Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].ClC(Cl)(Cl)C(=N)O[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A 5.00 g (22.4 mmol) portion of 8-bromooctanoic acid was dissolved in a mixed solvent of 2 ml dichloromethane and 10 ml hexane, and the solution was mixed with 8.00 ml (44.8 mmol) of tert-butyl 2,2,2-trichloroacetoimidate and 0.45 ml (3.66 mmol) of boron trifluoride-ether complex and stirred at room temperature for 1 hour. The reaction solution was mixed with 10 ml of hexane and 0.031 g (3.66 mmol) of sodium bicarbonate, the resulting precipitate was separated by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 2.34 g (yield, 38%) of tert-butyl 8-bromooctanoate.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:14][CH3:15])(=[O:13])[CH:10]([CH3:12])[CH3:11]>>[CH3:11][C:10]([CH3:12])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C)C
Reactant: O=Cc1ccccc1
Product: COC(=O)C(C)(C)C(O)c1ccccc1

Procedure:
A 50 milligram sample of the prepared hydroxy-ester is pyrolyzed in a sealed tube at 200° C. for 30 minutes. Analysis of the pyrolyzate by liquid chromatography indicates the following composition: 93% of unreacted starting material and 7% of a 1:1 mixture of benzaldehyde and methyl isobutyrate.
Reaction SMILES: C([N:8]1[C:12]([C:13](=O)[CH2:14][CH3:15])=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][C:25]2=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[CH:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:14][CH3:15])=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCC(=O)c1cncn1Cc1ccccc1
Product: CCC(c1c[nH]cn1)C1CCc2ccc(OC)cc21

Procedure:
The procedure of Example 12 is repeated except that 1-(3-benzyl-3H-imidazol-4-yl)-propan-1-one is used in place of 3-benzyl-3H-imidazole-4-carbaldehyde and 6-methoxyindan-1-one is used in place of 1-indanone. The product is a mixture of two diastereomers (1:1).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:22][CH2:23][C:24]([O:26]C)=[O:25]>C(Cl)Cl>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COC(=O)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.5 g, 7.8 mmol) suspended in 16 mL of CH2Cl2. To this suspension was added triethylamine (2.1 mL, 15.3 mmol) followed by methyl 3-bromopropionate (1.0 mL, 9.2 mmol). The reaction was stirred at room temperature for 4 h and at reflux for 2 h. The reaction mixture was washed with water, 1N HCl (2×20 mL), 1N NaOH (2×20 mL) and Brine (1×20 mL). The organic layer was separated, dried over Na2SO4, filtered; and solvent was removed under reduced pressure. To the crude product was added 2N NaOH (15 mL). The mixture was stirred at reflux for 1 h. The reaction mixture was washed with CH2Cl2 (3×20 mL) and neutralized with concentrated HCl. The aqueous solution was concentrated to dryness under reduced pressure, to give a solid residue. Sodium chloride in the residue was removed in the following way (three repeats): dissolving the residue in a minimum amount of water, treating the aqueous solution with acetone, removing the resultant solid material by filtration, and concentrate the filtrate to dryness under reduced pressure. This allowed the isolation of compound Q (159.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]3[O:30][CH2:29]3)=[CH:22][CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: CCCCN
Reactant: COc1ccc(C(c2ccc(OCC3CO3)cc2)C2CCCc3ccccc32)cc1
Solvent: CCO
Product: CCCCNCC(O)COc1ccc(C(c2ccc(OC)cc2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-(2,3-epoxypropyloxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg, 0.01 mol), n-butyl amine (1.0 ml, 0.01 mol) and ethanol (10 ml) was refluxed for 8 hrs. Ethanol was distilled off and the residue was passed through basic alumina using benzene:ethyl acetate as the eluent. The solvent was distilled off yielding the required product. Yield 230 mg (48.93%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH2:25][N:34]3[CH2:35][CH2:36][CH2:37][CH:33]3[CH3:32])[CH:8]=2)[N:3]=1
Reactant: CC1CCCN1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1CCCN1Cc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
150 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 53 μl of 2-methylpyrrolidine and 40 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 161 mg of sodium triacetoxyborohydride are added, and the mixture is stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:17]>C(O)C>[ClH:17].[CH:9](=[C:4]1[C:5](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
A solution of 57.0 g of 1-methyl-4-piperidone and 106.0 g of benzaldehyde in 400 ml of ethanol is cooled in an ice-bath and treated with hydrogen chloride gas until 250 g is absorbed. The solution is allowed to stand at room temperature for about 16 hours. The resulting solution is seeded, allowed to stand for about 16 hours at room temperature and the crystalline solid filtered on a sintered-glass funnel and washed with cold ethanol and then with ether. After drying in a desiccator, the solid (146 g) is digested in 400 ml of hot ethanol, cooled and filtered to give 120 g of product, melting point 242°-244° C, dec. Recrystallization of 11 g of this material from 35 ml of dimethylformamide gives 9.2 g of product, melting point 242°-244° C, dec.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]2[C:5]=1[C:6](=[O:17])[NH:7][S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>>[OH:15][C:13]1[CH:12]=[C:11]2[C:5]([C:6](=[O:17])[NH:7][S:8]2(=[O:10])=[O:9])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:14]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Yield: 95.7 %

Procedure:
To a solution of 1.0 g (0.0039 mol) of 4-isopropyl-6-methoxysaccharin in 15 ml of MDC was added at ambient temperature 1.28 g (5.12 ml) of a 1M solution of boron tribromide in MDC. When addition was complete the reaction mixture was heated under reflux for about five hours, cooled, taken to dryness in vacuo and the residue treated with ice and saturated sodium bicarbonate. The aqueous solution was extracted once with ethyl acetate and then acidified to pH 1 with concentrated hydrochloric acid. Extraction of the mixture with ethyl acetate/diethyl ether (8:2), drying the organic extracts and removal of the solvent in vacuo afforded 0.9 g (96%) of 6-hydroxy-4-isopropylsaccharin as a white crystalline solid which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH:30]=[CH:29]N=N1>ClCCl.CN(C=O)C.O>[Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:11])([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]2[O:15][CH:29]=[CH:30][N:26]=2)[CH:3]=1
Reactant: c1c[nH]nn1
Reactant: CC1(C)COc2c(Br)cc(C(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)COc2c(Br)cc(-c3ncco3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.1 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (example 3b) (1.8 g, 6.64 mmol) in dichloromethane (40 mL) was added several drops of DMF followed by a solution of thionyl chloride in dichloromethane (2.0M, 6.64 mL, 13.3 mmol) at 0° C. under argon. After the addition, the mixture was stirred at room temperature for 5 hours. The solvent and excess of thinoyl chloride were removed under reduced pressure. The residue was dissolved in tetramethylene sulfone (10 mL) and potassium carbonate (1.84 g, 13.3 mmol) and 1H-1,2,3-triazole (504 mg, 7.3 mmol) were added under argon and the mixture was heated to 140° C. for 16 hours. The solution was cooled to room temperature, water was added and the mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: EtOAc/5:1) to give 900 mg of 2-(7-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-oxazole (46%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.40 (s, 6H), 4.41 (s, 2H), 7.19 (s, 1H), 7.67 (s, 1H), 7.75 (d, J=0.88 Hz, 1H), 8.01 (d, J=0.88 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]([CH2:46][CH:47]=O)[CH2:29][C@H:30]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:47][CH2:46][N:28]([CH2:29][C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[C:26]([O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:27])[CH:15]=2)[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N(CC=O)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(-c2cccc(N)c2)cc2c1OCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)cc2c1OCC2

Procedure:
TLC Rf (4:1 hexane/ethyl acetate)=0.14; from 5-(3-aminophenyl)-2,3-dihydro-7-benzofurancarboxylic acid methyl ester (500 mg) and (R)-[(tert-butoxycarbonyl)-[2-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino]-acetaldehyde (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]=[O:17])[CH2:13][CH2:14]1
Reactant: OCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-acetaldehyde (35B) is prepared from 35A as described for 1E.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[N:5]1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36].[I-].[Na+]>O1CCCC1>[CH2:30]([S:27]([N:24]1[CH2:25][CH2:26][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH2:3][CH2:2][N:33]([CH2:34][CH2:35][OH:36])[CH3:32])[CH:8]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:22][CH2:23]1)(=[O:29])=[O:28])[CH3:31]
Reactant: CNCCO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCCl)c4)cc23)CC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN(C)CCO)c4)cc23)CC1
Yield: 27.5 %

Procedure:
A solution of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.065 mmol), 2-(methylamino)ethanol (500 μL, 6.5 mmol) and sodium iodide (3 mg, 0.016 mmol) in tetrahydrofuran (1 mL) was reacted in a microwave for 2 h at 130° C. An aqueous work-up was performed on the resulting mixture. This was then purified by Gilson Preparatory HPLC to give 9 mg of the title compound (17%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.O.OS([O-])(=O)=O.[K+]>CS(C)=O>[CH:2]([C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH2:5][S:6][CH3:7])=[O:1]
Reactant: CSCC[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100.2 %

Procedure:
A solution of Example 1A (9.05 g, 38.5 mmol), sulfur trioxide pyridine complex (30.64 g, 192.5 mmol), and triethylamine (26.8 mL, 192.5 mmol) in DMSO (30 mL) was stirred at ambient temperature for 30 minutes, cooled to 0° C., treated sequentially with water (20 mL) and saturated aqueous KHSO4 (120 mL), and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO4 and brine, dried (MgSO4), filtered, and concentrated to provide the desired product (9.00 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)[O:3]1.O.[NH2:21][NH2:22]>CO>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:21][NH2:22])=[O:14])=[CH:11][CH:10]=2)[O:3]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC1(C)OB(c2ccc(C(=O)NN)cc2)OC1(C)C
Yield: 98.7 %

Procedure:
20 g (76 mmol) of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate are dissolved in 150 ml of methanol, 6 g (120 mmol) of hydrazine hydrate are added, and the mixture is refluxed for 12 hours. Removal of 120 ml of methanol by distillation gives 19.8 g (75 mmol, 98%) of product. The compounds of the formula (III) are obtained analogously using the compounds shown in Table 3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
A mixture of 0.75 g (2.07 mmol) of (4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile and 0.08 g of 10% Pd on carbon in 75 ml of ethanol is shaken for 1.5 hours under 30 PSI of hydrogen. The mixture is filtered through a bed of celite and the filtrate concentrated in vacuo. Trituration with ether gives a precipitate which is filtered off and recrystallized from methylene chloride-ether to give 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile. (M.P. 156° C.-158° C.)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=S.[I-].ClC1C=CC=C[N+]=1C.[N:32]#[C:33][NH2:34].[H-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:33]([NH:34][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=[N:2][CH3:1])#[N:32]
Reactant: CNC(=S)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: N#CN
Agent: C[n+]1ccccc1Cl
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN=C(NC#N)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A mixture of 200 mg of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide, 192 mg of 2-chloro-1-methylpyridinium iodide, 209 μl of triethylamine and 5 ml of dried tetrahydrofuran was refluxed with heating for 2 hours and further cooled to room temperature. 42 mg of cyanamide and 30 mg of sodium hydride (60%) were added therein and the reaction mixture was refluxed with heating for 2 hours. Ice water was added therein and the resultant mixture was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, CH2Cl2) and recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 14 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-amidine with a melting point of 293°-294° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)[C:20]=2[C@H:19]([CH3:34])[CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:25]2[C:20]3[C@H:19]([CH3:34])[CH2:18][C@@H:17]([OH:16])[C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (20 mg, 0.0724 mmol) was added to a solution of 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.145 mmol) in DCM (0.5 mL) DMF (125 μL) was added to solubilize the starting material completely. DIPEA (126 μL, 0.724 mmol) was added, followed by the addition of HBTU (30 mg, 0.079 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified by reversed phase HPLC to yield N—((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide product as a solid (4 mg, 10%). m/z 504 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:47]4[CH:48]=[CH:43][CH:44]=[C:45]([N:49]5[CH2:50][CH2:51][CH2:52][CH2:53]5)[CH:46]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cccc(N3CCCC3)c2)OC1(C)C
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
1,1-Dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (350 mg, 0.599 mmol), 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (327 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (34.6 mg, 0.03 mmol), bis(triphenylphosphine)palladium(II) chloride (21.04 mg, 0.030 mmol) and potassium carbonate (249 mg, 1.8 mmol) were charged into a microwave vial. DMF (2.5 mL) and water (1.0 mL) were added and the suspension degassed under nitrogen for ca. 5 min before being subjected to heating in a microwave at 100° C. for 30 min. The reaction mixture was then filtered through celite, rinsed with ethyl acetate (ca. 50 mL) and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in DCM followed by 0-20% MeOH in DCM and then further purification by MDAP (acidic conditions) afforded the title compound (20 mg). LCMS (A) m/z: 550 [M+1]+, Rt 1.30 min (basic).