Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C([O-])(=O)C.[Na+]>O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13]([OH:16])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Yield: 134.9 %

Procedure:
A 3 L one neck flask fit with a reflux condenser, magnetic stirrer, and nitrogen inlet was charged with p-t-butylbenzaldehyde (145.5 g, 0.90 mol), acetic anhydride (106 mL, 1.12 mol), and sodium acetate (7.36 g, 0.90 mol). After refluxing for 48.5 hours the reaction was cooled and water was added slowly to roughly triple the total volume as a yellow solid formed. The solids were filtered and washed with water (200 mL), reslurried in water and refiltered and washed again with water (750 mL total). The product was partially dried in the vacuum oven to give 4-t-butlycinnamic acid (248 g). 1HNMR (CD3SOCD3, 500 MHz) mostly trans isomer δ7.58 (d, JAB=8.5 Hz, 2H); 7.54 (d, J=15.5 Hz, 1H); 7.41 (d, JAB=7.5 Hz, 2H); 6.46 (d, J=16.0 Hz, 1H); 1.26 (s, 9H).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[CH2:29][Cl:30])([O-:25])=[O:24].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[Cl-:30].[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[CH2:29][P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([P+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [Cl-]
Temperature: 35 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5 gms (0.0164 mole) of tri-p-tolyl phosphine and 25 gms of toluene. The slurry is heated to 35° C. then 4.3 gm (0.0199 mole) of 3,5-dinitrobenzyl chloride is added. This reaction mass is heated to 60° C. and maintained at that temperature for 3 hours, then heated to 80° C. and maintained at that temperature for 2 hours, then cooled to 60° C. and maintained at that temperature for 16 hours, then cooed to 26° C. and filtered. The salt is washed with 3 gms of toluene and 3 gms of ethyl acetate and then vacuum dried. There is obtained 3.5 gms of catalyst which has a melting point of >250° C. and a chemical shift of 23.8 ppm (phosphoric acid reference).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[P:12]([Cl:17])(Cl)(Cl)(Cl)[Cl:13].C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:13][P:12]([Cl:17])([NH:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cccc(C(N)=O)c1C
Reactant: O=CO
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(C(=O)NP(=O)(Cl)Cl)c1C
Reaction time: 0.33 h

Procedure:
Heated at 70° for 30 min. a mixture containing 23.3 g (0.16 mole) of 2,3-dimethylbenzamide, 32.5 g (0.16 mole) of phosphorus pentachloride and 250 ml of AR carbon tetrachloride. The resulting solution was cooled to 30° and 7.4 g (0.16 mole) of 97% formic acid added. Continued to stir at 30° for 20 min. then chilled to 0°, filtered, washed with AR carbon tetrachloride and air-dried to give 36.1 g, m.p. 88°-90°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:35][C:36]1[N:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=1.[C:43]([O-:46])([O-])=[O:44].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:43]([OH:46])=[O:44].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:39]3[N:38]=[N:37][C:36]([NH2:35])=[CH:41][CH:40]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)c1
Reactant: Nc1ccc(Cl)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)c2)nn1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 44.8 %

Procedure:
3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 3-amino-6-chloro-pyridazine (40.2 mg, 0.31 mmol) was added, followed by anhydrous K2CO3 (19.5 rug, 0.141 mmol). Then the vial was capped and microwaved at 250° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (35.5 mg of light-brown solid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:50][O:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:53](=[O:54])[CH2:52][O:51][CH3:50])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
To a suspension of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate D) (35 mg, 0.065 mmol) in DCM (0.5 mL) was added DIPEA (23 μl, 0.131 mmol) and methoxyacetyl chloride (7 μl, 0.072 mmol). The mixture was stirred at RT, until judged to be complete by LC-MS; diluted with saturated aq NaHCO3 (1.5 mL) and the layers were separated through a phase separator cartridge. The organics were collected, evaporated under reduced pressure and the residue subjected to SCX capture and release. The resulting residue was purified further by preparative RP HPLC to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)-2-methoxyacetamide (Example 18) as a white solid (5 mg, 13%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.37 (3 H, s), 3.20 (2 H, t), 3.37 (3 H, s), 4.06 (2 H, s), 4.38 (2 H, t), 6.33 (1 H, s), 6.95 (1 H, d), 7.19 (1 H, dd), 7.33 (2 H, m), 7.42-7.47 (3 H, m), 7.54 (1 H, m), 7.59 (1 H, d), 7.87 (1 H, d), 8.12 (1 H, d), 8.18 (1 H, bs), 8.23 (1 H, d), 8.67 (1 H, s), 8.84 (1 H, s), 9.89 (1 H, s).
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17]C)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[OH:1][C:2]1([C:15]([O-:17])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C1(O)c2ccccc2-c2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C([O-])C1(O)c2ccccc2-c2ccccc21

Procedure:
13.4 g (0.056 mol) of methyl ester 3a, 11.65 g (0.084 mol) of tropenol, and 0.3 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over magnesium sulfate (MgSO4), and the solvent is distilled off. The product is purified by recrystallization from diethyl ether. Yield: 11.40 g of white crystals (29% of theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([S:9][CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:18])[N:15]=1
Reactant: Cc1cc(O)nc(SCc2c(Cl)cncc2Cl)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 75 °C
Yield: 47.1 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.0 g, 6.62 mmol) and phosphoryl trichloride (20 mL) was heated at 75° C. for 1 hour. The solvent was evaporated, and the crude residue was extracted into ethyl acetate (2×100 mL). The organic layer was washed with 10% sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated, and the residue was purified by CombiFlash using 0-5% methanol in dichloromethane to provide 4-chloro-2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidine as a white solid (1.01 g, 47.1% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H), 4.70 s, 2H), 7.40 (s, 1H), 8.66 (d, 211); M+1 321.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=2)[S:6]1(=[O:16])=[O:15]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: COc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (456 mg) was coupled to m-methoxyphenylboronic acid to provide 3-(3-chloropropyl)-1-(3-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (63 mg):
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[H-].[Na+].CC1C=CC(S(O[CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])(=O)=O)=CC=1.O>CS(C)=O>[CH3:41][N:40]([CH2:39][CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:16]=1)[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 44; 200 mg, 0.62 mmol) in dimethylsulfoxide (8 ml) was added sodium hydride (17.98 mg, 0.75 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. 2-[{[(1,1-Dimethylethyl)oxy]carbonyl}(methyl)amino]ethyl 4-methylbenzenesulfonate (247 mg, 0.75 mmol) in dimethylsulfoxide (8 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to yield the title compound as a yellow oil. 140 mg.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH:11]2[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(O)C.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>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][CH:11]1[C:10]2[C:15](=[N:16][CH:17]=[C:8]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)[CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 26 %

Procedure:
Na2CO3 (2N, 53 μL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (9.0 mg) (1 eq), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4:1, v/v, 2 mL). The reaction was heated at 90° C. for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z=436 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J=9.1 and 13.3 Hz, 1H), 2.98 (dd, J=6.4 and 13.3H, 1H), 3.08-3.18 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.70 (m, 5H), 5.18 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.81-6.87 (m, 1H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.16 (d, J=1 Hz, 1H), 7.50 (dd, J=2.5 and 8.8 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[Cl-].[NH4+:10]>C(Cl)(Cl)Cl>[CH:3]1[C:4]2[N:10]([C:2]3[CH:7]=[CH:6][C:5]([N:10]4[C:7]5[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=5[C:5]5[C:4]4=[CH:3][CH:2]=[CH:7][CH:6]=5)=[CH:4][CH:3]=3)[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 0.17 h

Procedure:
The reaction was conducted for 10 minutes in the same experimental procedures as in Example 16 except for using 1,4-dichlorobenzene (4.6 g, 31.6 mmol, 1.0 equivalent) as an aryl halide. To the reaction mixture was added an aqueous solution of ammonium chloride, and the mixture was poured into chloroform (800 mL). The aqueous layer was separated off, and the organic layer was passed through a silica gel pad and concentrated to remove the excess chloroform under reduced pressure. To the thus-obtained suspension was added methanol (130 mL), and the crystal was collected from the suspension by suction filtration, washed with methanol and dried under reduced pressure to afford 12.6 g of pCP as a white powder.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:2]>CCO.[Ni]>[NH2:2][CH2:1][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1C#N
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CN
Yield: 66 %

Procedure:
A solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Ni in absolute EtOH was stirred under H2 atmosphere (50 PSI) for 24 hours. Filtration and evaporation of the solvent followed by flash chromatography (SiO2, 0-20% MeOH—CH2Cl2, gradient elution) provided the target compound, 14d, as a racemic mixture of trans isomers (286 mg, 66% yield): FIA (M+H) 229.33.
Reaction SMILES: Cl[CH2:2][Si:3]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:16].[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>C(O)C>[CH2:11]([O:10][Si:3]([O:13][CH2:14][CH3:15])([CH2:2][I:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:12]
Reactant: CCO[Si](CCl)(OCC)c1ccccc1
Reactant: [I-]
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CI)(OCC)c1ccccc1
Yield: 49.8 %

Procedure:
A mixture of 12.8 g (0.052 mol) of chloromethyl(diethoxy)phenylsilane, 9.4 g (0.062 mol) of sodium iodide and 0.21 g (0.52 mol) of tricaprylylmethylammonium chloride (Aliquat® 336) in 10 ml of ethyl alcohol was refluxed for 12 hours, cooled, filtered, and evaporated. The filtrate was diluted with water and extracted with ether. The ether solution was washed with brine, dried over magnesium sulfate, evaporated, and distilled to provide 8.7 g (50%) of the title compound as a clear liquid: b.p. 86°-100° (0.15 mm); nD19 1.5204; ir (neat) 2980, 1590, 1480, 1430, 1390, 1290, 1165 cm-1 ; nmr (CDCl3) 1.25 (6H, t, J=7) and 7.3-7.9 (5H, m).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12].C[Si](C)(C)Cl.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:38])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-methylmorpholine (46 ml) was added to a mixture of L-valyl-L-proline hydrochloride (34 g) in THF (850 ml), followed by trimethylchlorosilane (41 ml) maintaining the temperature below 30° C. The mixture was stirred for 2 hours and then cooled to 0° C. Further N-methylmorpholine (16.5 ml) was added, followed by a solution of 4-anisoyl chloride (18 ml) in THF (25 ml), maintaining the temperature below 5° C. After 15 minutes, the mixture was filtered and the filtrate concentrated in vacuo to a yellow oil. The oil was dissolved in ethyl acetate (100 ml) and basified to pH 7-8 with saturated potassium bicarbonate solution (100 ml). The aqueous layer was separated and washed with ethyl acetate (50 ml). The aqueous layer was then acidified to pH 2-3 with 2M hydrochloric acid solution and extracted with ethyl acetate (150 ml). The organic extract was concentrated under vacuum and toluene (150 ml) was added. The solution was again concentrated under vacuum until about 50 ml of toluene was collected. The solution was then added dropwise to hexane (400 ml) with stirring to give a white solid, which was filtered, washed with hexane and dried under vacuum to give N-(4-methoxybenzoyl)-L-valyl-L-proline (40 g), having a similar NMR to that given in Procedure 1, step (iii) above.
Reaction SMILES: O.[Br:2][C:3]1[S:7][C:6]2=[C:8](C(OC)=O)[N:9]=[CH:10][N:5]2[CH:4]=1.[I-].[Li+]>CS(C)=O>[Br:2][C:3]1[S:7][C:6]2=[CH:8][N:9]=[CH:10][N:5]2[CH:4]=1
Reactant: COC(=O)c1ncn2cc(Br)sc12
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cn2cncc2s1
Temperature: 180 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
Water (2.5 μl, 0.14 mmol) was added to a solution of methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (36 mg, 0.14 mmol) and lithium iodide (73 mg, 0.55 mmol) in dimethyl sulfoxide (8 ml) solution, and the mixture was stirred at 180° C. for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-bromoimidazo[5,1-b]thiazole (4.5 mg, 16%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C@H:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C@@H:9]([CH3:10])[O:11][C:21]2=[O:22])=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](O)CNCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
(R)-1-(4-bromobenzylamino)propan-2-ol (5F2) (0.034 mol, 8.2 g) was dissolved in THF (150 ml) and triethylamine (0.051 mol, 5.12 g) was added, followed by carbonyldiimidazole (0.037 mol, 6.0 g). The mixture was stirred at room temperature for 2 hours then heated to reflux for 20 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organics were washed with water and brine before drying over sodium sulphate. The crude mixture was purified on silica eluting with 35% EtOAc/Petroleum Ether to give (R)-3-(4-bromobenzyl)-5-methyloxazolidin-2-one (5F3) 6.7 g (74%); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H) 7.16 (d, 2H) 4.62 (m, 1H) 4.41-4.32 (m, 2H) 3.49 (m, 1H) 2.95 (m, 1H) 1.39 (d, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH3:6][C:7]1[C:8](N2C=NC=N2)=[N:9][C:10](=[O:13])[NH:11][CH:12]=1.C(O)(=O)C>CN(C)C=O>[CH2:3]([S:5][C:8]1[C:7]([CH3:6])=[CH:12][NH:11][C:10](=[O:13])[N:9]=1)[CH3:4]
Reactant: CCS
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCSc1nc(=O)[nH]cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
786 mg (18 mmol) of a 55% strength sodium hydride emulsion are added to 0.7 ml (9 mmol) of ethylmercaptan in 25 ml of dry dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at 0° C. 1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are then added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is neutralized by addition of acetic acid, concentrated and chromatographed on silica gel using dichloromethane/methanol 20/1. 0.64 g (62.7% of theory) of 4-ethylthio-5-methylpyrimidin-2(1H)-one is obtained with melting point 181°-184° C. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 11.45 (s, 1H), 7.55 (s, 1H), 3.10 (q, 2H), 1.90 (s, 3H), 1.25 (t, 3H).