Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[C:38]([CH3:40])[N:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2cc(C)nn2)c(C(=O)O)c1
Product: Cc1ccc(-n2cc(C)nn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting 5-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)benzoic acid. ESI-MS (m/z): 328 [M+1]+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14]=O>O>[CH2:14]1[O:4][C:3]([CH2:2][C:1]([OH:13])=[O:12])([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=O
Solvent: O
Product: O=C(O)CC1(CC(=O)O)OCOC1=O
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Anhydrous citric acid (1), (120 g, 0.625 mole) and paraformaldehyde (21 g, 0.70 mole) were mixed in a beaker which was then immersed in an oil bath preheated to 145° C. The mixture, with intermittent stirring, was held at this temperature for 2 hours. The mixture melted, then resolidified during this time. The cooled mixture was dissolved in a minimal amount of boiling water on the hot plate (total volume ≈225 ml). On cooling, crystals formed. The mixture was kept overnight in the refrigerator, then, the crystals were collected, washed with cold water and dried on the filter using a heat lamp to give 2 (69 g, 53%) as white crystals, mp 205°-207° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH2:9]1.[CH2:35]([C:37]1[S:38][C:39]([C:42]2([OH:49])[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:40][N:41]=1)[CH3:36]>>[CH2:35]([C:37]1[S:38][C:39]([C:42]2([OH:49])[CH2:43][CH2:44][CH:45]([N:8]3[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=5)[N:18]([CH2:29][C:30]([F:31])([F:32])[F:33])[N:17]=4)[CH2:9]3)[CH2:46][CH2:47]2)=[CH:40][N:41]=1)[CH3:36]
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNc1nn(CC(F)(F)F)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CC(F)(F)F)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-(azetidin-3-yl)-2-((1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1H-indazol-3-yl)amino)acetamide TFA salt (as prepared in Example 72, Step A) and 4-(2-ethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>>[OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2cccnc12
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2cccnc2c1O
Temperature: 170 °C
Yield: 79.8 %

Procedure:
8-Hydroxyquinoline (50.0 g) and potassium carbonate (142.8 g) are mixed together in a stainless steel bomb and heated at 170° C. under 1200 p.s.i. CO2 for 7 days. The reaction is then cooled and the resulting solid is partitioned between water (6 L) and EtOAc (1 L). The organic layer is extracted with water (2×300 mL). The combined aqueous layers are extracted with EtOAc (3×500 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and triturated with i-PrOH to yield 51.97 g of the title compound as a tan solid.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:7]([OH:19])[CH:6]=1)C=C.Cl[C:21]1[CH:26]=CC=C[C:22]=1Cl>>[OH:19][C:7]1[C:6]([CH2:26][CH:21]=[CH2:22])=[C:5]([OH:4])[CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)c(O)c1
Product: C=CCc1c(O)ccc(C(=O)c2ccccc2)c1O

Procedure:
Commercially available 4-allyloxy-2-hydroxybenzophenone (15 g) was rearranged by heating under reflux in ortho-dichlorobenzene (60 mL) for 26 hours. The product was isolated by dilution of the reaction mixture with 5 volumes hexanes to give a crystalline product as fine needles.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8]([C:10]1[CH:38]=[CH:37][C:13]([CH2:14][C@@:15]2([CH3:36])[N:19]3[C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:16]2=[O:35])=[CH:12][CH:11]=1)#[N:9]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C@@:15]2([CH3:36])[N:19]3[C:20]([S:23]([NH:2][C@@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])(=[O:25])=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:16]2=[O:35])=[CH:37][CH:38]=1)#[N:9]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)Cl)n21
Reactant: C[C@H](N)C(N)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
L-Alaninamide hydrochloride (0.151 g, 1.209 mmol) was dissolved in anhydrous DMF and DMAP (0.197 g, 1.612 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 h. Then, (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl chloride (0.24 g, 0.484 mmol) in anhydrous DMF was added to the reaction mixture and stirred for additional 10 min. The reaction solution was diluted with EtOAc and washed with water, 1 N HCl and then water. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 0.211 g of the title compound as a white scaly solid (M+1, 547.2).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCc1ccccc1)OCC
Temperature: 185 °C
Yield: 84.1 %

Procedure:
A mixture of 4-phenylbutyl chloride (8.0 g, 47.5 mmole) and triethylphosphite (15.0 ml, 72 mmole) was heated at reflux (bath temperature 185° C.) under argon for 41.5 hours. Distillation of the mixture gave pure diethyl (4-phenylbutyl)phosphonate (10.8 g, 84%) as a colorless liquid, b.p. 152°-154° C. (1.0 mmHg). TLC (EtOAc) single spot Rf =0.55.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](O)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Yield: 84 %

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at -40° C., was slowly added 22.3 g (0.10 mole) of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mMol) of the diamine and 7.08 g (49.2 mMol) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mMol) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mMol)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Anal. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; Cl, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; Cl, 16.77.
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)SCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn2c(n1)SCCC2
Temperature: -70 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Ethyl 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine-2-carboxylate (2.12 g, 10 mmol) was dissolved in dry dichloromethane (40 ml) under argon and cooled to -70%. Diisobutylaluminium hydride (1.5M in toluene, 12 ml, 18 mmol) was added below -68° C. and the reaction mixture stirred at -70° C. for 1 h. Water was added carefully and the cooling removed. The reaction mixture was stirred vigorously at ambient temperature for 15 minutes and Celite (2 g) added. The mixture was filtered through Celite, the filter bed washed with dichloromethane and water, the filtrate and the washings combined and evaporated to dryness under reduced pressure. The residue was evaporated from ethanol (2×) to give the title compound as a white solid (1.31 g, 78%); nmax (CH2Cl2) 1685, 1543 and 1453 cm-1 ; dH (250 MHz; CDCl3) 2.34-2.43 (2H, m); 3.20 (2H, t, J 6 Hz), 4.17 (2H, t, J 6 Hz), 7.58 (1H, s), 9.75 (1H, s).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:9]=[C:10]([C:15]#[C:16][Si](C)(C)C)[C:11]([NH2:14])=[N:12][CH:13]=1>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a 250 ml three necked round bottom flask, potassium tert-butoxide (4.2 g, 0.037 mole) was taken in THF (50 ml). To this, 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine (10.0 g, 0.037 mole) in THF (50 ml) was added dropwise at RT over 20 min under nitrogen atmosphere and the reaction mixture was stirred for 30 min at same temperature and 60 min at 65° C. The completion of the reaction was monitored by TLC using hexanes:ethyl acetate (8:2) as a mobile phase. After completion of the reaction, the reaction mixture was cooled to RT and diluted with ethyl acetate, filtered through high flow. Filtrate was collected and washed with water. The layers were separated and the aq. layer was re-extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 15-20% ethyl acetate in hexanes to yield 4.3 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: C(OC([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O)C.[CH3:24][O:25][CH2:26][CH:27]1[CH2:31]O[C:29](=[O:32])[O:28]1.N1C=CC=CC=1>>[CH3:24][O:25][CH2:26][CH:27]1[O:28][C:29](=[O:32])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:31]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(C2CCN(C(=O)OCC)CC2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(c2ccc(N3CC(COC)OC3=O)cc2)CC1
Reaction time: 18 h
Yield: 76.9 %

Procedure:
1.12 g (3.5 mmol) of ethyl 4-(4-ethoxycarbonylamino-phenyl)-piperidine-1-carboxylate were treated with 4.0 g (30.28 mmol) of (RS)-4-(methoxymethyl)-1,3-dioxolan-2-one in the presence of 276.8 mg (3.5 mmol) of pyridine and stirred intensively for 18 hours at an oil bath temperature of 160°. After cooling the reaction mixture was chromatographed on 125 g of silica gel 60 with ether. After recrystallization from methylene chloride/isopropyl ether there were obtained 976 mg of ethyl (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-piperidine-1-carboxylate. M.p.: 86°-88°.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I)[CH3:8]>N1C=CC=CC=1.[OH-].[NH4+]>[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:4][C:2]([CH3:5])([CH3:3])[CH3:1])[CH3:8]
Reactant: CCNC(=O)c1ccccc1I
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCNC(=O)c1ccccc1OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Potassium t-butoxide (12.25 g, 0.109 mol) was dissolved in pyridine (50 mL) and cuprous chloride (10.81 g, 0.109 mol) was added. The black suspension was stirred at RT for 30 min and N-ethyl-2-iodobenzamide (10.00 g, 36.4 mmol) dissolved in pyridine (20 mL) was added dropwise. The mixture was stirred at room temperature for 1 h and was poured in aq ammonium hydroxide and extracted with ether. The organic extracts were washed with 1N NaOH, brine, dried (MgSO4) and concentrated to afford a brown semi-solid. The crude product was purified by flash chromatography (ethyl acetate/hexanes) to afford the title compound as a light yellow solid (2.36 g, 29%). m.p. 34.5°-36° C.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[F:14][C:15]([F:30])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([CH2:25][C:26](O)=[O:27])[N:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:30][C:15]([F:14])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH:21]=[CH:20][C:19]=2[N:18]([CH2:25][C:26]([NH:1][C:2]2[S:10][C:5]3[CH2:6][O:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:11]([NH2:13])=[O:12])=[O:27])[N:17]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: NC(=O)c1c(N)sc2c1CCOC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2C=CCC3)sc2c1CCOC2
Temperature: 120 °C
Yield: 9 %

Procedure:
2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide (40 mg, 0.20 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-1-yl)acetic acid (50 mg, 0.20 mmol) were dissolved in DCM/DMF (3 mL/50 μL) and polymer supported carbonyldiimidazole (330 mg, 1.2 mmol/g, 0.396 mmol) added. The reaction mixture was heated at 120° C. for 10 min in the microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product as a white solid (7.6 mg, 0.018 mmol, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:24]2[N:20]([CH3:19])[C:21]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:23]=2[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 17.5 g. (0.1 mole) p-chlorobenzoyl chloride and 13.3 g. (0.1 mole) aluminum chloride in 150 ml. of dichloroethane is added rapidly to a solution of 25.3 g. (0.1 mole) of ethyl 1,4-dimethyl-3ethoxycarbonylpyrrole-2-acetate in 100 ml. of refluxing 1,2 -dichloroethane. The solution is refluxed for 3.5 hours and poured into ice-hydrochloric acid. The organic layer is separated, and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The solution is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue product is crystallized from cyclohexane and recrystallized from methanol to give ethyl 5-(p-chlorobenzoyl)-1,4 dimethyl-3 -ethoxycarbonylpyrrole-2-acetate as a white solid, m.p. 91-93° C.
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=4)=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)nc1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (Example 71, Step 1, 0.16 g, 0.38 mmol), 2-chloro-5-ethylpyrimidine (0.1 mL, 0.76 mmol) and K2CO3 (0.26 g, 1.91 mmol) in CH3CN (3 mL) was degassed, purged with N2 and heated at 80° C. overnight. After more CH3CN (2 mL) was added, the reaction mixture was heated at 80° C. for two days. The mixture was allowed to cool to ambient temperature, water was added and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 2:5 EtOAc/CH2Cl2 to give 0.114 g (66%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.5 Hz), 8.20 (bs, 2H), 8.01 (d, 2H, J=8.3 Hz), 7.82 (dd, 1H, Ja=8.7 Hz, Jb=2.6 Hz), 7.70 (d, 2H, J=8.3 Hz), 6.85 (d, 1H, J=8.5 Hz), 4.81 (bs, 2H), 4.24 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 3.05-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH:21]([N-]C(C)C)(C)[CH3:22].[Li+].C(I)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]([CH2:21][CH3:22])([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(CC)C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(7S)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 41f (148 mg, 0.50 mmol) was dissolved in 20 mL of tetrahydrofuran. The reaction solution was cooled down to −78° C. followed by the addition of lithium diisopropylamide (0.5 mL, 1 mmol), stirred for 30 minutes, then added with ethyl iodide (156 mg, 1 mmol) and stirred for another 4 hours. The reaction mixture was added with 50 mL of saturated ammonium chloride solution, concentrated under reduced pressure and and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-chloro-8-cyclopentyl-7,7-diethyl-5-methyl-pteridin-6-one 42a (100 mg, yield: 62.0%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=S)[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O1CCOCC1.C(O)(=O)C.[Ni]>[CH3:1][N:2]([CH2:3][CH:4]([C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:21]
Reactant: COc1ccc(C(C(=S)N(C)C)C2(O)CCCCC2)cc1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1

Procedure:
A solution of N,N-dimethyl-α-(1-hydroxycyclohexyl)-p-methoxyphenylthioacetamide in 5 ml per gram of thioamide in dioxan/acetic acid (9:1) is added to Raney nickel (20 grams per gram of thioamide) in 50 ml per gram of the thioamide of the same solvent at room temperature to 50° C. After 15 minutes to 10 hours the Raney nickel is filtered through kieselguhr and the solvent is evaporated under reduced pressure. The residue is partitioned between 2N sodium hydroxide solution and methylene chloride. The organic phase is dried and the solvent is evaporated. The residue is converted into the hydrochloride salt of the title compound using 4N isopropanolic hydrogen chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.[I:19]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Br)c(C2CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C2CC2)c(Br)cc1I
Yield: 99.2 %

Procedure:
A solution of 5-bromo-6-cyclopropylpyridin-2-amine (2.1 g, 9.81 mmol), trifluoroaceticacid (170 mg, 1.47 mmol), N-iodosuccinimide (2.2 g, 9.81 mmol) stirred at room temperature for 30 minutes. Reaction mass was quenched with water, basified with ammonium hydroxide solution. Solid separated was filtered and dried to get 3.3 g (100% yield) of titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.85 (s, 1H), 4.80-4.65 (bs, 2H), 2.39-2.25 (m, 1H), 1.0-0.90 (m, 4H). MS: m/z=338.9 (M+1).