Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[N:20][OH:21])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(C=NO)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of (s)-[1-(3-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6 mmol) in ethanol (50 mL) were added hydroxylamine hydrochloride (833 mg, 12 mmol) triethylamine (2.5 mL, 18 mmol), the reaction mixture was heated at reflux for 18 h, and the reaction mixture was cooled down to room temperature and concentrated in vacuo. The crude product was diluted in EtOAc (100 mL) and extracted with 0.5N HCl. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to provide the title compound (1.53 g, 96% yield) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[C:6]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])[NH:5][N:4]=1.C([O-])(O)=[O:21].[Na+]>>[Cl:8][C:7]1[C:3]([CH2:2][OH:21])=[N:4][NH:5][C:6]=1[C:9]1[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C([O-])O
Reactant: Cc1cc(C)c(-c2[nH]nc(CBr)c2Cl)cc1C(=O)O
Agent: [Na+]
Product: Cc1cc(C)c(-c2[nH]nc(CO)c2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-(bromomethyl)-4-chloro-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 304.1, 200 mg, 0.58 mmol) and NaHCO3 (0.3 M, 10 mL) was stirred for 30 min at room temperature, then concentrated under reduced pressure. This resulted in 200 ma (crude) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2ccc3cc[nH]c3c2)c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 3-chlorophenylboronic acid: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2.CC(O)=O.[NH:23]([CH3:25])[CH3:24]>O>[CH3:24][N:23]([CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2
Reactant: CNC
Reactant: O=C(O)c1cccc2nc3cccc(F)c3nc12
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1cccc2nc3cccc(C(=O)O)c3nc12
Yield: 95 %

Procedure:
A solution of 9-fluorophenazine-1-carboxylic acid [Rewcastle et al., J. Synth Comm, 1987, 17, 1171] (200 mg, 0.8 mmol) in Me2NH (40% aqueous, 20 mL) was heated at 100° C. in a bomb for 3 h. The resulting intensely purple solution was diluted with water and then neutralized with AcOH. The aqueous solution was then extracted with CHCl3 (3×50 mL) until all color was extracted. The organic layer was further washed with water (1×150 mL), then dried over Na2SO4 and the solvent removed under reduced pressure. The resulting purple solid was dissolved in a minimal amount of CH2Cl2, and peteoleum ether was added until crystallization occurred, giving 9-(dimethylamino)phenazine-1-carboxylic acid as dark purple needles (210 g, 95%), mp 186-187.5° C. 1H NMR (CDCl3) δ 3.16 [s, 6 H, N(CH3)2 ], 7.26 (dd, J=6.8, 1.8 Hz, 1 H, H-6 or H-8), 7.81-7.88 (m, 2 H, H-7 and H-8 or H-6), 8.01 (dd, J=8.7, 7.0 Hz, 1 H, H-3), 8.48 (dd, J=8.7, 1.2 Hz, 1 H, H-4) and 8..91 (dd, J=7.0, 1.3 Hz, 1 H, H-2). Anal. (C15H13N3O2) C, H, N. Activation and coupling of this as above gave bis[((9-dimethylamino)phenazine-1-carboxamido)propyl]methylamine (54) as a red-purple oil (78%). 1H NMR (CDCl3) δ 1.91-2.00 (m, 4 H, 2×CH2CH2CH2), 2.29 (s, 3 H, NCH3), 2.57 (t, J=7.3 Hz, 4 H, CH2NCH3), 3.05 (s, 12 H, 2×N(CH3)2, 3.68 (q, J=6.5 Hz, 2 H, CH2NH), 7.07 (dd, J t 7.2, 1.3 Hz, 2 H, H-6 or H-8), 7.65 (dd, J=8.7, 7.3 Hz, 2 H, H-7), 7.70 (dd, J=8.7, 1.3 Hz, 2 H, H-8 or H-6), 7.90 (dd, J=8.6, 7.1 Hz, 2 H, H-3), 8.27 (dd, J=8.6, 1.4 Hz, 2 H, H-4), 8.87 (dd, J=7.1, 1.4 Hz, 2 H, H-2) and 10.99 (br t, J=5.1 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for C37H42N9O2 644.3461 (MH+), found 644.3485.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:17]([N:27]=[C:28]=[O:29])=[C:18]([F:26])[S:19][C:20]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:27]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:28]2=[O:29])=[C:18]([F:26])[S:19][C:20]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)Cc1sc(F)c(N=C=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1Cl
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 4.75 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of anhydrous toluene was added dropwise to a solution prepared by suspending 1.14 g of sodium hydride (purity: 55%) in 110 ml of dimethylformamide. Said dropwise addition was conducted at 0° C. under stirring over a period of 15 minutes. The resulting mixture was further stirred at 0° C. for 15 minutes. Then the reaction mixture was cooled to -30° C., and a solution of 6.9 g of 4-chloro-2-fluoro-5-methoxycarbonylmethylthiophenyl isocyanate in 50 ml of anhydrous toluene was added dropwise thereto. The resulting reaction mixture was returned to room temperature and stirred for 2 hours. After distilling off the solvent, the residual solution was added with ethyl acetate, washed twice with a solution of 20 ml of 2N hydrochloric acid and 500 ml of water, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This crude product was preliminarily purified by silica gel column chromatography using CHCl3 as developing solvent and then purified by silica gel column chromatography using ethyl acetate/hexane (3:1) as developing solvent to obtain 1.5 g of the objective compound as viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[O:16][C:17]2[C:18]([N:28]=1)=[C:19]1[C:24](=[CH:25][CH:26]=2)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]5[O:16][C:15]([CH3:14])=[N:28][C:18]5=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1nc2c3c(ccc2o1)C(C)NCC3
Product: Cc1nc2c3c(ccc2o1)C(C)N(C(=O)c1cc2ncc(Br)cn2n1)CC3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-3-oxa-1,7-diaza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[H-].[Na+]>CN(C)C=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To an N,N-dimethylformamide solution (100 mL) of 4-hydroxybenzaldehyde (10 g, 82 mmol) and 2-fluoropyridine (8.0 g, 82 mmol) was added sodium hydride (3.3 g, 82 mmol, 60% in oil), which was stirred for 30 minutes at 120° C., then for 45 minutes at 140° C., and then for 2 hours at 160° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water (three times), and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (9.3 g, 57%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)CCC(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccco1

Procedure:
A solution of 2-tributylstannylfuran (1 mmol), 4-methylvaleroyl chloride (1.1 mmol), and PdCl2(PPh3)2 (0.05 mmol) in THF was stirred at 25° C. for 24 h. Extraction and chromatography gave 2-(4-methylvaleryl)furan.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 30.5 %

Procedure:
Cyclopentyl bromide (1.2 g, 8.1 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours under refluxing. After completion of the reaction, 1N hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.75 g, 2.06 mmol, 30.5% yield) was isolated by filtration. Spectral data and the like are as shown in Example 1.
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][C:45]([CH3:47])=[CH2:46])[C:28]([N:30]1[C@H:34]2[CH2:35][CH:36]3[C:39]([CH3:41])([CH3:40])[C:33]2([CH2:38][CH2:37]3)[CH2:32][S:31]1(=[O:43])=[O:42])=[O:29])[C:9]([N:11]1[C@H:15]2[CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[C:14]2([CH2:19][CH2:18]3)[CH2:13][S:12]1(=[O:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8](/[CH:25]=[CH:26]/[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:28]([N:30]1[C@H:34]2[CH2:35][CH:36]3[C:39]([CH3:40])([CH3:41])[C:33]2([CH2:38][CH2:37]3)[CH2:32][S:31]1(=[O:42])=[O:43])=[O:29])[C:9]([N:11]1[C@H:15]2[CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[C:14]2([CH2:19][CH2:18]3)[CH2:13][S:12]1(=[O:24])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C)C(=O)N1[C@H]2CC3CCC2(CS1(=O)=O)C3(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a round bottom flask was added a solution of (2S,3E,5S)-2-benzyl-1,6-bis((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-5-(2-methylprop-2-en-1-yl)hex-3-ene-1,6-dione (67 mg, 0.098 mmol) in AcOH (10.5 mL) and 10% Pd/C (12 mg, 0.011 mmol). The reaction was stirred under an atmosphere of hydrogen (balloon) for 2 hr. The reaction mixture was diluted with EtOAc and filtered. The catalyst was rinsed with EtOAc and the filtrate was concentrated to give (2S,3E,5S)-2-benzyl-1,6-bis((7aS)-8,8-dimethyl-2,2-dioxidotetrahydro-3a,6-methano-2,1-benzothiazol-1(3H,4H)-yl)-5-(2-methylpropyl)hex-3-ene-1,6-dione (54 mg, 0.079 mmol, 80% yield) as a syrup. Anal. Calcd. for C32H52N2O6S2 m/z 684.2. found: 685.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]([OH:22])CO)[N:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]=[O:22])[N:3]=1
Reactant: OCC(O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reaction time: 16 h
Yield: 92.8 %

Procedure:
To a mixture of 1-{4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-ethane-1,2-diol (320 mg, 0.88 mmol) in MeOH (5 mL) and water (5 mL) is added sodium meta-periodate (567 mg, 2.65 mmol) and stirred for 16 hours before adding water (50 mL), and extracted thrice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidine-2-carbaldehyde (270 mg, 93%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[NH2:1][C:2]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncccc1-c1ccccc1
Temperature: 150 °C
Yield: 70.9 %

Procedure:
A microwave vial was charged with 2-amino-3-bromopyridine (0.5 g, 2.9 mmol), phenylboronic acid (0.52 g, 4.3 mmol), sodium bicarbonate (0.31 g, 2.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol), dioxane (5 mL) and water (1 mL). The vial was capped, and the reaction mixture was heated at 150° C. for 10 min. The reaction mixture was then cooled, quenched with water (10 mL), and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated to leave a black oil. The crude product was purified by chromatography on silica gel using 10-40% ethyl acetate/hexanes as eluant to provide the title compound as a white solid (0.35 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([N:6]([CH3:16])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:10]#[N:11])[CH3:5]>CO>[CH2:4]([N:6]([CH3:16])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:10]([NH:2][OH:3])=[NH:11])[CH3:5]
Reactant: CCN(C)c1cc(C#N)cc(C)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCN(C)c1cc(C(=N)NO)cc(C)n1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of K tert butylate (574 mg, 5.11 mL) in methanol (10 mL), hydroxylamine hydrochloride (304 mg, 4.38 mmol) is added. To the stirred suspension, a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinonitrile (256 mg, 1.46 mmol) in methanol (10 mL) is added and the resulting mixture is stirred at 60° C. for 15 h. The mixture is filtered, and the filtrate is concentrated. The residue is treated with 1 N aq. HCl, washed with DCM and then basified by adding 1 N aq. NaOH. The mixture is extracted three times with EA. The combined EA extracts are dried over MgSO4, filtered, concentrated and dried to give the title compound as a pale yellow oil; LC-MS: tR=0.45 min, [M+1]+=209.10; 1H NMR (D6-DMSO): δ 1.06 (t, J=6.5 Hz, 3H), 2.29 (s, 3H), 2.98 (s, 3H), 3.56 (q, J=6.3 Hz, 2H), 5.82 (s, 2H), 6.64 (s, 1H), 6.69 (s, 1H), 9.74 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.[Cl:27][S:28](O)(=[O:30])=[O:29]>CC#N>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([Cl:27])(=[O:30])=[O:29]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Solvent: CC#N
Product: O=C(Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A solution of 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-(5-fluoroindol-1-yl)amide (0.35 g,) in dry CH3CN (20 mL) is treated with chlorosulfonic acid (0.5 mL) and stirred at rt for 24 h. The reaction mixture is poured onto ice/water (150 mL) and extracted with EtOAc. The organic layer is washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.43 g, 95%). MS: 449 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][C:3](=[O:11])[NH:4][C:5]=2[CH:10]=1)=[O:18]
Reactant: O=C1COc2ccccc2N1
Reactant: O=C(Cl)CCCCCl
Product: O=C1COc2ccc(C(=O)CCCCCl)cc2N1
Yield: 66.9 %

Procedure:
Using 2H-1,4-benzoxazin-3(4H)-one (10.0 g) and 5-chlorovaleryl chloride (12.5 g) according to the same method as that of Reference Example 1, the title compound (12.0 g) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O>>[Br:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Product: Cc1cc(-c2ccc(Cl)cc2)cc(Br)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyridin-2-one (example A.27 step 1) (4.00 g, 18.2 mmol) and phosphoryl bromide (15.66 g, 54.6 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a light brown solid (2.95 g, 57%). MS (ISP) 282 [(M+H)+], 284 [(M+2+H)+] and 286 [(M+4+H)+]; mp 92° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([C:19]2[C:13]3[C:14](=[CH:15][N:16]=[C:11]([C:4]4[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][CH3:2])[CH:12]=3)[NH:17][CH:18]=2)[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CCc1cccc(CC)c1-c1cc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)c[nH]c2cn1

Procedure:
A mixture of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.90 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.8 mmol), Cs2CO3 (586 mg, 1.8 mmol), and MeOH (6 mL) is refluxed for 18 h. MeOH is removed under reduced pressure. The residue is treated with acetic acid (0.5 mL) and water (3 mL) and is extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue affords 4-[5-(2,6-Diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:7]=1[CH2:8][C:9](=[CH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([N:31]1[C:2]2[N:3]=[N:4][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:6][C:7]=2[CH2:8][CH:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=C(Cc1cc(-c2ccccc2)nnc1Br)C(=O)OC(C)(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1Cc2cc(-c3ccccc3)nnc2N(Cc2ccccc2)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a stirred solution of compound 5E, (0.140 g, 0.37 mmol) in 1.5 mL of isopropanol at room temperature under argon was added (in one portion) benzylamine (0.055 mL, 0.50 mmol). After 15 h, the reaction mixture was heated to 65° C. for 4 h and then to 85° C. for 15 h. The reaction mixture was then cooled to room temperature and the solvent removed at reduced pressure. The residue was dissolved in EtOAc and washed once with saturated sodium bicarbonate solution. The organic extract was dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (1:9 Ether/CH2Cl2) provided the title compound, tert-butyl 8-benzyl-3-phenyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine-6-carboxylate, as a light yellow solid (0.084 g, 57%). MS [M+H]+: found 402.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O

Procedure:
1-(2,4-Dihydroxy-3-propyl-phenyl)-ethanone was treated with ethyl 2-bromoacetate and processed as described in the synthesis of example 20a. Yield, 80%, white solid; mp, 61-62° C.; MS (EI): 280 (M+), 265, 251 (100%), 193; analysis: C15H20O5 requires C, 64.27; H, 7.19; found: C, 64.56; H, 7.39%.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(C)(=O)=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.475 g, 3.769 mmol) in tetrahydrofuran/methanol (30 mL/30 mL) was added sodium hydroxide (26.5 mL, 53.126 mmol, 14.1 eq.). The mixture was heated to reflux and stirred for 0.5 h. LC-MS indicated that the reaction was completed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid. The precipitation was filtered, washed with water and dried to give 1.45 g of 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as off-white solid, yield: 86.3% (for two steps). MS (ESI+APCI) M+1=375.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH3:10].O.[NH2:13][NH2:14]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH3:10])=[N:13][NH:14]2
Reactant: NN
Reactant: CC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2cccc(F)c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
2′,6′-Difluoroacetophenone (0.468 g, 3 mmol) was dissolved in anhydrous hydrazine (2 ml), followed by irradiating microwaves thereon with stirring at 150° C. for 5 min. The addition of water (0.5 ml) at 0° C. terminated the reaction. Afterwards, the reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The residue was re-crystallized in dichloromethane to give the title compound (Yield 85%).