Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>O1CCCC1>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 30.3 g of trans-2-aminocyclopentanol in 900 ml of tetrahydrofuran under a nitrogen atmosphere was cooled by means of an external ice bath to approximately 10° C. Forty-five milliliters of triethylamine were added followed by the dropwise addition of a solution of 21.3 ml of acetyl chloride in 240 ml of tetrahydrofuran. The resulting mixture was stirred overnight at room temperature. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo to provide 43.59 g of the title intermediate as a red oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C#CCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCON=C(C(=O)O)c1csc(N)n1
Temperature: 30 °C
Reaction time: 5 h
Yield: 77.3 %

Procedure:
A mixture of ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 2.8 g.), methanol (23 ml.), tetrahydrofuran (20 ml.) and 1 N aqueous solution of sodium hydroxide (22.17 ml.) was stirred at 30° C. for 5 hrs. The reaction mixture was treated in a conventional manner to give 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.924 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 5-aminoindane (2.0 g, 15.0 mmol) in 5 mL of anhydrous pyridine at 0° C. was added acetic anhydride (2.1 mL, 22.5 mmol) and the solution was stirred at rt for 3 h. The solution was then added to 50 mL of water and the resulting solid filtered and washed with water, then dried under vacuum to yield the title compound (2.23 g, 78%). 1H NMR (CDCl3): 7.44 (s, 1H), 7.2 (bs, 1H), 7.12 (s, 2H), 2.88 (q, 4H), 2.18 (s, 3H), 2.09 (p, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:38]=[CH:37][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][C:18]=3[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=3[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:37][CH:38]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc2)c(CNS(C)(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
The product of step E (22 mg, 0.038 mmol) was diluted with methylene chloride (1 mL) followed by the addition of TFA (1 mL). After stirring for 1 hour, the reaction was concentrated, diluted with ether, sonicated and concentrated to yield 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid (15 mg, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3/CD3OD) 7.92 (m, 1H), 7.90 (d, 2H), 7.59 (m, 1H), 7.42 (m, 2H), 7.25 (m, 1H), 7.10 (d, 2H), 6.90 (d, 1H), 4.28 (s, 2H), 3.62 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[CH3:24]I.O>O1CCOCC1>[CH3:24][O:15][CH2:14][CH:13]([O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 67 %

Procedure:
6 g of β-[4-(4-trifluoromethylphenoxy)phenoxy]propanol was dissolved in 30 ml of dioxane and 0.46 g of sodium was added to the solution. The mixture was then heated for 3 hours while refluxing. 3.1 g of methyl iodide was added thereto and the resulting mixture was heated for 6 hours while refluxing. The reaction mixture was then poured into an appropriate amount of water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 4.2 g of the desired product having a boiling point of 160° to 165° C./2 mmHg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[S:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:2]1
Reactant: O=Cc1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cccc(-c2ccsc2)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
3.11 g of 3-thiopheneboronic acid (0.024 mol) are added to a solution of 3-bromobenzaldehyde (3 g, 0.016 mol) in 1,2-dimethoxyethane (80 ml), followed by addition of aqueous 2N sodium carbonate solution (5.15 g, 0.048 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.56 g, 4.9 10−4 mol). The reaction mixture is heated at 80° C. for 16 hours and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 90/10 cyclohexane/ethyl acetate). 2.61 g of a pale yellow solid are recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[NH2:50][CH:51]1[CH2:56][C:55]([CH3:58])([CH3:57])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]1>C1COCC1>[Cl:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[Cl:28])[NH:19][C:18]([C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH:50][CH:51]3[CH2:52][C:53]([CH3:60])([CH3:59])[NH:54][C:55]([CH3:58])([CH3:57])[CH2:56]3)=[O:14])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:26]2
Reactant: O=C(O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)c(OCc2ccccc2)c1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(OCc3ccccc3)c2)CC(C)(C)N1
Yield: 50.2 %

Procedure:
To a solution of 3-benzyloxy-4-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.14 g, 0.34 mmol), prepared as in Description 19, in THF (14 ml), WSC (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) (0.078 g, 0.408 mmol) and 1-hydroxybenzotriazole (0.0551 g, 0.408 mmol) was refluxed for 6 h. A solution of 4-amino-2,2,6,6-tetramethylpiperidine (0.064 g, 0.408 mmol) in THF (2 ml) was added dropwise and refluxed for additional 2 h. The solvent was removed under vacuum and the residue suspended in water. The solid was filtrated and dried under vacuum. The solid was triturated with CH3CN (5 ml) to give 0.094 g (yield 45%) of the title compound as a white powder, mp=220° C.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Product: CCOc1nc(C)c(CC)cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 83 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[C:36]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11]
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Yield: 66.4 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.00 g, 9.08 mmol, RN-59216-82-9), oxalyl chloride (0.871 mL, 9.99 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.17 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (2.41 g, 9.08 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 2.82 g (66%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.40-1.44 (m, 2H), 1.57-1.73 (m, 4H), 1.79 (s, 3H), 1.87-1.93 (m, 2H), 2.16 (s, 3H), 3.21 (quintet, 1H), 3.86 (s, 3H), 3.93 (s, 2H), 7.04 (d, 1H), 7.11-7.18 (m, 2H), 7.29 (t, 1H), 7.51 (dd, 1H), 7.54-7.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)CCc1ccc(-c2ccccc2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(O)CCc1ccc(-c2ccccc2)c(Cl)c1
Yield: 78 %

Procedure:
4-(2-Chloro-4-biphenylyl)-2-butanol was prepared analogous to Example 26 from 4-(2-chloro-4-biphenylyl)-2-butanone with a yield of 78% of theory. The product was obtained as a colorless, viscous, non-crystallizing oil after chromatography on silicagel (Rf -value 0.60, prepared silicagel plates, thickness of layer 0.25 mm; benzene/ethyl acetate, ratio by volume 1:1, as eluant), which was characterized by IR-, UV-, NMR-spectra and by elementary analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (10 g) in acetic acid (75 mL) at r.t. was added bromine (2.6 mL) slowly. After 30 min, the acid was neutralized by the careful addition of sodium hydroxide (10 N) at 0° C. The resulting orange precipitate was dissolved in ethyl acetate and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:1 v/v) of the residual solid provided the title compound as a pale yellow solid (14.8 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)/[CH:15]=[CH:16]\[O:17][CH2:18][CH3:19])CCC>C1(C)C=CC=CC=1.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:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2](/[CH:15]=[CH:16]/[O:17][CH2:18][CH3:19])=[CH:7][N:6]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C/c1cnc(Cl)nc1N
Yield: 31.8 %

Procedure:
To a degassed suspension of 5-bromo-2-chloropyrimidin-4-amine (preparation 37a, 2.50 g, 11.03 mmol) and (Z)-tributyl(2-ethoxyvinyl)stannane (4.76 g, 11.20 mmol) in toluene (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.42 g, 0.36 mmol) and the mixture was subjected to several vacuum-argon cycles and then heated to reflux for 24 hours. Further catalyst (0.42 g, 0.36 mmol) was added and the mixture was refluxed an additional 24 hours. Further (Z)-tributyl(2-ethoxyvinyl)stannane (1.20 g, 2.82 mmol) was added and the reaction was refluxed overnight. The mixture was cooled and concentrated in vacuo and the oily residue was treated with hexanes to give a solid which was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (0.70 g, 32%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][CH:5]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:6]([CH3:37])([CH3:36])[C:7](=[O:35])[CH:8]([CH3:34])[CH:9]([OH:33])[CH:10]([CH3:32])[CH2:11][CH2:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[C:18]([CH3:26])=[CH:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.N1C=CN=C1.[CH2:52]([Si:54](Cl)([CH2:57][CH3:58])[CH2:55][CH3:56])[CH3:53]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:46])[CH2:4][CH:5]([O:38][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:41])[CH3:40])[C:6]([CH3:36])([CH3:37])[C:7](=[O:35])[CH:8]([CH3:34])[CH:9]([O:33][Si:54]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:52][CH3:53])[CH:10]([CH3:32])[CH2:11][CH2:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[C:18]([CH3:26])=[CH:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: COC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1)C(C)C(=O)C(C)(C)C(CC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 115 mg (0.17 mmol) 15-acetoxy-3-(tert-butyl-dimethyl-silanyloxy)-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-12,16-dienoic acid methyl ester (289) and 36 mg (0.50 mmol) imidazole in 1000 μl absolute DMF was cooled to 0° C. After addition of 84 μl (0.50 mmol) triethylsilylchloride, the icebath was removed and the solution was stirred for 3 h 15 min at ambient temperature before 5.0 mL diethylether were added. The organic layer was washed with demi water (2×1000 μl) as well as with brine (1×1000 μl), dried over Na2SO4, filtrated and concentrated in vacuo. The remaining oil was purified via flash chromatography (column dimensions: 1.0×20.0 cm, diethylether/petroleum ether=1:1).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1>C1C=CC=CC=1.Cl>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CN
Reactant: COC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Temperature: 5 °C
Yield: 99.8 %

Procedure:
To a 5° C. stirring suspension of MeNH2.HCl (70 mg, 1.04 mmol) in benzene (1 ml) was added Me3Al (2M in toluene, 0.52 ml, 1.04 mmol) dropwise. The reaction mixture was stirred at RT for 1 h and a solution of 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-propionic acid methyl ester XXXI (160 mg, 0.52 mmol) in benzene (5 ml) was added. The mixture was stirred at 90° C. for 4 h, cooled to RT, and diluted with HCl (5% in water, 6 ml). The resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with H2O (20 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated to provide 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-N-methyl-propionamide XXXII (160 mg, quantitative yield) as a yellow film.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1>O.S(=O)(=O)(O)O>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([OH:2])=[N:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cnc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
Sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) was added dropwise to a cooled (0° C.) mixture of 2-amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol; Lancaster) in 2.6 M sulfuric acid (70 mL). The mixture was allowed to warm to ambient temperature, stir for 1.5 hours, filtered, and the filtercake was washed with cold water and air dried. The precipitate was dissolved in dichloromethane (100 mL), dried (MgSO4), and concentrated to provide the title compound as a solid (4.2 g, 84%). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccnc2Cl)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
2-Chloro-3-pyridinol (1.3 g), 1.88 g of p-methoxybenzyl chloride, and 1.4 g of potassium carbonate were added to 10 ml of dimethylformamide, followed by stirring at 60° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and a saturated sodium chloride aqueous solution. After drying, the solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 1:4 (by volume) mixture of ethyl acetate and hexane as a developing solution. The fraction containing the desired compound was concentrated to afford 2.18 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccnc1Cl
Yield: 47.5 %

Procedure:
To a solution of (2-chloro-3-pyridyl)methanamine (300 mg, 2.10 mmol) in dichloromethane (2 mL) at room temperature is added acetic acid anhydride (198.88 mL, 2.10 mmol) and triethylamine (293.26 mL, 2.10 mmol). After 1 h the reaction is quenched with saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and the solvent evaporated in vacuo to afford 184 mg of N-[(2-chloro-3-pyridyl)methyl]acetamide. MS (m/z): 185 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:13][C:12]2[CH:14]=[C:15]([F:22])[C:16]([S:18]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2)N1CCCC1
Yield: 73.7 %

Procedure:
To a solution of 2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl chloride (250 mg, 0.54 mmol) in diethylether (3 mL) was added pyrrolidine (0.11 mL, 1.35 mmol, 2.5 eq.). The reaction mixture was diluted with ethyl acetate (50 mL), washed with an aqueous solution of hydrochloric acid (1N), brine and water. The organic layer was dried over sodium sulfate and the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (198 mg, 74%) as a white foam.