Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A suspension of Example A1 (14.38 g, 57.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.08 g, 62.9 mmol) and Cs2CO3 (55.9 g, 171 mmol) in DMF (150 mL) was sparged with Ar, treated with tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4](6.60 g, 5.71 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to near-dryness. The residue was treated with EtOAc, washed with 5% LiCl (1×) and the aqueous layer back-extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (12.28 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=2.8 Hz, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.97 (dd, J=8.9, 2.8 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 6.97 (dd, J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5][N:6]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:7]([N:9]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:8])=[CH:5][N:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)c2cnc(Cl)s2)c2c(C)cccc2Cl)cc1

Procedure:
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:47]([C:49]([CH3:51])=[O:50])=[CH2:48].CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:48]=[CH:47]/[C:49](=[O:50])[CH3:51])=[CH:15][C:14]=3[F:22])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C=CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 5 (1.0 g), Pd(OAc)2 (9 mg), P(o-tolyl)3 (45.7 mg), methyl vinyl ketone (0.23 mL), and Et3N (0.78 mL) in 5.28 mL anhydrous DMF is heated in a sealed tube at 100° C. overnight. The reaction mixture is cooled to room temperature and then cooled in an ice bath. The cooled reaction mixture is poured into 20 mL ice cold 1N HCl. A brown solid precipitated and is collected. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 453.4 mg (52%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=1.Br[CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:24]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:20][C:4]2[CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:24]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1cc(O)cc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)COc1c(C)cccc1CBr
Product: CCOC(=O)COc1c(C)cccc1COc1cc(C)cc(OCc2ccc3ccccc3n2)c1

Procedure:
The title compound is prepared using essentially the same procedure used in example 35 except using 3-methyl-5-(quinolin-2-ylmethoxy)-phenol (example 55) in place of 3-(quinolin-2-ylmethoxy)-phenol and ethyl (2-bromomethyl-6-methyl-phenoxy)-acetate (example 43b) in place of (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[N:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:5]=2[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[O:1]=[C:2]1[C:10]2[N:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: N#Cc1cnc2c(c1)CCC2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cnc2c(c1)CCC2=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 7-hydroxy-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile (1.05 g, 6.56 mmol) in dichloromethane (50 ml) at 0° C. was added Dess-Martin periodinane (2.92 g, 6.88 mmol) and the mixture was stirred at 23° C. for 2 hours. Poured on 1 M Na2CO3-sol. and extracted twice with dichloromethane. The organic layers were washed with diluted NaHSO3 solution and brine, dried over Na2SO4, filtered and evaporated to give a grey solid. The residue was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 7-oxo-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile (855 mg, 5.14 mmol, 78.3%) as a dark green solid. MS (ISP): m/z=159.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:22]3[S:23][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:31])=[O:7])[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:18]=2)=[CH:41][N:42]=1
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine via General Procedure A. Purification on silica yielded 155. NMR (CDCl3): 2.57-2.60 (m, 4H, 2×CH2), 2.92 (s, 3H, CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.57 (m, 4H, 2×CH2), 3.86 (s, 2H, CH2), 3.89-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.28 (sbr, 2H, NH2), 7.29 (s, H, ArH), 7.33 (s, H, ArH), 9.29 (s, 2H, 2×ArH). MS: (ESI+): MH+ 528.44
Reaction SMILES: C(OC([N:11]1[CH2:42][CH2:41][C:14]2([O:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)[CH:15]2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][CH:15]2[C:14]3([CH2:13][CH2:12][NH:11][CH2:42][CH2:41]3)[O:19][CH2:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:24][CH:23]=2)=[CH:39][CH:38]=1
Reactant: CC(C)COc1ccc(CN2C(=O)COC3(CCN(C(=O)OCc4ccccc4)CC3)C2Cc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COc1ccc(CN2C(=O)COC3(CCNCC3)C2Cc2ccc(F)cc2)cc1

Procedure:
The spirocycle 103NLS33 (62 mg, 0.107 mmol) in ethanol (5 mL) was N-CBz-deprotected by hydrogenation in presence of Pd/C (10%, 40 mg) under H2-balloon pressure. The catalyst was filtered off and the filtrate evaporated under reduced pressure to give crude 5-(4-fluorobenzyl)-4-(4-isobutoxybenzyl)-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one. The residue was dissolved in methanol (3 mL), formaldehyde (37% in water, 0.017 mL) added, followed by the addition of acetic acid (0.03 mL) and sodium cyanoborohydride (60 mg, 0.95 mmol). The solution was stirred at rt for 5 h, then water was added and the mixture basified with 2 N aq. NaOH solution. The mixture was extracted three times with dichloromethane, the combined organic layers washed with sat. ammonium chloride solution and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with a stepwise gradient of 0-7% methanol in dichloromethane, giving 103NLS35B (43 mg, 88% over both steps) as a colorless oil. The compound was converted to its HCl form by treatment with 2 M HCl in diethylether as described above for 69NLS75, affording the salt as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(Oc3cnc(N)nc3)ccn2)cn1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine (676 mg, 3.04 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (758 mg, 3.64 mmol), potassium carbonate (1.259 g, 9.11 mmol) and Pd(PPh3)4 (175 mg, 0.152 mmol) were combined in dioxane (12 mL) and water (3 mL). The mixture was degassed with argon, and warmed to 85° C. overnight. The mixture was diluted with EtOAc (75 mL) and water (40 mL) and was filtered to collect an off-white solid. The organic phase was separated, washed with brine (40 mL) and evaporated at reduced pressure to give additional off-white solid. The two crops of solids were combined and triturated with EtOAc (15 mL) with sonication. The solid was collected by filtration, washed with EtOAc (2×5 mL) and dried under vacuum to provide 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-amine (455 mg, 55%). 1H NMR (DMSO-d6): δ 8.34 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 2H), 7.96 (s, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.77 (s, 2H), 6.67 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:15])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2([OH:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2CCC1Cc1cccnc1
Reaction time: 10 h

Procedure:
Methyl magnesium bromide (15 ml of a 3M solution in ether) was added dropwilse over 5 minutes to a stirred solution of 7-bromo-2-(3-pyridylmethyl)-1-tetralone (3.20 g) in dry tetrahydrofuran (50 ml). The resulting mixture was heated under reflux with stirring for 10 hours and then cooled. An excess of aqueous ammonium chloride solution was added and the mixture was extracted several times with ether. The combined ethereal extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 7-bromo-1-hydroxy-1-methyl-2-(3-pyridylmethyl)-1,2,3,4-tetrahydronaphthalene (2.87 g) as a mixture of isomers which was used directly in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[H-].[Na+].[CH3:11][NH:12][C:13](=[O:15])[CH3:14]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]([CH3:11])[C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ncc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-chloroprimidine (2.00 g, 10.34 mmol) in THF was added 60% NaH (0.34 g, 14.00 mmol) in mineral oil. After 20 minutes, N-methylacetamide (0.80 g, 11.00 mmol) was added dropwise. After 2 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(5-bromo-pyrimidin-2-yl)-N-methyl-acetamide.
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[CH2:15]([O:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:15]([O:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1N
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1NC(=O)CC(=O)C(C)(C)SCC
Temperature: 150 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 1 and 36.1 g of 2-octadecyloxyaniline was stirred in an oil bath at 150° C for 4 hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from ethanol to obtain 45.3 g (yield 85%) of Coupler (10) having a melting point of 60° to 62° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1>>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 5) following General Procedure E.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: Br
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 10.12 g of 4′-chloropropiophenone, 0.1 ml of hydrobromic acid (48% aqueous solution) and 60 ml of acetic acid was cooled to 0° C. under a nitrogen atmosphere. Into the mixture, 3.1 ml of bromine was added dropwise, then, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, to obtain 14.34 g of 2-bromo-4′-chloropropiophenone.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:12]=[C:13]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:14]4=[C:15]([Cl:20])[C:16]=3[CH2:17][C:18]=2[CH:19]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:12]=[C:13]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:14]4=[C:15]([Cl:20])[C:16]=3[CH2:17][C:18]=2[CH:19]=1
Reactant: COc1ccc2c(c1)Cc1c-2cc2ccc(OC)cc2c1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(c1)Cc1c-2cc2ccc(O)cc2c1Cl
Yield: 87 %

Procedure:
To a solution of 65 (0.8 mmol) in toluene (8 ml) was added PCl5 (4.8 mmol). After stirring the mixture for 2 hours at 20° C. it was poured into ice water and extracted with toluene. The organic layer was washed with NaHCO3 (aq), dried over MgSO4 and concentrated. The residue was dissolved in 12 ml m-xylene/toluene (2:1) palladium on carbon (10% w/w, 200 mg) was added and the mixture was refluxed for 2 hours. The catalyst was filtered off and the filtrate was concentrated. Chromatography (heptane/ethyl acetate) gave pure 2,8-dimethoxy-10-chloro-11H-benzo[b]fluorene 66a in 92% yield. (Rf=0.58 heptane/toluene (1:1)) BBr3 (3.5 mmol) was added to a solution of 66a (1.18 mmol) in 30 ml CH2Cl2 and after 1 hour another 2.1 mmol of BBr3 was added. After 1.5 hours the mixture was carefully poured into sat. NaHCO3 (aq) and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. Purification on silica (toluene/ethyl acetate) afforded pure 67a in 87% yield. (Rf=0.38 toluene/ethyl acetate (4:1)); ESI-MS: M+H=283.0, M−H=281.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([CH3:10])[C:4]=1[CH3:11].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:10][C:5]1[C:4]([CH3:11])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)(=[O:14])[CH3:13]
Reactant: COc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(COC(C)=O)c1C
Yield: 33.3 %

Procedure:
To 37.2 g of 4-methoxy-2,3-dimethylpyridine-1-oxide, 55.0 g (5.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 3 hours at 90 to 100° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 15.8 g of 2-acetoxymethyl-3-methyl-4-methoxy-pyridine as an oily matter.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-nitroaniline to yield 2-[(4-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](Cl)=[O:7])[C:2]#[CH:3].[CH3:9][NH:10][CH3:11]>O1CCCC1>[CH3:9][N:10]([CH3:11])[C:6](=[O:7])[CH2:5][O:4][CH2:1][C:2]#[CH:3]
Reactant: C#CCOCC(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Product: C#CCOCC(=O)N(C)C

Procedure:
Prop-2-ynyloxyacetyl chloride (1.74 g) in tetrahydrofuran (20 ml) was added dropwise over 5 min. to a stirred solution of dimethylamine (12 ml of 33% solution in ethanol) in tetrahydrofuran (15 ml) at ambient temperature. After 30 minutes the solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate (20 ml) and ethyl acetate (30 ml). The aqueous layer was separated and then re-extracted with ethyl acetate (20 ml). The combined ethyl acetate extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. There was thus obtained the title compound as a liquid (1.15 g). NMR Spectrum: (CDCl3) 2.47 (t, 1H), 2.96 (s, 3H), 3.02 (s, 3H), 4.27 (s, 2H), 4.33 (d, 2M); Mass Spectrum: M+H+ 142.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:12].[H][H]>CO.[Pd]>[ClH:12].[OH:1][C@@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: [H][H]
Reactant: CS(=O)(=O)OC[C@H](O)CC#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OC[C@H](O)CCN

Procedure:
To a solution of (R)-3-hydroxy-4-(methanesulfonyloxy)butyronitrile (14.6 g) in methanol (60 ml), 10 wt. % Pd on carbon (2.5 g) and conc. hydrochloric acid (15 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 8 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 1/9) to obtain pure (R)-3-hydroxy-4-(methanesulfonyloxy)butylamine hydrochloride (14.4 g). Yield, 80 %.