Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH:8]=[C:7]1[CH2:28][O:29][CH3:30])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:4][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([CH2:19][OH:20])[CH:8]=[C:7]1[CH2:28][O:29][CH3:30])[CH:2]=[CH2:3]
Reactant: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1COC
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a stirred solution of (2S,5R)-tert-butyl 5-(allyloxy(tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyloxy)methyl)-4-(methoxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 71, 35.55 mmol) in THF (100 mL) at 0° C., TBAF (39.11 mL, 39.11 mmol) was added. After 1 hr at 0° C., it was then concentrated to give a residue which was purified by silica gel column (0-100% EA/Hex) to give the desired product (8.82 g, 57.9% over 3 steps) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20](I)[CH3:21])[C:3]=1[OH:23].[NH:24]([CH3:26])[CH3:25]>C(Cl)Cl.CCO>[CH3:25][N:24]([CH3:26])[CH:20]([C:4]1[C:3]([OH:23])=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:21]
Reactant: CNC
Reactant: CC(I)c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C
Yield: 62 %

Procedure:
A solution of crude 6-fluoro-4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (ca. 44.5 μmol; Intermediate 104) in CH2Cl2 (1 mL) was treated with Me2NH (159 μL of a 5.6 M solution in EtOH, 890 μmol) at rt for 1.5 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH and purified by prep. HPLC (25-55% MeCN, 50 mM NH4HCO3) to yield the title compound as an off-white solid (10.0 mg, 62% over two steps). MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[N:49][CH:50]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:47]4[CH:48]=[N:49][CH:50]=[C:45]([Cl:44])[CH:46]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1cncc(Cl)c1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cncc(Cl)c4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 86 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross-coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 5-chloropyridin-3-ylboronic acid yielded the title compound (86% yield) as a white solid. MS (ISP): m/z=686.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][C:8]([NH:12][C:13](=[O:19])[C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:20][CH2:21][CH2:22][N:3]12.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[CH:23](=[C:20]1[C:4]2=[N:5][C:6]3[CH:7]=[C:8]([NH:12][C:13](=[O:19])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][C:11]=3[C:2](=[O:1])[N:3]2[CH2:22][CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(=O)Nc1ccc2c(=O)n3c(nc2c1)CCC3
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Temperature: 60 °C
Reaction time: 6 h

Procedure:
N-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-amino-oxoacetic acid, ethyl ester, m.p. 198°-200° C. (1.2 g) was reacted with benzaldehyde (0.84 g) in methanol (20 ml), in the presence of sodium methoxide (0.86 g) under stirring at 60° C. for 6 hours. After cooling the reaction mixture was concentrated in vacuo and diluted with ethyl ether: the precipitate was filtered, washed with ether and dissolved in water. Acidification with acetic acid gave a precipitate which was filtered and washed with water: crystallization from formic acid gave 0.4 g of N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-amino-oxoacetic acid, m.p. 220°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH:16]1OCCC[O:17]1.Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C1OCCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
To a stirred solution of Compound 39 (1.0 g) in acetone (30 ml) was added conc. HCl (4 ml) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and the residue was extracted with ether. The combined solution was washed with sat. NaHCO3 aq. , and brine, dried(MgSO4) and concentrated in vacuo to give crude product (790 mg) as a yellow solid. The crude product was purified by column chromatography on silica gel with hexane-isopropyl ether(10:1-3:1) to give Compound 40 (275 mg) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](C3(CCC(O)=O)C4C(=CC=CC=4)N(CCCCC)C3=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=C[C:37]([C:39]3(CC(O)=O)[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32]C1>>[CH2:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]2([CH2:37][CH2:38][C:33](=[O:32])[C:8]3[C:7]2=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=3)[C:40]1=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCN1C(=O)C(CCC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 21, and making non-critical variations using 3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoic acid to replace [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetic acid, the title compound was obtained (32%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.37-7.28 (m, 1H), 7.08-7.03 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 5.95-5.91 (m, 2H), 3.73 (t, 2H), 3.37-3.24 (m, 1H), 2.79-2.67 (m, 1H), 2.41-2.32 (m, 2H), 1.76-1.64 (m, 2H), 1.38-1.28 (m, 4H), 0.87 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 195.4, 177.4, 152.3, 148.0, 142.7, 138.9, 133.6, 128.8, 128.4, 124.1, 122.9, 108.9, 106.9, 106.6, 101.9, 51.7, 40.2, 33.1, 32.8, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 400.1 (M+23), 378.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:24]/[CH:25]=[O:26]
Reactant: O=Cc1ccc(-c2ncccn2)cc1F
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ncccn2)cc1F

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 2-fluoro-4-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 15) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 229 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:59])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (300 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-perbenzoic acid (117 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (230 mg) as a yellow amorphous material (Compound 37).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (7.5 g, 24.11 mmol) in ethanol (400 mL) was added sodium hydroxide (1.45 g, 36.17 mmol) in water (60 mL) and the reaction mixture was stirred at reflux for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (150 mL), and acidified with 2N HCl to pH˜2. The precipitated acid was collected by filtration, washed with ether (200 mL, and dried to afford 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylic acid as an off white solid (6.85 g, 95.6%). LCMS (ES−): 294.9 [M−H].
Reaction SMILES: [CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:28][CH2:27][C@H:26]([CH2:29][O:30]CC4C=CC=CC=4)[CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH3:42]O>C(Cl)Cl>[CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([N:23]([C@@H:24]3[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]3)[CH3:42])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N[C@@H]2CC[C@H](COCc3ccccc3)C2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN([C@@H]1CC[C@H](CO)C1)S(=O)(=O)c1ccc(-n2[nH]cc(Cc3ccccc3)c2=O)nc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 0.3 g (0.57 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}pyridine-3-sulfonamide in 2 mL of DCM cooled to −78° C. are added 1.7 mL of boron tribromide. The temperature is then allowed to rise to 0° C. and stirring is continued for 1 hour at 0° C. 10 mL of MeOH are then added at −10° C. and the medium is concentrated under reduced pressure. The medium is taken up in 100 mL of DCM, washed successively with saturated NaHCO3 solution (2×20 mL) and brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 90/10 DCM/MeOH mixture. 126 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[(1R,3S)-3-(hydroxymethyl)cyclopentyl]-N-methylpyridine-3-sulfonamide are obtained in the form of a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([CH3:20])[CH:22]=[CH:23]2
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CCOC(=O)c1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
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: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(O)c2cc(-c3ccc4c(ccn4C)c3)c(Cl)cc2[nH]c1=O
Temperature: 120 °C
Yield: 65.5 %

Procedure:
To a solution of ethyl 7-chloro-4-hydroxy-6-iodo-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Intermediate 100) (300 mg, 0.762 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL) were added (1-methyl-1H-indol-5-yl)boronic acid (Combi-Blocks, 140 mg, 0.800 mmol), cesium carbonate (373 mg, 1.143 mmol) and tetrakis(triphenylphosphine)palladium (8.81 mg, 7.62 μmol). The reaction vessel was sealed and heated to 120° C. for 20 min in a microwave. After cooling, the mixture was filtered, evaporated to dryness and the resulting residue was acidified with 1N HCl. The precipitate was filtered and dried to give ethyl 7-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydro-3-quinolinecarboxylate (198 mg, 0.499 mmol, 65.5% yield) as off-white solid. LCMS: (M+H)+=397; Rt=2.79 min. HRMS: calculated for C21H18ClN2O4 (M+H)+: 397.0955. found: 397.0927.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][CH3:18].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:17]([CH3:18])[C:26](=[O:28])[C:25]1[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=1
Reactant: CNc1cnccc1-c1cc(OC)c(F)cc1F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)c(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
To a solution of [4-(2,4-difluoro-5-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (70 mg, 0.28 mmol) in 2.5 mL pyridine were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) (90 mg, 0.34 mmol) and POCl3 (2.3 mL) dropwise at 25° C. and the reaction mixture was stirred for 12 hours at 25° C. The solvent was evaporated, the residue was dissolved in EtOAc (15 ml) and washed with 2M aqueous HCl solution (5 mL) followed by saturated NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the title compound as a light yellow solid (40 mg, 29%). MS (ESI): m/z=501.2 [M+H]+.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:25](N1CCCC1)=[O:26].[Cl-].[NH4+]>O1CCCC1.CO>[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:25]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)=[O:26]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Reactant: CCOC(OCC)n1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1ccccc1C(=O)c1ncc[nH]1
Temperature: -60 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
At −40° C., 6.9 g (0.0405 mol) of N-diethoxymethylimidazole (J. Org. Chem. Vol. 45, No. 20, 1980, page 4040) in 40 ml of tetrahydrofuran are mixed with 11.3 g (0.0405 mol) of 23% pure n-butyllithium, and the mixture is stirred at −60° C. for one hour. At −40° C., 6 g (0.0203 mol) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine are added, and the mixture is stirred for 30 minutes without any further cooling, on which the reaction mixture warms to 20° C. 5 g of ammonium chloride and 50 ml of methanol are added, and the mixture is heated at reflux for 15 minutes. The volatile components are distilled off under reduced pressure and the residue is admixed with water and extracted with ethyl acetate. The organic phase is dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate. 3.79 g (63.8% of theory) of 2[2-(2-methylphenoxymethyl)-benzoyl]-imidazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 6 h

Procedure:
A mixture of 3.47 g. of 2-chloro-5-nitrophenol, 3.74 g. of propyl iodide, 3.04 g. of anhydrous potassium carbonate and 20 ml. of acetone was refluxed with stirring for 6 hours to obtain 3.80 g of 4-chloro-3-propoxynitrobenzene having a melting point of 52° to 53° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(F)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(F)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 83 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated to give a solid (0.11 g, 13%); Mp=202-204° C.; 1NMR (DMSO-d6) δ 9.92 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.58 (dd, 1 H, J=8.7 Hz, 4.4 Hz), 7.39 (dd, 1 H, J=8.8 Hz, 2.5 Hz), 7.17 (d, 1 H, J=1.0 Hz), 7.10-7.06 (m, 1 H), 6.88 (d, 2 H, J=8.8 Hz); MS 227 [M−H]−
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[N:12]=[C:13](\[C:18](=[O:24])[CH2:19][C:20](OC)=[O:21])/[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O>ClC1C=CC=CC=1Cl>[OH:24][C:18]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[C:20](=[O:21])[CH:19]=1
Reactant: COC(=O)CC(=O)/C(=N\Nc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1O
Temperature: 180 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
The mixture of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl) hydrazono)-3-oxopentanedioate (7.0 g, 19.6 mmol) in 1, 2 dichlorobenzene (20 mL) was heated at 180° C. overnight. After cooling the reaction to room temperature, water 50 mL was added to the reaction mixture and stirred for 1 hour. The product was collected by filtration and further washed with water 20 mL and methanol (10 mL×3), then dried overnight under reduced pressure to yield 3.13 g (49.1%) of methyl 4-hydroxy-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate. MS (ESI) 325 (M+H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2-c2ccccc2)CC1

Procedure:
Under General Procedure B: Reaction of 3-phenyl-pyridine-2-carbaldehyde and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Huang, Y. et al. J. Med. Chem. 2001, 44, 4404-4415) in MeO4 with NaBH4 gave 4-[(3-phenyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.22 (m, 3H), 1.41 (s, 9H), 1.70 (m, 2H), 2.52 (m, 1H), 2.72 (m, 3H), 3.84 (s, 2H), 7.21 (q, 1H, J=4.03 Hz), 7.32 (m, 2H), 7.40 (m, 3H), 7.53 (dd, 1H, J=7.79, 1.72 Hz), 8.54 (m, 1H) ppm.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:25]2[CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][C:16]=1[Cl:32]>C(Cl)Cl>[Cl:32][C:16]1[CH:17]=[CH:18][C:19]2[CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH2:23][CH2:24][C:25]=2[C:15]=1[NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)Nc1ccccc1
Yield: 28 %

Procedure:
Combine phenyl isocyanate (15 μL, 0.137 mmol) and 6-(3-amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (48 mg, 0.137 mmol) in DCM and stir for 16 h. Concentrate, add DCM, filter and collect the solid to obtain 7-chloro-6-[3-(3-phenyl-ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (18 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][N:5]2[C:11]=1[S:12]([NH2:15])(=[O:14])=[O:13].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][N:5]2[C:11]=1[S:12]([N:15]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1c(Cl)nc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (2.00 g, 6.22 mmol) and N,N-Dimethylformamide dimethyl acetal (1.80 ml, 13.5 mmol) were heated under reflux for 4 hours in toluene (20.0 ml). The resulting reaction solution was left to cool to room temperature, and concentrated to dryness under reduced pressure to give the title compound as pale yellow crystals. The yield was 2.36 g (100%).