Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.P([O-])([O-])([O-])=[O:19].[Na+].[Na+].[Na+]>>[OH:19][CH2:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1N
Reactant: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1CO
Temperature: 75 °C
Reaction time: 4 h

Procedure:
5-Hydroxymethyldeoxycytidine is synthesized according to the published procedure of Itahara et al. (Chem. Lett. 1591-1594, 1991). To 5-methyl-2'-deoxycytidine (0.5 mmol, available from Sigma Chemical Company) in 100 mL of sodium phosphate buffer (pH 7.0) Na2S2O8 (0.5 mmol) is added and the reaction mixture stirred at 75° C. for 4 hours under argon. The reaction mixture is then concentrated and the crude 5-hydroxymethyldeoxycytidine is purified on a LiChroprep reversed-phase HPLC column by eluting with 0.05 M sodium phosphate (pH 7.0) and evaporation of the appropriate fractions.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34]([OH:36])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH:42](O[SiH3])[C@H:41](C(C)(C)C)[C:40]2(C)C)=[CH:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34]([O:36][C:11](=[O:13])[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:17][CH:16]=2)([CH3:15])[CH3:14])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:40]2)=[CH:27]1)([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@H]1OC(=O)C(O[SiH3])[C@H](C(C)(C)C)C1(C)C
Reactant: CC(C)(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(C(C)(C)C)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 160.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 858 mg of 2-(4-t-butylphenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethyl silyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.12 g of the title compound as a colorless foam.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27].Cl>CN(C=O)C>[CH3:29][O:28][C:26]([C:25]1[CH:24]=[C:23]([CH2:22][N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]2=[O:18])[CH:32]=[CH:31][CH:30]=1)=[O:27]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50 mL DMF was added to a suspension of NaH (0.8 g, 20 mmol) in 25 mL DMF. The suspension was stirred at ambient temperatures for 30 minutes, then heated to 50° C. for 30 minutes. A solution of methyl 3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then added and the reaction stirred for 10 min at 50° C. The mixture was poured into 1N HCl, filtered, washed with water and dried. Chromatography on silica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded 1.2 g of 3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:17])[CH2:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: COc1cccc(C(O)(Cc2ccncc2)c2cccc(OC)c2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1cccc(C(O)(CC2CCNCC2)c2cccc(OC)c2)c1

Procedure:
A solution of alpha,alpha-bis(3-methoxyphenyl)-4-pyridine-ethanol (63 g) in acetic acid (400 ml) was hydrogenated over platinum oxide (2 g; 100 p.s.i.; 50°). The reaction was stopped after the uptake of the theoretical amount of hydrogen (0.564 mol), then it was filtered to remove the catalyst and the solvent was evaporated under reduced pressure. After the residue was taken up in water (400 ml) and toluene (200 ml), the mixture was heated to reflux and then made basic with 10N sodium hydroxide. The mixture was cooled to 5°, and the resulting solid was collected by filtration, then was washed in turn with water, toluene, toluene-hexane (1:1) and hexane to give, after drying, 62.5 g of alpha,alpha-bis(3-methoxyphenyl)-4-piperidineethanol, mp 111°-113°.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1.CCN(C(C)C)C(C)C.O=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:26][N:25]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: COC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(OC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
rac-7-Methoxy-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate K) (80 mg, 0.232 mmol) in dry DCE (4 ml) at RT under nitrogen was treated with DIPEA (0.044 ml, 0.255 mmol) followed by ethyl 7-oxoheptanoate (80 mg, 0.463 mmol). The resulting mixture was stirred at RT for 10 minutes and treated with sodium triacetoxyborohydride (245 mg, 1.158 mmol). The mixture was heated at 60° C. for 16 hours. A further portion of sodium triacetoxyborohydride (245 mg, 1.158 mmol) was added and the mixture was heated at 50° C. for 3 days. After cooling to RT, the reaction mixture was diluted with DCM (50 ml) and washed with water (×2). The organic portion was isolated using a phase separating cartridge and the solvent was removed in vacuo. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCc1cc(C(=O)OCC)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 6.2 (s, 1H), 5.06 (s, 2H), 4.34–4.40 (q, 2H), 3.62–3.8 (m, 4H), 3.02–3.12 (m, 4H), 2.54–2.60 (t, 2H), 1.64–1.78 (m, 2H), 1.34–1.38 (t, 3H), 0.98–1.4 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160, 156.4, 152.2, 146.6, 132.8, 118.4, 118.2, 115.8, 115.4, 113.2, 61, 53, 50.6, 50.2, 45.2, 42, 28, 21.8, 14.2, 14.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[N:7]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(NS(C)(=O)=O)n2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine was treated with methanesulfonyl chloride (100 mg) and then stirred at 70° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was dissolved in EtOAc and washed with 1 N HCl, NaHCO3 (saturated), brine, dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 11.0 (s, 1 H), 8.37 (d, 1 H), 8.25 (d, 1 H), 7.82 (d, 2H), 7.72 (m, 1 H), 7.61 (d, 1 H), 7.42 (d, 2H), 7.17 (d, 1 H), 3.15 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 523.1, found 523.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:26])=O>>[NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:26])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reaction time: 1.5 h
Yield: 69 %

Procedure:
The flask was charged with thionyl chloride (600 ml, 978.6 g, 8.23 mol) and 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoic acid (320 g, 0.56 mol) was added in portions with stirring. The mixture was refluxed for one hour and an additional 100 ml of thionyl chloride was added. Refluxing was continued for 1.5 hours (total reflux time: 2.5 hours) until TLC indicated that the reaction was complete. Thionyl chloride was removed by vacuum distillation (30° C., 75 mmHg) until the consistency of the residue was pasty. The remaining traces of thionyl chloride were removed by three consecutive vacuum codistillations with 200 ml of THF. The resulting yellow paste was dissolved in 600 ml of THF and immersed in an ice bath while 500 ml of saturated NaCl was added. The pH of the aqueous layer (<1) was adjusted to approximately 6.9 with solid sodium carbonate (173 g, 1.63 mol) The mixture was filtered and the filter cake was washed with 200 ml of THF. The wash was combined with the mother liquor which was then allowed to separate into two layers. The organic layer was washed with 200 ml of saturated NaCl, the aqueous layer with 150 ml THF: the organic layers were combined and dried over 180 g of calcium chloride beads for one hour. The solution was concentrated to a volume of 400 ml and stirred with 200 ml of dry toluene for 16 hours. The creamy white solid thus formed was filtered, washed with 2×100 ml of dry cold toluene and dried under vacuum to give 228 g of product 2 (0.39 mol, 69%) as a pale yellow solid. 13C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 170.2, 150.4, 148.9, 148.7, 83.0, 75.3, 70.1, 25.8. TLC: One spot (EtOAc/MeOH/HOAc, 10/5/1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11](N4CCN(CCC(OC)=O)CC4)[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[CH:11][CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2ccc(F)cc2c1=O

Procedure:
2.9 g of the compound of Example 9 are dissolved in a mixture of 14 ml of acetic acid and 9.5 ml of water, and 1.4 ml of concentrated sulphuric acid are added. The mixture is heated at 150° to 160° C. for 1.5 hours and poured into 90 ml of water. The precipitate is filtered off with suction, washed with water and methanol and dried. 2.3 g (72% of theory) of 7-]4-(2carboxyethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid semisulphate semihydrate of decomposition point 258° to 261° C. are isolated.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1
Reactant: NC(CC(=O)O)c1cccc(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of (±)3-Amino-3-(3-iodo-phenyl)-propionic acid (3.1 g, 10.6 mmol) in methanol was added thionyl chloride (0.95 mL, 12.7 mmol) and the reaction was stirred at room temperature overnight. Concentration followed by trituration with ether gives a white solid. The solid is filtered, washed with ether and dried to afford the desired product (3.5 g, 10 mmol, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (br, 2H), 8.01 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.21 (dd, J=8.1, 7.8 Hz, 1H), 4.56 (br, 1H), 3.54 (s, 3H), 3.23-3.17 (m, 1H), 3.04-2.98 (m, 1H).
Reaction SMILES: Cl.N[C:3]1[C:17]([Cl:18])=[CH:16][C:6]([CH:7]([O:14][CH3:15])[CH2:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:4]=1[Cl:19].N([O-])=O.[Na+].[OH-].[Na+]>[PH2](O)=O.O>[ClH:18].[C:10]([NH:9][CH2:8][CH:7]([O:14][CH3:15])[C:6]1[CH:16]=[C:17]([Cl:18])[CH:3]=[C:4]([Cl:19])[CH:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(CNC(C)(C)C)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: COC(CNC(C)(C)C)c1cc(Cl)cc(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 163.2 %

Procedure:
A mixture containing 6.55 g of 4-amino-N-tert-butyl-3,5-dichloro-β-methoxyphenethylamine hydrochloride in 66 ml of 50% hypophosphorous acid is cooled to 5° C. and 1.52 g of NaNO2 in 15 ml of H2O is added dropwise. Rapid foaming occurs from gas evolution and after 0.5 hours at 5° C., the mixture is stirred further at room temperature for two hours. It is then made alkaline with 50% aqueous NaOH solution, and the mixture is kept at below 25° C. with addition of ice. The mixture is extracted with 3×100 ml of CH2Cl2 and the combined organic phases are washed with 200 ml of brine, dried (MgSO4), and evaporated to dryness in vacuo to give 5.1 g of the title compound in the form of the free base. This product is dissolved on 50 ml of EtOH and acidified at 5° with 4N HCl to afford a light orange precipitate, which is collected. This gives 3.36 g, mp 278°-280° dec, of the title compound which is recrystallized from isopropanol to give 2.35 g, mp 280° C. dec.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C-]#N.[K+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O.C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([CH:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:12][CH:11]=2)[OH:10])=[O:10])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(C(=O)C(O)c2ccc(OCOC)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-(methoxymethoxy)benzaldehyde (47 g) and potassium cyanide (6.5 g) in water (40 ml) and ethanol (52 ml) was refluxed with stirring for 21/2 hours. The resulting solution was cooled and poured into a solution of ammonium sulphate (300 g) in water (600 ml). The mixture was extracted with diethyl ether, and the ethereal solution was washed twice with water and dried over anhydrous MgSO4. Removal of the ether by distillation left 40 g of a light-brown oil. Thin layer chromatography showed this oil to consist of unreacted 4-(methoxymethoxy)benzaldehyde and 4,4'-di(methoxymethoxy)benzoin. The desired product was isolated by pouring the oil into an ice-cooled mixture of water (1900 ml) and ethanol (400 ml), filtering off the precipitated white solid (19 g) and drying it. Thin layer chromatography showed the solid to be almost entirely 4,4'-di(methoxymethoxy)benzoin and the filtrate to contain 4-(methoxymethoxy)benzaldehyde with only a trace of 4,4'-di(methoxymethoxy)benzoin.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:14][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[CH2:12]2)[N:17]=1)=[O:23]
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: COC(=O)c1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CCc3nc(SC)ncc3C2)n1
Temperature: 100 °C

Procedure:
A mixture of 2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (892 mg, 4.92 mmol), methyl-6-bromopicolinate (1.06 g, 4.92 mmol), Pd(OAc)2 (110 mg, 0.492 mmol), rac-BINAP (306 mg, 0.492 mmol), and Cs2CO3 (3.85 g, 11.81 mmol) in toluene (45 ml) was heated at 100° C. for 4.5 hours. The insolubles were filtered off and washed with ethyl acetate. The filtrate and washing were combined and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) gave the title compound as a viscous yellow oil which gradually solidified on standing (945 mg, 61%).
Reaction SMILES: Cl.[N:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=O)=[CH:13][CH:12]=2)=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.S(Cl)(Cl)=O.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:18](=[O:20])[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:3]2[N:2]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[CH:4]=2)=[CH:16][CH:15]=1)[CH3:21]
Reactant: CC(C(=O)O)c1ccc(-c2cn3ccccc3n2)cc1
Reactant: CN(C)CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C(=O)NCCN(C)C)c1ccc(-c2cn3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
6.2 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionyl chloride, which is produced by treating 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]-propionic acid hydrochloride with thionyl chloride in chloroform, is added to a solution of 2.6 g of N,N-dimethylethylenediamine in 50 ml of pyridine. The mixture is allowed to stand at room temperature for 3 hours, and concentrated under reduced pressure. The residue is neutralized with aqueous sodium bicarbonate solution. The crystalline precipitate is washed with water and recrystallized from toluene to give 2.3 g of N-(2-dimethylamino-ethyl)-2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionamide melting at 149°-150°C.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:15]C)[C:7]([Cl:14])=[CH:8][C:9]=2[Cl:13])[N:4]=[CH:3]1.[BrH:17]>>[BrH:17].[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([OH:15])[C:7]([Cl:14])=[CH:8][C:9]=2[Cl:13])[N:4]=[CH:3]1
Reactant: COc1c(Cl)cc(Cl)c2c(=O)n(N)cnc12
Agent: Br
Product: Nn1cnc2c(O)c(Cl)cc(Cl)c2c1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 5-3 (60 mg, 0.231 mmol) and 48% aqueous hydrobromic acid (2 mL) was heated at 120° C. for 2 h. The solution was cooled to room temperature and the precipitate was isolated via filtration, washed successively with dichloromethane and diethyl ether, and dried in vacuo to provide 3-amino-5,7-dichloro-8-hydroxy-3H-quinazolin-4-one hydrobromide (5-4) as a white solid (44 mg, 58%).
Reaction SMILES: [C:1]([O:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11](=[O:15])[CH:12]=[CH:13]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[C:1]([O:9][C:10]1[C:11](=[O:15])[CH:12]=[CH:13][O:18][C:16]=1[CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO
Solvent: CC(=O)O
Product: Cc1occc(=O)c1OC(=O)c1ccccc1
Yield: 81.2 %

Procedure:
4-Benzoyloxy-1-hydroxy-1-hexene-3,5-dione (54.20 g, 218 mmol) is refluxed for 2 hours in 400 ml of acetic acid, the reaction mixture is concentrated at 40° C. on a rotary evaporator, the residue is dissolved in 500 ml of dichloromethane and washed twice with 300 ml of saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, concentrated on a rotary evaporator and gives 40.75 g (81.2%) of 3-benzoyloxy-2-methyl-4-pyrone, content 73%, m.p.: 106°-110° C.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[CH:27]1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CO>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23][CH3:27])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (5 g, 14 mmol) in MeOH (120 mL) was added HOBt.H2O (143 mg, 0.94 mmol), N-methylmorpholine (1.42 g, 14 mmol) and EDC.HCl (3.64 g, 19 mmol). The reaction mixture was stirred at RT overnight. The MeOH was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (2×40 mL) followed by brine (40 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate, Compound (iv) (5 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.30 (d, 6H), 1.98-2.20 (m, 4H), 2.06-2.37 (m, 1H), 2.60-2.66 (m, 2H), 2.67-2.2.88 (m, 2H), 2.90-3.07 (m, 1H), 3.65-3.79 (m, 1H), 3.70 (s, 3H), 3.80-3.91 (m, 2H), 4.61-4.70 (m, 1H), 6.18 (s, 1H), 6.59 (s, 1H).