Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=2[CH:5]=1)(=O)[CH3:2].[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C.C(O)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([C:1]3[NH:20][C:14]4[C:19]([CH:2]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:5][C:6]=2[CH:12]=1
Reactant: CC(=O)c1cc2cc(Br)ccc2o1
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2oc(-c3cc4ccccc4[nH]3)cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 2-acetyl-5-bromobenzo[b]furan (commercially available, 5.0 g, 1 eq.) is initially charged in absolute ethanol. Phenylhydrazine (97%; 2.33 g, 1 eq.) is introduced. 20 drops of glacial acetic acid are added to this mixture and the reaction is stirred at room temperature for 24 h. Then phenylhydrazine (97%; 0.36 g, 0.15 eq.) is added and the mixture is stirred at room temperature for a further 5 h. The solids are filtered off and washed with distilled water. Dried under reduced pressure at 65° C. This gives 6.65 g of intermediate. This is introduced gradually into polyphosphoric acid (60 g), and the mixture is heated to 120° C. and stirred for a further 1 h. 0.5 l of distilled water is cautiously added dropwise to the reaction and the mixture is stirred for a further 2 h. The suspension obtained is neutralized with 50% sodium hydroxide solution. The suspension is filtered with suction and the solids are washed with distilled water. The solids obtained are dried under reduced pressure. This gives 6.07 g of slightly contaminated product (crude yield 93%). This is used in the next stage without purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH:11]1[CH:12]=[CH:13][C:8]([NH:14][C:15]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:16])=[CH:9][CH:10]=1
Reactant: OCCNCCO
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(CCO)CCO
Reaction time: 1 h
Yield: 119.7 %

Procedure:
A mixture of 15.62 ml (0.136 mol) of diethanolamine and 163 ml of methylene chloride is poured, at a temperature of 10° C., into a three-necked flask containing 18.25 ml (0.168 mol) of phenyl isocyanate dissolved in 37 ml of CH2Cl2. The mixture is left at that temperature for one hour, and then at room temperature overnight, and concentrated in vacuo to obtain 36.5 g of the expected product. (Yield=100%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+].[Cl:24][CH:25]=[CH:26][CH2:27]Cl>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:27][CH:26]=[CH:25][Cl:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1Br
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(C#N)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A stirred solution of nitrile 141 (5.78 g, 16.6 mmol) in dry DMF (50 mL) was treated at 0° C. with NaH (0.80 g, 20.0 mmol, 60% in oil). The resulting suspension was warmed to room temperature for 30 min, then cooled to 0° C. again and treated with 1,3-dichloropropene (4.8 mL, 52 mmol, mixed isomers). After stirring at room temperature for a further 6 h, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried, and concentrated to dryness under high vacuum at 80° C. The residue was chromatographed on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-cyano-2-naphthyl(3-chloro-2-propenyl)carbamate (142) (6.77 g, 96%) as a foam; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.69 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.13, 8.12 (2 d, J=8.6 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.69, 7.63 (2d, J=8.7 Hz, 1H), 6.42-6.29 (m, 1H), 6.17-5.99 (m, 1H), 4.55-4.45, 4.40-4.19, 4.15-3.98 (3 m, 2H), 1.48, 1.24 (2 s, 9H). HRMS (FAB) calcd. for C19H1979Br35ClN2O2(m/z 421.0318, found 421.0306.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)cc1

Procedure:
To a solution of 4-hydroxy-1-napthaldehyde (172 mg, 1.0 mmol) in DCM (10 mL) was added copper (II) diacetate (181 mg, 1.0 mmol), 4-cyanophenyl boronic acid (441 mg, 3.0 mmol), triethylamine (0.7 mL, 5.0 mmol) and 4 Å molecular sieves. After 48 h at rt the mixture was filtered. Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 3:7). The resulting solid was washed with ether (10 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound: δH (CDCl3) 7.06 (1H, d), 7.21 (2H, d), 7.49 (1H, t), 7.62-7.82 (3H, m), 7.96 (1H, d), 8.28 (1H, d), 9.36 (1H, d), 10.33 (1H, s).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[CH:10]=[CH:9][C:8]3[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]([CH3:17])[C:7]=3[C:6]=2[N:5]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CN(C)C=O>[CH2:23]([NH:25][C:26]([NH:3][C:4]1[N:13]=[CH:12][C:11]2[CH:10]=[CH:9][C:8]3[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]([CH3:17])[C:7]=3[C:6]=2[N:5]=1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ncc2ccc3c(C(=O)OCC)nn(C)c3c2n1
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
To a suspension of 18 mg (0.44 mmol) of sodium hydride 60% in mineral oil (0.37 mmol) in dry dimethylformamide, a solution of 100 mg of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (0.37 mmol) in 5 mL of the same solvent was added dropwise at 0° C. under stirring. After 5 minutes, 0.070 mL (0.88 mmol) of ethylisocyanate were added to the mixture and the reaction allowed to come to room temperature. After 8 hours the solvent was evaporated under reduced pressure, the residue redissolved with dichloromethane and washed with water. After drying over Na2SO4 the solvent was removed and the product purified by chromatography on a silica gel column (eluant dichloromethane/acetone) leading 64 mg (50% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH2:22])=[O:21])[CH:4]=1.O=[CH:24][C:25](Cl)([Cl:27])[Cl:26]>C1C=CC=CC=1>[Cl:26][C:25]([Cl:27])=[CH:24][NH:22][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=1)=[O:21]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(N)=O)c1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC=C(Cl)Cl)c1

Procedure:
1.0 g (0.0032 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in benzene and mixed with 0.93 g (0.0032×2.0 mol) of chloral, followed by treating the obtained solution under reflux for about 5 hours. The reaction solution was concentrated and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[C@H:32]([CH3:31])[CH2:36][O:35][C:34]3=[O:37])=[CH:3][C:4]=2[N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 87.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (492 mg) described in Preparation Example 181 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (448 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].N1CCCCC1>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]2[S:12][C:13](=[O:18])[NH:14][C:15]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Yield: 59.2 %

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g), 1,3-thiazolidine-2,4-dione (11.70 g), piperidine (1.70 g) and ethanol (300 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated. The obtained residue was washed with ethanol to give 5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione as yellow crystals (14.8 g, yield 59%). Recrystallization thereof from acetone-hexane gave pale-yellow prism crystals. melting point: 272-273° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:20][C:21](OC(C)=O)=[O:22]>C(Cl)Cl>[C:8]([O:7][C:6](=[O:12])[NH:5][CH:3]1[CH2:4][N:1]([C:21](=[O:22])[CH3:20])[CH2:2]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (100 g, 0.58 mol) and Et3N (88 g, 0.87 mol) in DCM (1500 mL) was added Ac2O (59.6 g, 0.88 mol) dropwise at 0° C. The mixture was then stirred at 0° C. for 2 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of water (1000 mL) and then stirred at 20° C. for 30 min. The organic phase was separated, dried (Na2SO4) and concentrated to give the crude product. Seven batches were run in parallel and produced a combined crude product weight of 530 g. This crude was used in next step without the further purification. LCMS (m/z): 215.1 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][N:12]=2)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([N:10]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:19]([F:20])([F:21])[F:22])=[N:9]2)[CH:16]=1)(=[O:33])=[O:32]
Reactant: OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 37 (215 mg, 0.695 mmol) in dichloromethane (6.95 mL) at 0° C. was added triethylamine (0.388 mL, 2.78 mmol) followed by methanesulfonyl chloride (0.163 mL, 2.092 mmol). The resulting solution was allowed to stir at room temperature for 1 h. The solvent was evaporated. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. Compound 38 was isolated as an orange solid and used as is for the next step. LRMS (ESI): calc. 387.1; found 388.1 (MH)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: OCC(F)(F)F
Product: N#Cc1cc(F)ccc1OCC(F)(F)F

Procedure:
2,5-difluoro-benzonitrile was reacted with 2,2,2-trifluoro-ethanol according to the method of Example 84A to provide the title compound. MS (DCI/NH3) m/z 220 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[F:29])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccccc2F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Yield: 41.9 %

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8 mg, 0.02 mmol), 2-fluorobenzoic acid (4.2 mg, 0.03 mmol), PyBOP (16 mg, 0.03 mmol) and DIEA (6.5 mg, 0.05 mmol) in 1,2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 374 as a white solid (4 mg, 42%). [M+H]+=478.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[NH:27][NH:28]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[N:27]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=2)=[N:28]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(NNC(=O)OC(C)(C)C)c1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 1.500 g), tert-butyl 2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-97, 1.0 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.02 (d, J=6.9 Hz, 6H), 2.44 (m, 1H), 4.28 (d, J=8.7 Hz, 2H), 7.28 (br s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.91 (d, J=8.1 Hz, 2H), 8.38 (m, 1H), 12.61 (m, 1H); MS (m/z): 495.7 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:46])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:46])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)c2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl)-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.03 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.06 gm of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[CH3:14][Sn](C)(C)C.C(Cl)(Cl)Cl>CN(C=O)C.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>[CH3:14][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 74.1 %

Procedure:
To a solution of 7-bromo-5-nitroindoline (0.65 g, 2.7 mmol) in 10 mL of DMF were added tetramethyltin (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.10 g) in a portion and resulting mixture was stirred in sealed tube for 12 h at 140° C. The reaction mixture was concentrated in vacuo, providing a dark oily residue which was subjected to column chromatography (CHCl3, neat) to yield 0.35 g (2.0 mmol, 74%) of the desired product.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([NH:31][C:32]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCN(C(=O)Nc2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg) and triethylamine (0.412 ml) in dichloromethane (6 ml) was added phenyl isocyanate (0.186 ml) at ambient temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The precipitate was filtered, then washed with dichloromethane and water. The residue was dried to give N-(4-phenylcarbamoyl-1-piperazinyl)-p-fluorobenzamide (0.23 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.46) (0.175 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.021 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 232° C.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]([OH:16])[CH3:19])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Al](C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C=O)co1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carbaldehyde (223 mg, 0.92 mmol) in CH2Cl2 (8.0 mL) was treated at 0° C. with trimethylaluminum (2.50 mL of a 2M solution in toluene, 5.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted twice with CH2Cl2 and twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=0.97 min, [M+H]+=258.30.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:22])=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[F:22][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: Fc1c(Cc2cnc3ccc(Cl)nn23)ccc2ncccc12
Reactant: CN1CCNCC1=O
Agent: Cl
Product: CN1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)CC1=O

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5-fluoro-quinoline (Intermediate N, 70 mg, 0.224 mmol), 1-methylpiperazin-2-one hydrochloride (67.4 mg, 0.448 mmol) (tR 3.31 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.47 (d, 1H); 7.85 (d, 1H); 7.78 (d, 1H); 7.69 (d, 1H); 7.66 (s, 1H); 7.61 (m, 1H); 7.50 (s, 1H); 4.42 (s, 2H); 4.03 (s, 2H); 3.74 (m, 2H); 3.35 (m, 2H); 2.84 (s, 3H)).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[C:15]2[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]1=2)#[CH:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([C:11]#[C:12][C:2]3[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=3)[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(S(N)(=O)=O)s2)CCN(C)C1

Procedure:
A mixture of 5-bromo-thiophene-2-sulfonic acid amide (200 mg, 0.8 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (222 mg, 0.9 mmol), TBAF.3H2O (756 mg, 2.4 mmol) and dichloro bis(triphenyl phosphine) palladium (II) (28 mg, 0.04 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by column chromatography using neutral alumina and 5% MeOH-DCM, followed by reverse phase HPLC to yield 5-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-thiophene-2-sulfonic acid amide. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.57 (d, 1H), 7.46 (d, 1H), 7.36 (m, 2H), 7.21 (d, 1H), 4.42 (s, 2H), 3.71 (s, 2H), 3.3 (m, 2H), 3.1 (s, 3H), 2.42 (s, 3H).