Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:28][CH:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)[CH2:27][CH2:26]2)[C@H:6]([C:13]#[N:14])[CH2:7][CH2:8]1)#[C:11][CH3:12]
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.030 g, 0.15 mmol, Example 88D) in acetonitrile (1 mL) at room temperature was added 4-(4-trifluoromethyl-phenoxy)-cyclohexylamine (79 mg, 0.31 mmol, Example 55A). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 434 (M+H)+; 1H NMR (DMSO) δ ppm 7.63 (d, 2H), 7.15 (d, 2H), 4.86 (m, 1H), 4.20-4.41 (m, 2H), 3.94 (m, 1H), 2.09-2.43 (m, 8H), 1.88 (d, 3H), 1.41-1.65 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:19])[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1>[NH2:19][C:7]1[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cn2nc(-c3ccco3)nc2c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Temperature: 70 °C
Yield: 67.7 %

Procedure:
A mixture of 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid methyl ester (200 mg; see Example 7 above), LiOH (2 M, 1 mL), and MeOH (a few drops) in THF (20 mL) was heated (at around 70° C.) for 30 minutes. The solvent was removed in vacuo and then the residue was triturated with 0.5 N HCl. The product was dried to afford 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid as a light yellow solid (128 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 6.73(dd, J=3.5, 1.8 Hz, 1H), 7.18(dd, J=3.5, 0.9 Hz, 1H), 7.7(br. s, 2H), 7.94(dd, J=1.8, 0.8 Hz, 1H), 8.68(s, 1H). MS: m/z 246 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:38]([C:40]1[C:41](O)=[N:42]C(C2C=CC(OCCCC)=CC=2)=N[CH:45]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(OCCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:41]([C:40]1[CH:38]=[N:12][C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[N:13][CH:45]=1)#[N:42]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Reactant: CCCCOc1ccc(C(=N)N)cc1
Agent: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from a p-n-butoxybenzamidine hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-butoxyphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 219.0°-220.0° C) with phosphorus oxychloride. The melting point of 2-(p-n-butoxyphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 81.0°-81.5° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][OH:15])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CCC(COP(=O)(Cl)Cl)C(C)CC(C)(C)C)CC(C)(C)C
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of [2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octyl]dichlorophosphate (34.7% in concentration).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.C(O[C:19](OCC)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20])C>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[CH2:20][C:4](=[O:6])[C:3]2[C:2](=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: CCOC(C)(OCC)c1ccccc1Cl
Reactant: COC(=O)c1cccc(C(=O)OC)c1N
Product: COC(=O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
Alternatively, to 8 grams of dimethyl 2-aminoisophthalate was added 9.2 grams of o-chloroacetophenone diethylacetal, the mixture was heated at 140° C. for 30 minutes, then at 200° C. for additional 20 minutes, and finally heated to reflux for 18 hours. The reaction mixture was cooled, crystals separated out were collected by filtration, and recrystallized from acetone to give 2.8 grams of the title product, melting point 166°-168° C.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.I[C:61]1[NH:65][C:64]([CH:66]2[CH2:69][O:68][CH2:67]2)=[N:63][C:62]=1[CH3:70].IC1NC(C)=NC=1C>>[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27]([C:61]2[NH:65][C:64]([CH:66]3[CH2:69][O:68][CH2:67]3)=[N:63][C:62]=2[CH3:70])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1nc(C2COC2)[nH]c1I
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3COC3)nc2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 5-iodo-4-methyl-2-(oxetan-3-yl)-1H-imidazole (compound 180.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 301 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[O-:11].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:11][C:3]2[CH:4]=[C:5]([Cl:10])[C:6]([S:8][CH3:9])=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]([CH3:21])[N:15]=1
Reactant: Cc1cc(Cl)cc(Cl)n1
Reactant: CSc1cc(Cl)c([O-])cc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Cl)c(Oc2cc(C)nc(Cl)c2)cc1Cl

Procedure:
A solution of 25.5 gm (0.1 mol) of potassium 2,5-dichloro-4-methylmercapto-phenolate and 16.2 gm (0.1 mol) of 2,4-dichloro-6-methyl-pyridine in 100 ml of dimethylformamide was heated under reflux for 5 hours. It was then cooled and poured into 300 ml of water. The precipitate which separated out was recovered by suction filtration, washed with water, and recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([CH3:31])[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH:29]([CH3:31])[CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccccc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(C)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-isopropoxy-benzaldehyde. MS (ESI) m/z 527.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>Br.O>[CH3:15][C:11]1[CH:12]=[C:13]([CH3:14])[N:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[N:10]=1
Reactant: COc1cccc(-n2nc(C)cc2C)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)n(-c2cccc(O)c2)n1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 1-(3-methoxyphenyl)-3,5-dimethyl-1H-pyrazole 1 (7.10 g, 35.11 mmol) in hydrogen bromide acid (45 mL, 48%) refluxed (110-120° C.) for 19 hours under a nitrogen atmosphere. Then the mixture was cooled to ambient temperature and neutralized with a solution of K2CO3 in water until there was no gas to generate. Then the precipitate was filtered off and washed with water several times. The collected solid was dried in air under reduced pressure to afford the product as a brown solid (6.33 g in 96% yield). 1H NMR (DMSO-d6, 400 MHz): δ 2.16 (s, 3H), 2.28 (s, 3H), 6.04 (s, 1H), 6.75-6.77 (m, 1H), 6.86-6.89 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 9.73 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 12.29, 13.30, 107.07, 111.10, 113.94, 114.43, 129.71, 138.95, 140.70, 147.57, 157.84.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCCCO)cc1
Temperature: 67.5 °C

Procedure:
To a flask was added 4-hydroxybenzonitrile (50 g, 0.41 mol, 1 eq.) and toluene (400 mL). The resulting mixture was heated to 65° C.±5° C. To the stirring reaction mixture was added 3-bromo-1-propanol (72.90 g, 0.51 mol, 1.25 eq.) and then, over the course of 20 minutes, sodium hydroxide (210 mL, 2.5 M, 0.52 mol, 1.25 eq.). The reaction was heated to 65 to 70° C. for 17 hours. The aqueous layer was separated from the organic layer at 60 to 65° C. The organic layer was then employed directly in the next step without further purification. LC purity 95.3%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1Br
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccccc3Br)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) (described in a previous experimental) and 2-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (1-5% EtOH/EtOAc) to give 7-amino-4-(2-bromobenzylamino)pyrido[4,3-d]pyrimidine (175 mg, 45%) as a light brown solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.85 (1H, t, J=5.7 Hz), 8.24 (1H, s), 7.64 (1H, d, J=7.8 Hz), 7.34 (1H, dd, J=7.7, 7.1 Hz), 7.31 (1H, dd, J=7.7, 2.4 Hz), 7.21 (1H, ddd, J 7.8, 6.9, 2.4 Hz), 6.50 (2H, brs), 6.39 (1H, s), 4.74 (2H, d, J=5.7 Hz).
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.C(C1CCCCCCCCC=1)=O>>[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: C1=CCCC=CCCC=CCC1
Agent: O=CC1=CCCCCCCCC1
Product: C1=CC=CCCCCCCC=C1

Procedure:
The hydroformylation of cyclododeca-1,5,9-triene is known (U.S. Pat. Nos. 3,312,742 and 3,354,229; French Pat. No. 1,411,448 or British Pat. No. 1,161,147). According to these patents, corresponding C13 -alcohols and mixtures containing formyl cyclodocane in addition to formyl cyclodecene, formyl cyclodocadiene and the C13 -alcohol can be produced from cyclododecatriene using cobalt catalysts. Even under controlled conditions, the yield of formyl cyclododecane does not exceed 40% of the theoretical. Hydroxymethyl cyclododecanes are always obtained as the main product. Even under conditions under which formyl cyclooctane is obtained in a 56.7% yield from cycloocta-1,5-diene, hydroxymethyl cyclododecane is almost exclusively formed from cyclododeca-1,5,9-triene.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Br[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][C:2]([CH3:5])([CH3:1])[C:3]#[C:4][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(C)O)c21

Procedure:
Using Method D above, 3-methyl-1-butyn-3-ol (150 mg, 1.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (101 mg, 0.32 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (16 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(CCC(F)(F)F)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 4.1 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoate (0.061 g; 0.132 mmol) in methanol (1.3 mL) was added a solution of sodium hydroxide 5 N (0.26 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. A purification by preparative TLC using a mixture ethyl acetate/heptane (1:1)+0.5% AcOH furnished 0.0024 g (9%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:13][S:14]([C:9]1[S:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:12])=[CH:11][CH:10]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1-c1cccs1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To the cold (-5 to 0° C.) solution of 2-(2-tolyl)thiophene (0.87 g, 5 mmole) was added chlorosulfonic acid (0.33 ml, 5 mmole) over a 15 min. period with constant stirring. After 10 min., phosphorous oxychloride (2 ml) and phosphorous pentachloride were added. The reaction mixture was slowly allowed to attain ambient temperature and stirred for 3 hours. The mixture was then poured onto crushed ice (50 g) and was extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica gel using 2% ethyl acetate in hexane to give 2-chlorosulfonyl-5-(2-tolyl)thiophene, (1.1 g, 72% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(Br)c2cc[nH]c2c1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of Example 1e (7 g, 18.36 mmol) and lithium hydroxide monohydrate (3.08 g, 73.4 mmol) in tetrahydrofuran (50 mL) and water (20 mL) was heated at 80° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 300 mL of water. The resulting solid was collected by vacuum filtration to give the title compound (3.92 g, 17.26 mmol, 94% yield).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:14][CH2:15][NH2:16].Cl[CH2:18][CH2:19]N.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>COCCOCCOC.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:19][CH2:18][NH:16][CH2:15][CH2:14]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCCl
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CC(C)(C)c1ccc(N2CCNCC2)cc1
Reaction time: 2 h

Procedure:
149 g (1 mole) of 4-tert-butylaniline, 178.5 g (1 mole) of bis-(2-chloroethylamine) hydrochloride and 138 g (1 mole) of potassium carbonate in 600 ml of diethylene glycol dimethyl ether are refluxed for 90 hours. The mixture is rendered strongly alkaline with 1 l of water and concentrated sodium hydroxide solution and stirred for 2 hours. The organic phase is extracted with 3×250 ml of methyl tert-butyl ether and the combined organic phases are washed with 2×250 ml of water, dried over sodium sulfate and evaporated down under reduced pressure. The residue is fractionated under reduced pressure to give 155 g (71% of theory) of a product of boiling point 114°-117° C./0.01 mbar and melting point 48°-52° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2([CH2:21][NH2:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1

Procedure:
A suspension of 1-[(4-benzyl-1-piperazinyl)methyl]cyclohexanecarbonitrile (3.2 g/10.8 mmol) and LAH (1.6 g/43.2 mmol) in tetrahydrofuran (100 ml) was refluxed for 3 h. After cooling down, the excess reagent was quenched with water saturated diethylether and the resulting gray suspension was stirred until the suspension turned to white suspension. The resulting suspension was filtered through a pad of Celite. The filtrate was dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude (3.2 g/quant.). MS(m/z) 301(M+)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([CH:14]([OH:16])[CH3:15])[CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)[C:21]1[CH:26]=[CH:25]C(C2C(C=O)=CSC=2)=[CH:23][CH:22]=1.C1([Mg]Br)C=CC=CC=1>>[C:15]1([CH:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)[S:13][CH:12]=2)[OH:16])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=Cc1cscc1-c1ccc(C(F)(F)F)cc1
Agent: Br[Mg]c1ccccc1
Product: OC(c1ccccc1)c1csc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of 1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126) using 4-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (intermediate 125) and phenyl magnesium bromide.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][CH2:36][OH:37]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)=[O:12])=[CH:32][CH:33]=1)#[N:2]
Reactant: OCCBr
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCN(CCO)CC3)c2)cc1
Yield: 72.7 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14 mmol) and 2-bromoethanol (0.214 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 76.2%, (M+1)=482+1.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:6]([F:19])[C:5]=1[F:20])C.Br.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:20][C:5]1[C:6]([F:19])=[C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[OH:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(F)c2F)CC1
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(O)c(F)c2F)CC1
Temperature: 30 °C

Procedure:
1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene (5) (50.0 g), 48% hydrobromic acid (44.8 g), and glacial acetic acid (250 ml) were put in a reaction vessel, and stirred under reflux for 64 hours. After completion of the reaction had been confirmed by means of gas chromatographic analysis, the reaction mixture was cooled to 30° C. Water (500 ml) and toluene (500 ml) were added to the solution obtained, and mixed. Then, the mixture was allowed to stand until it had separated into an organic phase and an aqueous phase, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue obtained was purified by recrystallization from heptane and dried, giving 41.8 g of 2,3-difluoro-4-(trans-4-propylcyclohexyl)phenol (6). The yield based on the compound (5) was 92.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[N:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[N:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Sc2ccnc3[nH]c(=O)cnc23)cc1
Product: O=C(Nc1ccc(Sc2ccnc3[nH]c(=O)cnc23)cc1)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-aminophenylthio)pyrido[2,3-b]pyrazin-3(4H)-one (36.7 mg, 136 μmol) and 2-fluoro-5-trifluoromethyl-phenylisocyanate (22.5 μL, 156 136 μmol) to afford the title compound. Yield: 53 mg (82%).