Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([CH:28]1[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:27]1=[O:34])=[O:6]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Br)c1OCCOC
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Br)c1OCCOC
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-Bromo-3-(2-methoxyethoxy)-4-ethylsulfonyl benzoic acid (6.1 g, 0.018 mol) was diluted in 50 mL of methylene chloride and 2 drops of DMF were added, followed by the slow addition of oxalyl chloride (3.81 g, 0.03 mol). After the addition was complete, the solution was refluxed for 1 hour, cooled and concentrated under vacuum. The crude acid chloride was diluted in 25 mL of methylene chloride and 2.24 g (0.02 mol) of 1,3-cyclohexanedione was added, followed by an excess of triethylamine (4.0 g). After stirring overnight, the organic layer was washed three times with dilute (1 N) hydrochloric acid, dried and concentrated. The crude enol ester was dissolved in 25 mL of acetonitrile and ten drops of acetone cyanohydrin and 4 mL of triethylamine were added and this reaction mixture was stirred at room temperature for 48 hours. The organic phase was washed three times with 1 N hydrochloric acid and then extracted with base. The base extracts were combined and acidified and extracted three times with 50 mL of methylene chloride. The methylene chloride extracts were dried, concentrated and chromatographed on silica gel using ether/methylene chloride/acetic acid to give 3.96 g of pure 2-[2'-bromo-3'-(2-methoxyethoxy)-4'-ethylsulfonylbenzoyl]-1,3-cyclohexanedione.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[C:38](N)[S:37][N:36]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.O>O1CCCC1>[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[CH:38][S:37][N:36]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1ncsn1
Yield: 73.4 %

Procedure:
A solution of t-butyl nitrite (3.2 g) in tetrahydrofuran (20 ml) was added dropwise to a solution of benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (10 g) in tetrahydrofuran (100 ml) at 50° to 53° C. under stirring, and the mixture was stirred at the same temperature for 25 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. The solution was evaporated and the residue was subjected to column chromatography on silica gel. The elution was carried out with a mixture of benzene and ethyl acetate (19:1) and the eluates containing the object compound were evaporated to give benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetate (syn isomer) (7.1 g), mp. 139° to 141° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)OC)[C:5]1=[O:28])(=[O:3])[CH3:2].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=C(NC1CCN(C)CC1)c1ccc([N+](=O)[O-])cc1)C(=O)N2C(C)=O

Procedure:
2.7 g (7 mmol) 1,5-diacetyl-3-[4-nitrophenyl-methoxy-methylidene]-2-indolinone (Ex. VI.2) are suspended in 20 ml of dimethylformamide and stirred with 0.9 g (7.7 mmol) 4-amino-N-methylpiperidine for 6 h at 80° C. Then the mixture is evaporated down and the acetyl-protected intermediate product is washed with a little water and suction filtered.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=C[N:13]=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1C=CC(C(O)=O)=N1>>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][N:38]([CH3:37])[N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccc(F)c2F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2cccc(F)c2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,3-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 226 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH2:16][C:17]([NH:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(N)no1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)CBr)no1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-methyl-isoxazol-3-ylamine (4.0 g, 40.8 mmol) and triethylamine (6.8 ml, 50 mmol) in chloroform (20 ml) cooled to −40° C., is added bromoacetyl bromide (3.9 ml, 44.9 mmol) in chloroform (20 ml). The reaction mixture is stirred at −40° C. for 30 minutes and then allowed to warm to room temperature. The resultant suspension is filtered, washed with DCM and dried in vacuo to yield the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH2-]C(C)=O.Br[CH2:35][CH2:36][C@H:37](O)[CH2:38][OH:39].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:35][CH2:36][C@@H:37]([CH2:38][OH:39])[O:18][C:16]2=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)CCBr
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [CH2-]C(C)=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C1O[C@H](CO)CC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of tetrahydrofuran was dissolved 1.01 g (10 millimoles) of diisopropyl amine, and 6.5 ml of 14.5% solution of n-butyl lithium in hexane was added to the solution to form lithium diisopropylamine. The solution was cooled to -20° C. and a solution of 1.21 g (5 millimoles) of 4-benzyloxyphenylacetic acid in 5 ml of tetrahydrofuran was added dropwise into the solution. Then 3 ml of hexamethyl phosphorictriamide was added to the mixture, and reaction was carried out at a temperature maintained at -5° to 0° C. with stirring for 30 minutes. The obtained di-anion solution was cooled to -30° C., and 2.3 g (9.6 millimoles) of (S)-4-bromo-1,2-butanediol acetonide was added dropwise into the solution. After the dropwise addition, the mixture was stirred for 2 hours at a temperature controlled to 10° to 20° C. Then, water was added to the mixture, tetrahydrofuran was removed by distillation, and the residue was neutralized with dilute hydrochloric acid. The reaction product was extracted from the solution with chloroform, and the extract was washed with water and dried over magnesium sulfate. The solvent was removed under a reduced pressure. The obtained product was purified by the silica gel column chromatography to obtain purified (2R,5S)-2-(4-benzyloxyphenyl)-5-hydroxymethyl-δ-valerolactone.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:35])[NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:31]([C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=4)[CH2:12][CH2:13]3)=[CH:22][CH:21]=2)=[O:35])[CH:30]=[CH:29][CH:28]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-benzoic acid was prepared from the LiOH monohydrate hydrolysis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl}-piperazin-1-yl]-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid above. HRMS m/z calcd for C28H31N3O3 [M+H]+: 458.2438. Found: 458.2439.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Reactant: NOC1CCCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-Benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (365 mg, 0.97 mmol) was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (328 mg) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1>C1COCC1.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.[Cu]I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][N:37]=[C:36]2[NH:35][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:20]([Cl:19])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester is prepared by adding prop-2-ynyl-carbamic acid tert-butyl ester (0.978 g, 6.31 mmol), diisopropylamine (1.77 ml, 12.63 mmol), Pd(PPh3)2Cl2 (210 mg, 0.30 mmol) and CuI (57 mg, 0.30 mmol) to a stirred solution of [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine (3.11 g, 5.74 mmol) in THF (40 ml). After stirring the reaction mixture at rt under N2 for 3 h, the THF is removed under reduced pressured and methylene chloride is added. The organic layer is washed with NH4Cl (sat) and brine, and dried (Na2SO4). The solvent is evaporated and the residual solid is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C@H:5]1[CH2:21][NH:20][C:19]3[C:6]1=[C:7]2[CH:16]=[CH:17][CH:18]=3>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C:5]1[C:6]3[C:19]([NH:20][CH:21]=1)=[CH:18][CH:17]=[CH:16][C:7]=32
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4c3[C@H](CN4)C[C@@H]21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Temperature: 25 °C

Procedure:
2 g of (5aR*,6aS*,12bS*)-4,5,5a,6,6a,7,8,12b-octahydro-7-methylindolo[4,3-ab]phenanthridine are dissolved in 250 ml of methylene chloride. 20 g of actively precipitated manganese dioxide are subsequently suspended in the solution, and the suspension obtained is stirred at room temperature until thin-layer chromatography reveals no more educt. The reaction solution is then filtered over diatomaceous earth, concentrated and the resultant oil crystallised from methylene chloride. The crystalline title compound is obtained. It melts at 215°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[C:12]1(=O)[NH:16][C:15](=O)[CH:14]2[CH2:18][CH2:19][CH:20]=[CH:21][CH:13]12>>[CH2:15]1[C@@H:14]2[C@@H:13]([CH2:21][CH:20]=[CH:19][CH2:18]2)[CH2:12][NH:16]1
Reactant: O=C1NC(=O)C2CCC=CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=CC[C@H]2CNC[C@H]2C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1 M LAH in THF (800 mL; 0.8 mole; 2.3 eq) at rt was added, portionwise, tetrahydrophthalimide (52.6 g; 0.348 mole; 1 eq). The reaction mixture was stirred at 60° C. for 16 hours, then cooled to RT and quenched carefully with sequential addition of 30 mL of water, 30 mL of THF, 15% aqueous KOH (30 mL), and water (100 mL). The mixture was diluted with 135 mL of ether, stirred at RT for 1 hour, and filtered through a pad of diatomaceous earth on a 600 mL fritted glass filter funnel, washing the pad with 400 mL of DCM. The filtrate was concentrated in vacuo to yield (3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-isoindole as an oil, which was used directly in the next reaction as is.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:38]2[CH:39]=[CH:40][C:35]([CH:33]=[O:34])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=Cc1ccc(B(O)O)cc1
Product: COc1cc(-c2csc3c(-c4ccc(C=O)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.120 g, 0.217 mmol), 4-formylphenylboronic acid (0.247 mmol) and the procedure described in General Procedure A.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10](C=O)[CH:9]=[CH:8]2)[CH3:2].ClC1C=CC=C([C:26](OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][CH2:14][O:15][CH3:16])=[C:10]([O:27][CH3:26])[CH:9]=[CH:8]2)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc2ccc(C=O)c(OCOC)c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cccc2ccc(OC)c(OCOC)c12
Reaction time: 2 h
Yield: 74.8 %

Procedure:
220 g of 8-ethyl-1-methoxymethoxy-2-naphthalenecarbaldehyde was dissolved in 1540 ml of dichloromethane, to which 186 g of 80 to 85% m-chloroperbenzoic acid was added portion by portion. The reaction solution generated heat and was gently refluxed. The reaction solution was ice-cooled, to which 200 ml of a saturated sodium thiosulfate aqueous solution was added. The precipitated insoluble matters were removed by filtration and washed with dichloromethane. The filtrate was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, 254 g of the resultant residue was dissolved in 500 ml of methanol, to which 89 g of potassium hydroxide preliminarily dissolved in 200 ml of water was added, followed by refluxing for 20 minutes. The reaction solution was poured into 700 mo of cooled 2N hydrochloric acid and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, from which the solvent was distilled off. 278 g of the resultant residue was dissolved in 600 ml of N,N-dimethylformamide, to which 500 g of anhydrous potassium carbonate and 256 g of methyl iodide were added, followed by agitation at 60° C. for 2 hours. The insoluble matters were filtered off and washed with ethyl acetate. Water was added to the resultant filtrate, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the resultant residue was purified by silica gel column chromatography to obtain 166 g of the caption compound as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: NC(=O)N1CCNCC1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C(N)=O)CC3)nn12

Procedure:
The title compound was prepared in analogy to Example 3 using (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C) and piperazine-1-carboxamide instead of piperazin-2-one (tR 3.16 min (conditions 1), MH+=438, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.46 (d, 1H); 7.80 (d, 1H); 7.65 (d, 1H); 7.61 (s, 1H); 7.60 (m, 1H); 7.08 (d, 1H); 6.07 (s, 2H); 4.98 (m, 1H); 3.15-3.40 (m, 8H); 1.88 (d, 3H)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
(R)-1-Benzyl-3-hydroxypyrrolidine (3.9 g, 22 mmol) was dissolved in toluene (100 mL) and the solution stirred and cooled to 0°-5° C. Triethylamine (2.66 g, 26.2 mmol) was added followed by methanesulfonyl chloride (3.0 g, 26 mmol). A slurry formed after 30 minutes. The mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added to the reaction mixture and the organic layer separated and washed with water (100 mL) and concentrated under reduced pressure to give (R)-1-benzyl-3-mesyloxypyrrolidine (5.7 g) as a yellow oil: 1HNMR (CDCl3), 60 MHz): δ1.9-2.7 (m, 4H), 2.78 (d, 2H, J=15), 2.90 (s, 3H), 3.65 (s, 2H), 4.9-5.3 (m, 1H), 7.28 (s, 5H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[NH:27][C:26]4=[O:33])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CN(C=O)C.C(O)(=O)C>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[NH:27][C:26]4=[O:33])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-n4cc(C)c(=O)[nH]c4=O)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3cccc(-n4cc(C)c(=O)[nH]c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)benzo[d]thiazol-6-yl)acetate (12.9 mg, 0.0212 mmol) and 5M NaOH (85 μL, 0.424 mmol) in MeOH (0.1 mL) and THF (1.2 mL) was stirred at 50° C. for 1.5 hours. DMF (0.3 mL) and acetic acid (75 μL) were added and reaction mixture was concentrated to ˜0.3 mL, filtered using a syringe filter, diluted with methanol. Purified using Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) and lyophilized to give product. LCMS-ESI+: calc'd for C31H29ClN3O5S: 590.1 (M+H+); Found: 590.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.07 (d, J=8.5 Hz, 1H), 7.94 (dd, J=1.8, 1.8 Hz, 1H), 7.84 (s, 1H), 7.71-7.47 (m, 5H), 7.43-7.22 (m, 2H), 5.25 (s, 1H), 2.60 (s, 3H), 1.92 (d, J=5.2 Hz, 3H), 1.34 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:49]1[CH2:52][CH:51]([N:53]2[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]2)[CH2:50]1>CN(C=O)C>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:49]4[CH2:52][CH:51]([N:53]5[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]5)[CH2:50]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Reactant: OC1CCN(C2CNC2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CC(N4CCC(O)CC4)C3)n(C)c2n1
Reaction time: 2 h
Yield: 26.3 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (215 mg, 0.53 mmol), 2-chloro-1-methylpyridinium iodide (324 mg, 1.27 mmol) and DIPEA (460 μL, 2.64 mmol) in DMF (2 mL) was stirred for 5 min before the addition of 1-azetidin-3-ylpiperidin-4-ol (140 mg, 0.90 mmol) in DMF (2 mL). The resulting mixture was allowed to stir for 2 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 797 as a pale yellow solid (76 mg, 26%). LCMS (method G): RT 5.26 min, [M+H]+ 546.4. 1H NMR (CDCl3, 400 MHz): δ 8.06-8.06 (1 H, m), 7.76-7.75 (1 H, m), 7.31-7.24 (2 H, m), 4.72-4.71 (1 H, m), 4.50 (1 H, dd, J=10.65, 5.40 Hz), 4.30-4.20 (1 H, m), 4.14 (3 H, s), 4.14-4.07 (1 H, m), 3.88 (4 H, t, J=4.71 Hz), 3.81 (1 H, s), 3.37 (2 H, q, J=7.47 Hz), 3.28-3.27 (1 H, m), 2.72 (2 H, d, J=27.26 Hz), 2.25-2.10 (2 H, m), 2.01-1.91 (2 H, m), 1.68-1.60 (5 H, m), 1.46-1.43 (4 H, m)