Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:18]([NH2:20])=O>CN(C=O)C.C(O)=O>[C:12]1([C:4]2[NH:3][C:2]3[N:1]=[CH:18][N:20]=[C:7]([OH:8])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1N
Solvent: CN(C)C=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccccc3)cc12

Procedure:
Under a protective gas, 2.30 g (10 mmol) of 2-amino-3-ethoxycarbonyl-5-phenyl-1H-pyrrole [for preparation see: Synthesis, 272 (1987)] in 20 ml of formamide, 10 ml of DMF and 5 ml of formic acid are heated at 150° C. for 24 hours. The reaction mixture is cooled and filtered and the residue is washed with isopropanol/hexane. Stirring in hot isopropanol yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =212.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:31][CH2:32][CH2:33][S:34]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12

Procedure:
3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 3-(4-piperidinyl)-5-(2-thienyl)-1H-indole-7-carboxamide (30 mg, 0.09 mmol) was reacted with triethyl amine (0.04 mL, 0.27 mmol) and 2-chloroethylsulfonyl chloride (0.02 mL, 0.18 mmol) to give 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].O[CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: C[C@H](CCO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](CCOc1c(Cl)cccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 302.6 %

Procedure:
To a solution of 2,6-dichlorophenol (14.9 mg, 0.091 mmol) in THF (1.5 mL) was added (R)-2-(4-hydroxybutan-2-yl)isoindoline-1,3-dione (20 mg, 0.091 mmol) and triphenylphosphine (47.9 mg, 0.182 mmol) and the reaction mixture was cooled to 0° C. in an ice/water bath. DIAD (0.035 mL, 0.182 mmol) was added drop wise and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and was stirred at rt overnight. The reaction mixture was concentrated under vacuum to yield a yellow oil that was diluted with a minimal amount of DCM, loaded onto a 12 g ISCO column and purified by ISCO. Intermediate 13A (0.1003 g, 96% yield) was isolated as a clear oil. LC-MS (ESI) 365 (M+H), RT=2.84 min (Method A). NMR indicated that the final product contained reduced DIAD.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1>COCCOC>[O:18]1[C:10]2[CH:9]=[CH:8][C:13]([CH:14]=[C:7]3[S:1][C:2](=[S:3])[NH:4][C:5]3=[O:6])=[CH:12][C:11]=2[O:16][CH2:17]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: COCCOC
Product: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a 24 ml vial was placed 1 g of commercially available rhodanine, 1.3 g of piperonal and 0.5 ml of TEA in 10 ml of DME. The reaction was stirred for 5 h at 120° C. and then cooled to room temperature upon which the final product precipitated. The solid was filtered and washed with DME affording 1.6 g (80%) of orange powder.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[O:12])[CH2:27][CH2:28]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCC2)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4)cc3)CC2)c(C)c1
Yield: 4.2 %

Procedure:
Using 4-(pyrrolidin-1-yl)benzoic acid (200 mg) and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (15.8 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[Cl:11]>[Pd].CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(Br)c1
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-1-chloro-4-nitrobenzene (1.57 g, 6.6 mmol) and 10% palladium on charcoal (297 mg, 2.8 mmol) in EtOAc (50 mL) was stirred under an atmosphere of hydrogen (balloon) for 4 h. The reaction mixture was filtered through a pad of celite washing with EtOAc. The EtOAc was removed under reduced pressure affording the title compound as brown oil which solidified upon standing. It was used in the next step without further purification. MS (ESI, pos.ion) m/z: 206.0/208.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH3:18][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]([OH:14])[CH3:18])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)c2cc(C(F)(F)F)nn12
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
The compound of Example 115 (1.63 g) was dissolved in THF (70.0 mL) in an argon atmosphere. While the solution was kept at −78° C., 0.90 mol/L methyl magnesium bromide/THF solution (8.90 mL) was added dropwise and the mixture was stirred for 1.5 hours as it was allowed to gradually warm to −40° C. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a white powder (1.64 g).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([O:26]CC)=[O:25])[C:14]3=[O:29])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[CH3:30][NH2:31]>O1CCCC1>[CH:21]1([C:17]2[CH:16]=[C:15]([C:24]([OH:26])=[O:25])[C:14](=[O:29])[N:13]3[C:18]=2[C:19]([CH3:20])=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([NH:31][CH3:30])[CH3:3])[CH:5]=2)[CH:11]=[CH:12]3)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(C(C)Br)c3)ccn2c1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C)c1cccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)c1
Reaction time: 10 h

Procedure:
46.1 mg of ethyl 8-[3-(1-bromoethyl)phenyl]-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was dissolved in 2 ml of tetrahydrofuran. 0.1 ml of a solution of 2.0 M of methylamine in tetrahydrofuran was added to the obtained solution and they were stirred for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 1 N hydrochloric acid. After washing the obtained solution with ethyl acetate, the aqueous layer was concentrated under reduced pressure. The obtained residue was dissolved in 2 ml of methanol. 1 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at 50° C. for 1 hour. The reaction mixture was made acidic with 1 N hydrochloric acid to obtain 8.1 mg of 1-cyclopropyl-9-methyl-8-[3-(1-methylaminoethyl)phenyl]-4-oxo-4H-quinolizine-3-carboxylic acid in the form of crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:31]=[CH:30][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].NC1C=CC=CC=1.[F:39][C:40]([F:44])([F:43])[CH2:41]O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:27])[CH:21]=3)/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:30][CH:31]=1)[CH3:1]
Reactant: OCC(F)(F)F
Reactant: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)O)ccc32)c2ccccc2)cc1
Solvent: Nc1ccccc1
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OCC(F)(F)F)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and 2,2,2-trifluoroethanol aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C27H24F3N3O3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[NH2:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20]
Reactant: COc1ccc(C(C)N)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(C)N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 73 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.10 g, 0.35 mmol) and 5-(1-amino-ethyl)-2-methoxyphenol hydrochloride (excess) were coupled in N,N-dimethylformamide (2 mL) with triethylamine (0.15 mL). The solid material is collected by Buchner filtration, washed with diethyl ether and acetonitrile, and then dried under house vacuum to give (4Z)-6-bromo-4-({[1-(3-hydroxy-4-methoxyphenyl)ethyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as a light tan powder (0.11 g, 73%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc(C#N)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol), 2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxide monohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml) and stir at 55° C. Afer 16 hours; cool to ambient temperature, pour the mixture onto ice chips and stir. After 1 hour, remove the resulting yellow precipitate by vacuum filtration. Dry the precipitate under vacuum, recrystallize in ethanol to give 5.15 g (54%) of fine, amber colored needles: mp 162-164° C.; mass spectrum (ion spray): m/z 254.0 (M+1).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C@@H:17]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])[CH2:18][CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C@@H:17]([CH2:18][CH3:19])[C:16]([O:15][CH3:14])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: CC[C@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:31][C:32](=[O:33])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CC(=O)N1CCCC1)CC2
Temperature: 70 °C
Yield: 27.1 %

Procedure:
To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and K2CO3 (72 mg, 0.52 mmol). The reaction mixture was heated to 70° C. and stirred at 70° C. until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one (35 mg, 27%) as a yellow foam. The free base was converted to the HCl salt to the give title compound (30 mg, 80%) as a yellow solid: mp 162-166° C.; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J=14.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 97.9% (AUC), tR=13.4 min.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][N+:22]([O-:9])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(-c2ccncc2)cc1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.5 g (10.2 mmol) of meta-chloroperbenzoic acid are added to a solution of 1.18 g (6.81 mmol) of 4-(4-fluorophenyl)pyridine in 5 mL of chloroform cooled to 0° C. The suspension is stirred for 30 minutes.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:16]([C:5]4[N:6]=[C:7]([CH2:9][N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)[S:8][C:4]=4[CH:2]([CH3:1])[CH3:3])=[O:18])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(C)c1sc(CN2CCOCC2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1sc(CN2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
To a solution of 5-(1-methylethyl)-2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylic acid (31 mg) in DMF (3 ml) was added HATU (44 mg) and the mixture stirred at 20° C. for 10 min, then 6-(1H-indol-4-yl)-1H-indazol-4-amine (13 mg) and DIPEA (0.037 ml) were added and the mixture allowed to stand for 18 h. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (8 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:35][C:36]#[N:37])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.80 g), N,N-dimethylformamide (10 mL), potassium carbonate (1.0 g) and bromoacetonitrile (0.25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and this mixture was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a light brown solid, 0.90 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:29]=[CH:28][C:17]4[N:18]=[C:19]([NH:21][C@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)[S:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>CN1C(=O)CCC1>[CH:39]1([S:42]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:22]([NH:21][C:19]3[S:20][C:16]4[CH:15]=[C:14]([O:13][C:11]5[CH:10]=[CH:9][N:8]=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[CH:12]=5)[CH:29]=[CH:28][C:17]=4[N:18]=3)[CH2:23]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCNC5)sc4c3)ccn2)cn1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCN(S(=O)(=O)C6CC6)C5)sc4c3)ccn2)cn1
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To the solution of (S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine (7.6 mg, 18 μmol) and DIPEA (35 μL, 200 μmol) in 400 μL of NMP was added cyclopropanesulfonyl chloride (10 mg, 98 μmol). The reaction solution was stirred at 55 for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine (6.2 mg, 12 μmol) as white powder. ES/MS m/z 511.2 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[CH:19][NH:18][CH2:17]2)[CH:11]=1.C([O-])(O)=O.[Na+]>>[N+:6]([CH:17]1[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:20]=[CH:19][NH:18]1)([O-:9])=[O:7]
Reactant: C1=CN(c2cccnc2)CN1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])C1NC=CN1c1cccnc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO3 (10 ml, fum.) was added at 0° C. 3-(3-pyridinyl)-1H-imidazole [CAS No. 51746-85-1, commercially available] (4.25 g, 29.3 mmol). The reaction mixture was stirred at room temperature for 45 min and at 50° C. for 6 h and poured into ice-water (100 ml). Solid NaHCO3 was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by filtration and washed with water and hexane to yield 2-nitro-3-(3-pyridinyl)-1H-imidazole (5.53 g, 99%) as an off-white solid; mp 261° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)(Cl)Cl)=[O:21]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[N:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccnc1Nc1cccc(F)c1
Solvent: ClCCCl
Product: O=c1oc(=O)n(-c2cccc(F)c2)c2ncccc12
Yield: 82 %

Procedure:
To a solution of methyl 2-(3-fluorophenylamino)-nicotinate (4.90 g, 16.2 mmol; synthesized according to WO, A, 01/42244) in 1,2-dichloroethane (80 ml ) was added at 80° C. trichloromethyl chloroformate (also called: diphosgene, 5.9 ml, 48.3 mmol) gradually dropwise over about 30 minutes. Three hours later, activated carbon (130 mg) was added, and the mixture was heated under reflux for 30 minutes, filtered off, and then evaporated. The resultant residue was washed with isopropyl ether, and dried to give 1-(3-fluorophenyl)-2H-pyrido[2,3-d][1,3]oxazin-2,4(1H)-dione(3.42g, 82%) as crystals.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH3:45])[N:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[H-].[Na+]>O1CCCC1.C(O)C>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH3:45])[N:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)s2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl (6-ethoxy-2-pyridyl) tin (see WO 00/74681) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 660/662 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).