Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>[Cu]I.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.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (0.096 g, 0.38 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.127 g, 0.41 mmol), triethyl amine (3 mL), copper(I)iodide (0.040 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.080 g, 0.11 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained as an oil (0.046 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.3 g, 1.33 mmol) and cyclopentanone (0.56 g, 6.6 mmol) in methanol (3 mL), acetic acid (0.159 g, 2.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.208 g, 3.3 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure to give the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](C)(C)[O:19][SiH2]C(C)(C)C)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A mixture of 1-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (630 mg, 1.4 mmol) and lithiumhydroxide-hydrate (119 mg, 2.8 mmol) in 20 mL MeOH and 10 mL water was stirred at RT for 32 h. The mixture was evaporated in vacuo and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4 and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 12.3 (bs, 1H), 8.36 (s, 1H), 7.81 (s, 1H), 7.23-7.31 (s, 4H), 5.34 (s, 2H), 5.18 (t, 1H), 4.47 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)=[O:25]>CS(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (100 mg, 0.4 mmol) in DMSO (2 ml), potassium tert-butoxide (106 mg, 0.941 mmol) was added. Stirring continued at RT for about 1 hour. 2-Bromo-3′-methoxyacetophenone (100 mg, 0.5 mmol) was then added to the mixture. After 2 hours, LCMS showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. Combined extracts were washed with brine, dried on (Na2SO4), filtered, and evaporated in vacuo. The residue was analyzed on a small RediSep column eluting with 0-10% acetone/DCM. Fractions containing the product were combined and evaporated in vacuo to afford 70 mg of 5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione as a pale yellow solid.
Reaction SMILES: [BH4-].[Li+].[CH3:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:5]1[C:16](OCC)=[O:17].CO>C1COCC1>[OH:17][CH2:16][C@@H:5]1[C@@H:4]([CH3:3])[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CCOC(=O)[C@@H]1[C@@H](C)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium borohydride (6.6 mmol, 3.31 mL of a 2M in THF solution) was added dropwise to an ice cold THF solution of 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate (850 mg, 3.3 mmol) and methanol (0.133 mL, 3.3 mmol). The reaction was warmed to room temperature and then stirred for 4 hours. The reaction was quenched with i-propanol then with saturated NaHCO3. The reaction mixture was extracted 3× with ethyl acetate. The organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound, which was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (t, J=7.0 Hz, 3 H) 1.3 (m, 9 H) 1.9 (m, 1 H) 2.2 (m, 1 H) 3.1 (m, 2 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 4.7 (m, 1 H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])[CH2:3]1.N1C=CN=C1.[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[Si:28]([O:18][CH2:17][C:10]1[C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[C:14]([F:15])[C:13]([F:16])=[CH:12][CH:11]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(c2c(CO)ccc(F)c2F)C[C@H](C)O1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To an ice cooled and stirred solution of [2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-phenyl]-methanol (Intermediate 2, 27.0 g, 105 mmol) in CH2Cl2 was added imidazole (8.5 g, 126 mmol) followed by t-butyl chlorodiphenylsilane (30 mL, 115 mmol) over a period of 15 min. The mixture was brought to room temperature and stirred for 12 h during which tlc showed the disappearance of starting material. The reaction mixture diluted with CH2Cl2 and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer dried (Na2SO4), filtered and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as a white solid. Yield: 45 g (94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11].[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([O:8][CH3:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: COc1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc(F)c(F)c1F
Temperature: 60 °C

Procedure:
To a solution of 1,2,3-trifluoro-4-methoxybenzene (1.6 g, 10 mmol) in acetic acid (20 mL) was added nitric acid (5 mL) and the mixture was heated at 60° C. for 3 hours. After cooling to ambient temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were concentrated to give the crude title compound, which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C=O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Reaction time: 16 h
Yield: 57.9 %

Procedure:
1.41 g (0.01389 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.01389 mol) of 3-nitrobenzyl bromide and 4.3 ml (0.03056 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.9 g (58%) of 1-(3-nitro-benzyl)-piperidin-4-ol were obtained as a yellow oil. MS: me/e=237 (C12H17N2O3+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.[CH:17]1([N:22]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:33]1([N:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([CH:28]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[OH:29])=[CH:30][CH:31]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1ccc(Br)cc1OC
Reactant: O=Cc1ccc(C(=O)N(C2CCCCC2)C2CCCC2)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 8, using 4-bromoveratrole (0.9 mL, 7.0 mmol), n-butyl lithium (4.38 mL of 1.6 M solution in hexane), terephthalaldehydic acid N-cyclopentyl-N-cyclohexyl amide (1.9 g, 6.36 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane to give the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[C:18]([OH:22])(=O)[CH2:19]O>>[CH2:9]([O:8][C:5]1[N:4]=[C:3]2[N:16]([CH3:17])[C:19]([CH2:18][OH:22])=[N:1][C:2]2=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNc1nc(OCc2ccccc2)ccc1N
Reactant: O=C(O)CO
Product: Cn1c(CO)nc2ccc(OCc3ccccc3)nc21
Yield: 46.5 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.50 g of 3-amino-6-benzyloxy-2-methylaminopyridine (prepared as described in Preparation 93) and 7.46 g of glycolic acid were reacted. After working up the product as described in Preparation 43 , the resulting crude product was purifying by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, and was then crystallized by trituration with ethyl acetate, to give 4.10 g of the title compound, melting at 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=1
Reactant: O=Cc1cccn1-c1cccnc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 6.05 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 5.72 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 4.22 g of 4-bromo-1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: COC1C=CC(C2N[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][S:18][C:11]=3[CH:10]=2)=CC=1.P(Cl)(Cl)(Cl)=[O:20]>>[CH3:10][C:11]1[S:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:20]
Reactant: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sccc1C(=O)O
Temperature: 120 °C
Yield: 131.3 %

Procedure:
6-(4-Methoxyphenyl)-5H-thieno[3,2-c]pyridin-4-one (9.1 g) was added to phosphorus oxychloride (90 g), and the mixture was heated at 120° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporate, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (6.6 g, yield; 73%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[C:25](=O)[CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[O:28]C(=O)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:25][CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[OH:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1CCC2CC1CC(=O)N2Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1CCC2CC1CCN2Cc1ccccc1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Diisobutylaluminumhydride (1.5 mol/L in toluene, 21 mL) is added to a solution of acetic acid 2-benzyl-3-oxo-2-aza-bicyclo[3.3.1]non-6-yl ester (1.50 g, for synthesis see J. Chem. Soc., Perkin Trans. 1 1999, 1157-1162) in toluene (30 mL) cooled to −70° C. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, another portion of diisobutylaluminumhydride (1.5 mol/L in toluene, 20 mL) is added and the solution is stirred for additional 4 h at room temperature. Then, the solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The aqueous phase is acidified using 4 M hydrochloric acid and extracted one more time with ethyl acetate. The combined organic extracts are dried (Na2SO4) and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->2:1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:10]1([S:20](Cl)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>O.[OH-].[Na+].O1CCCC1>[C:4]([CH2:3][C@H:2]([NH:1][S:20]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:22])=[O:21])[C:7]([OH:9])=[O:8])(=[O:6])[NH2:5]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
132.12 g (1 mol) of (S)-asparagine were dissolved in a mixture of 800 ml of water and 500 ml of 2 N sodium hydroxide. Then 500 ml of tetrahydrofuran were added. The mixture was cooled to 0° C., and while keeping the pH at 12.0-12.5 with 2 N sodium hydroxide a solution of 226.7 g (1 mol) of naphthalene-1-sulfonyl chloride in 500 ml of tetrahydrofuran was added within 1 h. The mixture was stirred for 1 h at 0° C. while maintaining the pH at 12.5. Then the mixture was allowed to warm to room temperature, stirred for further 2 h and left at room temperature overnight. The pH was adjusted to about 7 with concentrated hydrochloric acid and the tetrahydrofuran was removed in vakuum in a rotary evaporator. The remaining aqueous solution was cooled to 0° C. and with stirring acidified to pH 0.8 by addition of concentrated hydrochloric acid. After stirring for 30 min at 0° C. the precipitated product was filtered off, washed with water and dried in vacuo at 40° C. Yield: 240 g (75%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.13 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:30])=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The resin-bound dodecylamine (described in step a, 0.0426 mmol) was swelled in DCM (1.0 mL) for 15 min at rt. DIEA (28 mg, 0.213 mmol) and 4-chloromethylbenzoyl chloride (40 mg, 0.213 mmol) were added and the reaction mixture was shaken at 0° C. for 2 h then 14 h at rt. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound 4-chloromethyl-N-dodecyl-benzamide which was used directly in the next step.
Reaction SMILES: O.O.C[O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([NH2:16])=[NH:15])=[CH:8][CH:7]=1.CN(/[CH:21]=[CH:22]/[C:23]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)=O)C.C[O-].[Na+].[OH-].[Na+]>CO.O>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][N:16]=[C:14]([NH:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:4])=[O:17])=[CH:7][CH:8]=2)[N:15]=1
Reactant: COC(=O)c1ccc(CNC(=N)N)cc1
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Yield: 87.6 %

Procedure:
A suspension of 24 (6.2 g, 25.4 mmol) and 23a (3.0 g, 16.9 mmol) in anhydrous methanol (40 mL) was stirred and heated to reflux for 10 min, then a solution of sodium methoxide 95% (3.65 g, 67.6 mmol) in methanol (40 mL) was slowly added. After refluxing for 24 h, 20 mL of 2.5N NaOH in water were added and the refluxing was maintained for additional 24 h. The mixture was allowed to cool to the room temperature methanol was removed under reduced pressure, 100 mL of water were added and the resultant mixture was extracted with AcOEt. The aqueous phase was separated and acidified to pH 5-6 with 2N HCl to form a precipitate which was collected by filtration, rinsed with water and dried to afford the desired carboxylic acid 25a (4.55 g, 14.8 mmol, 87%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[CH3:11][CH:12]([CH:14]([OH:20])[C:15]([CH2:18][OH:19])([CH3:17])[CH3:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:7][C:4]([CH3:8])([C:5](=[O:6])[CH:2]([CH3:10])[CH3:1])[C:3]([O:19][CH2:18][C:15]([CH3:17])([CH3:16])[CH:14]([OH:20])[CH:12]([CH3:13])[CH3:11])=[O:9]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C(C)(C)C(=O)OCC(C)(C)C(O)C(C)C
Temperature: 120 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a 1-liter round bottom flask was charged 2,2,4,4-tetramethyl-1,3-cyclobutanedione (140.2 g, 1.0 moles), TMPD glycol (146.2 g, 1.0 moles) and potassium carbonate (73 g, 0.53 moles). The mixture was heated to 120° C. and held for 4 hours. Reaction was cooled and 200 mL of toluene added. Organic layer was washed 4 times at 70° C. Toluene removed to provide 275 g of product. GC assay of the product was 95.9% (4.6:1 mixture of two major isomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:33]2[CH:32]=[CH:31][C:30]([S:35]([N:38]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:37])=[O:36])=[CH:29][C:28]=2[C:26]#[N:27])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[CH:3]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(Cl)cc1-c1ccnc(OC2CCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3ccnc(OC4CCC4)c3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenol, (Preparation 862, 20.5 mg, 0.000074 mol) was dissolved in dimethylsulphoxide (1 mL). Potassium carbonate (24.6 mg, 0.00018 mol) was added and the reaction stirred for 10 minutes at room temperature. 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide, (Preparation 68, 32.2 mg, 0.000074 mol) was added and the reaction was stirred at room temperature for 15 hours under nitrogen. The reaction was partitioned between a saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (10 mL), the organic layer was washed with water (30 mL). The organic extracts were dried over anhydrous magnesium sulphate, filtered and the solvent removed in vacuo to give a colourless foam (56 mg). The material was purified using an ISCO™ companion (4 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (45 mg).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:24]([Li])[CH2:25][CH2:26]C.C(Br)C=C>O1CCCC1>[CH2:1]([C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH2:26][CH:25]=[CH2:24]
Reactant: [Li]CCCC
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
By reaction of 15.0 g of methylcarbonylmethylenetriphenyl phosphorane in 471 ml of tetrahydrofuran with 31.0 ml of butyllithium and 4.28 ml of allyl bromide analogously to 7, the title compound is obtained as crystallized oil with a melting point of 92°-93° C.