Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:30][CH2:29][CH2:28][O:27][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: COCCN
Product: COCCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-methoxyethylamine.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.26 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]2[CH2:15][C@H:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:33])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12][N:11]2C(OCC)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]2[CH2:15][C@H:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][C:26]4[C:27]([CH3:33])=[CH:28][CH:29]=[CH:30][C:31]=4[CH3:32])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12][NH:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CC[C@@H](N2CCN(CC(=O)Nc3c(C)cccc3C)CC2)C[C@@H]1Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Yield: 30 %

Procedure:
A mixture of intermediate 11 (0.0034 mol) and potassium hydroxide (0.034 mol) in 2-propanol (150 ml) was stirred and refluxed for 4 days. The solvent was evaporated. The residue was taken up in CH2Cl2/water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromato-graphy over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g (30%) of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (intermediate 13).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:16]1(=O)[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>C(O)C.CC(OC)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(O)cc12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Zinc chloride (28.3 g, 0.207 mol) was stirred in anhydrous ethanol (45 mL) then heated to 95° C. (reflux) under nitrogen atmosphere using oven dried glassware. Ethyl 4-chlorobenzoylacetate (44 g, 0.194 mol) was added as a single portion followed by dropwise addition of a solution of benzoquinone (22.6 g, 0.21 mol) in anhydrous MTBE (500 mL) over 2 hours. This was performed with a simultaneous distillation of MTBE from the reaction mixture such that the reaction volume remained approximately constant. A bath temperature of 145-155° C. and an internal temperature of 75-95° C. maintained throughout most of the addition. Halfway through the addition more anhydrous ethanol (45 mL) was added because the reaction mixture became thick and a loss of some of the original volume of ethanol through the distillation was suspected. After addition was complete, heating continued for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (250 mL). The insoluble solids were removed by filtration of the biphasic solution and the organic layer was then separated, washed with more water, dried and evaporated under vacuum. The residual brown solid was slurried in warm dichloromethane and the mixture cooled to room temperature and cooled further by refrigeration overnight. The tan solid was filtered from the dark brown solution and washed with a small volume of DCM and dried under vacuum to give ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (27 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6]([C@@H:8]1[C:12]([CH3:14])([CH3:13])[S:11][CH2:10][N:9]1[C:15](=[O:29])[C@@H:16]([OH:28])[C@@H:17]([NH2:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:7].C([O:37][C:38]1[C:39]([CH3:48])=[C:40]([CH:44]=[CH:45][C:46]=1[F:47])[C:41](O)=[O:42])(=O)C>>[CH3:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6]([C@@H:8]1[C:12]([CH3:14])([CH3:13])[S:11][CH2:10][N:9]1[C:15](=[O:29])[C@@H:16]([OH:28])[C@@H:17]([NH:27][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([F:47])=[C:38]([OH:37])[C:39]=1[CH3:48])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:7]
Reactant: CC(=O)Oc1c(F)ccc(C(=O)O)c1C
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Product: COc1ccc(C[C@H](NC(=O)c2ccc(F)c(O)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Yield: 67.6 %

Procedure:
The reaction was carried out in the same manner as in Step 3 of Example 1 using the compound obtained in Step 2 of Example 1 (94 mg) and 3-acetoxy-4-fluoro-2-methylbenzoic acid (45 mg). The resulting crude product was purified by recryatallization from a mixture of EtOAc and n-hexane to obtain the target compound (84 mg, 67%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[C:3]=1[NH2:4].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>>[I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([C:19]([F:20])([F:21])[F:22])[C:3]=1[NH:4][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline and 3-nitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NCCCOC1CCN(Cc2ccccc2)CC1

Procedure:
10 g (40.9 mmol) 3-(1-benzylpiperidin-4-yloxy)-propionitrile are dissolved in 100 ml ethanol and added to a spatula tip Raney-Nickel. The mixture is stirred at RT and under hydrogen atmosphere until the consumption of the theoretical amount of hydrogen to be taken up (ca. two days). Subsequently, this is filtered from the catalyst and the solvent is removed under vacuum. The residue is distilled in a bulb tube apparatus. Yield of a colorless oil: 7.5 g (73%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]([C:12]1[S:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:17][C:14]1[S:13][C:12]([C:10](=[O:11])[CH:3]([NH:2][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(N)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of ethyl 3-amino-4-(5-chlorothiophen-2-yl)-4-oxobutyrate hydrochloride (596 mg), 4-fluorobenzoyl chloride (380 mg) and sodium hydrogen carbonate (1.0 g) in ethyl acetate (10 ml) and water (10 ml) was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (30 ml) and water (30 ml), and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with hexane to obtain a crude product of ethyl 4-(5-chlorothiophen-2-yl)-3-[(4-fluorobenzoyl)amino]-4-oxobutyrate (732 mg) as colorless powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1.[CH3:39][Mg]Br>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)([OH:20])[CH3:39])=[CH:15][CH:14]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
To a -78° C. solution in THF (20 mL) of bis(4-(2-quinolylmethoxy)phenyl) ketone (992 mg, 2 mmol), prepared as in step 1, was added methylmagnesium bromide (3M solution in ethyl ether, 0.8 mL, 2.4 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 4:1) to afford 920 mg (90%) of 1,1-bis(4-(2-quinolylmethoxy)phenyl)ethanol: mp 129°-131° C.; 1H NMR (300 MHz, DMSO-d6) d 1.74 (s, 3H), 5.32 (s, 4H), 5.48 (s, 1H), 6.95 (d, 4H, J=9 Hz), 7.30 (d, 4H, J=9 Hz), 7.63 (m, 4H), 7.78 (m, 2H), 8.01 (m, 4H), 8.39 (d, 2H, J=8 Hz); MS (DCl--NH3) m/e 513 (M+H)+. Anal. Calc'd. for C34H28N2O3 : C, 79.67; H, 5.51; N, 5.46. Found: C, 79.48; H, 5.62; N, 5.25.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:22][O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][O:11][N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH2:21])(C(C)(C)C)(C)C>C(O)(=O)C>[CH2:28]([O:27][P:25]([CH2:24][O:23][CH2:22][CH:9]([OH:8])[CH2:10][O:11][N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH2:21])([O:30][CH2:31][CH3:32])=[O:26])[CH3:29]
Reactant: CCOP(=O)(COCC(COn1cnc2c(N)ncnc21)O[Si](C)(C)C(C)(C)C)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(COCC(O)COn1cnc2c(N)ncnc21)OCC
Yield: 74.5 %

Procedure:
A solution of 9-[2-(t-butyldimethylsilyloxy)-3-(diethoxyphosphorylmethoxy)propoxy]adenine (410 mg, 0.84 mmol) in 80% acetic acid (20 ml) was stirred at 85° C. for 4 h. The solvents were evaporated in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol 10:1, affording 9-[3-(diethoxyphosphorylmethoxy)-2-hydroxypropoxy]adenine (235 mg, 75%) as a white solid m.p. 84°-85° C. νmax (KBr) 3320, 1650, 1600 and 1460 cm-1 ; δH (CDCl3) 1.33 (6H, t, J6.8 Hz, 2×CH3CH2), 3.75 (2H, d, J5.5 Hz, CH2OCH2P), 3.87 (2H, d, J7.9 Hz, CH2P), 4.06 (1H, m, CHOH), 4.16 (4H, m, 2×CH3CH2), 4,42 (2H, m, CH2ON), 5.60 (1H, br.s, D2O exchangeable, OH), 5.84 (2H, br.s, D2O exchangeable, NH2), 8.01 (1H, s, H-2/H-8), 8.35 (1H, s, H-2/H-8). Found: C, 41.66; H, 5.95; N, 18.55%; M+ 375.1306.C13H22N5O6P requires C, 41.60; H, 5.91; N, 18.66%; M+ 375.1308.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[C:14]([C:17]([NH2:18])=[O:36])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (97 mg, 0.241 mmol), 6-aminoquinoline (50 mg, 0.347 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water was added to induce precipitation. The precipitate was collected, and dried on vacuum to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile as a solid. The solid 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile was dissolved in EtOH (4 mL) and DMSO (2 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 414.2 (M+H); UV 200.0, 263.4, 296.0, 356.1 nm; t 0.335 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([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)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][O-:46].[Na+]>CO>[CH3:45][O:46][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([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)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ccnc(Cl)n2)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)n1
Temperature: 75 °C
Yield: 77 %

Procedure:
A solution of 0.24 (0.4 mmol) (2S,4R)-2-Chloro-4-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 1 ml MeOH was treated at 0° C. with 0.16 ml (0.88 mmol) sodium methylate (5.5 M in MeOH) and kept at this temperature (2 h), warmed up and heated for 10 h at 75° C. After evaporation and extraction with aqueous saturated NH4Cl/Et2O (3×), the organic phases were washed with aq. 10% NaCl, dried (Na2SO4) and evaporated to give 0.19 g (77%) 2-Methoxy-4-[(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 628 (MH+), which was deprotected (see General method for S-deprotection, Method D) to give (3R,5S)-1-(2-Methoxy-pyrimidin-4-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol, MS: 386 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C>C1COCC1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]([OH:31])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:19])([CH3:20])[CH3:21]
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: CCCCC(C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Phenyl-1,3-dithiane (Aldrich) (3.79 g; 19.3 mmol) was mixed with dry distilled THF (20 mL) under a nitrogen atmosphere. The solution was cooled to −60° C. and n-butyl lithium (1.6M in pentane, 1.56 mmol, 9.74 mL) was added slowly by syringe. The reaction mixture was warmed to −20° C. and held at that temperature for 30 min., and then held at −10° C. for 15 min. The yellow solution was cooled to −78° C. and (1-formyl-pentyl)-carbamic acid tert-butyl ester (1.6 g, 1.4 mmol, in 5 mL THF) was added rapidly (over 20 seconds) and 60 seconds later a mixture of 2 mL acetic acid and 5 mL THF was added rapidly. After warming to 23° C. the solution was concentrated at reduced pressure. Excess 2-phenyl-1,3-dithiane was removed by its crystallization away from the desired product using a minimum of ethyl acetate in hexane. The mother liquors were concentrated and chromatographed using a hexane-ethyl acetate gradient to afford {1-[hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester. (1.7 g, 56% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.C(N)[CH2:22][NH2:23]>CN(C)P(N(C)C)(N(C)C)=O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1)#[N:23]
Reactant: Clc1ccc(C(c2ccccc2)c2ccccc2)cn1
Reactant: NCCN
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(C(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat a mixture of 16.5 g. (0.059 mole) of 2-chloro-5-(diphenylmethyl)-pyridine and 10.6 g. (0.059 mole) of cuprous cyanide in 120 ml. of hexamethylphosphoramide with stirring at 210°-220° C. for 7 hours. Pour the cooled reaction mixture into a solution of 200 ml. of ethylenediamine in 500 ml. of water, and extract with benzene. Wash the benzene extracts with 10% aqueous sodium cyanide, then with water, dry, treat with activated charcoal, filter, and concentrate to obtain 2-cyano-5-(diphenylmethyl)-pyridine. This compound is converted directly to the title compound by heating at reflux with 13 g. of potassium hydroxide pellets in 100 ml. water and 200 ml. ethylene glycol for 15 hours. Remove the ethylene glycol and water under reduced pressure, dissolve the residue in water, acidify with concentrated hydrochloric acid, and extract with chloroform. Dry the chloroform extracts. Concentrate the dried extracts to a residue and triturate the residue with isopropyl ether. Filter the solids, dry and recrystallize from ethanol to obtain 5-(diphenylmethyl)picolinic acid, m.p. 189°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.B#B>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC#N)cc1
Agent: B#B
Product: COc1ccc(CCCCN)cc1

Procedure:
Reduction of the butyronitrile by reaction with diborane gave 4-(4-methoxyphenyl)butylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Br[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccsc1
Product: COC(=O)c1cccc(C=O)c1N(Cc1ccsc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86 %

Procedure:
Following the procedure of Example 322, 1.0 g (2.865 mmol) of the product of Example 321 is reacted with 3-bromomethyl thiophene to give 1.10 g (86%) of the product as a white solid after chromatography on silica gel eluting with EtOAc/Hexanes (1:3). Electrospray Mass Spec: 446.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:5]=2[NH:6][C:7](=[O:10])[C:8]=1[OH:9].[C:17]1([Sn](C)(C)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:4]2[C:3](=[O:16])[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]([OH:9])[C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)c(Br)c1O
Reactant: C[Sn](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccccc2)c1O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-Bromo-8-chloro-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (400 mg) in THF (10 mL) was added phenyltrimethylstannane (600 mg) and trans-Benzyl(chloro)bis (triphenyl-phosphinepalladium(II) (50 mg). The solution was heated to reflux for 5 hours at which time a dark gray precipitate formed. The reaction mixture was cooled to room temperature and diluted with an ether-tetrahydrofuran mixture (1:1). This mixture was washed with a 10% solution of potassium fluoride, dried (Na2SO4), and evaporated to dryness. Chromatography, with ethyl acetate as the eluent, yielded the title compound as a white solid (230 mg); mp 193-196 degrees C.; NMR: 7.18(m,2H), 7.31(m, 4H), 7.52(s, 1H), 7.87(d, 1H, J=8.7), 10.28(brs, 1H), 11.81(s, 1H). Analysis for C16H10ClNO3 -0.3H2O: Calculated: C, 62.98, H, 3.50, N, 4.59: Found: C, 62.82, H, 3.33, N, 4.67.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:35]2[C:26](=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:39]2[CH2:38][CH2:37][N:36]([C:22]3[C:35]4[C:26](=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:25]=[CH:24][CH:23]=3)[CH2:41][CH2:40]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: c1ccc2cc3c(N4CCNCC4)cccc3cc2c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc4cc5ccccc5cc34)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(1-anthryl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.