Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(O)(=O)C.C(O)(=O)C.[I:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.S(=O)(=O)(O)O.[F:43][B-:44]([F:47])([F:46])[F:45].[K+]>O.C1(C)C=CC=CC=1>[F:43][B-:44]([F:47])([F:46])[F:45].[C:32]1([I+:31][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20](=[O:22])[C:21]=3[CH:8]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=c1c2ccccc2oc2ccccc12
Reactant: Ic1ccccc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2oc2ccc([I+]c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To 80 ml of acetic anhydride were suspended 9.8 g (0.05 mol) of xanthene-9-one and 16.1 g (0.05 mol) of iodobenzene diacetate, and 10 g (0.1 mol) of concentrated sulfuric acid was added dropwise thereto at 0 to 7° C. for 1 hour, followed by gradually warming to room temperature and reacting with stirring for 8 hours. After completion of the reaction, the obtained reaction solution was poured into 200 ml of ice water, and 150 ml of toluene was added thereto to dissolve insoluble substance. The solution was fractionated and 12.6 g (0.1 mol) of potassium tetrafluoroborate was added to the obtained water layer, followed by stirring at room temperature for 2 hours. The precipitated crystal was filtered off and dried at 50° C. under vacuum for 2 hours to obtain 11.4 g of 2-(phenyliodonio)xanthene-9-one tetrafluoroborate as pale orange crystal (yield: 47%).
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCC.[O:19]=[C:20]1[O:26][C@H:25]([C@H:27]([CH2:29][OH:30])[OH:28])[C:23]([OH:24])=[C:21]1[OH:22].[CH3:31][NH:32][C:33]([NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[O:47][C:46]([CH2:48][N:49]([CH3:51])[CH3:50])=[CH:45][CH:44]=1)=[CH:34][N+:35]([O-:37])=[O:36]>ClCCl>[CH3:31][NH:32][C:33]([NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[O:47][C:46]([CH2:48][N:49]([CH3:50])[CH3:51])=[CH:45][CH:44]=1)=[CH:34][N+:35]([O-:37])=[O:36].[O:19]=[C:20]1[O:26][C@H:25]([C@H:27]([CH2:29][OH:30])[OH:28])[C:23]([O-:24])=[C:21]1[OH:22]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Solvent: ClCCl
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.45 g of palmitic acid were dissolved in 10 ml of dichloromethane. Thereafter, 0.88 g (0.5 cmole) of ascorbic acid and 1.57 g (0.5 cmole) of ranitidine were added. The mixture was stirred for 3 hours at room temperature, was filtered and washed with the same liquors. Dry weight: 3.56 g. This solid is unaltered by ambient conditions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27][C:14]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[C:8]=1[CH3:13])=[O:16])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: CCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Yield: 70.6 %

Procedure:
This material was prepared from the reaction of 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (1.12 g, 5.11 mmole) 16c with oxalyl chloride (0.682 ml, 13.6 mmole) and butan-1-amine (1.51 ml, 15.33 mmole) in a manner as previously described for example 16d to give a yellow solid (0.990 g, 71%). 1H NMR (300 MHz, CDCl3) δ8.01 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=2.3, 8.6 Hz), 7.25 (1H, d, J=2.3 Hz), 6.32 (1H, s), 4.34 (3H, s), 4.09 (3H, s), 3.95 (2H, m), 3.16 (3H, s), 2.10 (2H, m), 1.92 (2H, m), 1.44 (3H, t, J=7.4 Hz); ESIMS (MH+): 275.15.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[S:17][CH:18]=[CH:19][N:20]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#N.C(O)=[O:24]>O.[Ni]>[CH:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[S:17][CH:18]=[CH:19][N:20]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=[O:24]
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Raney Ni (2.0 g) was added to a solution of (54) (1.5 g, 4.9 mmol) in HCO2H (18 ml) and water (6 ml). The mixture was stirred under argon at 110° C. for 1 hr. After cooling the mixture was filtered. The filtrate was concentrated, partitioned between a 5% aqueous NaHCO3 solution and ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure to give (55) (1.3 g, 87%).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)#[N:3].Cl.C(OC(=[NH:37])C1C=CC(C=CC2C=CC=CC=2)=CC=1)C.C(=N)([O-])C1C=CC=CC=1.N>CO.C(O)C.C1C=CC=CC=1>[ClH:1].[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]([NH2:37])=[NH:3])=[CH:5][CH:6]=1)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=N)c1ccc(C=Cc2ccccc2)cc1
Reactant: N#Cc1ccc(C=Cc2ccccc2)cc1
Agent: Cl
Agent: N
Agent: N=C([O-])c1ccccc1
Solvent: CCO
Solvent: c1ccccc1
Solvent: CO
Product: N=C(N)c1ccc(C=Cc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Hydrogen chloride is bubbled through a mixture of 4-cyanostilbene (13.5 g., 0.065 mole), obtained according to the method of Belgian Pat. No. 641,415 (Chem. Abs. 63: 3092g (1965)), in 35 ml. of dry benzene and 17.5 ml. of absolute ethanol at 0° to 5° C. or a period of 3 hr. The reaction is maintained at 0° to 5° C. for 48 hr. and the solvent and excess hydrogen chloride removed under reduced pressure. The residue stirred with 50 ml. of dry benzene and collected provides 13.0 g. of ethyl-4-styrylbenzimidate hydrochloride. A methanol solution of the benzimidate salt is cooled to 5° to 10° C., saturated with ammonia and heated at a temperature of 100° C. for a period of 3 hr. in an enclosed container. Concentration of the reaction mixture provides 4-styrylbenzamidine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][O-:18].[Na+].CO>CN(C=O)C.CCOC(C)=O>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 24 h
Yield: 41 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (197 mg, 0.810 mmol) in 1.5 mL of DMF was added 4 mL of 0.5 M NaOMe in MeOH (2.5 eq). The resultant solution was heated at 60° C. overnight, then at 90° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (20% EtOAc-hexane) gave 80 mg (41%) of the title compound, along with 80 mg (40%) of recovered starting material. 1H-NMR (CDCl3; 400 MHz): δ 7.95 (d, 1H, J=9.1 Hz), 6.51 (d, 1H, J=2.6 Hz), 6.46 (dd, 1H, J=2.6, 9.1 Hz), 3.87 (s, 3H), 3.01-3.04 (m, 4H), 1.72-1.78 (m, 4H), 1.60-1.64 (m, 2H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([NH2:79])=[O:78])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([NH2:79])=[O:78])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(N)=O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 26.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxamide (40 mg, 0.075 mmol) was hydrolyzed by lithium hydroxide (15 mg, 0.377 mmol) in THF/methanol/water (2/2/1 ml) to afford 10 mg (33.33% yield) of the titled compound after purification by preparative TLC(Silicagel-1000 micron) using 3% methanol in DCM as eluent. 1H NMR (DMSO-d6, 400 MHz): δ 11.7 (s, 1H), 8.46-8.41 (m, 2H), 8.27-8.26 (d, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.63-7.61 (d, 2H), 7.42-7.35 (q, 1H), 7.15-7.05 (m, 5H), 6.04 (s, 2H), 5.39 (s, 2H), 3.45-3.43 (m, 4H), 3.13-3.11 (m, 4H). MS: m/z=496.4 (M+1), HPLC: 92.43% in method B.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1ccccc1Cl
Yield: 128.9 %

Procedure:
(E)-2-(2-Chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (4.55 g, 12.3 mmol) was stirred for 15 minutes in a 1:1 mixture of trifluoroacetic acid and dichloromethane (18 mL). The solution was concentrated in vacuo to afford a solid. The solid was washed with dichloromethane (5 mL) and heptane (150 mL) and was collected by suction filtration. The solid was dried under vacuum at room temperature to afford crude (E)-2-(2-chloro-phenyl)-ethenesulfonic acid amide (3.45 g) which was taken on to the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:32][N:33]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:34]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O

Procedure:
A solution of Example 7C (0.3 g) and 3-(tert-butoxycarbonylamino)azetidine (0.46 g) in dichloromethane (60 mL) was stirred for 2 hours, diluted with dichloromethane, washed with water, 10% citric acid, and brine, and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CN(C=O)C.O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1
Reactant: OC1CCNCC1
Reactant: Clc1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCN(c2ccc3ccccc3n2)CC1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
Triethylamine (2.9 g, 29.6 mmol), 2-chloro-quinoline (purchased from Alfa Aesar™) (2.4 g, 14.8 mmol) and piperidin-4-ol (1.5 g, 14.8 mmol) were dissolved in DMF (20 mL). The resulting mixture was heated to 100° C. overnight. The mixture was then diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give 1-(quinolin-2-yl)piperidin-4-ol (2.0 g, 8.7 mmol, 60% yield) as white solid. ESI-MS (M+1): 229 calc. for C14H16N2O 228.
Reaction SMILES: C(C(CC)(C([O-])=O)C([O-])=O)C.[O-]CC.[Na+].[CH2:16]([O:18][C:19](=[O:41])[CH:20]([C:26]1[C:27](=[O:40])[N:28]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=[CH:30][C:31]=1[Cl:32])C(OCC)=O)[CH3:17].C(OC(=O)C(C1C=NN(CC2C=CC=CC=2)C(=O)C=1Cl)C(OCC)=O)C.[Na+].[Cl-]>C(OC(C)C)(C)C.CS(C)=O.O>[CH2:16]([O:18][C:19](=[O:41])[CH2:20][C:26]1[C:27](=[O:40])[N:28]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=[CH:30][C:31]=1[Cl:32])[CH3:17]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(Cl)cnn(Cc2ccccc2)c1=O
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: CCOC(=O)C(C(=O)OCC)c1cnn(Cc2ccccc2)c(=O)c1Cl
Agent: CC[O-]
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Diethylmalonate (1.73 g, 1.64 mL, 2.5 eq) was dissolved in isopropyl ether (2 mL), sodium ethoxide (0.73 g, 2.5 eq) was added thereto at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added the compound of Preparation 3-1) (1.10 g, 4.31 mmol), which was then refluxed for one day. The mixture was extracted with ethyl acetate (50 mL×2), washed with aqueous sodium chloride solution (100 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) to give 1.34 g (82%) of a 1:1 mixture of 2-(2-benzyl-5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl)-malonic acid diethyl ester and 2-(1-benzyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yl)-malonic acid diethyl ester. This mixture was dissolved in 12 mL of a solvent mixture (H2O:DMSO=1:5), NaCl (1.0 g, 5 eq) was added thereto, and the mixture was heated to 120° C. for one day. The mixture was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate (200 mL). The extract was washed with water, saturated sodium hydrogen carbonate solution (NaHCO3, 100 mL×2) and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) to give 530 mg (49%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:22].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1, 2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (200 mL), and the precipitate was collected by filtration to give the title compound (10 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH:16]=O.Cl.O>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(C=O)cc1C
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4-dimethylbenzaldehyde 1.07 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. The solution was cooled to room temperature, and water 200 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.21 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][O:13]C(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCCO2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc(F)cc2c1OCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.8 %

Procedure:
13.74 g (90.28 mmol) of 6-fluorochroman are dissolved in 250 ml of methylene chloride. The whole is cooled to 0° C. and 20.15 ml (0.18 mol) of TiCl4 are added dropwise. The solution becomes brown and is stirred for 10 minutes at room temperature. 8.78 ml (99.3 mmol) of α,α-dichloromethyl ether are then introduced. The whole is stirred overnight at room temperature, poured into ice-cold water and decanted. The organic phase is dried and evaporated to yield 17.7 g of a residue which is purified by chromatography on silica (eluant CH2Cl2 /cyclohexane: 50/50). 6.3 g of the expected product are obtained. Yield: 38.7%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[O:3]1.[CH2:9]=[O:10].O>CO.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:9][OH:10])[C:4](=[O:8])[O:3]1
Reactant: C=O
Reactant: Cn1oc(=O)[nH]c1=O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cn1oc(=O)n(CO)c1=O
Reaction time: 8 h

Procedure:
2-Methyl-1,2,4-oxadiazolidin-3,5-dione (2.0 grams; 0.0172 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (2.5 ml of 37% conc.; 0.0344 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred overnight. After this time the reaction mixture was stripped of methanol and water to yield an oil. The oil was then dissolved in methylene chloride, and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvent to yield the desired product 2-methyl-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=4)[N:25]=3)=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
8.0 g (30 mmol) of 4-[(5-chloro-2,6-dimethylpyrimidin-4-ylamino)methyl]phenol, 6.0 g (30 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine and 20.7 g (150 mmol) of potassium carbonate in 150 ml of anhydrous dimethylformamide are heated at 80° C. with vigorous stirring for 1 h. After cooling to room temperature, the mixture is poured into water (1 l) and extracted with ethyl acetate (3×500 ml). The combined organic extracts are washed with water (500 ml), dried over sodium sulfate and concentrated. The beige solid (12.5 g) remaining is purified by chromatography on silica gel (mobile phase: toluene/acetone=2:1). The fractions with Rf=0.4 are collected and concentrated. The residue is suspended in 100 ml of methanol and the suspension is stirred for 30 min. Following filtration, this operation is repeated. After drying in a vacuum drying cabinet at 40° C., 7.8 g (61%) of the title compound are isolated as an almost white powder. m.p.: 203° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[I-].[K+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 25 °C
Reaction time: 19 h
Yield: 72 %

Procedure:
To a solution of methyl [2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.175 g; 0.5 mmol) in dry DMF (2 mL) at −10° C. was added LHMDS 1N in THF (0.55 mL; 0.55 mmol), benzylbromide (0.122 mL; 1 mmol) and potassium iodide (0.166 g; 1 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 19 h. A saturated solution of ammonium chloride (4 ml) was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphatesulphate and concentrated under reduced pressure. The crude material was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (5 to 40%) in heptane to furnish 0.159 g (72%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]1[CH2:35][CH2:34][CH:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCC(N)C3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 94 mg of tert-butyl pyrrolidin-3-ylcarbamate and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC). Yield: 60 mg (51%) of {2-amino-6-[2-(3-aminopyrrolidin-1-ylmethyl)phenyl]quinazolin-4-yl}-(1,3-dihydroisoindol-2-yl)methanone;