Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccc2ccnc(Cl)c2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Product: Clc1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A mixture of 3.96 g 1,7-dichloroisoquinoline and 10.50 g of benzylpiperazine was stirred at 150° C. for 3 hours. To the residue water was added, followed by extraction with chloroform, washing with saturated aqueous sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (ethyl acetate) to provide 4.78 g (71%) of 1-(4-benzylpiperazin-1-yl)-7-chloroisoquinoline.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Sc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[4-(1-methylpropylthio)phenoxy]ethanol (4.26 g, 20.0 mmol) and triethylamine (4.2 ml, 30.0 mmol) in 100 ml methylene chloride at 0° is added dropwise methanesulfonyl chloride (1.7 ml, 22.0 mmol). The mixture is stirred at 0° for 20 min, after which it is poured into ice water. The methylene chloride layer is washed with ice water, with cold 10% sulfuric acid, with cold 5% sodium bicarbonate and with cold brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethyl methanesulfonate.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH:44](F)F>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH3:44]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1nccc(Cl)c1OC(F)F)C1CC1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
18.27 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 200 ml of anhydrous ether, 51.3 ml of phenyllithium (1.04 M) was dropped and the resulting mixture was stirred at a room temperature for 15 minutes. 145 ml of ether solution of 12.57 g of (4-chloro-3-difluoromethoxy-2-pyridyl)cyclopropylketone (X) was dropped to the mixture, which was stirred at a room temperature for 12 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.66 g of 2-(4-chloro-3-difluomethoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI).
Reaction SMILES: C[O:2][C:3]([CH:5]([C@H:9]([C:14](=[O:36])[NH:15][C@H:16]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:35])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:6]([OH:8])=[O:7])=[O:4].[Li+].[OH-]>C(O)C>[C:3]([CH:5]([C@H:9]([C:14](=[O:36])[NH:15][C@H:16]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:35])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:6]([OH:8])=[O:7])([OH:4])=[O:2]
Reactant: COC(=O)C(C(=O)O)[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R,10S)-2-Methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanoic acid was taken up in ethanol (25 mL) and then 1 N LiOH (0.3 mL, 3 eq) was added dropwise. The resulting homogeneous solution was stirred at room temperature for 3 hrs. Most of the ethanol was removed under reduced pressure at 30° C. Then water (5 mL) and ethyl acetate (30 mL) was added and with stirring, 4 N HCl was added until pH=2. The ethyl acetate layer was further washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purified by reverse phase HPLC to give 47 mg of (3R,10S)-2-carboxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19), 13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, as a white solid, MS: 484.5 (M-H)-.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.Cl.[N:21]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[C:30]1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(=O)C)[CH:35]=CC=C[CH:31]=1>O.ClCCl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[N:5][N:6]3[C:30]([CH3:35])=[CH:31][N:21]=[N:1][C:2]=23)=[CH:14][CH:15]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Reactant: Nc1[nH]nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cnnc2c(-c3ccc(F)cc3)c(-c3ccncc3)nn12
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a mixture of 5-amino-4-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazole (100 mg) and concentrated hydrochloric acid (0.2 ml) in water (0.4 ml) was added sodium nitrite (28 mg) in water (0.12 ml) under ice cooling. The mixture was stirred for 30 minutes and to the mixture were added cold dichloromethane (5 ml), an aqueous saturated sodium bicarbonate (2 ml) solution and 1-(triphenylphosphoranylidene)-2-propanone (126 mg) in dichloromethane (2 ml). The mixture was stirred at 10° C. for 2 hours. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diisopropyl ether to give 8-(4-fluorophenyl)-4-methyl-7-(pyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (41 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[F:29][C:30](I)([F:32])[F:31].[C:34]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:29][C:30]([F:32])([F:31])[CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)I
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(5-hydroxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.8 g, 2.09 mmol) in DMF (5 mL) cooled to 0° C. was added trifluoromethyliodide (548.9 mg, 2.614 mmol) and Cs2CO3 (1.3 gm, 4.18 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate three times. The organic layer was washed with water and brine solution, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1:19 acetone:hexane) to give the title compound (360 mg, 37%). 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=2.8 Hz, 1H), 7.31 (m, 2H), 7.0 (d, J=7.75 Hz, 1H), 6.89 (m, 3H), 6.33 (s, 1H), 4.33 (q, J=8 Hz, 2H), 3.49 (m, 2H), 3.39 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 1.47 (s, 9H); m/z (465.1, M+ H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[ClH:1].[ClH:1].[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([N:28]4[CH2:29][CH2:30][CH:25]([N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[CH2:26][CH2:27]4)[N:7]=[CH:6][N:5]=3)[NH:9][CH:10]=2)[CH:15]=1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: C1CCOC1
Product: Cl
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CCC(N3CCCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23 and 113 mg (0.7 mmol) of 4-pyrrolidin-1-ylpiperidine are initially charged in 3 ml of THF. The reaction mixture is reacted in a single-mode microwave oven (Emrys Optimizer) at 120° C. for 24 min. The cooled reaction solution is then concentrated on a rotary evaporator, and the residue is chromatographed by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 1 ml of a 4 N solution of hydrogen chloride in dioxane is added to the resulting formate salt of the target compound, and the mixture is stirred at RT for 30 min. The suspension is then concentrated under reduced pressure, and the residue is dried.
Reaction SMILES: C(O[C:5]1([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])O[C@H](C)[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=O)[CH3:9])(=O)C.[BrH:35].[C:36]([OH:39])(=[O:38])[CH3:37]>ClCCl>[C:36]([O:39][C@@H:9]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]([CH2:5][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[O:7][C@@H:8]1[Br:35])(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)(N2C(=O)c3ccccc3C2=O)O[C@@H]1C
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Yield: 91 %

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-6-deoxy-phthalimido-D-galactopyranose (4.2 g.) in dichloromethane (2 ml.) is treated with 30-32% hydrobromic acid in glacial acetic acid (10 ml.) for 1 hour. The reaction mixture is poured into ice-water, and the product is immediately extracted with dichloromethane. The organic layer is washed with cold aqueous sodium hydrogencarbonate and cold water, dried, and evaporated in vacuo to give the title compound as a syrup (4.0 g., 91%); n.m.r. (chloroform-d): ∂ 6.63 (d, J1,2 4.0 Hz, H-1), 7.58-7.90 (4 aromatic), 1.96, 2.07 and 2.13 (3 OAc).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.C(OCC)C>C(Cl)Cl>[NH:14]1[CH2:17][CH:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[CH2:15]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCN(c4ncccn4)CC3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: c1cnc(N2CCN(C3CNC3)CC2)nc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-pyrimidine (2.03 g, 5.27 mmol) in CH2Cl2 (20 mL) was added 1-chloroethyl chloroformate (1.704 mL, 15.79 mmol) at 0° C. under N2. The resulting mixture was stirred at 0° C. for 90 min and then methanol (4 mL) was added. The resulting mixture was refluxed for 1 h, then cooled. Diethyl ether (40 mL) was added to the resulting mixture. The solid was filtered and dried to yield 2-(4-azetidin-3-yl-piperazin-1-yl)-pyrimidine, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[Br:53][C:54]1[CH:55]=[C:56]([NH2:61])[C:57]([NH2:60])=[CH:58][CH:59]=1>CN(C)C=O>[NH2:61][C:56]1[CH:55]=[C:54]([Br:53])[CH:59]=[CH:58][C:57]=1[NH:60][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:29]1
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(Br)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.20 g, 3.16 mmol) was added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.25 g, 2.10 mmol) and N,N-Diisopropylethylamine (1.21 ml, 6.95 mmol) and 4-bromobenzene-1,2-diamine (0.472 g, 2.53 mmol) in N,N-Dimethylformamide (13.0 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to give the desired compound (1.2 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCC1CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CC1
Temperature: 96 °C
Reaction time: 15 h
Yield: 105 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.25 g, 42 mmol), cyclopropanemethylamine (4.49 g, 63.1 mmol) and N,N-diisopropylethylamine (13.5 g, 105 mmol) in ethanol (100 mL) is stirred at 96° C. for 15 h. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: ethyl acetate) to give 11.96 g of 4-bromo-N-(cyclopropylmethyl)-2-nitroaniline. Yield 100%, ES-MS: 271/273 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)=[N:16][N:17]=1)[CH3:2].Cl.O.O.CC(=O)OCC>O1CCOCC1>[CH2:1]([C:3]1[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:19]=3)=[N:16][N:17]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]=[O:11])[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 20 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D18) (42 mg) in 1,4-dioxane (15 mL) stirred under nitrogen at room temperature was added 6 M HCl/water (15 mL). The reaction mixture was stirred at 20° C. for 5 h. Water was added. EA was used to extracted the aqueous layer for 3 times. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated in vacuo to give the crude product (2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)acetaldehyde (D19) (40 mg), which was used directly for the next step. MS (ES): C22H21F3N2O2S requires 434. found 435.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.S(Cl)(Cl)=O.[NH3:21]>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: N
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
4,5-Dimethoxy-2-nitrobenzoic acid (1) was treated with thionyl chloride and then reacted with ammonia to give 4,5-dimethoxy-2-nitrobenzamide (2) as described by F. Nomoto et al. Chem. Pharm. Bull. 1990, 38, 1591-1595. The nitro group in compound (2) was reduced with sodium borohydride in the presence of copper sulfate (see C. L. Thomas Catalytic Processes and Proven Catalysts Academic Press, New York (1970)) to give 4,5-dimethoxy-2-aminobenzamide (3) which was cyclized by refluxing with formic acid to give 6,7-dimethoxyquinazoline-4(3H)-one (4). Compound (4) was refluxed with phosphorus oxytrichloride to provide compound (5), which is a useful intermediate for preparing compounds of formula I wherein X is NH. Reaction of compound (5) with the requiste aniline provided the following compounds of formula I:
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17]S(O)(=O)=O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:9]1[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(CCO)on1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 8.8 g of 2-(3-benzoylisoxazol-5-yl)ethanol, in 1 liter of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 150 ml of 9M H2SO4 was added 11.9 g (41 mmol) of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 1.5 hour. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was extracted with CH2Cl2, and the organics were washed with water and brine, and dried over MgSO4. Concentration gave a wet solid which was triturated with cyclohexane and collected to give 7.1 g of a solid. Recrystallization from toluene gave 4.0 g (43%) of a solid, m.p. 108°-110°.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc2c(cc1SC#N)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc2c(cc1SC#N)CCN2S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared in Example JJ; 4.5 g, 19 mmol) was taken in CH2Cl2 (50 mL) and treated with 4-cyanophenylsulfonyl chloride (3.91 g, 19.4 mmol) and pyridine (5 mL). The reaction mixture was stirred overnight, quenched with saturated NaHCO3 solution, and diluted with EtOAc. The organic layer was separated, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography (20%-75% EtOAc in hexanes as eluents). MS(APCI): 397 (M+).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=2)[CH2:10]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (0.596 g, 2.64 mmol,) in acetonitrile (25 mL) was added 2-chloro-5-nitro-6-picoline (0.685 g, 3.96 mmol,) and powder potassium carbonate (1.45 g, 10.6 mmol), then heated to 65° C. for 4.0 hr, then at 45° C. for 16 hr. The reaction mixture was then allowed to cool to room temperature and filtered through a 10 g Varian Bond Elut SCX (strong cation-exchange) cartridge eluting with 50 mL of (1:1) methanol in dichloromethane, 25 mL of methanol, followed by 7N ammonia in methanol (50 mL). The filtrate was concentrated under vacuum, to afford 0.633 g (82%) of the title compound.
Reaction SMILES: Cl.O1CCOCC1.[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[N:30]=[CH:29][N:28](OCC[Si](C)(C)C)[C:25]5=[N:26][CH:27]=4)[C:18]3=[O:38])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.CO>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[N:30]=[CH:29][NH:28][C:25]5=[N:26][CH:27]=4)[C:18]3=[O:38])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOn1cnc2cc(N3CCN(c4ccc5ncsc5c4)C3=O)cnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C1N(c2cnc3[nH]cnc3c2)CCN1c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.7 %

Procedure:
1,4-Dioxane HCl (5 ml) was added to 1-benzothiazol-6-yl-3-[3-(2-trimethylsilanyl-ethoxy)-3H-imidazo[4,5-b]pyridin-6-yl]-imidazolidin-2-one (I-183b: 100 mg, 0.2145 mmol) and the resulting mixture was stirred room temperature for 6 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated and washed with diethyl ether. Purification by preparative HPLC afforded 20 mg of the product (25.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:6](=O)C(OCC)=O)[CH3:2].C=O.C(=O)([O-])[O-].[K+].[K+]>O.CCCCCC>[CH2:1]([O:3][C:4](=[O:27])[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(OCc2ccccc2)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: C=C(C(=O)OCC)c1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To 2-(3-Benzyloxy-phenyl)-3-oxo-succinic acid diethyl ester (1.28 g, 3.6 mmol) in water (5 ml) was added formaldehyde (600 uL, 37% solution, 6.6 mmol) and potassium carbonate (0.37 g, 2.7 mmol). The reaction was stirred vigorously overnight The organic products were extracted into diethyl ether which was dried (MgSO4), and evaporated. The residue was purified by column chromatography over silica gel (silica gel 60, EM Science) using 5% ethyl acetate:hexane as eluent to afford 0.99 g (55% yield) of the title compound as an oil. 1H NMR (CDCl3, 400 MHz) δ 7.48-7.27 (m, 6H), 7.10-6.97 (m, 3H), 6.35 (s, 1H), 5.90 (s, 1H), 5.10 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).