Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C(=O)(O)[O-].[Na+].C(OC([NH:35][C@@H:36]([C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:37])=O)(C)(C)C>C(#N)C>[ClH:18].[NH2:35][C@@H:36]([C@@H:38]1[CH2:42][CH2:41][N:40]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:39]1)[CH3:37]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N2CC[C@@H]([C@@H](C)N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cl

Procedure:
A 0.35 g sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 0.73 g of sodium bicarbonate were dissolved in 24 mL of anhydrous acetonitrile, reacted with (3R,1R)-3-(1-(t-butoxycarbonylamino)ethyl)-pyrrolidine (0.51 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 29:1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 220°-222° C. MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) δ: 0.61 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H), 1.28 (d, 3H, J=6 Hz), 1.82 (m, 1H), 2.27 (m, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 3.57 (s, 1H), 3.92 (m, 1H), 7.90 (s, 1H), 8.17 (br s, 3H), 9.07 (d, 1H, J=11 Hz), 13.84 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][NH2:20])=[NH:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[NH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: N=C(NN)c1ccc(Cl)cc1
Product: Clc1ccc(-c2n[nH]c(-c3sccc3Cl)n2)cc1

Procedure:
Compounds of this invention with Formula V may be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of 3-chloro-thiophene-2-carbonyl chloride with 4-chloro-benzenecarboximidic hydrazide produces the product 3-(4-chloro-phenyl)-5-(3-chloro-thiophen-2-yl)-1H-[1,2,4]-triazole.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][C:24]1=[O:32].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
Methyl isobutyl ketone, 1.0 g (0.004 mole) of 4-(diphenylmethylene)piperidine, 0.96 g (0.004 mole) of 1-(1-bromo-2-ethyl)-2-benzimidazolone, 0.53 g (0.008 mole) of Na2CO3 and a few crystals of NaI are heated for 9 h at the reflux temperature.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[F:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=1.O>C(OCC)C>[F:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[O:26])=[C:23]([C:33]([F:34])([F:35])[F:36])[CH:22]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1C(F)(F)F
Reactant: Cc1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccnc(C(=O)c2ccc(F)cc2C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
2-bromo-4-methylpyridine (4.7 g) was dissolved in diethylether (150 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (16.8 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 4-fluoro-N-methoxy-N-methyl-2-trifluoromethylbenzamide (6.2 g) in diethylether (50 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 2-(4-fluoro-2-trifluoromethylbenzoyl)-4-methylpyridine (4.5 g) as pale yellow amorphous.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:35][CH2:36][C:37](=[O:40])[CH2:38][CH3:39].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:37]([CH2:38][CH3:39])([OH:40])[CH2:36][CH3:35])[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
1.43 ml (3.58 mmoles) of butyllithium (as a 2.5M hexane solution) was added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 0.50 ml (3.57 mmoles) of diisopropylamine in 10 ml of anhydrous tetrahydrofuran. The mixture was then stirred for 30 minutes, after which a solution of 500 mg (1.61 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 5 ml of anhydrous tetrahydrofuran was added thereto. The mixture was then stirred for a further 1 hour, and then 0.38 ml (3.59 mmoles) of distilled 3-pentanone was added to the mixture and stirred for a further 2 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a 10% w/v aqueous solution of citric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (using a 1:1 by volume mixture of hexane and diethyl ethyl as eluent), followed by recrystallization from hexane, to give 425 mg (yield 67%) of the title compound as white crystals, melting at 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Yield: 84.8 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(1H)-quinolinone (20.0 g), pyridine (26 g) and dichloromethane (200 ml) was added dropwise 2-methylbenzoyl chloride (26 g) at room temperature with stirring. The mixture was stirred under reflux for 4 hours. The reaction mixture was poured into 500 ml of water, then shaken with additional dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) and once with saturated aqueous NaCl solution, then dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the residue was recrystallized to obtain 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone (yield 28 g) as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6](I)=[C:5]2[O:16][CH2:17][CH3:18].[F:19][C:20]([F:39])([F:38])[O:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:36]=[CH:37][C:22]([O:21][C:20]([F:19])([F:38])[F:39])=[CH:23][CH:24]=3)=[CH:32][CH:31]=1)=[C:5]2[O:16][CH2:17][CH3:18]
Reactant: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOc1c(I)c(C)nc2cc(OC)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)nc2cc(OC)c(Cl)cc12
Temperature: 85 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 6-chloro-4-ethoxy-3-iodo-7-methoxy-2-methylquinoline (1.56 g, 4.13 mmol), (4-(4-(trifluoromethoxy)phenoxy)phenyl)boronic acid (1.85 g, 6.20 mmol) and palladium (0) tetrakis triphenylphosphine (239 mg, 0.207 mmol) in degassed dimethylformamide was added 8.25 ml of a 2 N aqueous potassium carbonate solution. The reaction mixture was stirred 18 hours at 85° C., filtered through celite and concentrated in vacuo. The resulting residue was resuspended in dichloromethane and water. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-20% ethyl acetate in dichloromethane) provided 1.18 g 6-chloro-4-ethoxy-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline (57% yield) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.43 (s, 1H), 7.31-7.36 (m, 2H), 7.22-7.26 (m, 2H), 7.07-7.14 (m, 4H), 4.04 (s, 3H), 3.71 (q, J=7.1 Hz, 2H), 2.49 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: O=CCCCBr
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: BrCCCC1OCCCO1

Procedure:
To a solution of 4-bromobutanal (prepared as described in J. Org. Chem., 1979, 44, 3230-3238: 450 mg, 2.98 mmol) in tetrahydrofuran (10 mL) at room temperature was added 1,3-propane diol (1.0 mL, 13.7 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The mixture was heated at reflux for 2 hours, cooled and suspended in a mixture of water and diethyl ether (200 mL of 1:1). The two layers were separated and the organic layer was dried over magnesium sulfate, filtered, and then concentrated in vacuo to give the title compound as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH2:11][CH3:12])=[C:6]([Cl:13])[C:5]=1[OH:14])([O-])=O>[Ni].C(O)(C)C>[ClH:10].[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH2:11][CH3:12])=[C:6]([Cl:13])[C:5]=1[OH:14]
Reactant: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Agent: [Ni]
Solvent: CC(C)O
Product: CCc1c(Cl)cc(N)c(O)c1Cl
Product: Cl

Procedure:
525 ml of isopropyl alcohol, 125 g of the same 2-nitro-4,6-dichloro-5-ethylphenol as described above in (1) and 7.5 g of Raney nickel were placed in 1 liter of autoclave, and then the mixture was stirred until absorbing the theoretical amount of hydrogen gas under 10 kg/cm2 of initial pressure of hydrogen at 50° C. or less. Raney nickel catalysts were removed by filtration from the reaction mixture, and 165 g of concentrated hydrochloric acid was added to the resulting filtrate. Then, the resulting solution was stirred for 30 minutes at 40° to 50° C. to obtain white crystalline precipitates. Thereafter, the resulting crystal was cooled for 1 hour at 5° C. or less, and separated out, washed with 140 ml of acetone and dried to obtain 2-amino-4,6-dichloro-5-ethylphenol.hydrochloride. Yield was 112.5 g (87.5%).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1([C:15]([OH:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[CH2:18](O)[CH3:19]>>[NH2:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: NC1(C(=O)O)CCc2ccccc21
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(N)CCc2ccccc21
Yield: 84 %

Procedure:
Thionyl chloride (0.617 mL, 8.465 mmol) was added dropwise to anhydrous ethanol (6 mL) cooled to −30° followed by 1-amino-2,3-dihydro-1H-indene-1-carboxylic acid (0.300 g, 1.693 mmol) the reaction was then refluxed for 4 hours. The reaction was concentrated by rotary evaporation and diluted with water (5 mL) and the pH was adjusted to 9 with 6N aqueous sodium hydroxide. The solution was extracted with ethyl acetate (2×25 mL) and the organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.293 g, 1.43 mmol, 84%). 1H NMR (300 MHz, DMSO-D6) □ ppm 1.12 (t, J=7.17 Hz, 3 H) 1.85-2.07 (m, 1 H) 2.31 (s, 2 H) 2.51-2.66 (m, 1 H) 2.93 (t, J=6.99 Hz, 2 H) 3.90-4.21 (m, 2 H) 7.13-7.34 (m, 4 H). MS (DCI) m/z 206 (M+H)+, 223 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Cl)cc1

Procedure:
A suspension of 300 g of 4-chlorocinnamic acid (J. Am. Chem. Soc., 89:3803, 1967) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, and filtered to give as a white solid, p-chlorocinnamic acid methyl ester, mp 74°-5° C.
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([OH:36])([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[CH:26][N:27]=2)[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([OH:36])([C:23]2[NH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1nccn1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncc[nH]1

Procedure:
A solution of 9-fluoro-10-(3-hydroxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (200 mg, 0.39 mmol, 1.00 equiv) and TFA (1.5 mL) in dichloromethane (4.5 mL) was stirred for 5 h at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The pH value of the solution was adjusted to 9 with saturated potassium carbonate. The resulting mixture was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10/1) to give the titled compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[N:20]1.CCN(CC)CC>CC#N.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([NH:25][CH2:24][C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Reactant: Cn1ccc(CN)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1ccc(CNc2nc3ccnc(Cl)c3c3cc(Br)ccc23)n1
Temperature: 120 °C

Procedure:
To a solution of 9-bromo-1,6-dichloro-benzo[c][1,6]naphthyridine (0.10 g, 0.31 mMol) in anhydrous CH3CN (4.0 mL) was added C-(1-methyl-1H-pyrazol-3-yl)-methylamine (0.040 g 0.36 mMol) and anhydrous Et3N (0.22 mL, 1.6 mMol). The reaction mixture was heated in a sealed tube at 120° C. After 3 hours the solvent was removed and the solid obtained was re-dissolved in EtOAc (10 mL). The EtOAc layer was washed with water (2×5 mL), brine (1×10 mL), and dried over MgSO4. The filtrate was concentrated and the resulting residue was purified using preparative HPLC to afford 9-bromo-1-chloro-N-[(1-methyl-1H-pyrazol-3-yl)methyl]benzo[c]-1,6-naphthyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) 11.34 (br d, 1H), 10.11 (d, 1H), 8.61 (t, 1H), 8.32 (d, 1H), 7.75-7.73 (dd, 1H), 7.55 (d, 1H), 7.37 (t, 1H), 6.40 (d, 1H), 6.18 (d, 1H), 4.74 (d, 2H), 3.77 (s, 3H). LRMS calculated for C17H14BrClN5 [M+H]+, 404.0; found 403.9.
Reaction SMILES: [C:1]([SH:3])#N.N.C(Cl)(=O)C1C=CC=CC=1.[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:21]=2[N:22]=1>CC(C)=O>[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([N:27]=[C:1]=[S:3])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: N#CS
Reactant: Nc1ccc2nc(Oc3ccccc3F)sc2c1
Agent: N
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: Fc1ccccc1Oc1nc2ccc(N=C=S)cc2s1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
An amount of 17 g of ammonium rhodanide is dissolved in 200 ml of absolute acetone; an addition is then made to the solution, with stirring, of 31 g of benzoyl chloride. The reaction mixture is allowed to boil with refluxing for 5 minutes; a solution is then added of 57 g of 2-(2'-fluorophenoxy)-6-aminobenzothiazole (obtained from 2-(2'-fluorophenoxy)-6-nitrobenzothiazole by catalytic hydrogenation, cp. Example 6) in 400 ml of acetone. Stirring is continued for 2 minutes at the boiling temperature, and the mixture then poured, with stirring, into 5000 ml of ice water. Filtration is performed, the filter residue washed with water, and suspended in 350 ml of 10% sodium hydroxide solution. The suspension is quickly brought to boiling temperature and allowed to boil for a further 2 minutes. Cooling is then rapidly carried out in an ice bath; the suspension is neutralised with 2-n hydrochloric acid, and the pH-value adjusted with 2-n ammonia to 8. Filtration is again performed, the filter residue washed wth water until neutral, and dried at 80° in vacuo. The finely powdered material is suspended in 500 ml of anhydrous chlorobenzene and refluxed for 14 hours. After the solvent has been evaporated off, the residue is chromatographed through aluminium oxide with methylene chloride as the eluant. The obtained 2-(2'-fluorophenoxy)-6-isothiocyanobenzothiazole melts at 115° - 117°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:22]1(Br)[CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][CH:13]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
To a stirred solution of 4-[N-(tert-butoxycarbonyl)amino]phenol (3.1 g, 14.81 mmol) in DMF (40 mL) was added cesium carbonate (12.1 g, 37.02 mmol) and cyclobutyl bromide (2.0 g, 14.81 mmol). The reaction mixture was stirred at r.t. for 3 days, and then at 60° C. for 19 h. The reaction mixture was cooled to r.t., filtered and partitioned between water (50 mL) and Et2O (100 mL). The layers were separated, and the aqueous fraction was further extracted with Et2O (3×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 5-8% EtOAc/hexanes) gave the title compound (1.6 g, 41%) as a white solid. δH (CDCl3) 7.24 (2H, d, J 8.9 Hz), 6.82-6.72 (2H, m), 6.31 (1H, br. s), 4.67-6.54 (1H, m), 2.52-2.36 (2H, m), 2.25-2.08 (2H, m), 1.94-1.78 (1H, m), 1.77-1.62 (1H, m), 1.53 (9H, s). LCMS (ES+) 208.0 ((M−tBu)+H)+, RT 3.10 minutes (Method 3).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[CH2:17]1[O:20][CH:18]1[CH3:19].O>C1(C)C(C)=CC=CC=1>[OH:20][CH:18]([CH3:19])[CH2:17][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC1CO1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(O)CN1c2ccccc2Sc2ccccc21

Procedure:
A solution of phenothiazine (5 g, 25.1 mmol) and sodium amide (95%, 1.2 g, 29 mmol) in xylene (30 ml) was heated under reflux for 3 hours. Then propylene oxide (2.5 ml, 37 mmol) was added thereto under ice-cooling, and the reaction mixture was heated under reflux for 3 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained black-brown solution containing xylene was purified by column chromatography on silica gel to give a dark black oil. Yield 4.19 g (65%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]([C:24]1[S:28][C:27]([SH:29])=[N:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21].C([O-])([O-])=O.[K+].[K+]>>[CH:20]([C:24]1[S:28][C:27]([S:29][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:7][C:8](=[O:12])[O:9]3)=[CH:4][CH:3]=2)=[N:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]
Reactant: CCC(C)c1cnc(S)s1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1

Procedure:
Employing the procedure described in Example 1, Step 3, but using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, 5-sec-butyl-1,3-thiazole-2-thiol and K2CO3, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 7.58-7.67 (m, 3H), 7.52 (d, 1H), 7.46 (d, 1H), 7.32-7.42 (m, 3H), 6.38 (s, 1H), 3.08 (sextet, 1H), 1.83-1.67 (m, 2H), 1.32 (d, 3H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>>[Br:22][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C#N)cc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1ccc(CBr)c(OC(F)(F)F)c1

Procedure:
4-Methyl-3-Trifluoromethoxybenzonitrile is brominated with NBS according to Example 1A to give 4-bromomethyl-3-trifluoromethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 4.51 (s, 2H), 7.55 (br s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH:19]([C:25]([OH:27])=O)[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.Cl.CNC.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.C(#N)C>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH:19]([C:25]([N:3]([CH3:4])[CH3:2])=[O:27])[C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)NC(=O)C(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
WSC (6.5 g) was added to an acetonitrile solution of 7-methoxy-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), HOBt (2.85 g) and triethylamine (8.5 g). The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue was diluted with ethyl acetrate. The organic layer was washed with 1N aqueous hydrochloric acid solution, 10% aqueous potassium carbonate solution, and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (1.63 g).