Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.07 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) bromide and 50 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 14.0 g (0.060 mol) of 2-bromobiphenyl and 1.7 g (0.072 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 30° C. to 35° C. After the dropwise addition was completed, stirring was conducted at a reflux temperature for 4 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain coarse crystals. The coarse crystals were recrystallized from MeOH to obtain 13.2 g (purity: 99.0%) of the aimed di-tert-butyl(2-phenylphenyl)phosphine. The yield was 87.5%. Melting point: 84-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@H:11]([OH:30])[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C=CC[C@@H]12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C[C@H](O)C[C@@H]12
Temperature: 25 °C

Procedure:
0.81 g (3 mmol) of 3-methoxy-13α-estra-1,3,5(10),16-tetraene is dissolved under a cover gas in 10 ml of anhydrous tetrahydrofuran and mixed with 0.73 g of 9-bora-bicyclo[3.3.1]nonane. It is stirred at room temperature until the reaction is completed. Then, it is mixed with 15 ml of water. After gas generation is completed, 7.8 ml of 3 M sodium hydroxide solution is added. 7.8 ml of hydrogen peroxide solution (30%) is then slowly added in drops to the reaction mixture while being cooled. It is stirred for 1 hour at room temperature and extracted with ethyl acetate. The chromatography of the crude product on silica gel (eluant: cyclohexane/ethyl acetate 4+1) yields 604 mg of 3-methoxy-13α-estra-1,3,5(10)-trien-16α-ol in the form of a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C[N:14](C)[CH:15]=[CH:16][C:17]#N.N>O.C(O)CC>[NH2:14][C:15]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:17][CH:16]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=CC#N
Agent: Cl
Agent: N
Solvent: CCCO
Solvent: O
Product: Nc1ccnn1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
7.65 g (50 mmol) of 4-nitrophenylhydrazine was suspended in 70 mL of water and 10 mL of n-propanol and the suspension was heated to about 50° C. At this temperature, 5 g (50 mmol) of concentrated hydrochloric acid and 4.81 g (50 mmol) of 3-dimethylaminoacrylonitrile were then added. After an additional 15 minutes, 3.8 mL (50 mmol) of a 25% ammonia solution was added dropwise within 15 minutes. The reaction mixture was then allowed to agitate at about 50° C. until the 3-dimethylaminoacrylonitrile had completely reacted (about 1 hour) after which the resulting dark-brown suspension was cooled in an ice bath. The precipitate was filtered off, washed 3 times with small portions of cold water and then dried. Yield of crude product: 9.4 g (46 mmol. 92% of the theoretical).
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]([CH3:21])[N:18]2[CH:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:25])[CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.[CH:26]1([CH2:29]Br)[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][O:25][CH:22]([C:15]2[N:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C@H:10]2[N:18]3[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]2)[CH2:23][CH3:24])[CH2:28][CH2:27]1
Reactant: CCC(O)c1ccc2c(n1)N1C(C)CN(C(=O)OC(C)(C)C)CC1C2
Reactant: BrCC1CC1
Product: CCC(OCC1CC1)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene di-trifluoroacetate (32 mg) was made from 6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (52 mg), using cyclopropylmethyl bromide (29 μl) in place of methyl iodide, according to the procedures described in Example 63 to afford the product as a colorless oil. HPLC [Xterra; 50/80; 255 nm] 100%, 1.44 min; MS (ES) 302.1 (MH+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36](Cl)[CH:35]=4)[CH2:29][CH2:28]3)=[O:26])[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.Cl.[H][H]>[Pd].CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:31][CH2:32]3)=[O:26])[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccccc2)CC1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A suspension of 1.0 g (1.72 mmol) of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(3-chlorophenoxy)piperidine oxalate, 0.3 g of 5% palladium on carbon, 40 ml methanol and 0.02 ml of saturated methanolic hydrogen chloride was heated at 50° under 50 psi hydrogen for 4 hours and allowed to cool to room temperature. The mixture was filtered and the methanol evaporated. The residue was dissolved in ether, washed with saturated sodium carbonate and saturated sodium chloride, and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The oxalate was recrystallized from ethanol to provide 0.42 g (45%) of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-phenoxypiperidine oxalate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([CH:24]([CH3:26])[CH3:25])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@H:14]([CH:24]([CH3:26])[CH3:25])[CH2:13]1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (16 mL) dissolved in DCM (200 mL) was placed in a three-neck flask equipped with a stirrer and two addition funnels. One funnel contained DMSO (23 mL) in DCM (100 mL) and the other tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (37 g) in DCM (100 mL). The contents of the flask were cooled to −78° C., and the DMSO solution was added dropwise. After 15 minutes, tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate was added. The reaction mixture was stirred for 30 minutes, and triethylamine (110 mL) was added. The cooling bath was removed, and water (100 mL) was added at room temperature and stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over magnesium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (petroleum ether/ethyl acetate, 15/1) to afford tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[O:11][C:10]=2[C:9]([CH2:21][CH2:22][CH3:23])=[C:8]2[C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][CH2:7]2.[I-].[Li+].Cl>[OH-].[K+].O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:21][CH2:22][CH3:23])=[C:8]2[C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)OC)oc13)C(=O)CCC2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)C(=O)CCC2
Yield: 82.9 %

Procedure:
The product from step (b) (200 mg; 0.61 mmole) in potassium hydroxide dried pyridine (5 ml) was heated on a steam bath with anhydrous lithium iodide (1 g; 7.5 mmole) for 1 hour. The mixture was cooled and concentrated hydrochloric acid diluted with an equal volume of water was added until the resulting suspension was at pH2. The product was extracted with ethylacetate, washed with water and dried (anhydrous sodium sulphate) to yield a red solid which was recrystallised from ethanol to give the title compound as red crystals (160 mg; 80%) mp 244° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](O)([CH3:14])[CH3:13])=[N:7][N:6]=[CH:5]2.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([F:22])([CH3:14])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CC(C)(O)c1nncc2cc(Cl)ccc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1nncc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 2-(6-chlorophthalazin-1-yl)propan-2-ol (154 mg, 0.69 mmol) in 5 mL of DCM at −78° C. was treated with DAST (0.11 mL, 0.76 mmol) slowly. It was warmed slowly to room temperature overnight, then quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The DCM layer was dried over MgSO4, filtered and concentrated. Purification on an ISCO (12 g column, 10-35% EtOAc:Hexanes) afforded 6-chloro-1-(2-fluoropropan-2-yl)phthalazine (84 mg, 54% yield) as a pale yellow, viscous oil. MS (ESI, pos. ion) m/z: 225.1 (M+1).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:21])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:21])=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)OCc2ccccn2)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)OCc2ccccn2)cc1Cl

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl]pyrimidine (prepared in Example 81) 0.1500 g is treated with m-chloroperbenzoic acid (80%) 78.9 mg at 0° C. for 15 minutes. Piperazine 0.2398 g is added thereto. The reaction mixture is treated in the same manner as Example 82-(1). The resulting residue is purified with silica gel chromatography (solvent; ethyl acetate sole-ethyl acetate:methanol=1:1) and recrystallized from ethyl acetate:isopropyl ether (1:1) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl)pyrimidine as a colorless powder, 75.1 mg. mp 101-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11]([NH2:13])[CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH2:7][NH:13][CH2:11][CH3:12]
Reactant: CCN
Reactant: O=Cc1cc(Br)ccc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-2-iodo-benzaldehyde (15.0 g, 48.3 mmol) in methanol (60 mL) was added ethylamine (2.0M in methanol; 48 mL, 72.0 mmol), followed by acetic acid (3.0 mL, 53.4 mmol), and the mixture was stirred at room temperature for 30 minutes, after which a precipitate formed. Sodium cyanoborohydride (6.00 g, 95.4 mmol) was then added in 3 portions and the precipitate disappeared. The reaction was stirred at room temperature for 24 hours then quenched with saturated aqueous sodium bicarbonate. The resulting mixture was evaporated then diluted with dichloromethane and washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-4% methanol in dichloromethane) to give the title compound.
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:38]=[CH:37][C:18]2[N:19]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH2:20][CH2:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.[Li+].C[Si]([N-:44][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:17]3[CH:16]=[C:15]([NH2:44])[CH:38]=[CH:37][C:18]2=3)[CH2:29][CH2:28]1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(Br)ccc32)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(N)ccc32)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of Pd2(dba)3 (0.107 g, 0.1172 mmol) in dry THF (5 mL) was treated with PtBu3 (10% in Hexanes, 1.42 mL, 0.4688 mmol). The mixture was then treated with compound 3 (0.9594 g, 2.344 mmol) in dry THF (15 mL) and LiHMDS (4.69 mL, 4.688 mmol) at room temperature. The solution was stirred at 100° C. for 3 hours. At room temperature, the solution was quenched with 1M TBAF in THF solution (5 mL) and was stirred for 20 minutes. The reaction was the diluted with 3N NaOH solution (50 mL) and was extracted with ethyl acetate (150 mL). The organic layer was dried (Na2SO4) and was concentrated. The crude product was subject to flash chromatography on silica gel using 2.5% 2M NH3 methanol/CH2Cl2, which resulted in a dark brown foam, compound 4 (0.691 g, 85%). 1H NMR (CDCl3) δ 6.79 (d, J=5.1 Hz, 1H), 6.51-6.44 (m, 2H), 4.06-4.03 (m, 2H), 3.56-3.51 (m, 1H), 3.28 (tt, J=7.2, 21.3 Hz, 1H), 2.92-2.77 (m, 4H), 2.68-2.64 (m, 2H), 1.82 (d, J=11.1 Hz, 2H), 1.66-1.40 (m, 7H), 1.36 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([CH3:13])[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:7][C:8]2[N:12]([CH3:13])[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:24]2[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)(C)C)c1
Reactant: Cn1c(CC2CCCCC2)ccc1S(N)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1CC1CCCCC1
Temperature: 110 °C
Yield: 39.4 %

Procedure:
A mixture of compound 25e (67.1 mg, 200 μmol), 2-(3,5-di-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (72.8 mg, 230 μmol), Cs2CO3 (326 mg, 1.0 mmol) and Pd(dppf)Cl2 (22 mg) in dioxane and water was heated at 110° C. under microwave irradiation for 1 h. The solvent was removed and purified by prep-TLC to afford compound 25 (35 mg, 40%) as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 7.43 (t, J=1.5 Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=1.5 Hz, 1H), 4.68 (s, 2H), 3.44 (s, 3H), 2.49 (d, J=7.8 Hz, 2H), 1.55-1.41 (m, 6H), 1.34 (s, 18H), 1.00-0.98 (m, 3H), 0.69-0.65 (m, 2H). MS Calcd.: 444.3; MS Found: 445.3 (M+1).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)C12CC1CCC2=O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
In argon atmosphere, potassium cyanide (260 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to hexamethylphosphoric triamide (3 ml). The mixture was stirred at the room temperature for 24 hours and was treated in accordance with the process of Preparation 4 to obtain 300 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 55%.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:27]>C(#N)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(CC(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 11.7 g. (50 mmole) ethyl 4-(piperazin-1-yl)-benzoate, 13.8 g. (0.1 mole) powdered anhydrous potassium carbonate, 125 ml. acetonitrile and 11.7 g. (50 mmole) 2-bromo-4'-chloroacetophenone (p-chlorophenacyl bromide) is stirred for 20 hours at 20° C. The reaction mixture is then suction filtered and the filter cake is washed with acetone. The combined organic phases are evaporated to dryness in a vacuum to give 15.4 g. (80% of theory) of crude product. After recrystallisation from ethyl acetate, there are obtained 9.8 g. (51% of theory) of pure product; m.p. 152°-153° C. and from the mother liquor a further 1.4 g. (7% of theory) (m.p. 150°-152° C.) of product are obtained.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Na+].Cl>>[C:12]([C:4]1[CH:3]=[C:2]([SH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)([OH:14])=[O:13]
Reactant: COC(=O)c1cc(S)n2nc(C)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2nc(C(=O)O)cc(S)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 7.7 g (34 mmole) of 7-mercapto-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 70 ml of a 2N NaOH was stirred at room temperature for 2 hours and then ice-cooled. The pH of the mixture was adjusted to 2 with 6N HCl. The precipitates were collected by filtration and washed with water and then acetone, followed by drying, to obtain 7.08 g of the title compound (Yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:30]=1)[C:20](=[O:29])[C:21]([C:24](OCC)=[O:25])=[CH:22][N:23]=2.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:24]([C:21]2[C:20](=[O:29])[N:19]3[CH:30]=[C:15]([I:14])[CH:16]=[CH:17][C:18]3=[N:23][CH:22]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a solution of 4-chlorobenzylamine (0.071 mL) in toluene (1.5 mL) at 0° C. is added trimethylaluminum (2M solution in toluene, 0.29 mL). After stirring the solution at 0° C. for 5 min, ethyl 7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (Preparation 2, 200 mg) is added. The solution is stirred at 0° C. for an additional 10 min, then allowed to stir at room temperature overnight. The reaction mixture is poured into 3 N HCl (7.5 mL) and water, then extracted with CH2Cl2 (3×). The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford a solid. The impurities are removed by dissolving the crude product in CH2Cl2 and filtering the insoluble solid. The filtrated is concentrated to afford 148 mg (58%) of title compound as a yellow solid. Physical characteristics: m.p. 191-194° C.; 1H NMR (300 MHz, DMSO-d6) δ9.36, 9.27, 9.03, 8.38, 7.68, 7.40, 4.57; IR (drift) 3319, 1683, 1637, 1612, 1560, 1541, 1507, 1478, 1347, 1339, 1295, 837, 792, 641, 625 cm−1; MS (ESI+) m/z 440 (M+H)+; Anal. found: C, 43.58; H, 2.48; N, 9.38.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.C(OC(CCC=C(C)C)(C=C)C)(=[O:14])C.CC(=CCC/C(=C/CO)/C)C.C(OC1CCCCC1C(C)(C)C)(=O)C.OC/C=C(/C)\CCC=C(C)C.C(OCC1C=CC=CC=1)(=O)C>>[CH3:5][C:3]1[CH2:6][CH2:7][C:8]([OH:14])([CH:9]([CH3:11])[CH3:10])[CH2:1][CH:2]=1
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(=O)OC1CCCCC1C(C)(C)C
Agent: CC(C)=CCC/C(C)=C/CO
Agent: CC(C)=CCC/C(C)=C\CO
Solvent: CC(=O)OCc1ccccc1
Product: CC1=CCC(O)(C(C)C)CC1

Procedure:
linalool; linalyl acetate; geraniol; nerol 2-(1,1-dimethylethyl)cyclohexanol acetate; benzyl acetate; terpenes (orange)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[O:25]=[C:26]([CH3:30])[C:27](O)=[O:28]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[C:27]([OH:28])[C:26](=[O:25])[CH3:30]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: CC(=O)C(=O)O
Product: CSc1ccc(/C=C2/C(C)=C(CCON=C(O)C(C)=O)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2-oxopropionic acid by the method of Example 1.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[N:13](C)[C:12](=[O:21])[CH:11]([C@H:22]3[CH2:27][CH2:26][C@H:25]([N:28]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:24][CH2:23]3)[O:10][C:9]2=1>ClCCl.CO>[NH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH:11]2[O:10][C:9]3[C:8]4[C:17](=[CH:18][CH:19]=[C:6]([O:5][CH3:4])[N:7]=4)[N:16]=[CH:15][C:14]=3[NH:13][C:12]2=[O:21])[CH2:23][CH2:24]1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)C(=O)N3C
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrazine hydrate (2M solution in methanol, 3.56 mL, 7.12 mmol, 8.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (420 mg, 0.89 mmol, 1.0 eq) in dichloromethane (10 mL) and methanol (20 mL). After 16 hours stirring at room temperature and 2 hours stirring at 55° C., solvent is removed and the residue is purified by preparative HPLC to afford 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one as a light grey solid (160 mg, 56% yield).