Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[C:49]1([C:62](O)=[O:63])[C:61]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[C:49]1([C:62]([N:16]2[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)=[O:63])[C:61]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc2c1Cc1ccccc1-2)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of 10 mg (0.03 mnmol) of 3-(RS)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 10 mg (0.07 mmol) of DIEA and 10 mg (0.04 mmol) of bis (2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) in 2 mL of CH2Cl2 (2 mL) at 0° C. was treated with 7 mg (0.16 mmol) of 1-fluorene carboxylic acid. The cooling bath was removed; the reaction was stirred at rt for 2 h and then was concentrated in vacuo . Preparative thin layer chromatography (silica gel GF, 20×20 cm, 1000 microns) using 95:5 v/v MeOH/CH2Cl2 as the eluant afforded 14 mg (88%) of the title compound as a foam. 1H NMR (500 MHz, CDCl3): δ7.12-7.87 (17H), 1.28-4.13 (19H). Mass Spectrum (NH3 -CI): 513 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C=O)C>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
(S)-3-Amino-1-benzylpyrrolidine (10 g) and triethylamine (24 ml) were dissolved in DMF (100 ml). Under ice-cooling, 1-adamantanecarbonyl chloride (12.4 g) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-benzylpyrrolidin-3-yl)-1-adamantanecarboxamide (14.8 g), melting point 130-132° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[C:18]=1[C:19]([OH:21])=[O:20])[CH:14]=[CH2:15].[CH3:51][CH:52](O)[CH3:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[C:22]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:39]=[CH:40][C:41]([CH2:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:18]=1[C:19]([O:21][CH:52]([CH3:53])[CH3:51])=[O:20])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)O)cc2)cc1
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Diethyl azodicarboxylate (108 μl, 0.68 mmol) was added to a solution of 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoic acid (150 mg, 0.29 mmol), 2-propanol (26 μl, 0.34 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in tetrahydrofuran (3 ml) at room temperature. After the mixture was stirred at room temperature for 1 hour, the solvent of the reaction mixture was removed under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to give isopropyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (141 mg, yield: 87%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[Cl:10][C:4]1[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:13][C:12](=[NH:11])[NH2:14]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: N=C(N)SCc1cccc(Cl)c1Cl

Procedure:
2,3-Dichlorotoluene (8.05 g., 0.05 mol.) dissolved in 150 ml. of carbon tetrachloride containing N-bromosuccinimide (8.9 g., 0.05 mol.) was heated to reflux and irradiated with a 275-watt sunlamp for two hours. The mixture was cooled, filtered and evaporated to give α-bromo-2,3-dichlorotoluene. The α-bromo-2,3-dichlorotoluene (2.4 g., 0.01 mol.) and thiourea (0.38 g., 0.005 mol.) were dissolved in 25 ml. of ethanol and refluxed for about sixteen hours. The mixture was cooled, concentrated, treated with ether, filtered and the filter cake recrystallized from water to give carbamimidothioic acid 2,3-dichlorobenzyl ester, m.p. 238°-243° C. (dec.).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1.[CH3:16][O:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[CH3:28].S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Cl:7][C:8]1[C:13]([NH:14][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH3:27])[C:18]([O:17][CH3:16])=[C:19]([CH3:28])[CH:20]=2)=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1ccc(Cl)nc1Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)Nc2ccc(Cl)nc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With ice cooling, a solution of 2.7 ml of absolute pyridine in 5 ml of dry dichloromethane was initially added dropwise to a solution of 5.00 g of 2,6-dichloropyridin-3-ylamine in 50 ml of dry dichloromethane. 6.70 g of 4-methoxy-3,5-dimethylbenzoyl chloride, dissolved in 15 ml of dry dichloromethane, were then added, and the reaction was stirred at 0° C. for 1 h and then at room temperature for 16 h. 10% strength aqueous sodium bisulfate solution was then added, and the mixture was stirred for 15 minutes. The phases were then separated, and the aqueous phase was extracted twice with dichloromethane. The collected organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 10.00 g (100%) of the product, which was used for the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=C1Cc2[nH]c3cc(F)ccc3c2CCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc2c3c([nH]c2c1)CCNCC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask containing THF (10 mL) at −78° C. under argon was added a 1 M solution of iBU2AlH in CH2Cl2 (16.3 mL). After 5 min, a solution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture was allowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenched with MeOH (4.5 mL). It was partitioned between CH2Cl2 and aqueous 1 M KO2CC(OH)C(OH)CO2Na. The CH2Cl2 extracts were washed with brine, dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography (92.5:7.5 CH2Cl2/satd NH3 in MeOH) to give the free amine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH (4.0 mL) at rt under argon was mixed with a solution of fumaric acid (0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution was stirred overnight at rt. The MeOH was evaporated. The residue was dissolved in hot MeOH, and the salt was permitted to crystallize. The crystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40 (1H), 3.11 (4H), 2.91 (4H); Anal. C 63.90, H 5.83, N 10.63.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[CH2:17]([OH:19])[CH3:18].[BH4-].[Na+]>C1COCC1>[C:17]([NH:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:19])[CH3:18]
Reactant: Cc1c(F)cc([N+](=O)[O-])c2c1C(=O)CCC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (4) above (1.35 gm) was dissolved into 5 ml of ethanol and 15 ml of THF. To the solution was added 114 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, the reaction mixture was concentrated. To the concentrate were added 25 ml of toluene and 840 mg of p-TsOH, followed by heating under reflux for 30 minutes. Upon the addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into 20 ml of ethyl acetate and catalytically hydrogenated with the addition of 400 mg of platinum oxide for 4 hours. The catalyst was removed, the fitrate was concentrated, and 10 ml of dichloromethane was added to the concentrate. After the further addition of 1.2 ml of triethylamine and 0.81 ml of acetic anhydride, the mixture was stirred for 40 minutes. The reaction product was diluted with 50 ml of chloroform, washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1.23 gm of the title compound.
Reaction SMILES: O[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:15]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: O=C(O)c1cc2ccccc2cc1Nc1ccccc1

Procedure:
reacting 3-hydroxy-2-naphthoic acid and aniline to produce 3-anilino-2-naphthoic acid;
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:14]([N:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:17](=[O:27])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:15]>>[CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[CH:7][C:6]([S:9]([N:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH2:18][C:17]([N:16]([CH2:14][CH3:15])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cn1
Reactant: CCN(Cc1ccccn1)C(=O)CNc1ccc(C)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(N(C)C)nc1

Procedure:
prepared by reaction of 6-dimethylamino-pyridine-3-sulfonyl chloride with N-ethyl-N-pyridin-2-ylmethyl-2-p-tolylamino-acetamide
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18]CCl.S(Cl)(Cl)=O>O>[Cl:18][CH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: ClCCl
Reactant: COc1ccc(N2CCC(CCO)CC2)nn1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(N2CCC(CCCl)CC2)nn1
Reaction time: 8 h

Procedure:
A solution of 7.3 parts of 1-(6-methoxy-3-pyridazinyl)-4-piperidineethanol in 130 parts of dichloromethane was added dropwise to 7.3 parts of thionyl chloride at room temperature. Upon complete addition, stirring was continued overnight at room temperature. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 1.8 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine. The aqueous layer was neutralized with an ammonium hydroxide solution. The precipitated product was filtered off and taken up in dichloromethane. The organic layer was dried, filtered and evaporated, yielding a second fraction of 4.0 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine. Total yield: 5.8 parts (73.4%) of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine as a residue (int. 96).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])(O)=O.[Na+].[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[CH3:15])[N:3]=1
Reactant: CC1CCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution containing 2,4,6-trichloropyrimidine (8 g, 44 mmol) in MeOH (80 mL) and NaHCO3 (10 g) add slowly and dropwise a methanolic solution (20 mL) of 2-methylpyrrolidine (46 mmol). Allow the mixture to warm to 25° C. and stir overnight. Dilute with water, vigorously stir for 1 hour, and filter to give white crystalline solid as a mixture of regioisomers. Chromatograph the mixture using flash column chromatography (ethyl acetate/hexanes eluent systems) to give 4,6-dichloro-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH3:36])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([C:19](=[O:37])[C:20]([N:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:26]([CH2:36][C:39]([O:41][CH3:42])=[O:40])[O:25][CH2:24]2)([CH3:22])[CH3:21])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)c2cc(F)cc(F)c2)CO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.5 ml of 1.0M solution) was added to a solution of 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-propan-1-one (0.5 g) in tetrahydrofuran, under an inert atmosphere at -5° C. After stirring for 0.5 hours, methyl chloroformate (1.22 g) was added and the solution allowed to warm to 20° C. After 18 hours, the solution was poured onto water, extracted (ether) and evaporated. Purification by dry column chromatography on silica gel, eluting with hexane/ethyl acetate (4:1), gave 1-(3,5-difluorophenyl)-2-(2,3-dihydro-6-methoxycarbonylmethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-one (Compound 700, 0.065 g), NMR 1.5 (s,6H), 3.1 (s,2H), 3.6 (s,3H), 5.4 (s,2H), 6.8 (m,1H), 7.0 (m,2H), 7.2 (m,3H), 7.5 (d,2H).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: C1COCCO1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 2.5 g of 2-difluoromethoxyphenyl-sulfonyl isocyanate, 1.75 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine and 30 ml of absolute dioxane is stirred at a temperature of 70°-75° C. for 2 hours. The solution is evaporated and the residue is crystallised from ether to give 4.0 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-difluoromethoxy-6-methyl-pyrimidin-2-yl)-urea of melting point 163°-164° C.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C.[Li].[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=O)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]>C1COCC1>[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=[CH:10][CH2:9][N:8]([CH3:30])[CH3:7])=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [Br-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCOC(=O)c1[nH]c2ccccc2c1C=CCN(C)C
Reaction time: 0.5 h

Procedure:
Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide in THF (0.2 M) at 0° C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-1H-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give 3-(3-dimethylaminopropenyl)-1H-indole-2-carboxylic acid ethyl ester as a brownish-red waxy solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(O)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N+:36]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(CN)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(C[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A solution of 2,4,6-triphenylpyrylium tetrafluoroborate (2.97 g, 7.5 mmol) in ethanol (15 mL) was treated with 4-methylbenzylamine (1 g, 8.25 mmol). The reaction was stirred overnight at room temperature and diluted with diethyl ether to precipitate the product. The product was recrystallized from ethanol/diethyl ether to give 3.15 g of N-(4-methylbenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.24 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.27 g, 70%). MS (ISP) 387.2 [(M+H)+]; mp 158° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:24])[C:7](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)[C:27](O)=[O:28]>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>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]2[O:24][C:27](=[O:28])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(C=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)cc1C
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 80 °C
Yield: 66 %

Procedure:
A solution of 645 mg (2.0 mmol) of a mixture of 2,4-di-tert-butyl-6-(3,4-dimethyl-benzylidene)-cyclohexa-2,4-dieone (compound (301), Table 3) and the corresponding dimer (compound (401), Table 4), prepared according to Example 1b in 7 ml of toluene is degassed using argon and then 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 23 mg (0.20 mmol) of trifluoroacetic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 5 bar is then applied. The reaction mixture is maintained at 80° C. for 20 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 464 mg (66%) of 5,7-di-tert-butyl-3-(3,4-dimethyl-phenyl)-3H-benzofuran-2-one (compound (101), Table 1), m.p. 130-132° C. Analysis, calculated: C 82.24; H 8.63%. Analysis, found: C 82.20; H 8.68%.
Reaction SMILES: C([O:5][C:6](=[O:31])[C@H:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:8][C:9]([O:11][CH2:12][CH2:13][CH:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]1[C:15]2[CH:14]([CH2:13][CH2:12][O:11][C:9]([NH:8][C@H:7]([C:6]([OH:31])=[O:5])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:10])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C[C@H](NC(=O)OCCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
To a stirred solution of 6.63 g (15.6 mmol) of N-[(9H-fluoren-9-ylethoxy)carbonyl]-L-leucine tert-butyl ester in 10 mL of methylene chloride was added 10 mL of trifluoroacetic acid. The mixture was stirred for 2.5 h and solvent was removed at reduced pressure. The crude product was chromatographed on 150 g of flash silica gel eluting with 25% EtOAc in hexane followed by 50% EtOAc in hexane to afford 5.32 g (92%) of product as a white solid, mp 42°-43° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[CH2:11](S)[CH2:12][CH2:13][SH:14].CS(O)(=O)=O>C(O)(=O)C>[CH2:11]1[O:10][C:4]2([CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[S:14][CH2:13][CH2:12]1
Reactant: O=C1CN2CCC1CC2
Reactant: SCCCS
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: C1COC2(CN3CCC2CC3)SC1
Yield: 99.8 %

Procedure:
A mixture of 3-quinuclidinone hydrochloride (10 g, 62 mmol), 1,3-propanedithiol (13.4 g, 124 mmol), acetic acid (40 ml), and methanesulfonic acid (2 ml) was refluxed overnight. Most of the acetic acid was evaporated, 200 ml of water was added, and the solution was washed twice with ether. The pH of the solution was adjusted to basic by the addition of 1 M aqueous sodium hydroxide and the product was extracted with two portions of ethyl acetate. Drying over magnesium sulfate and evaporation of the solvent gave the title compound (13.3 g, 61.9 mmol, 100%) as a colorless solid 71-72° C.