl 3-pyridinyl ketone (19.5 g, 0.092M), NaOH (8.0 g), hydrazine hydrate (8 ml, 85% in H2O) and diethylene glycol (125 ml) to 240° C. for 4 hours.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]1)=[N+:2]=[N-:3].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22].CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[C:20]2[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=2)[CH2:11]1)=[N+:2]=[N-:3]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](N)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a stirred solution of (3R)-1-(cis-2-azidocyclohexyl)-pyrrolidin-3-amine (0.453 g, 1.842 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (0.478 g, 1.934 mmol) in CH2Cl2 (15 mL) was added Et3N (0.57 mL, 4.06 mmol) followed by EDC (0.389 g, 2.03 mmol) and HOBt (0.287 g, 2.13 mmol). The mixture was stirred at room temperature for 3 h. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.745 g of the title compound. MS (EI) calcd: (M+H)+=439.3. Found: 439.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[OH:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[O:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: COc1ccc(I)c(OC)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: COc1ccc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c(OC)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
In a sealed tube purged with nitrogen, 1-iodo-2,4-dimethoxybenzene (40) (3.02 g, 11.4 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (2.50 g, 10.4 mmol), Cs2CO3 (5.10 g, 15.6 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.50 g, 2.1 mmol), CuI (0.16 g, 1.0 mmol), diglyme (10 mL) and toluene (30 mL) were placed. The reaction mixture was stirred at 130° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (600 mL) and washed with water (200 mL). The solid material was removed by filtration. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1S,2R,4aS,8aS)-1-(2,4-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (41) (2.50 g, 64%) as an off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].C[O-].[Na+].[OH:15][C:16]1C=CC=C2C=1N=CC=C2.O>CO.C(OCC)(=O)C>[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:15][CH3:16])(=[O:11])[CH3:10]
Reactant: Oc1cccc2cccnc12
Reactant: CC(=O)Nc1ccccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1NC(C)=O
Yield: 945.4 %

Procedure:
Then, 2.14 g of the 2-bromo-1-acetylaminobenzene was added to a solution containing 2.3 ml of a 28% methanol solution of sodium methoxide, 100 mg of cuprous chloride, and 145 mg of 8-hydroxyquinoline in 40 ml of methanol, and the mixture was heated under reflux for 50 minutes. After cooling with water, ethyl acetate was added thereto, and the resulting mixture was washed with water and dried over Glauber's salt. The solvent was distilled off, and the obtained crude crystals were recrystallized from an n-hexane/ethyl acetate solvent mixture, to obtain 1.56 g (yield: 95%) of the desired compound. The spectrum data of the compound was in agreement with the spectrum data of the separately synthesized reference compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([O:43][CH3:44])=[N:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([O:43][CH3:44])=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccccc1

Procedure:
(S)-1-(2-Methoxy-1-phenylethyl)-3-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (143 mg, 0.245 mmol) and triethylsilane (0.060 mL, 0.376 mmol) were stirred in TFA (2.5 mL) at room temperature for 30 min. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-10% MeOH-EtOAc) gave (S)-1-(2-methoxy-1-phenylethyl)-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C12H19N5O3 [M+1]+ 342. found 342. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 7.96 (br s, 1H), 7.48 (s, 1H), 7.34-7.30 (m, 4H), 7.25-7.21 (m, 1H), 4.98-4.93 (m, 1H), 3.96 (s, 3H), 3.55 (d, J=5.5 Hz, 2H), 3.25 (s, 3H).