Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](Cl)(C)C.[NH2:6][CH:7]([C:9]([OH:11])=[O:10])[CH3:8].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCl.O>[NH3:6].[C:19]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])(=[O:22])[CH2:20][CH3:21]
Reactant: CC(N)C(=O)O
Reactant: CCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@@H](C)C(=O)O
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.6 %

Procedure:
Trimethylsilyl chloride (52.4 ml, 0.41 mol) was added dropwise to an ice-cooled solution of D,L-alanine (16.71 g, 0.188 mol) and triethylamine (57.5 ml, 0.41 mol) in dichloromethane (190 ml). Once addition was complete, the solution was stirred at room temperature for 1 h, followed by 1 h at 40° C. The solution was then cooled to −10° C., propionyl chloride (16.29 ml, 0.188 mol) was added dropwise over 15 minutes and, once addition was complete, the reaction was stirred at −10° C. for 2 h, then 16 h at room temperature, before cooling in an ice-bath. Water (100 ml) was added, the mixture was stirred for 15 minutes, then the phases separated. The aqueous layer was evaporated under reduced pressure and the residue triturated with acetone. The resulting solid was filtered off, and the filtrate concentrated under reduced pressure, to give an oil. This oil was purified by column chromatography using DCM:MeOH:0.88 NH3(aq) (89:10:1) as eluant, to give the title compound (20 g; containing 33% triethylamine).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 65.9 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (60 mg, 0.19 mmol), β-alanine (862 mg, 9.68 mmol) and NaOMe solution (14.5 mL, 7.26 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-80% EtOAc/hexanes+2% AcOH) to give 46 mg of the title compound as a light yellow solid. MS: (+) m/z 368.08 (M+1).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([CH:16]1OCC[O:17]1)CC.[CH2:21]1[O:23][CH2:22]1>C([O-])(=O)C1C=CC(C([O-])=O)=CC=1.C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C>[C:1]([O:12][CH2:21][CH2:22][OH:23])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:13][CH2:16][OH:17])=[O:7])=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: CCCC1OCCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])c1ccc(C(=O)[O-])cc1
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Temperature: 155 °C

Procedure:
A 2-liter stirred autoclave was charged with 600 grams of crude terephthalic acid (3.61 moles), 1600 ml. of 2-propyldioxolane reaction medium, 0.11 mole of tetraethyl ammonium terephthalate catalyst and then purged with nitrogen. Liquid ethylene oxide (473 grams, 10.75 mole) was then pumped in and the reactor heated quickly to 155°C. by passing steam through internal coils. After about 31/2 minutes the reaction was terminated by pressuring the contents of the autoclave into a vessel where the ethylene oxide was flashed and then the unreacted terephthalic acid removed by filtration. Cooling of the filtrate to about 18°C. gave about 742 grams of crude bis(2-hydroxyethyl) terephthalate.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][CH:30]([OH:34])[C:31]([OH:33])=[O:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:27][CH2:28][CH2:29][CH:30]([OH:34])[C:31]([OH:33])=[O:32])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: NCCC(O)C(=O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCCC(O)C(=O)O)c(-c2ccn[nH]2)c1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 20 mg, 0.05 mmol), 4-amino-2-hydroxybutanoic acid (23.4 mg, 0.200 mmol), K3PO4 (106 mg, 0.501 mmol) and NMP (0.4 mL) were added to a MW vial, which was sealed, flushed with argon and stirred at 170° C. for 1 h. The RM was filtered and the residue washed with NMP. The combined organic phases were acidified with TFA, diluted with water and MeCN, filtered and purified by preparative HPLC (Condition 11—gradient to 50% B in 7 min). The MeCN was evaporated off under reduced pressure to give an aqueous solution which was left for 2 days at 4° C. The resulting precipitate was filtered, washed with water and dried to afford the title compound as a white solid. UPLC-MS (Condition 8) tR=0.93 min, m/z=482.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.91 (m, 1H) 1.99-2.17 (m, 1H) 3.58-3.82 (m, 2H) 4.07 (s, 1H) 5.22-5.50 (m, 1H) 6.97 (s, 1H) 7.36 (d, J=8.44 Hz, 2H) 7.89 (d, J=8.80 Hz, 2H) 7.95 (s, 1H) 8.42 (s, 1H) 8.68 (s, 1H) 8.91 (br. s, 1H) 10.23 (s, 1H) 12.47 (br. s, 1H) 13.19 (br. s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:26][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][C:7]=1[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine hydrochloride (25 mg, 0.067 mmol), benzoic acid (10 mg, 0.080 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.4 mg, 0.080 mmol) in dichloromethane (5 ml) was stirred at room temperature for 24 h. The mixture was rotary evaporated to dryness and the residue was purified by column chromatography to give a white solid (14 mg, 47%). 1H NMR (CDCl3): 9.66 (s, 1H), 8.75–8.71 (m, 1H), 8.67 (bs, 1H), 8.40 (s, 1H), 8.08 (dd, J=1.2, 8.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.90–7.86 (m, 2H), 7.81 (s, 1H), 7.55–7.38 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:30]=1.[C@@H:31]12[C:40](=[O:41])[O:39][C:37](=[O:38])[C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36]2>C(Cl)Cl>[CH2:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:6]2[CH:30]=[C:2]([NH:1][C:40]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]3[C:37]([OH:39])=[O:38])=[O:41])[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)C3CCCCC3C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.6 g (1.5 mmol) of 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 150 ml of methylene chloride with heating and cooled to ambient temperature. After the addition of 240 mg (1.55 mmol) of cis-cyclohexan-1,2-dicarboxylic acid anhydride the mixture is stirred for 5 hours at ambient temperature. The reaction product which crystallises out is suction filtered, washed with,methylene chloride and dried in a vacuum drying chamber at 50° C. Yield: 0.58 g (69.8% of theory), Melting point: 186°-188° C. C33H35N3O5 (553.66) Calculated: C 71.59 H 6.37 N 7.59 Found: 71.42 6.56 7.56
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1>>[BrH:9].[CH3:7][C:5]1[N:6]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:2](=[NH:1])[S:3][C:4]=1[CH3:8]
Reactant: BrCC1CCCCO1
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CC2CCCCO2)c1C

Procedure:
A mixture of 2-amino-4,5-dimethylthiazole and 2-(bromomethyl)tetrahydro-2H-pyran were processed using the method described in Example 12A to afford the title compound 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.31 (m, 1H) 1.36-1.52 (m, 3H) 1.64-1.85 (m, 2H) 2.18 (d, J=4 Hz, 6H) 3.19-3.33 (m, 1H) 3.49-3.63 (m, 1H) 3.77-3.89 (m, 1H) 3.94-4.02 (m, 2H) 9.34 (s, 2H),), MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(OC)(C)(C)C>O>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccc(S(=O)O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of p-toluenesulfinic acid sodium salt (30 g) in H2O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HCI (15 mL). After stirring 5 min, the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether. The organic phase was dried (Na2SO4) and concentrated to near dryness. Hexane was added and the resulting precipitate collected to afford p-toluenesulfinic acid; yield 22 g. p-Toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503 mmol) and camphor sulphonic acid (4 g, 17.3 mmol) were combined and stirred at 60° C. 18 h. The resulting solid was broken up and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) then filtered. The solid was resuspended in MeOH/hexanes (1:3, 200 mL) and stirred vigorously to break up the remaining chunks. Filtration afforded the title compound (27 g, 62% yield): 1H NMR (400 MHz, CDCl3) d 8.13 (s, 1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1.[H-].[Na+].Br[CH2:31][C:32]([O:34]CC)=O.[CH3:37][N:38](C=O)C>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH2:31][C:32]([NH:38][CH3:37])=[O:34])[C:19]2=[O:27])[CH2:14][CH2:13]1
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CCOC(=O)CBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)Cn1c(=O)n(C2CCN([C@@H]3CCCc4c(C)cccc43)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(R)-1-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol 2-one (995 mg) was dissolved in DMF (10 ml). Sodium hydride (132 mg, 60%) was added, and the suspension was stirred at room temperature for 40 min. Ethyl bromoacetate (458 μl) was added, and the mixture was stirred for 4 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over sodium sulfate, and concentrated. To the residue was added 40% methylamine-methanol solution (30 ml), the mixture was stirred at room temperature for 2.5 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol), and crystallized with ethyl acetate to give the title compound (1.0 g) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([NH2:19])=[N:16][C:15]=2[CH3:20])=[CH:10][CH:9]=1>O1CCOCC1>[CH2:1]([NH:3][C:4]([NH:19][C:17]1[S:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[C:15]([CH3:20])[N:16]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(-c2sc(N)nc2C)cc1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)cc2)s1

Procedure:
Ethyl isocyanate (1.2 ml, 14.18 mmol) is added to 5-(4-methoxy-phenyl)-4-methyl-thiazol-2-ylamine (Example 28b) (1.56 g, 7.09 mmol) in dioxane (100 ml). After 5 hours at 85° C. the reaction mixture is concentrated to yield 1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([OH:18])=O)[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.N[C@H](C(Cl)=O)CCSCC.[CH3:31][N:32]([CH2:34][CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([NH:37][CH2:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])=[O:18])[O:8][C@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Agent: CCSCC[C@H](N)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Product: Cl
Yield: 162.4 %

Procedure:
cis-6-Chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.91 g., 10 mmoles), ethionyl chloride (10 ml) and dry DMF (4 drops) were refluxed in 100 ml of dry CH2Cl2 for 2 hrs. Removal of solvent and excess reagent under reduced pressure afforded the crude acid chloride which was then redissolved in CH2Cl2 (50 ml) and treated with dimethylaminopropyl amine (1.53 g., 15 mmloes). The reaction was somewhat exothermic and the stirred mixture was maintained at 20° for 35 mins., and then at reflux for 45 mins. After solvent removal, the residue was partitioned between 5% Na2CO3 solution and CH2Cl2 (2 portions). The organics were then washed with brine, dried (MgSO4) and treated with HClg. Solvent removal and crystallization of the residue from isopropyl alcohol gave the product as a white solid (3.34 g., 81.3%). Recrystallization from abs EtOH:Et2O afforded pure material (mp 213° -216° d).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)[CH2:7]1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:13][N:12]=2)[CH2:7]1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
In a sealed vessel, heat a mixture of (S)-(2,4-dichlorobenzyl)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-amine (404 mg, 1.01 mmol), (trimethylsilyl)acetylene (250 μL, 1.76 mmol), dichlorobis(triphenylphosphine)palladium (II) (71.4 mg, 0.10 mmol), copper(I) iodide (20.7 mg, 0.11 mmol) and triethylamine (3 mL) at 100° C. for 4 hours. Cool to room temperature and dilute with water (30 mL). Filter through a pad of Celite®, washing with ethyl acetate. Extract the aqueous with additional ethyl acetate (3×50 mL) and wash the combined organics with saturated aqueous sodium chloride (50 mL). Concentrate and dissolve the residue in dichloromethane, filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (337 mg, 80%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:71]>ClCCl>[Br:17][C:7]1[CH:2]=[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]([CH:16]=2)=[N:13][O:14][N:15]=3)[CH:4]=[C:5]([OH:71])[CH:6]=1
Reactant: Oc1ccccc1-c1ccc2nonc2c1
Reactant: O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Oc1cc(Br)cc(-c2ccc3nonc3c2)c1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 5-(2-hydroxyphenyl)benzofurazan (11.2 g, 52.8 mmol), and tetrabutylammonium tribromide (25.5 g, 52.8 mmol) in dichoromethane (530 mL) is stirred at 18° C. for 18 h. The solvent is evaporated off under reduced pressure to yield a residue which is treated with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 5-(3-bromo-5-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid, m.p. 179-181° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[NH2:13].CCN(C(C)C)C(C)C.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCCCO>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[CH:7]=[C:6]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NC1CCCCC1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(N)cc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NC3CCCCC3)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
100 mg of 4,6-dichloropyrimidine, 106 mg of 3-chloro-4-methoxyaniline and 103 mg of DIPEA were dissolved in 1 mL n-BuOH and the mixture obtained was charged into a microwave vial and kept overnight in a heating block at 120° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., 100 mg of cyclohexylamine and 139 mg of DIPEA were added and mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and pure product was precipitated out from n-BuOH. The precipitate obtained was washed with cold n-BuOH. Pure N4-(3-chloro-4-methoxyphenyl)-N6-cyclohexylpyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O=[CH:6][C@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8].I.N1C=C[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:4])[O:8][C@@H:7]([C@H:9]2[O:10][C@H:15]([OH:16])[C@H:13]3[O:14][C:20]([CH3:21])([CH3:19])[O:12][C@@H:11]23)[CH2:6][O:3]1
Reactant: CC(C)=O
Reactant: c1ccncc1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)O[C@@H]2[C@H]1COC(C)(C)O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannose and 100 mg of hydrogen iodide and the mixture was refluxed with stirring in a water bath at 60° C.for 5 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure to give 11.5 g (80%) of 2,3:5,6-di-O-isopropylidene-α-D-mannofuranose. After recrystallization from petroleum ether, it melted at 122°-123° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CS(C)=O>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[CH:20]1[CH2:4][CH:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1c(Cl)ccc2nn(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1c(Cl)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a suspension of sodium hydride (0.453 g, 10.4 mmol) in dimethyl sulfoxide (50.0 mL) was added a solution of trimethylsulfoxonium iodide (2.29 g, 10.4 mmol) in dimethyl sulfoxide (89 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(5-chloro-2-methyl-2H-indazol-4-yl)acrylate (4.20 g, 18.2 mmol) in dimethyl sulfoxide (50.0 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.10 g, yield 80%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2=[N:27][CH:25]=[N:26][C:16](=[O:18])[CH:11]2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=CN
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N=CN=C2CCN(Cc3ccccc3)CC12

Procedure:
Various 6 substituted 5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidines are prepared using a general procedure shown above. Ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride is reacted with formamidine acetate to yield 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(4aH)-one, which, in turn, is reduced to 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one. The intermediate coupled with 5 chloro 2 methyl pyridine to produce 5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one. Chlorination of the resulting product using POCl3 and displacement of the chloride using various benzylamines via microwave displacement will afford various 6 substituted 5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidines.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:5])C.CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15].[C:18]([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:3]([O:5][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:2][C:1]#[CH:18]
Reactant: C#CC(C)O
Reactant: CS(=O)(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCCOS(C)(=O)=O

Procedure:
A solution of 3-but-1-ynol (5.62 g, 80.2 mmoL) and Et3N (14.5 mL, 104 mmol) in DCM (40 mL) was treated with MsCl (7.48 mL, 96.2 mmol) at 0° C. for 10 min. Work-up (water; sat. aq. NaHCO3), drying (Na2SO4), and concetration gave the title compound as a pale orange oil. 1H NMR (CDCl3) δ 4.32 (t, 2H), 3.07 (s, 3H), 2.67 (td, 2H), 2.09 (t, 2H).