Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[CH:16][CH:15]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu]I.CS(C)=O>[CH3:11][N:7]1[C:6]2[CH:12]=[C:2]([N:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]4[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:21][C:22]3=[O:26])[CH:3]=[CH:4][C:5]=2[N:9]=[C:8]1[CH3:10]
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cc1nc2ccc(Br)cc2n1C
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
A mixture of 6-bromo-1,2-dimethyl-1H-benzimidazole (500 mg), 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (487 mg), CuI (423 mg), N,N′-dimethyl-1,2-ethanediamine (0.236 ml), potassium carbonate (921 mg) and DMSO (10 ml) was stirred at 150° C. for 1 h. 28% NH3 solution was added to the resulting mixture, and the solid was washed with water. The solid was purified by NH silica gel column chromatography (hexane/EtOAc), followed by recrystallization from EtOAc-hexane to give the title compound (200 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]2SCCCS2)[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:33]([CH3:35])[CH3:34])[S:14]2)[C@H:10]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:45].[Ca+2].CI>CC(C)=O.O.ClCCl>[CH2:26]([O:25][C@H:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:33]([CH3:35])[CH3:34])[S:14]2)[C@@H:10]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:19]=[O:45])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](OCc3ccccc3)C3SCCCS3)O[C@@H]2S1
Agent: [Ca+2]
Solvent: CI
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](C=O)OCc3ccccc3)O[C@@H]2S1
Reaction time: 20 h

Procedure:
To a solution of 97 (3 g, 4.7 mmol) in acetone (16 mL) and water (4 mL) was added CaCO3 (4.7 g, 47 mmol) and CH3I (13.2 g, 94 mmol). After kept 20 hours at 50° C., the resulting solution was diluted with dichloromethane (30 mL), filtered and extracted with dichloromethane (2×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude 98, which was used in next step directly; (ES, m/z) [M+H]+ 547.0.
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% PMCD solution (0.01 M phosphate buffer, pH 7.0) and a solution of 0.1% 1α-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of PMCD relative to 1 mol of 1α-hydroxytvitamin D3). After cultivation for a further 2 hours, methylene chloride was added to the flask, and analysis was carried out according to the method as described in Example 3. The peak fraction having a retention time of 12 minutes was collected, concentrated at 40° C. or below under reduced pressure and applied to HPLC on Zorbax ODS column (4.6 mm×25 cm, made by Du Pont Co., USA) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak fraction having a retention time of 5.6 minutes was collected and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 650 μg (65% of the conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. On the other hand, following the same procedure as above but without PMCD, the amount of 25-hydroxyvitamin D3 obtained was 350 μg/ml (35% of the conversion ratio from the material).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25](=O)[CH3:26])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[CH2:51]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([NH:67][NH2:68])[CH2:63][CH2:62]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH2:51]([O:58][C:59]([N:61]1[CH2:62][CH2:63][CH:64]([N:67]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[CH:24][C:25]([CH3:26])=[N:68]2)[CH2:65][CH2:66]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(C)=O
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 308d, (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192f) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and 4-hydrazino-piperidine-1-carboxylic acid benzyl ester (CAS Reg. No. 280111-51-5) to give the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:6][CH:7]=1)[NH2:16]
Reactant: NN
Reactant: Cc1nccn1-c1ccc(Cl)nn1
Solvent: O
Product: Cc1nccn1-c1ccc(NN)nn1

Procedure:
6.7 g (35 millimoles) of 3-chloro-6-(2-methyl-imidazol-1-yl)-pyridazine are taken up in 30 ml of hydrazine hydrate and the mixture is heated for 5-10 hours at 100°-130° C. under nitrogen as a protective gas; the reaction mixture becomes homogeneous in the course of the first few hours. When the mixture has cooled, the crude product which has precipitated is filtered off. It is also possible to pour the reaction mixture into ice water and extract the mixture repeatedly with methylene chloride. Continuous extraction by means of a rotary perforator, using methylene chloride or chloroform as the extraction solvents, has also proved an advantageous method. Yet a further possibility is to distil off the hydrazine hydrate under reduced pressure.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:17]([Br:22])[N:18]3[CH3:21])=[CH:14][CH:13]=2)=[O:11])[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].C(O)(=O)C>C(O)CC.O>[Br:22][C:17]1[N:18]([CH3:21])[C:19]2[C:15]([C:16]=1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:5]1([C:3]([OH:4])=[O:2])[CH2:8][CH2:7][CH2:6]1)=[O:11])[CH:20]=2
Reactant: COC(=O)C1(NC(=O)c2ccc3c(C4CCCC4)c(Br)n(C)c3c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(Br)c(C2CCCC2)c2ccc(C(=O)NC3(C(=O)O)CCC3)cc21
Temperature: 89 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid methyl ester (20.00 g, 46.15 mmol) in n-propanol (100 mL) and water (100 mL) was added 50% NaOH (4.06 g, 50.77 mmol). The mixture was heated at 89° C. until no starting material was left (0.5 h). The clear solution was cooled to 50° C. and acetic acid (4.23 mL, 73.85 mmol) was added dropwise to adjust the pH to 5-6. The product was precipitated as a white solid. The suspension was brought to reflux for 0.5 h and then allowed to cool to room temperature in no less than 1 h. The solid was collected by filtration, washed by 1:1 water/n-propanol (100 mL) and water (200 mL). The 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino}-cyclobutanecarboxylic acid, obtained as a white solid was dried under vacuum until constant weight (17.78 g, 97%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].Cl.N1C=CC=CC=1>O>[CH2:11]([C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CCCc1c(OC)cccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(O)cccc1O
Temperature: 180 °C
Reaction time: 7.5 h
Yield: 133.1 %

Procedure:
A mixture of solid 1,3-dimethoxy-2-propylbenzene (33.70 g, 190 mmol) and solid pyridine hyrochloride (150 g, 1.30 mol) were warmed to 180° C. After 7.5 hours, the reaction was cooled to 110° C. and 50 mL of H2O was added slowly. After the reaction cooled to room temperature, it was diluted with 100 mL of water and extracted several times with EtOAc. The EtOAc extract was washed once with 2N HCl and then dried over MgSO4. Filtration and solvent removal gave 38.5 g of an orange solid. The product was purified by recrystallization from dichloromethane providing 11.86 g (41%) of yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47]>ClCCl.O>[C:21]1(=[O:30])[N:20]([CH2:19][C:18]([N:10]2[C@@H:11]3[CH2:17][CH2:16][CH2:15][C@@H:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:45](=[O:48])[CH2:46][CH3:47])=[CH:37][CH:36]=3)[C:8]3[CH:35]=[CH:34][CH:33]=[CH:32][C:9]2=3)=[O:31])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a suspension of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one (148 mg, 0.3 mmol) and triethylamine (50 μL, 0.36 mmol) in dichloromethane (3 mL) was added propionyl chloride (28 μL, 0.33 mmol) and the mixture was stirred at room temperature for 10 minutes. This reaction mixture was diluted with water and stirred. The aqueous layer was separated and the organic layer was dried over NaSO4 and concentrated under reduced pressure. The residue was crystallized from dichloromethane-ethanol-diethyl ether to provide 131 mg (yield 79%) of the title compound. m.p. 286.0°-286.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20]CC2C=CC=CC=2)[N:7]=1.Cl>CO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1
Reactant: COC(=O)COc1cc(C)n(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)COc1cc(C)n(Cc2cc(Cl)ccc2O)n1

Procedure:
A solution of [1-(2-benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazol-3-yloxy]-acetic acid methyl ester, 8, (1.19 g, 2.97 mmol), PtO2 (0.17 g) and conc. HCl (2 ml) in MeOH was stirred under a H2 atmosphere for 3 hours. The catalyst was removed by filtration, the volatiles were removed in vacuo and the crude product was purified on silica to yield [1-(5-chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-3-yloxy]-acetic acid methyl ester, 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[N:4]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)nc(CCCO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)nc(CCCOS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4,6-dimethoxypyrimidin-2-yl)propan-1-ol (100 mg, 0.50 mmol) in DCM (2.0 mL), Et3N (0.21 mL, 1.51 mmol) was added. After stirring for 5 min at rt, the reaction mixture was cooled to 0° C. and methansulfonylchloride (0.05 mL, 0.61 mmol) was added. The reaction mixture was stirred for 10 min at 0° C. and for 20 min at rt, then poured onto ice water. The aq. layer was extracted with DCM, the org. layer was washed with 1 N aq. HCl-solution followed by sat. NaHCO3-solution, then dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the tiltle compound as a yellow oil which was used immediately in the next step. The LC-MS conditions B: tR=0.60 min, [M+H]+=277.09.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[H-].[Na+].[NH2:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1>O1CCOCC1>[NH2:10][C:11]1[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: CC(O)CN(C)C
Reactant: N#Cc1ncc(N)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CN(C)C)Oc1nc(N)cnc1C#N
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1-(Dimethylamino)propan-2-ol (187 mg, 1.81 mmol) was added to a stirred suspension of sodium hydride (123 mg, 60% in mineral oil, 1.81 mmol) in 1,4-dioxane. After 30 minutes, 5-amino-3-chloropyrazine-2-carbonitrile (140 mg, 0.906 mmol) was added. The vial was capped and the reaction mixture was heated to 100° C. overnight. The reaction mixture was concentrated, diluted with methanol and adsorbed onto an SPE (TsOH) cartridge (pre-conditioned with methanol). The cartridge was rinsed with methanol and the product was eluted with 2 M NH3 in methanol. The basic fractions were concentrated to give the title compound as an orange oil which was used without further purification (79.2 mg, 0.358 mmol, 40%). LC-MS (1) Rt=1.33 m/z (ESI+) 222 (MH+).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
Methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate (7.11 g) is reacted with 3.61 g of 4-chlorothiophenol in methanol, as in Example 16, to give a yellow oil which is bulb distilled at 0.01 mm to afford a colorless oil (188° C.) which solidifies to give white crystals, mp 71°-75° C. A portion is recrystallized from hexane to give white needles, mp 74°-75.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([Cl:14])[CH:5]=[C:6]([CH:11](Cl)[CH3:12])[C:7]=1[O:8][CH2:9][CH3:10].[CH3:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH2:26])[NH:19][N:18]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([CH:11]([N:19]2[C:20]3=[N:21][CH:22]=[N:23][C:24]([NH2:26])=[C:25]3[C:17]([CH3:16])=[N:18]2)[CH3:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[CH3:15]
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C)c1Br
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-ethoxy-2-methylbenzene (150 mg, 0.50 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol), potassium iodide (9 mg, 0.05 mmol) and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) was stirred at 140° C. for 1 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2 (103 mg, 50%). LCMS calculated for C17H20BrClN5O (M+H)+: m/z=423.1; Found: 423.0. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 4% ethanol in hexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide two enantiomers. Peak 1, retention time: 8.64 min; Peak 2, retention time: 10.64 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CN(C)C=O.ClC(Cl)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:20][C:21]([CH3:22])=[O:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)COC(=O)C(C)c1ccc(O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
After 49.9 g of 4-hydroxyphenylpropionic acid was dissolved in 160 ml of dimethylformamide, 21.8 g of potassium carbonate was added to the solution at room temperature. Then 29.1 g of monochloroacetone was added dropwise to the solution at 60° C. and the reaction with 4-hydroxyphenylpropionic acid was carried out at 80°-90° C. for 1 hour. After the reaction, dimethylformamide was distilled off from the reaction solution to give a residue. After the residue was dissolved in dichloroethane, the solution was washed with water. The layer of dichloroethane was removed and the solvent was distilled off to give 64.7 g (yield 97%) of acetonyl 4-hydroxyphenylpropionate. After recrystallization from isopropylether, the product was a colorless crystalline material having a melting point of 64.5° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH2:24]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[CH:23]=[CH2:22]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: C=CCBr
Product: C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 64.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and allyl bromide were reacted by the same way with the example 45-1 to obtain the titled compound (211 mg, yield: 64.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CCN(C(C)C)C(C)C.[N:52]1[CH:57]=[CH:56][C:55]([CH:58]([CH3:61])[CH2:59][NH2:60])=[CH:54][CH:53]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:60][CH2:59][CH:58]([C:55]3[CH:56]=[CH:57][N:52]=[CH:53][CH:54]=3)[CH3:61])=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccncc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNC(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (0.350 g, 0.882 mmol), 1-hydroxybenzotriazole (0.149 g, 1.103 mmol), and EDC (0.211 g, 1.103 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir at room temperature for 15 minutes before adding Hunig's Base (0.321 mL, 1.838 mmol) and 2-(pyridin-4-yl)propan-1-amine (0.100 g, 0.735 mmol) as a 2 mL DCM solution. The reaction was allowed to stir overnight. The reaction was dissolved in water and ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride. It was then dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in ethyl acetate to obtain product. (Yield: 151 mg) 1H-NMR (500 MHz, CDCl3) 8.59-8.51, 7.65, 7.34, 7.22-7.12, 7.06-6.99, 6.62, 5.46, 5.31, 4.69-4.03, 3.64-3.53, 3.36-3.27, 3.06-2.95, 2.89-2.78, 2.23-2.13, 1.87-1.25
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[N:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27]1)[C:21]#[N:22]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 21.6 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (150 mg, 0.684 mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (140 mg, 0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a clear dark brown solution. It was cooled to room temperature, diluted with DMSO (2 mL) and purified using preparative HPLC (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions containing product were concentrated in vacuo and crystallized with water (3 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (60.2 mg, 0.148 mmol, 21.65% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.03 (m, 3H) 2.11-2.24 (m, 1H) 2.44-2.49 (m, 4H) 3.07-3.22 (m, 4H) 3.34-3.42 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.03 (m, 1H) 6.97 (d, J=2.02 Hz, 1H) 7.11 (t, J=8.72 Hz, 1H) 7.56 (dd, J=8.46, 1.64 Hz, 1H) 7.61 (d, J=2.02 Hz, 1H) 7.69 (dd, J=13.39, 2.02 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C22H23FN6O, 407. found, 407; melting point 226° C.