Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C=C(C)C=1)C([O:7][CH2:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17](=[O:26])[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=O.[OH-].[Na+]>CO>[Cl:34][C:29]1[CH:28]=[C:27]([CH:10]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17](=[O:26])[C:18]2[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=2)[CH2:9][CH2:8][OH:7])[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(C)cc(C(=O)OCCC(Cn2ccnc2C(=O)c2cc(C)cc(C)c2)c2ccc(Cl)c(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(C(=O)c2nccn2CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butyl 3,5-dimethylbenzoate (0.93 g) (see Preparation 31) was dissolved in methanol (10 ml) and 2N aqueous sodium hydroxide solution (2 ml) added. A thick gum formed, additional methanol was added (50 ml) and the resulting suspension sired at room temperature overnight. The methanol was then removed under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (10 ml). The organic phase was separated, washed with brine and the solvent removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol, to give 3-(3,4-dichlorophenyl)-4-[2-(3,5-dimethylbenzoyl)imidazol-1-yl]butan-1-ol (0.67 g) as a white foam.
Reaction SMILES: [CH:1]1([N:7]([CH3:31])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][OH:28])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C1COCC1>[CH:1]1([N:7]([CH3:31])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][O:28][C:32](=[O:34])[CH3:33])[C:15]([NH:17][C:18]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[O:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCO)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCCn1c(NC(=O)c2cccs2)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.8 %

Procedure:
To a solution of 1-(3-hydroxy-propyl)-2-[(thiophene-2-carbonyl)-amino]-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide (Example 4) (0.07 g, 0.16 mmol) in THF (10 mL) was added acetic anhydride (0.02 mL, 0.19 mmol), followed by triethylamine (0.02 mL, 0.17 mmol), and the mixture was stirred at room temperature for 48 h. The resulting solution was washed with 1M HCl (10 mL) and the organic layer was dried over magnesium sulfate. The solvent was evaporated and the resulting oil was purified by flash chromatography with 5% MeOH/dichloromethane to give the title compound (0.05 g, 65%), m.p. 74-76° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: BrCc1cccnc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccnc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and pyridin-3-yl-methyl bromide. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C[O-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCCCCCCCCCCCCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
12.3 g of 1,4-dihydroxy-2-naphthoic acid was dissolved in 100 ml of dimethylformamide, and to the solution was added 23.2 g of a 28% methanolic solution of sodium methylate in a nitrogenous atmosphere at 40° C. with stirring. The mixture was heated to 60° C., and 15.3 g of hexadecyl bromide was added thereto dropwise over a period of 30 minutes. The resulting mixture was heated for 3 hours while stirring, cooled, and then poured into 1 liter of ice-water to which 50 ml of concentrated hydrochloric acid had already been added with stirring. The precipitated crude crystals were filtered and washed with water. After addition of 1 g of activated carbon, the mixture was dissolved in 100 ml of methanol while heating. The activated carbon was filtered, and the filtrate was cooled. The precipitated crystals were filtered, washed with methanol and dried to obtain 9.4 g of 1-hydroxy-4-hexadecyloxy-2-naphthoic acid. Melting Point: 121°-124° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:26])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:35](=[O:36])[C:32]4[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=4)[CH:17]=3)[O:12][CH:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(N)cc32)C(F)(F)COC1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)COCC2(F)F)nc1

Procedure:
The condensation of (2RS,4R)-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.3) and 5-cyanopicolinic acid yielded the title compound as an off-white solid. MS (ISP): m/z=490.2 [M+H]+. In a manner analogous to that described in Example 19, the following compounds were obtained:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Br:8].[N+:10]([O-])([OH:12])=[O:11]>O>[Br:8][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]([CH3:9])=[CH:3][C:2]=1[Br:1]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c(Br)c1
Solvent: O
Product: Cc1cc(Br)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
3,4-dibromotoluene (108.11 mL, 800 mmol) was added dropwise over 4 hours to nitric acid (90%, 280 mL, 6000 mmol) that was cooled to 0° C. under a nitrogen atmosphere with mechanical stirring. The internal temperature of the mixture was maintained below 10° C. during the addition and was stirred for 1 hour at 0° C. after completion of addition. Water (840 mL) was added drop-wise to the mixture maintaining the internal temperature below 10° C. The crude product was collected by filtration and was washed with water (5×500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to produce 180.9 g (77% yield) of the desired product as a solid. 1H NMR (400 mHz, CDCl3) δ 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H)
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH:11]1[NH2:20])[CH2:17]2.[OH-:21].[Na+]>O>[NH2:20][CH:11]1[CH:12]2[CH2:18][C:16]3([OH:21])[CH2:15][CH:14]([CH2:19][CH:10]1[CH2:17]3)[CH2:13]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Concentrated sulfuric acid (35 mL) was mixed with concentrated nitric acid (4.5 mL) and 2-adamantylamine (5.10 g, 4.57 mmol) under cooling with ice, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water and adjusted to pH 10 with 7.5 M aqueous sodium hydroxide. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (2.79 g, yield 61%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].[CH3:31][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](=[O:25])[CH3:31])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Reactant: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(C)=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5-1.7(m,4H), 0.95(t,6H)ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Temperature: 120 °C
Yield: 71.5 %

Procedure:
A stirred mixture of 7-(benzyloxy)-6-methoxyquinazolin-4-ol (5.10 g, 18.09 mmol) and phosphorous oxychloride (10 mL, 109 mmol) in dry toluene (30 mL), was heated to 120° C. for 2 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with sat aqueous NaHCO3 solution (2×100 mL). The organic layer was separated and dried over MgSO4 then concentrated under reduced pressure to afford 7-(benzyloxy)-4-chloro-6-methoxyquinazoline as a cream solid (3.89 g, 72%) which was taken into the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 7.49 (m, 2H), 7.33-7.43 (m, 5H), 5.33 (s, 2H), 4.07 (s, 3H); LC-MS (ESI) m/z 301 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[N:29]1([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:37]4[CH2:38][CH2:39][CH:34]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:35][CH2:36]4)=[O:21])=[CH:17][CH:16]=3)=[CH:14][C:6]1=2
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 47 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (34 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a pale yellow solid (47% yield). M.p. 202-204° C., LCMS: m/z=518.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.55-1.58 (m, 2H), 1.77-1.84 (m, 4H), 1.88-2.02 (m, 2H), 2.2402.30 (m, 1H), 2.56-2.62 (M, 4H), 2.90-3.12 (m, 2H), 3.44-3.48 (m, 2H), 3.64-3.68 (m, 2H), 3.77-3.87 (m, 1H), 4.49 (s, 2H), 4.55-4.63 (m, 1H), 4.95 (bs, 1H), 6.76 (s, 1H), 6.93-7.09 (m, 3H), 7.39 (dd, J=8.3 Hz, 4H), 7.72 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [Br:1][C:2]1(N)[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:16])[CH:8]=2)[NH:3]1.[CH3:18][N:19](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Br:1][C:2]1([C:18]#[N:19])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:16])[CH:8]=2)[NH:3]1
Reactant: CN(C)C=O
Reactant: NC1(Br)C=C(C(F)(F)F)c2cc(Cl)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#CC1(Br)C=C(C(F)(F)F)c2cc(Cl)ccc2N1
Temperature: 140 °C
Reaction time: 1.33 h
Yield: 51 %

Procedure:
2-Bromo-6-chloro-4-(trifluoromethyl)-quinolineamine (5, 476 mg, 1.46 mmol) was dissolved in anhydrous DMF (5 mL) under N2. Zn(CN)2 (103 mg, 0.88 mmol) was added and the solution was degassed with a stream of N2. Pd(PPh3)4 (34 mg, 0.029 mmol) was added and the solution was degassed again and then heated to 140° C. The reaction was complete by TLC after 80 min. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL), The organic phase was washed with H2O (2×20 mL) and brine (1×20 mL) then dried over MgSO4. Concentration and chromatography (SiO2, 40 g, 10% EtOAc-hexane) provided the desired material 6 as a yellow crystalline solid (202 mg, 51%). mp 188° C. Rf 0.34 (10% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ 7.95 (d, J=8.8 Hz, 1H), 7.94 (m, 1H), 7.52 (dd, J=2.2, 8.8 Hz, 1H), 5.34 (br s, 2H, NH2); 19F NMR (CDCl3, 300 MHz) δ −54.51; 13C NMR (CDCl3, 75 MHz) δ 140.21, 139.00, 138.39, 132.27, 128.25, 126.65, 126.10, 122.98, 121.90, 121.84, 114.43; IR (KBr) υmax 3485, 3410, 3386, 2230, 1650, 1639, 1574, 1492, 1430, 1352, 1322, 1221, 1158, 1130, 1121, 1095, 975, 822 cm−1.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:11][CH2:12][CH2:13]I)[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:36](=[CH:37][CH:38]=1)[CH2:35][C:29]1([CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:28][CH2:27]2.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:36](=[CH:37][CH:38]=1)[CH2:35][C:29]1([CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:13][CH2:12][CH2:11][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]#[N:10])[CH2:28][CH2:27]2
Reactant: N#CCC(CCCI)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CCC1(CCCCN1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC1(CCCCN1CCCC(CC#N)(c1ccccc1)c1ccccc1)C2
Yield: 34 %

Procedure:
3,3-Diphenyl-6-iodohexanenitrile (1.5 g), 3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride (1.39 g), triethylamine (0.53 g), and potassium carbonate (0.72 g) were stirred in acetonitrile (25 ml) at 70° C. overnight. The insoluble matter in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The group was purified by silica gel column chromatography to provide the hydrochloride salt of the title compound (0.7 g) as light-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[C:49]([CH2:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:50][C:51]([O:54][CH3:55])=[N:52][CH:53]=1>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:48]2[CH:53]=[N:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[CH2:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:44][C:43]([CH3:45])=[CH:42][C:41]=2[Cl:46])=[CH:9][CH:10]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: COCCCc1cc(OC)ncc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: COCCCc1cc(OC)ncc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 5-bromo-2-methoxy-4-(3-methoxypropyl)pyridine (V.17) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)[O:52][C@H:51]([CH2:53]O)[CH2:50][O:49]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[O:27][CH2:53][C@@H:51]([OH:52])[CH2:50][OH:49])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OC[C@@H](O)CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (99 mg, 271 μmol) in THF (2 mL), PPh3 (107 mg, 406 μmol) and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (36 mg, 271 μmol) were added. The mixture was cooled to 0° C. and DEAD (177 mg, 406 μmol, 186 μL of a 40% solution in toluene) was added. Stirring was continued at 0° C. for 10 min, then at rt for 1 h before another portion of PPh3 (107 mg, 406 μmol) and (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (36 mg, 271 μmol) was added. Stirring was continued for 1 h and the reaction mixture was separated by prep. HPLC. The product containing fraction were combined, evaporated and dissolved in MeCN (1.5 mL) and 1N aq. HCl (0.4 mL). The mixture was stirred at rt for 10 min before it was again separated by prep. HPLC to give the title compound as a colourless resin (27 mg). LC-MS**: tR=0.56 min; [M+1]+=440.21; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 2.15 (s, 3H), 2.36 (s, 3H), 2.42-2.47 (m, 5H), 2.75 (q, J=7.3 Hz, 2H), 3.50 (d, J=4.8 Hz, 2H), 3.56 (s, 2H), 3.72-3.78 (m, 1H), 3.83-3.89 (m, 2H), 7.47 (s, 1H), 7.79 (s, 2H), 7.91 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:14])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:17]>>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:11])[NH:17][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(C)c1c(Cl)ncnc1Cl
Agent: [OH-]
Product: CC1CC(=O)Nc2ncnc(Cl)c21
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Add methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (24.00 g, 96.35 mmol) to 30% aqueous ammonium hydroxide (100.00 mL, 7.5 eq) in a sealed tube. Seal and stir the mixture at 60° C. overnight. Cool the mixture in an ice bath. Filter the solid and wash with cold water to give 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (11.35 g, 60%). MS (ES) m/z=198 [M]+.
Reaction SMILES: C1(C[C@H](N[C:18](=[O:30])[C@H:19]([CH2:24][C:25]2[N:26]=[CH:27][S:28][CH:29]=2)[CH2:20][C:21]([OH:23])=[O:22])[C@@H](O)[C@@H](O)CC(C)C)CCCCC1.[O:31]1CCNC1=O.[OH-].[Li+].OO>>[S:28]1[CH:29]=[C:25]([CH2:24][C@H:19]([CH2:20][C:21]([OH:23])=[O:22])[C:18]([OH:30])=[O:31])[N:26]=[CH:27]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)O)Cc1cscn1
Reactant: O=C1NCCO1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](Cc1cscn1)C(=O)O

Procedure:
4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-(4-thiazolylmethyl)butanoic Acid: The desired 2-oxazolidinone of the previous section (4.02 g, 10.5 mmol) was reacted with lithium hydroxide-hydrogen peroxide according to the procedure of section C(g) of this example to give the monoprotected dicarboxylic acid of formula 2, i.e. the 4-tertbutyl ester of 2(R)-(4-thiazolylmethyl)butanedioic acid. Subsequent coupling of the latter compound (2.83 g, 10.4 mmol) with 2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride (3.21 g, 11.5 mmol) according to the coupling procedure section C(g) of this example gave the desired protected amido acid of formula 3 wherein W1 is tert-butoxy, R2 is 4-thiazolylmethyl and B is 1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl, as a white solid (3.75 g, 72%); 1H NMR (CDCl3) δ8.70 (s, 1H), 7.10 (s,1H), 5.96 (d, J=8.3 Hz, 1H), 4.40-4.25 (m,2H), 3.40-2.70 (m,6H), 2.40 (dd, J=4.4 Hz,16.8 Hz, 1H), 1.95-1.10 (m, 17H), 1.40 (s,9H), 0.90 (d, J=6.6 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H). The latter compound was deprotected as follows: The compound (3.7 g, 7.45 mmol) was dissolved in CH2Cl2 (30 mL). Under a N2 atmosphere at 0°, TFA (6 mL) was added to the solution. The reaction mixture was stirred for 5.5 h. At this point, another portion of TFA (6 mL) was added to the reaction mixture at 0°. The mixture was stirred at room temperature for 3 h. Thereafter, the mixture was diluted with Et2O and concentrated to dryness under reduced pressure to give the desired amido acid (4.70 g); FAB mass spectrum, m/z: 441 (M+H)+. The compound was used without further purification for ensuing coupling steps.
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>>[F:1][C:2]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])([F:6])[CH:3]([F:5])[F:4]
Reactant: FC(F)=C(F)F
Reactant: CCNCC
Product: CCN(CC)C(F)(F)C(F)F

Procedure:
1,1,2,2-tetrafluoroethyldiethylamine is prepared by the addition of tetrafluoroethylene at pressures of up to 700 kPa (100 psig) to an agitated solution of diethylamine. Equipment used for this preparation consists of a one liter bomb in a barricaded rocker arm, on account of the explosive nature of tetrafluoroethylene at elevated pressures. The reaction is carried out between 25 and 91° C. The obtained crude product is fractionated at 14 kPa of pressure (100 mm Hg) to yield a liquid product having a boiling point between 70 and 90° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CC(C)=[O:13]>O>[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[OH2:13]
Reactant: CC(C)=O
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
In 50 volume parts of water are dissolved 19.0 parts of TRH. H2O and 7.5 parts of L-tartaric acid, followed by the addition of 700 volume parts of acetone. The resultant oil is rubbed with a glass rod and the crystals formed are recovered by filtration, washed with hot ethanol and dried under reduced pressure. The described procedure yields 24.5 parts of TRH tartrate-water as crystals melting at 127°C-129°C. [α]D25 =-49.45° (c=1.0 in water)