Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)C=CC=CC=1.C[O-].[Na+].[OH:35][C:36]1[C:48]([CH3:49])=[C:47]([CH3:50])[C:46]2[O:45][C:41]3([CH2:44][CH2:43][CH2:42]3)[CH2:40][CH2:39][C:38]=2[C:37]=1[CH:51]=O>C1COCC1>[CH3:49][C:48]1[C:47]([CH3:50])=[C:46]2[C:38]([CH2:39][CH2:40][C:41]3([O:45]2)[CH2:42][CH2:43][CH2:44]3)=[C:37](/[CH:51]=[CH:9]\[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[C:36]=1[OH:35]
Reactant: Cc1c(C)c2c(c(C=O)c1O)CCC1(CCC1)O2
Reactant: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(/C=C\c3ccc4ccccc4n3)c1O)CCC1(CCC1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MS (m/z)=404 (M+H+). To a suspension of 0.35 g of triphenyl(quinolin-2-ylmethyl)phosphonium bromide in 5 mL of THF was added 3 mL of 0.5 M sodium methoxide at 0° C under Argon, followed by a solution of 6-Hydroxy-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-5-carbaldehyde 0.18 g) in 10 mL of THF. The solution was stirred for 1 hr at 0° C., warmed to room temperature, and stirred for 2 hrs. The tetrahydrofuran was evaporated, and the residue was partitioned between EtOAc and H2O, washed with brine, then dried over Na2SO4. The crude material was purified on a silica column eluting with 1:8 EtOAc/Hexane. 50 mg of 7,8-dimethyl-5-[2-quinolin-2-ylvinyl] 3,4-dihydrospiro-[chromene-2,1′-cyclobutan]-6-ol which was precipitated with hexane. 1H-NMR (300 MHz, CDCl3) δ=1.70-1-76 (m, 3H), 1.78-1.97 (m, 5H), 2.09-2.30 (m, 8H), 2.81-2.85 (t, 2H), 5.70 (brs, 1H), 7.18-7.24 (d, 1H), 7.50-7.56 (m, 2H), 7.71-7.82 (m, 3H), 8.08-8.13 (m, 2H) ppm. 13C-NMR (75 MHz, CDCl3) δ=12.24, 12.34, 12.60, 21.25, 29.31, 34.10, 76.51, 117.47, 119.17, 119.65, 112.33, 126.29, 126.46, 127.45, 127.55, 129.23, 129.88, 130.01, 133.47, 136.49, 145.10, 155.55 ppm. MS (m/z)=372 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[O:10]=[C:8]1[NH:9][CH:3]([CH2:2][O:1][S:20]([CH3:19])(=[O:22])=[O:21])[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]1=2
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(CO)c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1NC(=O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-hydroxymethyl-6,7-dihydro-dibenzo[c,e]azepin-5-one in pyridine (2 mL) at 0° C. is added MsCl. The mixture is stirred at 0° C. for 20 min then is quenched with ice/water. The mixture is extracted with EtOAc and the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:24]=O)=[C:13]([CH:23]=1)[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl>C(=O)(OCC)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:24]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][O:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCOc1cc(OCc2ccccc2)ccc1C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Ethyl 4-[5-(benzyloxy)-2-formylphenoxy]butyrate (8.2 g) was dissolved in diethyl carbonate (100 mL), and potassium t-butoxide (4 g) was added, and the mixture was stirred overnight at room temperature. 1 M hydrochloric acid was added, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated to give the title compound (5.2 g) as crude crystals. A part thereof was recrystallized from ethyl acetate-hexane to give crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>>[C:13]([O:1][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: OCCN1Cc2ccccc2C1
Product: CC(=O)CC(=O)OCCN1Cc2ccccc2C1
Yield: 21.5 %

Procedure:
A solution of 4.67 g (0.029 mol) of 2-(2-hydroxyethyl) isoindoline and 3.72 g (0.029 mol) of ethyl acetoacetate was heated at 100°-110° C. under nitrogen for 36 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was subjected to flash chromatography (silica gel, 1:1 ethylacetate/petroleum ether) to give 1.54 g (22%) of a dark oil. NMR (CDCl3) δ 2.2 (3H, s), 2.94 (2H, t), 3.4 (2H, s). 3.9 (4H, s), 4.24 (2H, t), 7.04 (4H, s).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: BrCc1cccc(Br)c1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(Br)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-bromobenzyl bromide instead of benzyl bromide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-naphthylamine (1.43 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) in 10 mL of CH2Cl2 is cooled to 0° C. under an atmosphere of nitrogen. To this solution is added dropwise a solution of acetyl chloride (0.86 g, 11 mmol) in 10 mL of CH2Cl2. The mixture is allowed to warm to room temperature and stirred overnight. The mixture is concentrated in vacuo and then 1 N HCl is added to the residue to bring the mixture to pH 4. The mixture is extracted 3 times with 20 mL of EtOAc and the combined organic layers are washed with 20 mL each of H2O, saturated aqueous NaHCO3 and saturated brine. The organic layer is dried over MgSO4, filtered and the solvents are removed in vacuo to give 2-acetylaminonaphthalene as a solid which is used without further purification. A solution of NaClO3 in (0.33 g, 30 mmol) in 0.77 mL of H2O is added dropwise to a mixture of 1.0 g of 2-acetylaminonaphthalene in 5 mL of concentrated HCl and 6 mL of HOAc at 0° C. The mixture is allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The mixture is poured over 20 g of ice and is extracted three times with 20 mL of CH2Cl2. The combined organic layers are washed with 20 mL each of water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The mixture is filtered and the solvents are removed in vacuo to give an oil which is purified by flash chromatography on silica gel (CH2Cl2) to give 1-chloro 2-acetylaminonaphthalene as a solid. A mixture of 0.17 g (0.77 mmol) of 1-chloro 2-acetylaminonaphthalene in 3.9 mL of 6 N HCl is heated to 85° C. and is stirred for 8 hours. The mixture is cooled to 0° C. and solid Na2CO3 is carefully added to bring the mixture to pH 8. The mixture is extracted 3 times with 20 mL of CH2Cl2. The combined organic layers are washed with 15 mL of saturated brine, dried over Na2SO4 and the solvents are removed in vacuo to give 1-chloro 2-aminonaphthalene as a solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]=[CH:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH:10]([CH3:14])[CH2:9][CH:8]=[C:7]2[CH3:15])[O:3]1.[OH:16]C1(C#CC(O)C)C(C)(C)C(C)CCC1C.OS(O)(=O)=O>CO>[CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH:10]([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:15])[OH:16])[O:3]1
Reactant: CC1=CCC(C)C(C)(C)C12C=CC(C)O2
Reactant: CC(O)C#CC1(O)C(C)CCC(C)C1(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC1CCC2(O1)C(C)(O)CCC(C)C2(C)C

Procedure:
2,6,9,10,10-Pentamethyl-1-oxa-spiro[4.5]deca-3,6-diene, used as starting material in step a) hereinabove could be prepared from 1-hydroxy-2,5,6,6-tetramethyl-1-(3-hydroxybut-1-yn-1-yl)-cyclohexane by treating said carbinol with a 30% aqueous solution of H2SO4 as indicated in Swiss Pat. No. 544,733. The compound possessed moreover very interesting organoleptic properties and consequently could advantageously be used as flavouring and perfuming agents. It develops a very powerful natural fruity, minty character reminiscent of certain perfuming notes typical of black-currant fruits.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([F:12])=[CH:6][C:5]=1[O:13][CH3:14].[OH-].[Na+]>C(O)C>[C:10]([C:8]1[C:7]([F:12])=[CH:6][C:5]([O:13][CH3:14])=[C:4]([CH:9]=1)[C:3]([OH:15])=[O:2])#[N:11]
Reactant: COC(=O)c1cc(C#N)c(F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(F)c(C#N)cc1C(=O)O
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A stirring suspension of 5-cyano-4-fluoro-2-methoxy-benzoic acid methyl ester (2.98 g, 14.25 mmol) in ethanol (30 mL, 0.5 M) was treated with 1.25 M NaOH (68 mL, 85.5 mmol). Within 10 minutes, the solution was clear and by TLC, all of the starting material was consumed. The solution was concentrated and then treated with 2N HCl until the pH was 1. The white precipitate formed was collected by suction filtration, dissolved in dioxane, and was washed with aq saturated NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to afford 5-cyano-4-fluoro-2-methoxy-benzoic acid (1.9 g, 70%) as a white solid. Rf=0.34 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 8.13 (d, J=8.1 Hz, 1H), 7.36 (d, J=12.0 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:20]([N:11]2[C@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:35][CH3:36])[N:9]=[C:10]2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH:32]([CH3:33])[CH3:34])=[O:21])[CH2:45][CH2:46]1)=[O:40]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(C(=O)N(C)C)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 666.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.O.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:37][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(F)c2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)c2)cc1
Temperature: 150 °C
Yield: 76 %

Procedure:
8-Chloro-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)imidazo[1,2-α]pyridine (0.10 g, 0.29 mmol) was dissolved in cyclopentylamine (5 mL). This solution was heated in a glass tube at 150° C. for 72 hours. Ethyl acetate and water were added to the reaction mixture and the phases were separated. The organic phase was washed with water, dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 4-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine (90 mg, 76%) as a white foam. 1H NMR (CDCl3): δ 8.26 (d, 1H), 8.06 (d, 1H), 7.73 (q, 2H), 7.34 (d, 1H), 7.05 (t, 2H), 6.77 (t, 1H), 6.65 (dd, 1H), 6.4 (s, 1H), 4.85 (d, 1H), 3.92 (m, 1H), 2.0–1.4 (m, 8H); 19F NMR (CDCl3) δ −114.07; MS m/z 407 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([C:7]1[C:8]([OH:18])=[C:9]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:10]2=[N:11][CH:12]=1)=O.Cl.[NH2:23]O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[C:9]4[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:10]4=[N:11][CH:12]=3)[O:18][N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(Cl)c3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(Cl)c4)c3cnc21

Procedure:
5-(3-Chlorobenzoyl)-1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (4.25 g) was refluxed overnight in 100 ml of pyridine containing 4.5 g of hydroxylamine hydrochloride. The reaction mixture was then evaporated and the residue triturated with 5% hydrochloric acid. The resulting product was then filtered off and washed with methanol. Recrystallization from ethyl acetate gave analytically pure product (1.91 g), mp 178°-179° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([N:7]=[C:8]=[O:9])([CH3:6])[CH3:5].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:6])([CH3:5])[NH:7][C:8](=[O:9])[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)N=C=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)cc1

Procedure:
A solution of 17.0 g (119 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester in 150 ml of absolute tetrahydrofuran was added, over a 15 minute period to 15.1 g (119 mmol) of p-chloroaniline in 300 ml of absolute tetrahydrofuran. After refluxing the mixture for three days, the solution was evaporated to dryness. The product, after two recrystallizations from methylene chloride, was dried for 6 hours at 40° C., under greatly reduced pressure, to yield N-[(4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, m.p. 147°-148° C.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN([CH:11]=[C:12]([C:18](=O)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)C.CCOCC>[C:2]([N:6]1[C:18]([CH3:19])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
In ethanol (10 mL) was placed the tert-butylhydrazine hydrochloride (1.35 g, 10.8 mmol) and ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (2.00 g, 10.8 mmol). The mixture warmed to reflux and stirred for 2 hrs, cooled to RT and stirred overnight. The mixture was evaporated at reduced pressure to give an oil which was dissolved in ether (25 mL) and washed successively with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4), evaporated at reduced pressure and purified by chromatography (Biotage S1-25 column, 10-40% ethyl acetate/Hex) to give ethyl 1-tert-butyl-5-methyl-1 H-pyrazole-4-carboxylate (1.48 g, 65% yield) as an oil. MS (ESI) m/z: 211.0 (M+H+).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH:5]1[CH2:7][CH2:6]1.[Br:8][CH:9]([CH2:13][CH2:14]Cl)[C:10](Cl)=[O:11].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH:5]1([CH2:4][N:3]2[CH2:14][CH2:13][CH:9]([Br:8])[C:10]2=[O:11])[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: O=C(Cl)C(Br)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1C(Br)CCN1CC1CC1
Temperature: 25 °C
Yield: 108 %

Procedure:
In a 1.5-liter 4-necked flask, equipped with a stirrer, dropping funnel, reflux condenser, thermometer and argon inlet, 54.4 g sodium hydroxide pearls (1.36 mol) and 9.26 g tetrabutylammonium hydrogensulfate (27.3 mmol) were suspended with stirring at room temperature under argon in 500 ml dichloromethane. To the suspension 35.6 g aminomethylcyclopropane (500 mmol) were added. A solution of 100.0 g 2-bromo-4-chlorobutyric acid chloride (400 mmol, product of Example 1) in 100 ml dichloromethane was added during 10 min. After the first 3 min. of addition, reflux was reached and maintained during the addition. After completed addition, the mixture was refluxed for 1 h, during which its color changed from dark green to dark brown. The suspension was cooled to room temperature during 10 min., and a mixture of 50 g ice and 250 ml deionized water was added under stirring. The phases were separated and the organic layer was successively washed with a solution of 60 g ammonium chloride in 300 ml deionized water, followed by 300 ml deionized water. The organic layer was concentrated to yield 94.2 g of N-cyclopropylmethyl-3-bromopyrrolidine-2-one as a dark oil.
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([CH3:27])[C:11]=1[S:28][C:29]([F:32])([F:31])[F:30].[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:26][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:20]([Cl:21])[C:15]=1[N:14]1[C:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:11]([S:28][C:29]([F:32])([F:31])[F:30])[C:12]([CH3:27])=[N:13]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: c1ccccc1
Agent: CCCCCON=O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-c2ccccc2)c1SC(F)(F)F
Yield: 49 %

Procedure:
2 ml (0.015 mol) of n-pentyl nitrite are added to 4.1 g (0.01 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-methyl-4-trifluoromethylthio-pyrazole in 30 ml benzene at room temperature with stirring, and the mixture is stirred for a further 15 hours at room temperature. The mixture is worked up by concentrating in vacuo and the residue is purified by chromatography (silica gel; eluant: petroleum ether/ethyl acetate 9:1). 2.3 g (49% of theory) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl-5-phenyl-4-trifluoromethylthio-pyrazole are obtained as an oil.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:7]2[CH:33]=[CH:34][S:35][C:6]=2[C:5](=[O:36])[N:4]1[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[ClH:1].[O:2]=[C:3]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][CH2:14]2)[C:7]2[CH:33]=[CH:34][S:35][C:6]=2[C:5](=[O:36])[N:4]1[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]
Reactant: CCOC(=O)CCCCn1c(=O)c2sccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCCn1c(=O)c2sccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A mixture of ethyl 5-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-3-yl]valerate (2.54 g, 4.11 mmol) obtained in Example 135, 2N sodium hydroxide (4.0 ml), tetrahydrofuran (6 ml) and ethanol (6.0 ml) was stirred at room temperature for 6 hours, neutralized with 2N hydrochloric acid, and then extracted with chloroform. The extract was washed with water, dried (MgSO4) and then concentrated. The residue was treated with ethyl ether to give the title compound (2.27 g, 86%) as an amorphous powder.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:32][C:33]1[CH:58]=[CH:57][C:36]([CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(=O)CN(C)CC(=O)O3)=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:43]2[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:58][CH:57]=3)=[CH:45][CH:44]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:31])[F:29])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Palladium (II) acetate (6.61 mg, 0.029 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.294 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (120 mg, 0.324 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (24.18 mg, 0.059 mmol) and potassium phosphate tribasic (469 mg, 2.208 mmol) in dioxane (2 ml) and water (0.4 ml) stirred for 16 h at 80° C. and stirred in a screw-capped pressure vessel. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-100% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)-phenyl)-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)acetate 155 mg (82%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.38 (m, 2H), 7.22-7.21 (m, 1H), 7.15 (t, J=8.4 Hz, 2H), 7.02-6.98 (m, 3H), 5.92 (br. s, 1H), 4.96 (br. s, 1H), 4.23 (t, J=6.6 Hz, 2H), 3.42 (br. s, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.60 (br. s, 2H), 2.46 (s, 3H), 2.06 (br. s, 1H), 2.04 (s, 3H), 1.88-1.70 (m, 2H), 1.62-1.52 (m, 2H), 1.19 (d, J=6.2 Hz, 3H), 1.13 (br. s, 12H). UPLC (M+H)=647.4.