Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][C:5](=[O:19])[CH2:6][C:7]1[C:8]([NH2:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[OH-].[Na+].O>CCO>[NH2:18][C:8]1[C:7]([CH2:6][C:5]([OH:19])=[O:4])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)Cc1c(N)n[nH]c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c(-c2ccccc2)c1CC(=O)O
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A solution of 4.1 g (0.014 mole) of 3-amino-5-phenyl-1H-pyrazole-4-acetic acid ethyl ester (Example I free base) in 50 ml of absolute EtOH was treated with 1.23 g (0.016 mole) of 50% NaOH and 10 ml of water, and the mixture was refluxed for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was dissolved in water (10 ml). The pH was adjusted to approximately 6.5 with glacial acetic acid, and a solid precipitated. The solid was collected by filtration to give 1.6 g of product, mp 214°-216° C. with effervesence (50% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.[Cu](I)I>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([C:27]#[C:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=[N:4][CH:5]=1)[CH3:11]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
To a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethyl acetate (20 mL) under an N2 atmosphere, was added triethylamine (1.1 mL, 7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.), dichloro-bis(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05 eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reaction mixture was heated at 50° C. for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil. Silica gel column chromatography (9/1-4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%). 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.8 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.39 (dd, J=1.8, 2.1 Hz, 1H), 7.56-7.53 (m, 2H), 7.40-7.30 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESI-MS m/z 251.9 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH2:15].[O:16]1[CH2:20][CH2:19][CH2:18]C1>CS(C)=O>[C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:18][CH2:19][C:20]([OH:16])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: C1CCOC1
Reactant: O=CC=CC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CC=CC=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-phenyl-2,4-pentadienal (15 g) and 3-(triphenylphosphonium)-propionic acid chloride (35.2 g) in 140 mL each of anhydrous tetrahydrofuran and anhydrous dimethyl sulfoxide was added dropwise to sodium hydride (4.6 g) at 0-5° C. under nitrogen over a period of four hours. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0-5° C. and water (280 mL) was added dropwise over a period of 30 minutes. The aqueous layer was extracted with ethyl acetate (280 mL) twice, acidified with 12 N hydrochloric acid (24 mL) to a pH of 1, extracted again with ethyl acetate (280 mL) twice. The combined organic layers were washed with water (500 mL) twice, dried over anhydrous sodium sulfate and concentrated under vacuum to give an oil. The oily crude product was chromatographed on a Biotage 40M silica gel column and eluted with methylene chloride:ethyl acetate (95:5). The fractions containing the desired product were combined and the solvents were removed under vacuum to afford 0.7 g of 8-phenyl-3,5,7-octatrienoic acid. 1H NMR (acetone-d6, 300 MHz), δ (ppm) 7.46 (m, 2H), 7.26 (m, 3H), 6.95 (m, 1H), 6.60 (d, 1H), 6.34 (m, 3H), 5.87 (m, 1H), 3.17 (d, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O1CCCC1.[CH2:29]([O:36][C:37]1[CH:61]=[CH:60][C:59]([CH:62]2[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][O:70][Si](C(C)(C)C)(C)C)[CH2:64][CH2:63]2)=[CH:58][C:38]=1[C:39]([NH:41][C:42]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:43]=1[C:44]([O:46][CH3:47])=[O:45])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(OCC)(=O)C>[CH2:29]([O:36][C:37]1[CH:61]=[CH:60][C:59]([CH:62]2[CH2:63][CH2:64][N:65]([CH2:68][CH2:69][OH:70])[CH2:66][CH2:67]2)=[CH:58][C:38]=1[C:39]([NH:41][C:42]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:49]=[CH:48][C:43]=1[C:44]([O:46][CH3:47])=[O:45])=[O:40])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.38 mL) was added to a tetrahydrofuran (1.3 mL) solution of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.13 g), followed by stirring at room temperature for 4 hours. Under ice-cooling, water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.085 g of methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[C:11]#[CH:12]>C(Cl)(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([CH2:10][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[O:9][N:8]=2)[CH:2]=1
Reactant: C#CCN1CCCC1=O
Reactant: ON=Cc1cccnc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1Cc1cc(-c2cccnc2)no1
Yield: 35.4 %

Procedure:
The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.0 g (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) to obtain 352.2 mg (35.4% yield) of 1-(3-pyridin-3-yl-isoxazol-5-yl-methyl)-pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:12][CH2:13][S:14][CH2:15][C:16]([OH:18])=O)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][S:14][CH2:13][CH2:12][C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCc1cc2c(cc1CCSCC(=O)O)OCO2
Reactant: CCNCC
Product: CCc1cc2c(cc1CCSCC(=O)N(CC)CC)OCO2
Yield: 87.1 %

Procedure:
2.1 g of the title compound was prepared from 2.0 g of [{2-(6-ethyl-1,3-benzodioxol-5-yl)ethyl}thio]-acetic acid by using 2.7 g of diethylamine as a pale yellow oil according to the same procedure as that described in Example 32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]([C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[OH:20])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at −78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). The mixture was stirred at −78° C. for 0.5 h., 4-fluorobenzaldehyde (42.4 mmol, 5.3 g) was added. The mixture was stirred at −78° C. for 1 h and then warmed to r.t. The reaction mixture was diluted with EtOAc, washed with NaHCO3 and brine. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the title compound.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73]C4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH:100]1[C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][C:103]=2[N:102]=[C:101]1[CH2:109]CN>>[ClH:45].[NH:100]1[C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][C:103]=2[N:102]=[C:101]1[CH2:109][CH2:73][NH:72][C:70]([NH:69][C@@H:66]1[CH2:67][CH2:68][N:64]([C:62]2[N:61]=[C:60]3[C:56]([N:57]=[CH:58][N:59]3[C@@H:80]3[CH2:84][C@H:83]([N:85]4[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]4)[C@@H:82]([OH:92])[C@H:81]3[OH:93])=[C:55]([NH:54][CH2:53][CH:52]([C:94]3[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:63]=2)[CH2:65]1)=[O:71]
Reactant: NCCc1nc2ccccc2[nH]1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCCc6nc7ccccc7[nH]6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 2-(1H-benzoimidazol-2-yl)-ethylamine. MS (ES+) m/e 783.55 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=O)=[CH:19]1.[CH2:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH3:30].CC(C)=O>C(O)C>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)[N:5]=[C:4]2[CH3:17])=[CH:19]1.[CH2:29]([NH+:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH3:30]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Reactant: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCO
Product: CC1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1=Cc1c[nH]c2ccccc12
Product: CC[NH+](CC)CC
Reaction time: 12 h

Procedure:
2.55 g of 5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazole, 1.45 g of indole-3-carboxaldehyde and 1.05 g of triethylamine in 25 mL of ethanol were heated at 60° C. After 12 hours, the mixture was cooled, acetone was added dropwise so as to induce crystallization, and the mixture was then filtered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15]1
Reactant: NCC1CCC(CN)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
A solution of 2.37 g of 4-fluorophenylsulfonyl chloride (12.2 mmol) in 30 ml of dichloromethane was added over 10 minutes to a stirred solution of 5.20 g of 1,4-bis-aminomethylcyclohexane (36.6 mmol) and 3.15 g of diisopropylethylamine (24.4 mmol) in 100 ml of dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 16 hours, concentrated, and chromatographed on 200 g of silica packed with 5% MeOH (containing 2M NH3)-CHCl3, eluted with 5%, 7.5%, 10% (1 liter each) to give 3.63 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](C2C=CC=CC=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]3[N:33]([C:34]=2[CH:35]=O)[CH:32]=[CH:31][S:30]3)=[CH:23][CH:22]=1.[OH-:37].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:37])/[CH:12]=[CH:35]/[C:34]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2sccn12
Reactant: [OH-]
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)/C=C/c2c(-c3ccc(F)cc3)nc3sccn23)cc1OC
Temperature: 27 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a stirred solution 3,4-dimethoxyphenyl acetophenone (180 mg, 2.7 mmol) and a 6-(4-fluorophenyl)imidazo[2,1-b]thiazol-5-carbaldehyde (246 mg, 2.7 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by columnchromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (8e) as yellow solid (306 mg, 75% yield). Mp: 221-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH2:18])=[S:17])=[CH:5][CH:4]=1.[CH3:19][I:20]>CO>[IH:20].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[NH:18])[S:17][CH3:19])=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(-c2ccccc2NC(N)=S)cc1
Solvent: CO
Product: COc1ccc(-c2ccccc2NC(=N)SC)cc1
Product: I

Procedure:
Reaction of N-(4'-methoxy-2-biphenylyl)thiourea (14.7 g) with methyliodide (9.3 g) in methanol (60 ml) at gentle reflux on a hot water bath for 3 hours gave 1-(4'-methoxy-2-biphenylyl)-2-methyl-2-thiopseudourea hydroiodide as a semisolid. Reaction of the above hydroiodide (8 g) in dichloromethane (100 ml) with 10% aqueous sodium hydroxide solution (25 ml) at 0° C. gave 1-(4'-methoxy-2-biphenylyl)-2-methyl-2-thiopseudourea as a pale yellow solid (m.p. 94°-96° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>O>[C:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([CH2:25][CH2:24][CH2:23][NH2:26])[C:3]4[S:22][CH2:21][CH2:20][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: CCCN
Solvent: O
Product: NCCCc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Yield: 76 %

Procedure:
0.83 g (2.5 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) is combined with 8.3 mL of n-propylamine, reacted for 0.2 hours at 130° C. in the microwave. Then the reaction mixture is added to water and extracted with dichloromethane. The organic phase is concentrated by evaporation, the residue is crystallized. The aqueous phase is extracted with ethyl acetate, the organic phase evaporated to dryness. The solids are combined and stirred with methanol. 0.68 g of the product (76%) is obtained as a powder.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([C:12]([CH2:19]OS(C)(=O)=O)([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11].SC(O)C1C=CC=CC=1.Cl>C(N(CC)CC)C.COCCOCCOC>[CH2:10]([C:12]([CH2:19][S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([CH:15]=[CH:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11]
Reactant: CCCCC(C=O)(CC)COS(C)(=O)=O
Reactant: OCc1ccccc1S
Agent: Cl
Agent: OC(S)c1ccccc1
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: CCC=CC(C=O)(CC)CSc1ccccc1CO
Yield: 107.8 %

Procedure:
A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO4 and concentrated in vacuo to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])CCC.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[N:18]=1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:21]1[CH:22]=[CH:17][N:18]=[C:19]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[N:20]=1
Reactant: Cn1ccc2ccccc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-methyl-indole (244 mg, 1.86 mmol) in 10 ml of THF was treated with n-butyllithium (0.74 ml of a 2.5M solution in hexanes, 1.86 mmol) at −78° C. and the mixture was stirred under argon for 2 hours. In the meantime, a solution of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (250 mg, 0.93 mmol) in 10 ml of THF was treated with n-butyllithium (0.74 ml of 2.5M solution in hexanes, 1.86 mmol) at −78° C. under argon for 15 minutes and the above solution containing the lithiated 1-methyl-indole was added with a syringe. The reaction mixture was stirred for 15 minutes at 0° C. and for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution (5 ml) and extracted with EtOAc. The organic layer was dried over sodium sulfate and evaporated. Purification by column chromatography on silicagel (EtOAc/MeOH/ammonia:2/1/0.02) gave the title compound. Yield: 92.5 mg (27%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[Cl:22]Cl.O>C(O)(=O)C>[Cl:22][C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: ClCl
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 3(2-chloro-4-trifluoromethylphenoxy)-benzoic acid (5 g) in glacial acetic acid (30 ml) was heated under reflux while chlorine was passed through the solution for 5 hours. The solution was left to stand for two days at room temperature and then poured into cold water (500 ml). An off-white gummy solid separated. This was extracted with ethyl acetate and the extract dried and evaporated. The brown oil remaining was dissolved in sodium bicarbonate solution and the solution extracted with ethyl acetate. The aqueous chloride was acidified with hydrochloric acid. The solution was decanted from the precipitated gum, and the gum taken up in boiling hexane. The hexane solution was filtered and allowed to cool. The required 2-chloro-5(2-chloro-4-trifluoromethylphenoxy)benzoic acid was obtained (1.0 g) as crystals of melting point 103°-104°. This acid was used as starting material for compounds 7 and 8.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]2[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[CH:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1C=C2C(=C3CCC[C:36]=13)N(C(OC(C)(C)C)=O)C(C)(C)C(=O)C2C.[CH2:51](I)C=C>>[CH2:25]([C:5]1([CH3:51])[C:4]2[CH:3]=[C:2]([Br:1])[C:11]3[O:12][CH2:13][O:14][C:10]=3[C:9]=2[N:8]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6]1=[O:24])[CH:27]=[CH2:36]
Reactant: CC1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2CCC1
Reactant: CC1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2OCO1
Reactant: C=CCI
Product: C=CCC1(C)C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2OCO1
Yield: 100 %

Procedure:
Using tert-butyl 4-bromo-6,8,8-trimethyl-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]quinolin-7-one-9-carboxylate (500 mg) obtained in Example 68, 10) instead of tert-butyl 6-bromo-2,2,4-trimethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate of Example 1, 8), allyl iodide instead of iodomethane of Example 1, 8) and according to a similar method, the title compound (584 mg, 100%) was obtained.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:7].CC(C)=CC(C)(C)C.C(Cl)C=C>>[CH3:5][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][Si:2]([Cl:4])([Cl:3])[Cl:1]
Reactant: C=C(C)CC(C)(C)C
Reactant: Cl[SiH](Cl)Cl
Agent: CC(C)=CC(C)(C)C
Solvent: C=CCCl
Product: CC(CC(C)(C)C)C[Si](Cl)(Cl)Cl

Procedure:
The process described in Example 2 is repeated, except that 1.2 liters of trichlorosilane, 1.8 liters of diisobutylene (a mixture of 2,4,4-trimethylpentene-1 and 2,4,4-trimethylpentene-2) and 10 ml of the catalytic solution are substituted for the trichlorosilane, allyl chloride and catalytic solution. About 98.6 mol percent of the trichlorosilane employed is reacted and 11.6 moles per hour of 2,4,4-trimethylpentyltrichlorosilane are obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:45]1([C:51]2[N:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[CH:53][N:52]=2)[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:48]1[CH2:49][CH2:50][N:45]([C:51]2[N:52]=[CH:53][C:54]([C:57]3[CH:58]=[CH:59][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:61][CH:62]=3)=[CH:55][N:56]=2)[CH2:46][CH2:47]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 86 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-(4-trifluoromethylphenyl)-pyrimidine, dihydrochloride (0.250 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.360 g), to yield the title compound as an off-white solid (0.480 g, 86%).