Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) were added tert-butyl 4-[2-(aminooxy)ethoxy]piperidine-1-carboxylate 71 (0.240 g, 0.543 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 72 (0.276 g, 98%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=614.1)=95%.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:20]3[C:21]4[C:26]([CH:27]=[C:18]([CH3:17])[C:19]=3[CH:9]=[CH:8]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(O)c2ccccc2c1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Product: Cc1cc2ccccc2c2c1C=CC(c1ccccc1)(c1ccccc1)O2

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 3-methyl-1-hydroxynaphthalene was used in place of methyl,1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-5-methyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:6]1[C:7]([O:39][CH2:40][O:41][CH3:42])=[CH:8][C:9]([O:35][CH2:36][O:37][CH3:38])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](S(C)(=O)=O)=[N:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]>CS(C)=O>[CH:3]([C:6]1[C:7]([O:39][CH2:40][O:41][CH3:42])=[CH:8][C:9]([O:35][CH2:36][O:37][CH3:38])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](=[O:1])[NH:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Yield: 95 %

Procedure:
At room temperature, aqueous sodium hydroxide (1.0 M aqueous solution, 5 mL) was added to a dimethylsulfoxide (5 mL) solution of 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methanesulfonyl-[1,2,4]triazole (F652-08, 1.07 g, 1.86 mmol), and the mixture was heated for 3 hours under reflux. An additional aqueous sodium hydroxide (1.0 M aqueous solution, 5 mL) was added, and the mixture was heated under flux for further 1 hour. After returned to room temperature, the reaction mixture was extracted with ethyl acetate and chloroform. The combined extracts were washed twice with water and then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica, chloroform, methanol) to obtain 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (F652-09, pale yellow foam, 900 mg, 95%)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)(O)[O-].[Na+].C(=O)=O.[CH3:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CO.CN(C)C=O>[C:1]([O:5][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]1[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=1[CH3:14])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: Cc1ccccc1OCCCCBr
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CC(=O)OCCCCOc1ccccc1C
Temperature: 40 °C
Yield: 37.2 %

Procedure:
A mixture of 10 g of propiolic acid, 12 g of anhydrous sodium bicarbonate in 150 ml of anhydrous methanol was heated to 40° C. with stirring. When evolution of carbon dioxide ceased, the reaction mixture was cooled to a temperature 10° C. or less. The resultant precipitate was collected and dried under reduced pressure for two days. A mixture of 1 g of the sodium propiolate thus obtained and 2.64 g of 4-(2-methylphenoxy)butyl bromide in 30 ml of anhydrous N,N-dimethylformamide was heated at 110° C. under nitrogen atmosphere for four hours with stirring. After the reaction was completed, the reaction solution was poured into ice-water, and extracted twice with toluene. The combined toluene layer was washed successively with a saturated aqueous ammonium chloride solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.937 g of 4-(2-methylphenoxy)butyl propiolate (compound 10).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]2[C:22]([CH:25]=O)=[CH:23][S:24][C:20]=2[CH:19]=1>>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]2[C:22]([CH2:25][N:15]3[CH2:16][CH:13]([CH2:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:14]3)=[CH:23][S:24][C:20]=2[CH:19]=1
Reactant: O=Cc1csc2cc(Cl)ccc12
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Product: O=S(=O)(CC1CN(Cc2csc3cc(Cl)ccc23)C1)c1ccc(F)cc1

Procedure:
Prepared according to the method of Example 23 using 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 6-chloro-1-benzothiophene-3-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.92–7.88 (2H, m), 7.81 (1H, d, J=1.8 Hz), 7.72 (1H, d, J=8.5 Hz), 7.32 (1H, dd, J=1.9, 8.6 Hz), 7.26–7.22 (2H, m), 7.19 (1H, s), 3.73 (2H, s), 3.44 (2H, t, J=7.5 Hz), 3.37 (2H, d, J=7.3 Hz), 2.92 (2H, t, J=7.1 Hz), 2.87–2.80 (1H, m). m/z (ES+) 394 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>>[F:31][C:28]1([F:30])[O:27][C:26]2[CH:32]=[CH:33][C:23]([N:18]3[CH2:19][CH2:20][N:15]([C:5]4[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[C:6]=4[CH3:14])[CH2:16][CH2:17]3)=[CH:24][C:25]=2[O:29]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc4c(c3)OC(F)(F)O4)CC2)c(C)c2c1OC(C)(C)C2
Yield: 47.9 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference Example 96 and 5-bromo-2,2-difluoro-1,3-benzodioxole (614 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference Example 59 to synthesize 321 mg of the title compound (yield 48%). Melting point was 149 to 151° C. (hexane).
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4]1.[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[O:27])[CH3:26])[CH:15]([CH3:17])[CH3:16].Cl>O.CCO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10](/[CH:12]=[CH:26]/[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:27])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1ccccc1OCC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccccc1C(=O)/C=C/c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask was added EtOH (20 mL) and potassium hydroxide (320.0 mg, 8 mmol). The mixture was stirred until homogeneous before benzo[d][1,3]dioxole-5-carbaldehyde (0.83 mL, 4.0 mmol) and 1-(2-isobutoxyphenyl)ethanone (770 mg, 4 mmol) were added. The reaction was stirred at room temperature for 16 h, and 5 mL of water was added. The reaction mixture was acidified with 1N HCl until pH=6. The resulting orange precipitate was filtered and submitted to the next step without further purification. MS (EI) for C20H20O4: 325 (MH+).
Reaction SMILES: C[N:2]1CCN[CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][C:16]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[C:17]([N+:20]([O-])=O)[C:18]=1Cl)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:18]2[C:17](=[N:20][CH:4]=[CH:3][N:2]=2)[C:16]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[N:15][C:14]=1[CH3:35])=[O:12])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(C)nc(N2CCN(c3ccccc3)CC2)c([N+](=O)[O-])c1Cl
Product: CCOC(=O)c1c(C)nc(N2CCN(c3ccccc3)CC2)c2nccnc12

Procedure:
By substituting N-phenylpiperazine for N-methylpiperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(4-phenyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed as described in Example 1 c-e, 7-methyl-5-(4-phenyl-1piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is formed, m.p. 85°-87° (ligroin).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C:16]2[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=2)[C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CC[C@@H]1NC[C@@H]1NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CC)nc1C
Yield: 83.7 %

Procedure:
The same operation as in Example (232c) was performed using cis(±)-3-(tert-butoxycarbonyl)amino-2-ethylazetidine obtained in Example (235f) (66 mg, 0.33 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (82 mg, 0.33 mmol) and diisopropylethylamine (0.12 mL, 0.66 mmol), to obtain 102 mg of the title compound as a white solid (84%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:34]1([P:40]([CH2:47][SH:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)(=O)C>[C:34]1([P:40]([CH2:47][S:48][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)NCC(=O)O
Reactant: SCP(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCC(=O)SCP(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
N-Acetylglycine (1.90 g, 16.2 mmol) was dissolved in anhydrous DMF (75 mL). HOBt (2.48 g, 16.2 mmol) was added to the resulting solution followed by DCC (3.34 g, 16.2 mmol). Once precipitate (DCU) was observed, phosphinothiol 1b was added (3.77 g, 16.2 mmol). The reaction mixture was allowed to stir under Ar(g) for 3 h. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a white solid. This solid was dissolved in ethyl acetate and purified by flash chromatography (silica gel, ethyl acetate). Compound 51 was isolated in 96% yield. Spectral Data. As reported previously.4b
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[CH2:20]([O:22][CH2:23][CH2:24][C@H:25]1[CH2:30]N[CH2:28][CH2:27][NH:26]1)[CH3:21]>>[CH2:20]([O:22][CH2:23][CH2:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:19]([C:8]2[C:7]3[N:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:30]1)[CH3:21]
Reactant: CCOCC[C@H]1CNCCN1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Product: CCOCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1

Procedure:
In a manner similar to that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.523 g, 1.77 mmol) and (S)-2-(2-ethoxyethyl)piperazine (0.561 g, 3.54 mmol) to obtain the title compound: mass spectrum (APCI): m/z =400.2 (M+1).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].C(O)C.[CH2:15]([N:17]([CH2:20][CH2:21]Cl)[CH2:18][CH3:19])[CH3:16]>[OH-].[Na+]>[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH2:19][N:8]1[C:9]2[C:10](=[O:11])[NH:1][C:2](=[O:3])[NH:4][C:5]=2[N:6]=[CH:7]1)[CH3:16]
Reactant: CCN(CC)CCCl
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Yield: 15 %

Procedure:
Xanthine (30.4 g) was dissolved in aqueous sodium hydroxide solution (8 g in 500 ml) containing ethanol (100 ml). The solution was stirred, and diethylaminoethyl chloride (liberated from its salts) (27.0 g) was added at room temperature. The mixture was stirred on a steam bath for 18 hours, then evaporated to dryness. The residue was fractionally recrystallised from isopropyl alcohol to give 7-(2-diethylaminoethyl)xanthine (7.5 g). The solid was stirred in dry tetrahydrofuran (1 liter) at -15° C. under nitrogen. Butyl lithium (90 ml) was then added by syringe, and the mixture was stirred for 2 hours. Methyl iodide (12.8 g) was then added and the mixture was stirred and allowed to warm to room temperature. It was then stirred overnight, quenched with water and extracted with chloroform. The extracts were then washed, dried, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in ethanol and treated with ethanolic hydrogen chloride, then evaporated to dryness. The residue was recrystallised from isopropyl alcohol to give 8-methyl-7-(2-diethylaminoethyl)theophylline hydrochloride (3.1 g), mp 230°-232° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]1([CH2:19][CH2:20][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(C)(C)C1CCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 88.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3-tert-butylcyclopentanone (750 g, 5.36 mol) and pyrrolidine (362 mg, 5.092 mol) in methanol was refluxed overnight. The reaction mixture was removed in vacuo. The residue was diluted with an equal volume of H2O and then added HCl until pH=1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (0.8 g, 89%). 1H NMR (CDCl3): 0.77 (s, 9H), 1.34 (m, 1H), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, 1H), 7.47 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>CCOCC.CC#N>[I:46][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[N:21]=1
Reactant: II
Reactant: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCO)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CN1CCN(C(=O)OC(C)(C)C)c2nc(CCI)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The mixture of tert-butyl 6-(2-hydroxyethyl)-1-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (5.6 g, 19.09 mmol), triphenylphosphine (6.51 g, 24.82 mmol), imidazole (1.82 g, 26.72 mmol), and a mixture of CH3CN and dry ether (1:1) was cooled to 0° C. Iodine (6.78 g, 26.72 mmol) was slowly added. The resulting mixture was stirred for 2 hour and then ether (150 mL) was added, washed successively with saturated aqueous Na2S2O3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 20% EtOAC/Hex) to afford a yellow solid (6.6 g, 86% yield). H NMR (CDCl3) δ 1.55 (s, 9H), 2.93 (s, 3H), 3.18 (t, 2H), 3.30 (t, 2H), 3.458(t, 2H), 3.85 (t, 2H), 6.85(q, 2H). LC-MS (M+H) 404.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C#N)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C#N)C1

Procedure:
Prepared from the title compound of Step A according to Example 1 Step E using 2-trifluoromethylphenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:15][CH2:14][CH2:13]3)O)[CH:7]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:15][CH2:14][CH2:13]2
Reactant: COc1ccc(CN2CCCc3cc(C(O)c4cc(Br)ccc4Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CN2CCCc3cc(Cc4cc(Br)ccc4Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To an ice cold solution of (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol (2.2 g, 4.7 mmol) in dichloromethane (50 mL) was added Et3SiH (3.7 mL, 23.3 mmol) followed by BF3.OEt2 (1.5 mL, 11.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of aq. NaHCO3. The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with dichloromethane (2×50 mL), washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 6-(5-Bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (1.48 g).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1>CCOCC.[Zn]>[F:15][C:9]([F:16])([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C1(O)CCCCC1
Yield: 69.3 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.01 mmol) in a solution of cyclohexanone (0.491 g, 5.0 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.031 g, 10.01 mmol) in an. THF (5 mL) was sonicated for 4-5 h and then heated to reflux for 1-2 h. The reaction mixture was cooled and diluted with ether and washed with 1 N HCl, satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(1-hydroxycyclohexyl)acetate as a clear oil (770 mg, ˜70%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.37 (q, J=7.2 Hz, 2H), 2.10-2.01 (m, J=3.4 Hz, 1H), 1.82-1.69 (m, 3H), 1.68-1.54 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.20 (br. s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[O:27][CH3:28])C.CS(O[CH2:35][CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)(=O)=O>>[CH3:28][O:27][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:35][CH2:36][C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:3])=[O:29]
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(CCc4cccs4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.07 g (0.18 mmol) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester and 0.05 g (0.25 mmol) of 2-thiophen-2-yl-ethyl methansulfonate. After the standard purification, 0.009 g (10% of yield) of the expected acid was obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([NH2:21])=[NH:20])[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([CH2:25][C:26](=O)[CH3:27])(=O)[CH3:23]>>[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[N:21]=[C:26]([CH3:27])[CH:25]=[C:22]([CH3:23])[N:20]=2)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CC(C)=O
Reactant: N=C(N)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Product: Cc1cc(C)nc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)n1

Procedure:
Using trans-4-(benzyloxycarbonylamino)-1-cyclohexanecarboxamidine hydrochloride (a compound of Reference Example 8-35 (5)) (348 mg) as a starting material, by reacting the same with acetylacetone according to the method of Libman et al. (J. Chem. Soc., p. 2305, 1952), trans-1-benzyloxycarbonylamino-4-(4,6-dimethylpyrimidin-2-yl)cyclohexane (220 mg) was obtained. By treating this compound (205 mg) with trimethylsilyl iodide in the same manner as in Reference Example 8-35 (7), trans-4-(4,6-dimethylpyrimidin-2-yl)cyclohexylamine (Reference Example 8-36 in Table 9) (129 mg) was obtained.