Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(NB)(C)(C)C.[CH2:11]([O:13][C:14]([N:16]1[CH2:23][CH:22]2[CH:18]([CH2:19][C:20]3[C:26]([CH2:27]O)=[C:25]([Cl:29])[S:24][C:21]=32)[CH2:17]1)=[O:15])[CH3:12].[OH-].[Na+]>C(Cl)Cl>[CH2:11]([O:13][C:14]([N:16]1[CH2:23][CH:22]2[CH:18]([CH2:19][C:20]3[C:26]([CH3:27])=[C:25]([Cl:29])[S:24][C:21]=32)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1CC2Cc3c(sc(Cl)c3CO)C2C1
Agent: BNC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CC2Cc3c(sc(Cl)c3C)C2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (131.7 mg, 0.990 mmol) was added to a round bottom flask, cooled to 0° C. and diluted with anhydrous CH2Cl2 (3.3 ml). Next, tert-butylaminoborane (172 mg, 1.98 mmol) was added and the contents were stirred for 30 minutes. A solution of 5-Chloro-6-hydroxymethyl-3,3a,7,7a-tetrahydro-1H-4-thia-2-aza-cyclopenta[α]pentalene-2-carboxylic acid ethyl ester (99.7 mg, 0.33 mmol) in CH2Cl2 (330 μl) was added to the AlC13/t-butylaminoborane complex. The reaction mixture slowly warmed to room temperature and stirred for 16 hours. Next, the contents were carefully poured into 15% NaOH and extracted with CH2Cl2 (2×50 ml). The organic layer was dried (MgSO4), solvent evaporated in vacuo, and the residue purified by preparative TLC (hexanes:EtOAc-7:3) to give the subtitle compound. MS calculated for C13H16ClNO2S+H 286, observed 286.
Reaction SMILES: [Cl:1]C(OC1C=CC=CC=1)=O.[NH2:11][C:12]1[N:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:15]=[C:14]([CH3:22])[N:13]=1>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[ClH:1].[NH2:11][C:12]1[N:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:15]=[C:14]([CH3:22])[N:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(OC(F)F)nc(N)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cl
Reaction time: 24 h

Procedure:
3.9 g (0.025 mol) of phenyl chloroformate and 0.05 g of 4-dimethylamino-pyridine are added in succession to a solution of 9.0 g (0.05 mol) of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine in 30 ml of absolute tetrahydrofuran. The solution is stirred at 20°-25° C. for 24 hours and the reaction mixture is then diluted with 250 ml of ethyl acetate and the precipitate is separated off. 3.1 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine hydrochloride of melting point 204°-205° C. (decomposition) are thus obtained. To remove the residual starting material, the filtrate is eluted over a column containing the ion exchanger I® (MERCK), and the eluate is dried over sodium sulfate and evaporated. 4.0 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine are obtained as the crude product in the form of a viscous oil. After crystallisation, the product has a melting point of 56°-58° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26].O>CN(C)C=O>[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:18]=2[S:17]1(=[O:26])=[O:27]
Reactant: SCc1ccccc1
Reactant: CN1Cc2cccc(Cl)c2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccc(SCc3ccccc3)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 12 g of potassium-t-butoxide in 100 ml of dry dimethylformamide was added 12.9 mls of benzyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 12.2 g of 2-methyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixturewas stirred at room temperature for 16 hours and poured into water to give a gummy solid. The water was decanted and extracted with ethyl acetate. The gummy solid was slurried in ethyl acetate and filtered to give 5.9 g of the title compound as a light orange solid, m.p. 119°-122° C. The combined ethyl acetate extract and filtratewere washed with water and brine, dried over MgSO4 and concentrated toa solid which was slurried in either and filtered to give an additional 7.6g of product, m.p. 121°-124° C. Total yield was 13.5 g.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[OH:33])[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([O:33][C:31]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:32]=4[CH:23]=[N:24][CH:25]=[CH:26]5)[CH:7]=3)[CH2:9][CH2:10]2)[CH3:15])=[CH:17][CH:18]=1
Reactant: Oc1cccc2ccncc12
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(F)ncn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4ccncc34)ncn2)CC1
Temperature: 115 °C

Procedure:
A mixture of 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine, Example 33(a), (0.05 g, 0.17 mmol), isoquinolin-8-ol (0.037 g, 0.25 mmol, Monomer Chem, Inc.) cesium carbonate (0.081 g, 0.25 mmol), and DMSO (1 mL) was heated in a microwave synthesizer at 115° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, diluted with H2O (30 mL) and extracted with DCM (2×50 mL). The combined organic extracts were washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient: 0-8% MeOH/DCM) to give the title compound as a white solid. Mp: 114° C. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([O:6]CC)=[O:5])C.Br[Si](C)(C)C>CN(C=O)C>[P:4]([CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(CCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OCCCP(=O)(O)O)c(=O)[nH]1
Reaction time: 24 h
Yield: 48.6 %

Procedure:
To a solution of 9-[3-(diethoxyphosphoryl)propoxy]guanine (110 mg, 0.32 mmol) in dry DMF (2 ml) was added bromotrimethylsilane (0.25 ml, 1.91 mmol). The solution was left at ambient temperature for 24 hours, evaporated to dryness under reduced pressure, the residue dissolved in methanol and the solution evaporated to dryness again. The resulting solid was washed again with methanol. The solid was suspended in water (2 ml) and 0.880 NH3 added to obtain a solution. The solution was passed through a column of Dowex 50W-X8(H) ion-exchange resin (previously washed with water) and the column eluted with water. The UV absorbing fractions were collected and evaporated to dryness to give the title compound as a white solid (45 mg, 50%), m.p. >300° C. UV: λmax (EtOH) 255 mm. IR: υmax (KBr) 3700-2100 (broad), 1743, 1700, 1662, 1552, 1474, 1419, 1327, 1240, 1164, 1080, 1029, 1011, 969, 775, 694 cm-1 . 1H NMR: δH ((CD3)2SO) 1.6-1.9 (4H, m, CH2CH2P), 4.28 (2H, t, J=7 Hz, O--CH2), 6.59 (2H, bs, D2O exchangeable, NH2), 7.92 (1H, s, H-8), 10.63 (1H, bs, D2O exchangeable, NH), 2.5-4.5 (2H, broad, D2O exchangeable, PO(OH)2). C8H12N5O5P. 0.75 H2O requires C, 31.74; H, 4.34; N, 23.14%. Found: C, 31.96; H, 4.13; N, 23.01%.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:19])([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([CH3:19])([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH3:9])[CH2:6][CH2:7]1)=[O:22])[CH3:25]
Reactant: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-1,2,3,6-tetrahydro-pyridine (5.2 g) was dissolved in toluene (100 mL) and ethyl chloroformate (2.4 g). The mixture was heated at reflux for overnight and cooled to RT. The toluene solution was washed with NaHCO3 (aq., sat., 100 mL) then brine (100 mL) and dried over Na2SO4. The organic phase was concentrated in vacuo to give the desired compound which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][C:1]([C:20]3[CH:19]=[CH:15][C:14]([OH:13])=[CH:22][C:21]=3[OH:23])=[N:5][C:4]=2[CH:6]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)c(O)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. greater than 300° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[OH:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][OH:46])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCO)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (1.9 mg, 14%). MS (m/e): 327.3 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21][C:22](=[O:24])Cl>ClCCl>[CH3:20][S:21][C:22](=[O:24])[NH:10][CH2:9][C:4]1[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: NCc1nccnc1Cl
Reactant: CSC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=O)NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (5.13 g, 0.0285 mol) in dichloromethane (60 mL) were added N,N-diisopropylethylamine (15 mL, 0.085 mol) and carbonochloridothioic acid S-methyl ester (3.15 g, 0.0285 mol) at 0° C. After 5 min, the mixture was warmed to rt and kept at rt overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (30 mL), sat. aq. NaHCO3 (2×30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography (Hex:EtOAc=70:30→50:50) to give the title compound as a light-yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.41 (s, 3H), 4.76 (d, J=4.6 Hz, 2H), 6.67 (br s, 1H), 8.34 (d, J=2.5 Hz, 1H), 8.48 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2([C:24](Cl)=[O:25])[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C.[CH2:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2([C:24]([O:31][CH2:29][CH3:30])=[O:25])[CH2:9][CH2:10][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Cl)(c3cccc(Cl)c3C)CC2)cc1
Product: CCOC(=O)C1(c2cccc(Cl)c2C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 36.5 parts of 4-(3-chloro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride and 240 parts of ethanol is stirred and refluxed overnight. The reaction mixture is treated with activated charcoal while hot. The latter is filtered off and the product is allowed to crystallize from the filtrate by cooling spontaneously to room temperature. The product is filtered off and dried, yielding 33 parts (89.1%) of ethyl 4-(3-chloro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylate; mp. 134° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C(C2[C:47]([CH2:48][O:49][CH2:50][C:51]3[C:56](C4C(=CC=C(O)C=4)O)=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:46][CH:45]=[CH:44][CH:43]=2)=CC(=CC=1)O)O.N(C(OCC)=O)=NC(OCC)=O.[ClH:77]>C1C=CC=CC=1.CCOCC>[ClH:77].[CH2:50]([O:49][C:48]1[CH:43]=[CH:44][C:45]([O:8][C@@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:46][CH:47]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 14.2 g of cis-1-methyl-3-phenyl-4-piperidinol, 21.4 g of triphenylphosphine, 16.3 g of hydroquinone monobenzyl ether and 375 ml of anhydrous benzene is added dropwise under nitrogen at 5° C. a solution of 14 g of diethyl azodicarboxylate in 375 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature and the precipitated solid is filtered and washed with benzene. The filtrate is concentrated in vacuo to a dark brown oil which is triturated overnight with 500 ml of hexane in a stoppered flask. The hexane is decanted and the gummy solid is triturated with a little ether. The resulting solid is filtered and washed well with ether. The combined filtrates are concentrated in vacuo, and the residue is dissolved in 750 ml of ether and extracted with 2 N hydrochloric acid (1×300 ml, 1×150 ml). The acid washings are extracted with dichloromethane (1×300 ml, 1×150 ml). The dichloromethane extracts are washed with 10% sodium hydroxide solution (300 ml), water (300 ml), and sodium chloride solution (300 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a brown gum. The gum is triturated with hexane, then with ether, filtered, washed with ether, and the filtrate concentrated in vacuo to afford a solid. The solid is dissolved in 500 ml of ether and treated dropwise with 20 ml of saturated ethereal hydrogen chloride. The precipitate is filtered, washed with ether, dried and recrystallized from 75 ml of absolute ethanol to afford product as nearly colorless crystals, mp 213.5°-214.5° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>N1C=CC=CC=1>[CH2:1]([NH:8][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)c1cccnc1NCc1ccccc1
Yield: 84.3 %

Procedure:
Benzylamine (14 mL, 126.8 mmol) was added to a solution of chloronicotinic acid (10 g, 63.4 mmol) in pyridine and refluxed overnight. The pyridine was distilled and the residue was dissolved in 1N NaOH. The solution was diluted with water to adjust the pH to 10 to 11 and washed by dichloromethane. The aqueous phase was neutralized with cold aqueous 10% HCl solution to adjust the pH to 6 to 7. The solids formed were filtered, washed with cold water, and dried in a vacuum oven to yield 12.2 g (84%) of 2-benzylamino nicotinic acid (1) as white solids. MP: 148° C.; 1H-NMR (DMSO-d6): δ 4.69 (d, J=3.6 Hz, 2H), 6.61 (dd, J=4.9, 7.7 Hz, 1H), 7.23 (m, 1H), 7.29 (m, 4H), 8.08 (dd, J=1.8, 7.0 Hz, 1H), 8.28 (dd, J=1.8, 7.0 Hz, 1H), 8.47 (br. s, 1H), 13.10 (s, 1H); EIMS: 229 (M+1), 251 (M+23).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:25]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:26]([C:39](O)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:25]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:26]([C:39]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
The obtained wet crystals of Leu-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (13 mL), Fmoc-D-Lys(Boc)-OH (481 mg, 1.03 mmol) and HOBt (13.9 mg, 103 μmol) were added at room temperature, and EDC HCl (216 mg, 1.13 mmol) was further added under ice-cooling. The mixture was warmed to room temperature, stirred overnight and concentrated under reduced pressure. The residue was precipitated with methanol (10 mL) to give Fmoc-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.14 g, 86% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([O:28]C)=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+]>CO.O>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]3)=[CH:19][CH:20]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OC)CC=CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)O)CC=CC2)cc1

Procedure:
A solution of the product of Step 5, above (5.76 g, 14.9 mmol) and lithium hydroxide monohydrate (6.23 g, 148 mmol) in 148 ml of methanol and 148 ml of water was heated at reflux for 2 hours. The reaction was then concentrated in vacuo, the residue was taken up in water and the pH was adjusted to 4 with concentrated HCl when the title compound precipitated as a colorless solid which was filtered off, dried in vacuo and recrystallized first from ethyl acetate/methanol, then from methanol to yield 1.9 g of title compound which was contaminated with 2.5% of 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]-2-vinylcyclopropane-1-carboxylic acid. Another recrystallization from methanol yielded 1.5 g of title compound, mp 232°-233° C., now about 98.3% pure, as determined by reverse-phase HPLC using a C-18 Beckman 25 cm long column and 30% pH 2.3 phosphate buffer in acetonitrile as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.[CH2:23]([N:25](CC)CC)C>C(O)C>[CH3:23][NH:25][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 81.4 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (50 mg, 0.16 mmol)(described in a previous experimental) with methylamine hydrochloride (32 mg, 0.47 mmol) and triethylamine (70 μL, 0.55 mmol) in ethanol (10 mL) in a pressure vessel at 100° C. for 18 h gives 6-methylamino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine (43 mg, 81%). 1H NMR (CDCl3) δ 8.81. (1H, brs), 8.61 (1H, s), 8.19 (1H, t, J=1.8 Hz), 7.86 (1H, d, J=9.1 Hz,), 7.83 (1H, dt, Jd=7.7 Hz, Jt=1.8 Hz), 7.28-7.21 (2H, m), 6.92 (1H, d, J=9.1 Hz), 4.97 (1H, q, J=5.0 Hz), 3.13 (3H, d, J=5.0 Hz)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)C>O>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:17][NH:23][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCc1ccco1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(-c2csc3ncnc(NCc4ccco4)c23)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 4-chloro-5-phenylthieno[2,3-d]pyrimidine (2.2 g, 0.009 mol), furfurylamine (1.26 g, 0.013 mol), triethylamine (1.3 g) and ethanol (20 ml) was heated under reflux for 2 hours then cooled to ambient temperature and poured into water (50 ml). The resulting solid was collected by filtration, washed with water (30 ml), dried in vacuo and crystallised from a mixture of hexane and toluene to give furan-2-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine as a pale yellow solid, m.pt. 77-79° C.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(O)(=O)C>[CH2:11]([N:1]1[CH2:10][CH2:9][CH2:8][C@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 500 ml 3-necked roundbottom flask, was placed ethyl prolinate (20.0 g, 140. mmol). This was followed by the addition of a solution of benzaldehyde (14.8 g, 140. mmol) in dichloromethane (100 ml). This was followed by the addition of a solution of sodium triacetoxyborohydride (60.0 g, 280. mmol) in acetic acid (20 ml). The resulting solution was allowed to stirring for 12 hours at room temperature. Adjustment of the pH to 7 was accomplished by the addition of solid potassium carbonate. The resulting solution was extracted one time with 500 ml of EtOAc and concentrated by evaporation to afford ethyl 1-benzylprolinate that was used without further purification.
Reaction SMILES: [CH:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:20]([Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])=[CH2:21]>C1(C)C=CC=CC=1>[CH:1]([O:4][CH:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:21][CH2:20][Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])([CH3:3])[CH3:2]
Reactant: CC(C)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: C=C[Si](OC)(OC)OC
Solvent: Cc1ccccc1
Product: CO[Si](CCc1ccccc1C(=O)C(OC(C)C)c1ccccc1)(OC)OC
Reaction time: 8 h
Yield: 65.8 %

Procedure:
10.17 g (40 mmol) of benzoin isopropyl ether, 6.7 ml (44 mmol) of vinyltrimethoxysilane, 335 mg (0.4 mmol) of RuH2 (CO) (PPh3)3 and 75 ml of anhydrous toluene were mixed and stirred at reflux for 2 hours. At intervals of 2 hours, a further 3×200 mg (0.2 mmol) of RuH2 (CO) (PPh3)3 were added. The mixture was left to stand overnight, a further 200 mg (0.2 mmol) of RuH2 (CO) (PPh3)3 and 1 ml (6.6 mmol) of vinyltrimethoxysilane were added, the mixture was stirred at reflux for 8 hours, concentrated and worked up by chromatography (Florisil or silica gel, CH2Cl2 /ethyl acetate/heptane mixtures). 10.6 g of oil were obtained which after distillation in a bulb tube (220° C., 0.08 mbar) gave 9.0 g (56%) of a yellowish oil. 1H-NMR (DCDl3): 0.61-0.96 ppm (2H, mc, Et-H2); 1.21 ppm (6H, d, isopropyl-CH3, 3JH,H =6.2 Hz); 2.61 ppm (2H, mc, Et-H1); 3.53 ppm (9H, s, Si(OCH3)3); 3.71 ppm (1H, hept, sec. isopropyl-H); 5.55 ppm (1H, s, benzoin-H); 7.14-7.39 ppm (8H, m, Ph-H); 7.51 ppm (1H, dd, Ph-H6)