Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:8]=[N:9][NH:10][N:11]=2)=[C:5]([C:12]2[CH:40]=[CH:39][C:15]([C:16]([N:18]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:17])=[CH:14][CH:13]=2)[CH:4]=[N:3]1.Cl.O1CCOCC1>CO>[CH3:25][C:24]1[C:19]([N:18]([C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[C:16](=[O:17])[C:15]2[CH:39]=[CH:40][C:12]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[C:7]3[N:8]=[N:9][NH:10][N:11]=3)=[CH:13][CH:14]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2-c2nn[nH]n2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2-c2nn[nH]n2)cc1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
Preparation 25, tert-butyl (3R)-3-(4-(1-methyl-5-(2H-tetrazol-5-yl)-1H-pyrazol-4-yl)-N-(3-methylpyridin-2-yl)benzamido)piperidine-1-carboxylate (100 mg, 0.185 mmol) was dissolved in methanol (0.925 mL). To this was added HCl in dioxane (0.694 mL, 4M solution, 2.78 mmol) at room temperature. The reaction was stirred at room temperature. After 2 h, reaction was concentrated under reduced pressure, and then concentrated with toluene (3×10 mL). The crude material was triturated with EtOAc/MeOH (20:1) and filtered to afford N-(3-methylpyridin-2-yl)-4-[1-methyl-5-(2H-tetrazol-5-yl)-1H-pyrazol-4-yl]-N-[(3R)-piperidin-3-yl]benzamide (89.3 mg, 94%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Brc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(Br)cccc32)nc(N2CCOCC2)cc1=O
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 352 mg of 4-bromoindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 201 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 161 mg of 2-[2-(4-bromo-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Li][Li].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(C)=O>[CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li][Li]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
A mixture of the title compound of Example 2, 2-ethyl-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-oxy]-4-quinolinecarboxylic acid, dilithium salt (700 mg, 1.6 mmol), triethyl amine (245 microliters, 1.76 mmol), triphenylmethyl chloride (468 mg, 1.68 mmol) and acetone (8 mL) was stirred at room temperature for 36 hours. The mixture was concentrated in vacuo to yield the crude product as a waxy solid (1.35 g, 100%).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CN([CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][CH:11]=1)C.COS(OC)(=O)=O>CCO>[N+:19]([C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH:4]([N+:1]([O-:3])=[O:2])[CH3:5])([O-:21])=[O:20]
Reactant: CN(C)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC[N+](=O)[O-]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: CC(Cc1c[nH]c2ccc([N+](=O)[O-])cc12)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 0.3 g (0.013 mole) of Na in 65 ml of abs EtOH was added 2.93 g (0.039 mole) of nitroethane dropwise. To the white suspension was added 2.19 g (0.01 mole) of 5-nitrogramine suspended in 40 ml of abs EtOH, followed by 2.5 g (0.02 mole) of dimethylsulfate in 20 ml of abs EtOH dropwise over 15 minutes. The mixture was stirred for 2 hours, then poured into 350 ml of ice water. The yellow solid was filtered, washed with ice water and air-dried to give 1.63 g (64%) of product: m.p. 130-131.5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 6-chlorohexan-1-ol (25.0 g, 0.183 mol) in dichloromethane (DCM) (166 ml) and pyridine (33 ml) was cooled to −5° C. Toluene-p-sulphonyl chloride (40.1 g, 0.210 mol) was slowly added to the stirred solution and left to react overnight. The reaction mixture was treated with ice (80 g) and left stirring for 1 h. The organic layer was washed with ice cold 2M-sulphuric acid and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder 40.20 g, 85%; mp 27-28° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1
Yield: 10.8 %

Procedure:
Using 5.00 g of (4-nitrobenzyl)malononitrile, 60 ml of N,N-di-methylformamide, 1.10 g of sodium hydride (60% in oil), and 4.85 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.80 g of 2-(4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (18)).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[NH2:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[CH:31]=[N:32][C:27]([NH2:26])=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Nc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Yield: 58 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45 mmol), Pd(Ph3P)2Cl2 (15 mg), and aqueous Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13]C)=O)[CH2:7][C:6]=2[CH:15]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:13])[CH2:7][C:6]=2[CH:15]=1
Reactant: C=CCN
Reactant: COC(=O)C1COc2ccc(Cl)cc2C1
Solvent: ClCCl
Solvent: CCO
Product: C=CCNC(=O)C1COc2ccc(Cl)cc2C1

Procedure:
A mixture of 500 mg of 6C, 5 ml of 2-propenamine and 25 ml of ethanol was refluxed for 18 hours. The sovlent was then stripped off and the residue was taken up in methylene chloride, triturated with hexane and cooled to give a solid. The solid was redissolved in ethanol, the solution was passed through a short silica gel column and the eluent was stripped of solvent. The residue was recrystallized from methylene chloride/hexane to give 6, as white needles, mp: 171°-171.5° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClCC1CO1
Product: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Yield: 69.7 %

Procedure:
4.93 g (0.25 mol) of dibenzylamine and 25.4 g (0.275 mol) of epichlorohydrin are stirred for 3 hours under nitrogen at 85° to 90° C. The golden yellow oil obtained is distilled under a high vacuum. 50.5 g (70%) of a colourless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@@H:4]1[CH2:14][OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@H:4]1[CH2:14][O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
A mixture of the above alcohol (621 g) and sodium hydride (141 mg, 60% dispersion in oil) and benzyl bromide (0.41 ml) in dry N,N-dimethylformamide (2.5 ml) was stirred for 10 hrs at room temperature. After the mixture was cooled to 0° C., the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave benzyl [(1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)cyclohexyl]methyl ether (726 mg, 83% yield).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:18][N:17]=[CH:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Temperature: 14 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution of tert-butyl 4-formylpiperidine-1-carboxylate (50.0 g, 234 mmol) in MeOH (200 mL) and water (200 mL) was cooled in an ice-bath and then hydroxylamine hydrochloride (19.5 g, 272 mmol) and sodium carbonate (12.4 g, 117 mmol) were added. The resulting mixture was stirred at 13-15° C. overnight. The solution was concentrated in vacuo to an aqueous suspension, which was extracted with EtOAc. The organic extract was washed with 100 mL brine, dried (MgSO4), filtered, concentrated to provide tert-butyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (53.1 g, 99.2% yield) as a white crystalline solid.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>CN(C=O)C>[F:12][C:7]1[CH:6]=[C:5]([C:2]#[N:3])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1F
Temperature: 150 °C
Yield: 58 %

Procedure:
Copper(I) cyanide (Aldrich, 3.6 g, 40 mmol) was added to a solution of 4-bromo-2-fluorotoluene (Aldrich, 5 g, 27 mmol) in DMF (60 ml). The reaction mixture was heated at 150° C. for 11 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc (500 ml each). The organic layer was dried (MgSO4), and solvent was removed under vacuum to give the title compound (2.08, 58%). 1H NMR (CDCl3) δ 2.36 (s, 3H), 7.30 (m, 3H), 7.35 (d, 1H, J=8.1 Hz).
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[F:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>>[F:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:57]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 76 mg, 0.37 mmol) except this was purified by column chromatography (0 to 50% ethyl acetate/petrol) followed by a trituration in pentane/diethyl ether to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:17][CH:16](C(=O)N)[N:15]2[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](CCC)=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)[C:44]([OH:46])=O>ClCCl>[CH2:8]([NH:7][C:44]([C:23]1[N:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:31][C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[F:40])[CH2:13][C:14]=12)=[O:46])[CH2:9][CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2C(N)=O
Solvent: ClCCl
Product: CCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
(R)-[3-(1-Propylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, 0.118 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (270 mg, 2.37 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 1 hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid propylamide 44 (25 mg, yield 43.1%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@@H]1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH2:28][C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.2 mg, 75%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH2:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH:24]=[CH2:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(NC2CCNCC2)cc1
Reactant: C=CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine, 12 parts of N,N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts of benzene. Upon completion, the whole is stirred first for 20 h. 30 at room temperature and further for 40 minutes at reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated charcoal. The latter is filtered off and the 1,1'-oxybisethane is evaporated again, yielding 2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidinamine; mp. 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[O:13][C:14](=[O:15])[C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.[CH3:23][NH2:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:16])[NH:24][CH3:23])[C:6]([C:14]([OH:13])=[O:15])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN
Reactant: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-9-phenylfuro[3,4-b]quinoline-1,3-dione (100 mg, 0.32 mmol, 1 eq) in THF (2 ml) was added methyl amine (2M in THF, 807 μl, 1.61 mmol, 5 eq) and the reaction mixture was stirred overnight. The resultant precipitate was filtered and washed with ether. The solid was purified by flash column chromatography (10% AcOH in ethyl acetate) to give the title compound as a white solid. MS (ESI): 338.9 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:27]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)=[O:28])[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
In 40 ml of dichloromethane, are dissolved 2.3 g (0.01 mole) of 1-(3-trifluoromethylphenyl)piperazine and 1.0 g (0.01 mole) of triethylamine. To the resulting solution, while being cooled and stirred, is added dropwise a solution of 1.05 g (0.01 mole) of cyclopropanecarbonyl chloride in 10 ml of dichloromethane. The mixture is allowed to react at room temperature for 3 hours. The reaction mixture is washed successively with water, dilute hydrochloric acid and water, then dried over anhydrous sodium sulfate, and removed of the solvent by distillation to obtain oily 1-(cyclopropanecarbonyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:16]=[N:15][C:14]1=2>C(#N)C>[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24]([NH:11][CH2:1][C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:25])[CH:16]=[N:15][C:14]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
0.500 g (3.31 mmol) of piperonylamine was placed into a 10 ml round bottom flask with a magnetic stirring bar and heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring amine. The solution was heated for 40 minutes at which time the reaction mixture had solidified. 10 ml of acetonitrile was added to the residue and the solution was stirred for about 20 min. The white precipitate was collected by Buchner vacuum filtration and was washed with acetonitrile and then with ether. This yielded 245 mg of (AIT-0066) as a white solid. Yield: 68%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18]C(Cl)Cl.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:6]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: CCOC(=O)c1cc2cccc(OC)c2o1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C=O)ccc(OC)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 7-methoxybenzofuran-2-carboxylate (10 g) was dissolved in anhydrous methylene chloride (200 ml), to which were dropwise added dichloromethyl methyl ether (8.2 ml) and titanium tetrachloride (10 ml) with cooling with ice, and directly stirred for 30 minutes. After being allowed to stand for heating to the room temperature, the mixture was stirred for 1.5 hours, to which was dropwise added an aqueous HCl (1 mol/liter) solution to decompose the remaining titanium tetrachloride. Then, this was extracted with chloroform. The organic layer was washed with an aqueous NaOH (1 mol/liter) solution and a saturated saline solution, and dried over sodium sulfate, and the solvent was evaporated. The residue was suspended in ether and taken out through filtration to obtain Compound IIcc-a (8.9 g, 79%) as colorless crystals.