Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:14]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[N:13][N:12]=[N:11]1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:8][C:7]([N:11]1[N:12]=[N:13][C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][CH:22]=2)=[N:10]1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: C=C(C)c1ccccc1
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)n1nnc(-c2ccc(C=O)cc2)n1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of 6.9 g (58 mmol) of 2-phenyl-propene (Fluka, Buchs, Switzerland) and 22 ml of toluene is added dropwise to 10 g (57 mmol) of 4-(tetrazol-5-yl)-benzaldehyde and 1 g (5.7 mmol) of methanesulfonic acid in 44 ml of boiling toluene and the mixture is then stirred under reflux conditions for 1 hour. The cooled reaction mixture is washed 2× with sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation to form the title compound: 1H-NMR (DMSO-d6) δ 10.09 (s, HCO), 8.29 and 8.08 (2d, J=8, each 2H), 7.33 and 7.17 (2m, 5H), 2.17 (s, 6H).
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[F:1][C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1F)OCc1ccccc1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A mixture of spray-dried KF (200 mg, 3.48 mmol), intermediate 1 (250 mg, 0.696 mmol) and catalytic amount of 18-crown-6 in dry DMSO (5 mL) was stirred at 140-150° C. for 30 min. After completion (TLC), the reaction mixture was poured into ice cooled water (100 mL) and stirred for 5 min. The solution was extracted with EtOAc (3×50 mL). The combined solution was dried over anhyd Na2SO4. The solution was filtered and evaporated the solvents. The residue was chromatographed over silica gel column using hexane:acetone (80:20) as eluents to give the product as a pale yellow color solid (106 mg, 46%), mp 104-106° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, t, J=8.0 Hz), 8.13 (1H, dd, J=8.6, 1.4 Hz), 8.04 (1H, dd, J=11.0, 1.8 Hz), 7.38 (5H, s), 5.25 (2H, s), 4.33 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1([CH:10]([CH3:12])[CH3:11])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:5]2[C:4](=[O:9])[C:3]([CH2:1][CH3:2])([CH:10]([CH3:11])[CH3:12])[NH:7][C:6]2=[O:8])=[CH:18][CH:19]=1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Reactant: CCC1(C(C)C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(C(C)C)NC(=O)N(CC(=O)Nc2ccc(Br)cc2)C1=O

Procedure:
A mixture of 5-Ethyl-5-(1-methylethyl)-2,4-imidazolidinedione, (CAS #98492-91-2 (50 mg, 0.29 mmol), N-(4-bromophenyl)-2-chloro-acetamide (CAS #2564-02-5) (80 mg, 0.32 mmol), K2CO3 (48 mg, 0.35 mmol) in acetone was stirred at ambient temperature for 18 h. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and solvent removed. The crude product was purified by preparative TLC. The title compound was isolated as white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(I)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1CSc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a stirred mixture of m-iodothiophenol (2.67 g, 11.31 mmol) and N-(tert-butoxy carbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (3.34 g, 9.43 mmol) in pyridine (9.4 mL) was added 8 N KOH (1.77 mL). The resulting mixture was stirred at room temp overnight. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat. NH4Cl solution, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.79 g (45%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 3-iodophenyl sulfide as an oil. 1H-NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.78–2.01 (br m, 4H), 2.71 (dt, 1H), 3.32–3.49 (br m, 3H), 3.90–4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.57 (dd, J=2.0, 8.3 Hz, 2H); MS (FAB) m/z 420 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.8 %

Procedure:
A solution of 10.0 g (0.056 mol) of 4,4-dimethylthiochroman and 4.4 g (0.056 mol) of acetyl chloride in 150 mL of CS2 was added dropwise over a 45-minutes period to a stirred CS2 suspension of AlCl3 (11.22 g, 0.084 mol) in a 500-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The resulting yellowish-orange mixture was allowed to stir for 10 hours at room temperature; 80 mL of ice water was added and the two layers separated. The aqueous layer was extracted with ether (3×50 mL); the ether layers were combined and dried (Na2SO4, 6 h). After evaporation, the resulting light yellow oil was vacuum distilled to give 10.83 grams (87.6%) of 6-acetyl-4,4-dimethylthiochroman as a yellowish viscous oil: bp 168°-173° C./1.0 mm; IR (neat) 1680 cm-1 ; 1H NMR (DCCl3 δ1.31 [s, 6 H, (CH)3)2 C], 1.89 [m, 2 H, ArSCH2CH2 ], 2.52 [s, 3 H, CH3C=O]3.01 [m, 2 H, ArSCH2CH2 ], 7.11 [d, 1 H, J=8.1 Hz, H(8)], 7.57 [dd, 1 H, J=1.7 Hz, J=8.1 Hz, H(7)], 8.00 [d, 1 H, J=1.7 Hz, H(5)]; 13C NMR ppm 23.1 [ArSCH2CH2 ]26.2 [CH3C=O], 29.8 [(CH3)2C], 32.8 [(CH3)2C], 36.8 [ArSCH2CH2 ], 125.8, 126.2, 132.9, 139.4, 141.7, 196.7 [CH3C=O]. ##STR14##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=[C:14]([Br:16])Br)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\[Br:16])/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=C(Br)Br)COC1(C)C
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccccc2)COC1(C)C

Procedure:
In analogy to example 162b (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with phenylboronic acid to give (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Light yellow crystalline solid.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](Cl)[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH:2][CH3:1])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1nc2c(cc1F)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (150 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (150 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethanol was added to the residue, and solids deposited were collected by filtration to obtain the title compound (40 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH3:27])=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH3:27])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CO/C=C/c1cccc(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-methyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D96) (690 mg, 1.721 mmol) and sodium iodide (516 mg, 3.44 mmol) in Acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.440 mL, 3.44 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-methylphenyl]acetaldehyde (D97) (666 mg) as a yellow oil, which was used for the next step without further purification. MS (ES): C20H19ClN2O2S requires 386.0. found 387.0 (M+H+).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Temperature: 150 °C
Reaction time: 19 h

Procedure:
6.64 g (40 mmol) of triethyl phosphite was added to 2.29 g (10 mmol) of methyl 4-(bromomethyl)benzoate, and they were stirred at 150° C. for 19 hours. The reaction solution was treated by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH2:2]([NH:6][C:20]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:21])[CH2:3][C:4]#[CH:5]
Reactant: C#CCCN
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a suspension of but-3-yn-1-amine hydrochloride (200 mg, 1.89 mmol) and triethylamine (425 μL, 3.78 mmol) in DCM (60 mL) was added morpholine-4-carbonyl chloride (218 μL, 1.89 mmol). The reaction was stirred at RT overnight and then washed with aq hydrochloric acid (2 M, 2×20 mL), saturated aq sodium bicarbonate (2×20 mL), dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0-100% ethyl acetate in heptane, to afford the title compound (13) (164 mg, 48%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 2.28 (2H, td), 2.82 (1H, t), 3.09-3.18 (2H, m), 3.20-3.27 (4H, m), 3.48-3.57 (4H, m), 6.74 (1H, t).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:9]2[CH2:10][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:12]2)[CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-methylcyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 1 H), 8.11 (s, 1 H), 8.04 (t, J=4.9 Hz, 1 H), 7.71-7.82 (m, 2 H), 6.80 (d, J=7.3 Hz, 1 H), 4.59 (sxt, J=6.4 Hz, 1 H), 4.27 (d, J=5.3 Hz, 2 H), 3.60 (t, J=7.3 Hz, 2 H), 2.95 (t, J=6.6 Hz, 2 H), 2.15 (br. s., 1 H), 1.49-1.61 (m, 1 H), 1.27-1.49 (m, 8H), 0.91 (d, J=6.8 Hz, 3 H); ESI-MS (m/z): Calcd. For C21H26F3N5O: 421.21. found: 422 (M+H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[CH:49]=[N:50][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:53]=2)=[O:47])=[CH:44][N:43]=[N:42]1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[N:42]=[N:43][CH:44]=3)([C:48]3[CH:49]=[N:50][C:51]([C:54]([F:55])([F:57])[F:56])=[CH:52][CH:53]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.85 mL, 4.62 mmol) was added dropwise by syringe to a mixture of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (0.31 g, 0.72 mmol, Intermediate 12: step d) and (1-methyl-1H-1,2,3-triazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (0.29 g, 1.16 mmol, Intermediate 53: step b) in dry THF (8 mL) at −78° C. over a three minute period. The mixture was stirred at −78° C. for 10 minutes then was immersed in an ice H2O bath and stirred at 0° C. for 1 hour. The solution was quenched with saturated aqueous NaHCO3, warmed to room temperature, and the layers were separated. The aqueous layer was further extracted with EtOAc and the organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by FCC [(30% EtOH in EtOAc)/heptane, gradient] to provide the title compound. MS (ESI) 608 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH3:9])=[CH:3][N:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][CH3:9])=[CH:3][N:2]=1
Reactant: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CCC(N)c1ccnnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2-[1-(Pyridazin-4-yl)propyl]isoindoline-1,3-dione (91.8 mg, 0.34 mmol) in methanol (1 mL) was mixed with hydrazine monohydrate (83 μL, 1.7 mmol) at room temperature and stirred at 60° C. for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product (100% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:6]([O:10][CH2:28][CH2:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:8][CH:9]=1)[OH:11]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(Cc2ccccc2)Cc2ccccc2)c1O

Procedure:
2,3-dihydroxybenzoic acid methyl ester is reacted in the presence of potassium carbonate in acetonitrile with 1.1 equivalents of 1-dibenzylamino-2-chloroethane for 18 hours at 82°. The crude 3-(2-dibenzylaminoethoxy)salicylic acid methyl ester obtained after working up is put to further use without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (2.71 g, 5.00 mmol) in CH2Cl2 (20 mL). Add trifluoroacetic acid (5.88 mL, 77.79 mmol). Stir at room temperature for one hour and then add 5 N NaOH to pH=8-10. Collect a white/yellow precipitate via vacuum filtration, and wash the solid with EtOAc followed by Et2O. Dry the solid overnight in vacuo at about 50° C. to give 2.21 g (>99%) of the title compound. ES/MS m/z (35Cl) 442.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1>C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:29]1[CH2:30][C:27]([F:31])([F:26])[CH2:28]1)[C:11]([C:12]1[N:13]=[N:14][NH:15][N:16]=1)=[C:10]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1cc2nc(N3CC(F)(F)C3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B), 3,3-difluoroazetidine hydrochloride and triethylamine. Light brown solid. MS (ESI): 417.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]([CH3:46])([C:44]#[CH:45])[CH3:43])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:45]#[C:44][C:42]([CH3:46])([N:39]3[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]3)[CH3:43])[S:17][C:10]=12
Reactant: C#CC(C)(C)N1CCN(C)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Product: CN1CCN(C(C)(C)C#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 18.8 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine (11.2 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.16) eluting with 10% MeOH/DCM. The compound was re-purified by preparative TLC (0.5 mm thickness, Rf=0.84) eluting with 15% MeOH (containing 7N NH3) in CHCl3, to obtain product of adequate purity. The product was obtained as a beige powder (4 mg, 18%). HPLC: 95% purity (220 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 629 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.40 (br s, 1H), 7.73 (m, 1H), 7.54 (s, 1H), 7.44 (m, 2H), 7.21 (m, 2H), 7.06 (t, J=9 Hz, 2H), 6.54 (d, J=5 Hz, 1H), 2.84 (m, 4H), 2.65 (m, 4H), 2.39 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H), 1.51 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].[Cl:33][C:34]1[C:35]([C:41]([NH2:43])=[O:42])=[N:36][CH:37]=[CH:38][C:39]=1Cl>CN(C=O)C>[Cl:33][C:34]1[C:35]([C:41]([NH2:43])=[O:42])=[N:36][CH:37]=[CH:38][C:39]=1[O:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:10][C:11]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:5]=1[F:9]
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of N-(2,5-difluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (395 mg, 1.1 mmol) in DMF (5.0 mL) was added t-BuOK (202 mg, 1.8 mmol) and the mixture was stirred at rt for 30 minutes. Then 3,4-dichloropicolinamide (190 mg, 1.0 mmol) was added and the mixture was microwaved at 120° C. for 2 hours, then cooled to rt, quenched with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a pale yellow solid (310 mg, 60%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21]>>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and glycine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=152-153.5° C.). The reaction was monitored by tlc (Rf=0.10 in 50% EtOAc/hexanes).