Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[N:6]=1)=[O:4].[OH-].[K+:19]>CCO.CCOCC>[K+:19].[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][N:7]1[CH:8]=[N:9][C:5]([C:3]([O-:4])=[O:2])=[N:6]1
Reactant: COC(=O)c1ncn(COCC[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (as prepared in the previous step, 257 mg, 1.00 mmol) in EtOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed in vacuo and the resulting residue was dried for 4 hr to obtain 1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylic acid potassium salt (273 mg, 97%) which was directly used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.[F:19][CH2:20][CH2:21]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][CH2:20][F:19])[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: OCCF
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: FCCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reaction time: 0.33 h

Procedure:
To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.9 g, 3.42 mmol), 2-fluoroethanol (0.3 mL, 5.13 mmol) triphenylphosphine (1.35 g, 5.13 mmol) in THF (22.5 mL) at 0 C is added DIAD (1.0 mL, 5.13 mmol) in drops over 5 min. After 20 min the reaction mixture is allowed to warm to 25 C. After 18 h the mixture is concentrated in vacuo, absorbed onto silica gel using ether and chromatographed on silica gel eluting with hexane/ethyl acetate. 3-(6-Chloro-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane was obtained as a yellow solid (560 mg). MS m/z=312 (M+H). This material (550 mg) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (583 mg), aq. Na2CO3 (1.3 mL, 2M), and tetrakis triphenylphosphine palladium (50-100 mg) in 1:1 toluene:ethanol (11 mL). The reaction mixture was heated in a microwave at 12° C. for 20 min. It was then dissolved in CH2Cl2 and chromatographed on silica gel using hexane/ethyl acetate as the eluant to give 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a white foam (0.51 g). MS m/z=369 (M+H). A solution of this material (500 mg, 1.36 mmol) and triethylamine (0.95 mL) in dichloromethane was treated with triphosgene (202 mg, 0.68 mmol). After 30 min one tenth of the solution was treated with excess methylamine (2N in THF). Reverse phase HPLC gave the title compound (29 mg) MS m/s=426.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:9]=[C:8]([C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(O)c2cccnc2)cc1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)c2cccnc2)cc1F

Procedure:
2-Fluoro-4-(1-hydroxy-1-pyridin-3-yl-methyl)-benzonitrile (1.04 g, 4.55 mmol) and MnO2 (3.96 g, 45.5 mmol) were stirred in CH2Cl2 (100 mL) for 4 h. The solution was filtered through a celite pad and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Solvent: CCOCC
Product: CCC(=O)Nc1cc(OC)cc2c1CC(C)O2

Procedure:
The compound of the title is prepared according to the procedure described in Example 10 by reacting the starting 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with propionyl chloride instead of ethylchlorocarbonate. M.p. 101°-02° C. (from ethyl ether). Yield 44 grams (75 percent of theoretical).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.0 g, 7.69 mmol), benzyl alcohol (796 □L, 832 mg, 7.69 mmol) and 4-dimethylaminopyridine (9.4 mg, 77 μmol) in dichloromethane (5 mL) was added DCC (1.59 g, 7.71 mmol) and the mixture was at stirred RT for 3 h. The mixture was filtered and the filtrate concentrated. The residue was purified by chromatography using a 0-30% gradient of heptane/ethyl acetate to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH:5]=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][NH:22][C:21]1[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(C)(CNc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methyl-3-oxo-propionic acid methyl ester (2.35 g, 6.71 mmol) in methanol (25 mL) was added 4-fluoroaniline (0.53 mL, 5.59 mmol) and acetic acid (0.16 mL, 2.80 mmol). A solution of sodium cyanoborohydride (188 mg, 2.99 mmol) in methanol (25 mL) was added dropwise and the reaction mixture stirred for 3 hours at room temperature post addition. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL). The organic solution was treated with aqueous sodium carbonate solution (20 mL, 1N), stirred for 20 min, and the aqueous layer removed. Concentration of the organic layer followed by purification of the residue using flash chromatography (SiO2, DCM) afforded the title compound as a yellow oil (970 mg, 53%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][NH2:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccccc2)on1
Agent: NN
Solvent: O
Product: NCc1cc(-c2ccccc2)on1

Procedure:
2-[(5-Phenylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (3.48 g, 11.4 mmol) was treated with hydrazine hydrate (1.35 g, 22.9 mmol) according to the method described in Part E of Example 35 to provide (5-phenylisoxazol-3-yl)methylamine as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Reactant: C1=CCNCC1
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CC=CCC1)=NC2
Reaction time: 72 h

Procedure:
A stirred mixture of 8-Chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (2.65 g., 0.01 mole) and 1,2,3,6-tetrahydropyridine (15 ml.) was refluxed for 32 hours with a slow stream of nitrogen passing through the mixture. It was then kept at ambient temperature for three days, mixed with water and extracted with methylene chloride; the aqueous layer was saturated with sodium chloride and re-extracted with methylene chloride. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from methylene chloride/ethyl acetate to give 3.41 g. of crude product. This material was chromatographed over silica gel (180 g.) with 5% methanol in methylene chloride. The first material eluted from the column was crystallized from a methylene chloride/ethyl acetate/Skellysolve® B mixture to give 0.37 g., melting point 224°-225.5° of the titled compound (Ib). The analytical sample was recrystallized from a methylene chloride/ethyl acetate and had melting point 224°-225°.
Reaction SMILES: [Cl:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].CS(O)(=O)=O.[CH3:12][C:13](=[CH2:15])[CH3:14].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2](=[CH2:6])[C:3]([O:5][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:4]
Reactant: C=C(C)C
Reactant: C=C(Cl)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
32 g of α-chloroacrylic acid was dissolved in 600 ml of dichloromethane and, to this, 20 ml of methanesulphonic acid and 300 ml of isobutylene were added at −5° C. After stirring for 30 hours at room temperature, the reaction liquid was poured into 500 ml of saturated aqueous sodium bicarbonate solution and the dichloromethane layer separated off. After drying with anhydrous sodium sulphate, the solvent was distilled off and t-butyl α-chloroacrylate obtained. 10 g of the t-butyl α-chloroacrylate obtained plus 200 mg of azobisisobutyronitrile were dissolved in 100 ml of toluene and reaction carried out at 80° C. Poly-t-butyl α-chloroacrylate was obtained. The molecular weight of the copolymer obtained determined by gel permeation chromatography (GPC) was, by polystyrene conversion, a number average molecular weight of 215,000 and a weight average molecular weight of 537,000. The polymer obtained was irradiated with an electron beam, and the value of the main chain scission efficiency Gs calculated from the number average molecular weight determined by GPC was 3.8.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:18][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OC(=O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic-trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[C:19]=1[C:20]#[N:21])([O-:17])=[O:16]>>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[C:20]#[N:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Product: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 46 %

Procedure:
Prepared as in Example 215c from 5-(tert-butyldimethyl-silyloxy)pentan-1-ol and 2,6-dinitrobenzonitrile as a pale yellow solid in 46% yield. MS 365 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Temperature: 50 °C
Yield: 93 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300.13 mg, 1.098 mmol) from Example 1A and (4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from the previous step (300 mg, 1.098 mmol) in THF was added Cs2CO3 (532.7 mg, 1.64 mmol), and the mixture was heated at 50° C. for 12 h. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the solution was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (525 mg, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.40 (m, 2H), 7.22 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.50 (m, 2H), 4.00 (m, 5H), 1.28 (s, 9H); LC-MS (ESI) m/z 512 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]([NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N:21][C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:29])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:37][CH3:38])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:36][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30][C:20]([NH:21][C:22]1[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:28])=[N:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:37][CH3:38])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(NC(=Nc3c(C)cccc3C)NCCCN(C)C)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1O
Temperature: 70 °C
Yield: 91.1 %

Procedure:
A mixture of N-(7-benzyloxy-6-methoxyquinazolin-4-yl)-N′-(3-dimethylaminopropyl)-N″-(2,6-dimethylphenyl)guanidine (2.21 g) and trifluoroacetic acid (40 ml) was stirred and heated to 70° C. for 16 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulphate, filtered and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was thus obtained the title compound (1.66 g); NMR Spectrum: (DMSOd6, 100° C.) 1.77 (m, 2H), 2.07 (s, 6H), 2.29 (s, 6H), 2.36 (t, 2H), 3.59 (t, 2H), 3.81 (s, 3H), 7.0 (s, 1H), 7.19 (m, 3H), 7.67 (s, 1H), 8.4 (s, 1H), 9.4 (br s, 1H), 10.8 (br s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][Br:12])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C@@H:10]([OH:13])[CH2:11][Br:12])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
(R)-2-Methyl-CBS-oxazoborolidine (1.38 mL of a 1.0 M solution in toluene) was added to a solution of α-bromoketone 45 (5.00 g, 13.80 mmol) in tetrahydrofuran (80 mL). After stirring for 15 min, borane tetrahydrofuran complex (8.5 mL of a 1 M solution in tetrahydrofuran) was added dropwise over a 15 min period. After stirring at ambient temperature for 1.5 h, the reaction was quenched by the slow addition of methanol (8.5 mL). The solvent was removed under vacuum. The residue was taken up in a mixed solvent of hexanes and ethyl acetate (2:1). The solid was vacuum filtered through a pad of silica gel. Concentration of the filtrate and drying under vacuum gave 46 (4.86 g, 97%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 3.32-3.58 (m, 1H), 3.64-3.68 (m, 1H), 3.81 (s, 3H), 4.78-4.80 (m, 1H), 5.21 (s, 2H), 5.83 (d, 1H), 7.22 (d, 1H), 7.31-7.33 (m, 1H), 7.38-7.49 (m, 5H), 7.61 (s, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BH4-].[Na+]>CO>[CH2:1]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:11]=2)[CH:7]1[CH2:6][NH2:5])[CH2:2][CH3:3]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC1Cc2cc(C3=NNC(=O)CC3)ccc2C1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Propanal (1.51 g) dissolved in 5 ml of methanol was added dropwise to 6.15 g of 2-aminomethyl-5-[4,5-dihydro-pyridazin-3(2H)-on-6-yl]indane dissolved in 60 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, 1.03 g of sodium borohydride was added to the mixture. The resulting mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 1 hour. After methanol was removed, water was added to the residue, and the residue was extracted with ethyl acetate. The organic layer was collected by filtration, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol (15:1)) to obtain 5.22 g of 2-propyl-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]=[C:19]([NH:22][C:29]([NH:28][CH2:27][C:26]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:24]([Cl:23])[CH:25]=2)=[O:30])[S:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC1C[C@H](c2csc(N)n2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(=O)OC1C[C@H](c2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
(R)-4-Acetoxy-2-(2-amino-thiazol-4-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (327 mg, 1 mmol) was combined with 3,4-dichlorobenzyl isocyanate (303 mg, 1.5 mmol) in DCM (10 mL) and stirred overnight. The reaction mixture was concentrated and purified by chromatography (silica gel, DCM/MeOH/NH4OH) to afford (R)-4-acetoxy-2-{2-[3-(3,4-dichloro-benzyl)-ureido]-thiazol-4-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1

Procedure:
A solution of 3.6 g of 3-[1-(4-(5-methoxycarbonylindol-3-yl)butyl)-4-piperidyl]indole in 40 ml of THF is added dropwise to a suspension of 0.6 g of lithium aluminum hydride in 20 ml of THF with stirring. The mixture is then stirred for a further hour at 25°, 20 ml of dilute sodium hydroxide solution are added, the mixture is filtered and the filtrate is worked up in a conventional manner. 3-[1-(4-(5-hydroxymethylindol-3-yl)butyl)-4-piperidyl]indole is obtained.
Reaction SMILES: [C:1]([O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7].OO.[C:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:1]([O:21][CH:22]1[CH2:23][C:24]([CH3:32])([CH3:31])[N:25]([O:30][CH2:36][C:35]([CH3:38])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:37])[C:26]([CH3:29])([CH3:28])[CH2:27]1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH2:36][C:35]([CH3:38])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:37])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC1(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: OO
Solvent: CC#N
Product: CC(C)(CON1C(C)(C)CC(OC(=O)CCCCC(=O)OC2CC(C)(C)N(OCC(C)(C)c3ccccc3)C(C)(C)C2)CC1(C)C)c1ccccc1

Procedure:
The title compound is prepared from the reaction of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) adipate, aqueous hydrogen peroxide, ferric chloride hexahydrate; acetonitrile, and tert-butylbenzene following a procedure similar to that of Example 6.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[H-].[Na+].[CH2:22]([OH:25])[C:23]#[CH:24]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:25][CH2:22][C:23]#[CH:24])=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Product: C#CCOc1nccnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 28 using propargyl alcohol as solvent (3 mL), 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3 g) and sodium hydride (0.2 g of a 60% dispersion in oil) at room temperature for 16 h. Yield 0.27 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]#[N:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: COc1cc(Br)cc(C#N)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C#N)cc(-c2ccccc2)c1
Yield: 91.7 %

Procedure:
3-bromo-5-methoxybenzonitrile (8.3 g, 39.1 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (S-Phos) (1.286 g, 3.13 mmol), phenylboronic acid (5.84 g, 47.0 mmol), Pd2(dba)3 and 200 mL toluene were charged in a flask and refluxed overnight. The reaction was cooled down and 200 mL of ethyl acetate was added. The crude mixture was run though a silica gel plug, and the product was confirmed by GC. After distillation under vacuum, 7.5 g of a white product was obtained.