Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[F:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:20][N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)=[N:3][CH:4]=1
Reactant: Nn1cccc1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Product: CC(C)Oc1ccc(Nc2nc(Nn3cccc3)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reacted with 1-aminopyrrole to provide 5-fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.93 (s, 1H), 9.21 (s, 1H), 7.97 (d, 1H, J=4.1 Hz), 7.47 (d, 2H, J=8.8 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.67 (d, 2H, J=8.8 Hz), 6.02 (dd, 2H, J=2.3 and 4.7 Hz), 4.48 (sept, 1H, J=5.8 Hz), 1.21 (d, 6H, J=5.8 Hz). LCMS: ret. time: 23.44 min.; purity: 90%; MS (m/e): 328 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:3]=1[C:4]([CH2:6][CH:7]=[O:8])=[O:5].[CH3:25]OC(OC)N(C)C.C(OCC)(=O)C.O>C1C=CC=CC=1.CN(C)C=O>[CH:7]([C:6]1[C:4](=[O:5])[C:3]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:2]=2[O:1][CH:25]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: CS(=O)(=O)Nc1cc(O)c(C(=O)CC=O)cc1Oc1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
25 g of 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetaldehyde was dissolved in 260 ml of benzene and 130 ml of N,N-dimethylformamide. Thereto was added 26 ml of N,N-dimethylformamide dimethylacetal. The mixture was stirred for 8 hours at room temperature. The reaction mixture was introduced into a mixture consisting of 200 ml of ethyl acetate and 200 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting oily matter was purified by a column chromatography (eluant: a 20 : 1 mixture of toluene and ethyl acetate) to obtain 13 g (yield: 50.4%) of 3-formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: FC(F)(F)C1C=CC2NC3C=CC=CC=3N=C(N3CCN[C@@H](CCOC)C3)C=2C=1.Cl.[CH3:31][C:32]1[S:41][C:40]2[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=[C:35]([NH2:46])[C:34]=2[CH:33]=1.[O:47]([CH2:54][C@H:55]1[CH2:60]N[CH2:58][CH2:57][NH:56]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[O:47]([CH2:54][C@@H:55]1[NH:56][CH2:57][CH2:58][N:46]([C:35]2[C:34]3[CH:33]=[C:32]([CH3:31])[S:41][C:40]=3[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=2)[CH2:60]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: c1ccc(OC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: Cl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](COc2ccccc2)C1
Yield: 39.9 %

Procedure:
By using a method similr to the coupling method for (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine, 2-methyl-4H-3-thia-4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (1.2 g) and (R)-2-phenoxymethyl-piperazine (2.6 g) gives the title compound as a yellow solid (728 mg): mp=64-81° C.: 1H NMR (CDCl3) δ 2.32 (s, 3H), 2.86 (dd, 1H), 3.14-2.94 (m, 3H), 3.32-3.24 (m, 1H), 3.98-3.87 (m, 2H), 4.02 (dd, 1H), 4.11 (bd, 1H), 4.96 (bs, 1H), 6.32-6.30 (m, 1H), 6.61 (dd, 1H), 7.00-6.86 (m, 5H), 7.04 (dd, 1H), 7.34-7.25 (m, 2H); MS (APCI) m/z (rel intensity) 405.4 (100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[I:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:9]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
Cesium carbonate (25.3 g, 77.6 mmol) was added to 3-iodo-5-nitro-1H-pyrazolo[3,4-b]pyridine (15 g, 52 mmol) in DMF (500 mL). Then 1-(chloromethyl)-4-methoxybenzene (10.57 mL, 77.58 mmol) was added, which was stirred at room temperature for 16 hours. Water (1 L) was then added to the reaction mixture, which resulted in a precipitate. The solids were collected by filtration and transferred into a flask with the aid of i-PrOH. The concentrate was triturated with EtOAc/Et2O (3:1 EtOAc/Et2O, 750 mL) to give 3-iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (12.1 g, 29.5 mmol, 56.9%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[OH:19])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:36](Cl)(=[O:40])[C:37]([CH3:39])=[CH2:38]>O.C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:20])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:36](=[O:40])[C:37]([CH3:39])=[CH2:38])=[CH:14][C:13]=2[OH:19])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)Nc2ccc(N)cc2O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: C=C(C)C(=O)Nc1ccc(NC(=O)Nc2ccc(C#N)cc2)c(O)c1
Yield: 28.2 %

Procedure:
10.8 g (0.04 mol) of 2-(4-cyanophenylureido)-5-aminophenol was added to 100 ml of acetonitrile and to which were added 17.6 ml (0.2 mol) of pyridine and 0.3 ml of nitrobenzene while cooling with stirring. To the solution was added dropwise 5.0 g (0.048 mol) of methacrylic chloride and the mixture was stirred for about 1.5 hours. 200 ml of water was added to the reaction mixture and the crystals thus deposited were collected by filtration and recrystallized from acetone to obtain 3.8 g (28.3%) of Monomer Coupler (18).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:7]=[CH:6][N:5]=1.Br[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=2)[N:26]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:25]=1.[F-].[Cs+]>CN(C=O)C.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].[Cu]I>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=3)[N:26]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:25]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(COC)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COCc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 120 °C

Procedure:
A mixture of 2-methoxymethyl-4-tributylstannanyl-pyridine 8AN (0.1 g, 0.24 mmol), 3-bromo-5-nitro-1-trityl-1H-indazole 1AJ (0.12 g, 0.24 mmol), CsF (0.08 g, 0.53 mmol), [Pd2(dba)3] (5 mg, 0.005 mmol), Pd[P(t-Bu)3)2, and CuI (4 mg, 0.024 mmol) in DMF (2 ml) was degassed for 5 minutes. Then it was heated at 120° C. for two hours. Cooled to room temperature and diluted with EtOAc (10 ml). It was then filtered on a celite pad. Filtrate was washed with water (3 ml) and the organic extracts were dried over MgSO4. It was filtered again on a celite pad and concentrated. The residue was purified on silica gel eluting with 2/1 EtOAc/Hexane to give the desired product 3-(2-methoxymethyl-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 9AN (0.095 g, 76%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]>O1CCCC1.CO>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCOCC)c1
Yield: 62 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 14 eq) of sodium hydroxide and methyl 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane and isopropyl ether, 245 mg of 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=63° C.). Yield=62% over the two steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH3:15])[C:11](=[S:14])[NH:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(O)(=O)C>C(O)C>[Cl:20][CH2:19][CH2:18][CH2:17][S:14][C:11]1[N:10]([CH3:15])[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13][N:12]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2ccc(F)c(F)c2)n[nH]c1=S
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(SCCCCl)nnc1-c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 5-(3,4-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.72 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.26 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.36 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CN2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.3 %

Procedure:
Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g, 130 mmol) in chloroform (75 ml). The reaction mixture was stirred for 1 h at room temperature and then made basic with a sodium hydroxide solution. The product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 1-(3,4-dichlorobenzyl)piperazine (35.8 g) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: Nc1nc(N)c2nc(CN3CCN(Cc4ccccc4)CC3)nnc2n1
Temperature: 90 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (48 mg; 0.23 mmol) and N-Benzylpiperazine (0.12 mL) in ethanol (0.1 mL) were heated to 90° C. in a sealed tube for 2 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 26 mg of yellow colored 3-(4-Benzyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].CC[O-].[Na+].[Na].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[O:3]=[C:2]1[NH:4][C:13](=[O:12])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:1]1
Reactant: NC(N)=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
Urea (12 g, 200 mmol) was added to EtOH (300 mL) containing NaOC2H5 previously prepared from sodium (5.52 g, 240 mmol, 1.2 eq). Diethyl 2-(ethoxymethylene)malonate (43.2 g, 200 mmol, 1.0 eq) was added and the solution was stirred at 20° C. for 24 h, and then stirred at 90° C. for 24 h. The alcohol was removed by reduced pressure distillation. Ice-water (100 mL) was added to dissolve the residue. The product was precipitated by adding cold dilute hydrochloric acid. The solid was filtered off to afford ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8.5 g, 23%), which was used in next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:16])=O)[CH2:6][CH2:5]2>C1COCC1.Cl>[NH2:16][CH2:14][C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN)O2
Yield: 55 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1.0 g, 4.0 mmol) in THF (30 mL) was added boranemethyl sulfide complex (10 M, 1.9 mL, 19 mmol). The resultant mixture was refluxed for 7 h. To the resultant reaction mixture was added IN hydrochloric acid (9.6 mL) under ice-cooling, and the resultant mixture was further refluxed for 2 h followed by concentration under reduced pressure. The residue was extracted with ethyl acetate after addition of 1N aqueous solution of sodium hydroxide. The organic layer was washed with 10% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica-gel column chromatography to give an amine, 2-aminomethyl-6-hydroxy-2,5,7,8-tetramethylchroman (yield 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:20][CH:21]=1
Reactant: COc1cc(C=Nc2ccc(C)cc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Yield: 92.4 %

Procedure:
To a solution of (108a) (6.0 g, 21.1 mmol) in ethanol (100 mL) was added NaBH4 (4.06 g, 98%, 105 mmol) in portions. The reaction mixture was stirred at reflux under argon for 2 h. The solvent was removed under reduced pressure. Saturated aqueous NaCl (30 mL) was added to the residue and the mixture extracted with ether (100, 40 and 40 mL). The combined ether layer was washed with saturated NaCl solution (30 mL), and dried over anhydrous Na2SO4. Evaporation of the filtrate gave 109a (5.6 g, 92.7%) as white crystals: mp 94°-6° C. after recrystallization from ethanol. 1H NMR (200 MHz, CDCl3) δ7.00 (d, J=8 Hz, 2H), 6.61 (s, 2H), 6.58 (d, J=8 Hz, 2H), 4.23 (s, 2H), 3.84 (s, 9H), 2.24 (s, 3H). CIMS (isobutane) m/e 288 (MH+ 76).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of 2.0 g of 2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo [1,2-a][1,4]benzodiazepine in 50 ml of dioxan was treated with a solution of 0.62 g of sodium hydrogen carbonate in 18 ml of water and the mixture was stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with dichloromethane. The dichloromethane extracts were dried over magnesium sulphate and chromatographed over 100 g of silica gel. 1.7 g of the desired product were eluted with dichloromethane/ethanol mixtures containing 8 to 12% ethanol. After recrystallization from ethyl acetate/diethyl (sic) ether there were obtained 1.65 g of 8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C., which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=O)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[N:22][OH:23])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: COCCOc1cccc2c1C(=O)CO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cccc2c1C(=NO)CO2
Temperature: 23 °C
Yield: 72.2 %

Procedure:
A mixture of the above described 4-(2-methoxy-ethoxy)-benzofuran-3-one (1.9 g, 9 mmol), sodium acetate (1.5 g, 19 mmol) and hydroxylamine hydrochloride (1.3 g, 19 mmol) in ethanol (15 mL) was refluxed for 4 h. Cooled to 23° C., filtered the precipitate off, washed with water and ethanol and dried in high vacuum to give the title compound as a white solid (1.45 g, 71%); MS: m/e=224.1 (M+H−).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:10]1=[O:26]>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(CCN(c3ccccc3Cl)C2=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Reaction time: 2 h

Procedure:
Hydrogen chloride (4.0 M in 1,4-dioxane, 2.0 mL) was added to a solution of tert-butyl (5S)-2-(2-chlorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (0.103 g, 0.000283 mol) in ethyl acetate (0.5 mL) and the mixture was stirred for 2 h. Then the solvent was removed in-vacuo to afford the desired product. LC-MS: 265.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:12][CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15]>>[CH3:20][C:19]1[C:13]([CH3:12])=[C:14]([OH:15])[C:6]2[C:4](=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=[CH:8][CH:7]=2)[N:5]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccccc1C(F)(F)F
Product: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C

Procedure:
Prepared according to procedure R using 2-(trifluoromethyl)aniline (1.61 g, 10 mmol) and ethyl 2-methyl-3-oxobutanoate (2.89 g, 20 mmol) in PPA (4 g, 40 mmol). The resulting precipitate was collected by filtration, washed with water, and dried to give 2,3-dimethyl-8-(trifluoromethyl)quinolin-4-ol. Mass Spectrum (ESI) m/e=242 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2Cl.[O:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[NH:24][CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 96.9 %

Procedure:
On a larger scale, ethyl 6-bromo-4-chloroquinoline-3-carboxylate (2196 g, (1976 g active), 6.28 mol) was charged to the vessel with DMA (16 L). Tetrahydro-2H-pyran-4-amine (1224 g, 12.10 mol) was added over 10 minutes with an observed exotherm of 21-27° C. DIPEA (3.5 L, 20.09 mol) was added with no observed exotherm. The mixture was heated to 75-85° C. and the resulting solution stirred for 18.5 h at 80° C. HPLC indicated consumption of starting material and 99.2% product. The reaction was cooled to 50° C. and then poured into water (50 L). The resulting suspension was stirred for 2 h at r.t. and the solids isolated by filtration, washing with water (8 L then 2×4 L). The solid was dried under vacuum at 40° C. for 55 h to give 2307 g of desired material. Analytical data was consistent with that obtained from previous batches.