Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Br[C:39]1[C:49]([O:50][CH2:51][CH3:52])=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][C:40]=1[O:53][CH2:54][CH3:55]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:53][C:40]1[CH:41]=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:48]=[C:49]([O:50][CH2:51][CH3:52])[C:39]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:55]
Reactant: CCOC(=O)c1cc(OCC)c(Br)c(OCC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OCC)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Palladium acetate (1.98 g), tripotassium phosphate (112 g), (4-fluorophenyl)boronic acid (43.1 g), and tricyclohexylphosphine (20% toluene solution, 31.2 mL) were added to a mixture of ethyl 4-bromo-3,5-diethoxybenzoate (55.8 g) in toluene (300 mL) and water (150 mL), and the resultant mixture was heated with stirring overnight at 90° C. in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (50.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC(C)([O-])C.[Na+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>[Pd].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:12])[CH3:13]
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: C1COCCN1
Agent: Cl[Pd+]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)n1ncc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 98 °C
Yield: 47.3 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (250 mg, 0.84 mmol), sodium tert-butoxide (178 mg, 1.85 mmol), Pd-XPhos precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]Pd(II); Me-t-butylether adduct) (34.8 mg, 0.042 mmol) and morpholine (81 mg, 0.93 mmol) in Dioxane (4 mL). The resulting mixture was degassed with nitrogen for 10 minutes. The vessel was sealed and the mixture was heated at 98° C. for 20 hours. The contents were diluted with water and 1N HCl was added to adjust the pH˜3-4. The contents were extracted with EtOAc and DCM/isopropanol (8:2), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM and purified by SiO2 chromatography (eluent: Hexanes/EtOAc gradient 0 to 100% EtOAc). Fractions were evaporated and solids were dried to afford the title compound as a light yellow solid (115 mg, 46%). LC-MS (ES) m/z=290.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1H) 8.18 (s, 1H) 7.56 (d, J=2.02 Hz, 1H) 7.26-7.29 (m, 1H) 5.00 (quin, J=6.57 Hz, 1H) 3.77-3.81 (m, 4H) 3.22-3.26 (m, 4H) 1.46 (s, 3H) 1.44 (s, 3H)
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]1)([O:10][CH2:11][CH3:12])=[O:9].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>O1CCCC1>[CH:26]1([C:29]([O:20][C:15]2[CH2:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH:16]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)CC(=O)C1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)C=C(OC(=O)C2CC2)C1
Reaction time: 1 h

Procedure:
0.94 g (9.4 mmol) of triethylamine was added to a solution of 2.4 g (9.4 mmol) of 5,5-biscarbethoxy-cyclohexane-1,3-dione in 25 ml of anhydrous tetrahydrofuran. A solution of 0.98 g (9.4 mmol) of cyclopropanecarboxylic chloride in 5 ml of tetrahydrofuran was added dropwise to this mixture at 0° to 10° C. After the mixture had been stirred at 0° to 10° C. for about 1 hour, no more starting material could be detected by thin-layer chromatography. Subsequently, the solvent was removed and the residue was taken up in ethyl acetate. The organic phase was washed twice with 1% strength acetic acid and twice with water, dried and evaporated down. The tube [sic] product was purified chromatographically (developer: cyclohexane/ethyl acetate 8:2). Yield: 1.2 g.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[BH4-].[Na+].C(O)(=O)C>CO>[OH:19][CH:1]1[C:2]2[C:3](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:14])[N:5]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(O)N1CSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 4.01 g (14.8 mmol) of 4-(phthalimidomethylthio)pyridine in 25 ml of methanol, a solution of 1.08 g (29.7 mmol) of sodium borohydride in 20 ml of methanol was added. The mixture was stirred at room temperature for 4 hours. Glacial acetic acid (0.5 ml) was added to quench the reaction, and then the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, and the solvent was distilled off. The residue was purified by recrystallization (recrystallization solvent: ethanol) to obtain 2.35 g of the desired compound (yield: 58.3%, yellow crystals).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>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.O1CCOCC1>[OH:11][C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:6]2=[N:7][C:2]([C:32](=[O:34])[CH3:33])=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
An oven-dried scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), and (Ph3P)4Pd (0.07 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5 min, and anhydous dioxane (13 volume equivalents), triethylamine (3.0 equiv), and tributyl(1-ethoxyvinyl)stannane (1.5 equiv) were added by syringe. The resulting mixture was heated to 80° C. overnight. The reaction was quenched with 1 N KHSO4 and stirred for 30 min. The mixture was then diluted with EtOAc, washed twice with NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 10%-66% EtOAc/Hexanes) provided the title compound (33%) as a white solid. LCMS m/z (APCI)=283.1 (M+H).
Reaction SMILES: C([S:9][CH2:10][CH2:11][CH:12]([CH3:23])[C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])(=O)C1C=CC=CC=1.C(SCCCC(N1CCC[C@H]1C(O)=O)=O)(=O)C1C=CC=CC=1>>[SH:9][CH2:10][CH2:11][CH:12]([CH3:23])[C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14]
Reactant: CC(CCSC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(SCCCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: CC(CCS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-(4-benzoylthio-2-methylbutanoyl)-L-proline for the 1-(4-benzoylthiobutanoyl)-L-proline in the procedure of Example 45, 1-(4-mercapto-2-methylbutanoyl)-L-proline is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:37][O:36][C:34](=[O:35])[CH2:33][N:17]1[C:16]2[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]=2[C:20](=[O:30])[N:19]([CH3:31])[C:18]1=[O:32]
Reactant: COC(=O)Cn1c(=O)n(C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(=O)n(C)c(=O)c2c1nc(N1CCNCC1)n2-c1ccccc1Cl

Procedure:
4-[7-(2-Chlorophenyl)-3-methoxycarbonylmethyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (26 mg) was dissolved in trifluoroacetic acid, and concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 8.09 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:20]([C:18]2[N:17]([CH3:23])[N:16]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:19]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2CC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (78 mg, 76%) which was obtained as a white solid. MS: m/e=371.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]1[CH2:18][O:17]1)[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=2)=[O:4].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[N:31]1[CH2:38][C@H:37]2[NH:39][CH2:40][C@@H:32]1[CH2:33][CH:34]=[CH:35][CH2:36]2.CCN(C(C)C)C(C)C.C(O)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]([OH:17])[CH2:18][N:39]1[CH2:40][CH:32]3[N:31]([C:22]4[CH:23]=[CH:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:21]=4)[CH2:38][CH:37]1[CH2:36][CH:35]=[CH:34][CH2:33]3)[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(CCC3CO3)cc(OC)cc2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc2c(CCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cc(OC)cc2[nH]1

Procedure:
6-Methoxy-4-(2-oxiranyl-ethyl)-1H-indole-2-carboxylic acid methyl ester (120 mg, 0.43 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (114 mg, 0.43 mmol), DIPEA (0.2 mL, 1.13 mmol), ethanol (3 mL), dichloromethane (2 mL) were heated for 1200 sec. at 130° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid which was then purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: FC1C=CC=CC=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:61][C:62]1[CH:63]=[C:64](N=C=S)[CH:65]=[CH:66][CH:67]=1>>[F:61][C:62]1[CH:67]=[C:66]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[CH:65]=[CH:64][CH:63]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: Fc1cccc(N=C=S)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 55 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-fluorophenyl isothiocyanate. The compound of example 55 was used directly without isolation for the preparation of compound of example 56.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)[O-])cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
6,8-Dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid (22.78 g, 43.26 mmol) was dissolved in THF (100 ml) and 0.5M NaOMe solution in MeOH (86.52 ml, 43.26 mmol) was added at ambient temperature. The mixture was stirred for 1 hour and concentrated. A very thick light brown solid was obtained. The crude solid was treated with EtOH-hexanes and filtered to provide 23.4 g of the title compound as a white solid (99%). MS (apci) m/z=520.1 (M+2H-Na).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][O:28]C2CCCCO2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][OH:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
4.1 g 2-Chloro-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile were dissolved in 50 ml methanol. 320 mg p-toluenesulfonic acid monohydrate were added and the mixture was stirred for one hour at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethylacetate and washed twice with saturated NaHCO3 solution and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 3.4 g 2-Chloro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.Cl[C:18]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])=[N:27][C:22]=2[CH:21]=[N:20][N:19]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O.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>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[NH:28][C:26]1[CH:25]=[CH:24][C:23]2[C:18]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])=[N:19][N:20]=[CH:21][C:22]=2[N:27]=1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1nncc2nc(Nc3ccc(F)cc3F)ccc12
Temperature: 130 °C

Procedure:
A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (252 mg, 1.12 mmol), 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine (300 mg, 1.02 mmol) and tetrakis (36 mg, 31 μmol) in 4.0 mL of dioxane and sodium carbonate (2.0 mL of 1 N solution) was heated in a microwave at 130° C. for 35 min. It was diluted with 10 mL of EtOAc and 2.0 mL water and extracted. An additional extraction with DCM (15 mL) was done. The combined extracts and an insoluble tan solid were dried over MgSO4. Filtration through a sintered glass frit washing with 1:1 MeOH:DCM resulted in complete solubilization of the tan solid. The solution was concentrated and washed with Et2O (2×15 mL), EtOAc (15 mL) and hexanes (2×15 mL) to afford a tan amorphous solid which was purified on the ISCO to afford the title compound as a yellow amorphous solid. MS (ESI, pos.ion) m/z: M+1=354.0
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@H]1CNCCN1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
2-Bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol), (S)-2-methylpiperazine (1.03 g, 10.28 mmol) and triethylamine (1.5 mL, 10.76 mmol) were stirred in toluene (10 mL) at 110° C. for 26 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude mixture was purified by automated silica gel flash column chromatography (gradient eluent 0-20% MeOH/dichloromethane) to afford 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (926 mg, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 4.29-4.20 (m, 2H), 3.16-3.12 (m, 1H), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[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:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][C:38]([CH3:46])=[N:37]2)=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[C:38]([CH3:46])[CH:39]=2)=[O:44])[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:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccnc4cc(C#CCN5CCN(C)CC5)sc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)n1
Yield: 14 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 2-(4-fluorophenyl)-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 4.5 mg (14%) of the desired product. LRMS (ESI pos) m/e 627.3 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.32 (s, 1H), 8.0 (dd, 1H), 7.62 (m, 3H), 7.45 (d, 1H), 7.34 (t, 1H), 7.27 (t, 2H), 6.65 (d, 1H), 3.66 (s, 2H), 2.77 (m, 8H), 2.56 (s, 3H), 2.34 (s, 3H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −113.2, −127.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Li][CH2:14][CH2:15][CH2:16]C.ICCC>C1COCC1.CCCCCC>[CH2:14]([C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: COc1cc(OC)cc(OC)c1
Solvent: CCCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To the stirred solution of 1,3,5-trimethoxybenzene (10.0 g, 59.4 mmol) in 150 mL of dry THF at 0° C. in nitrogen atmosphere was added 23.7 mL (59.3 mmol) of 2.5 M n-BuLi in hexane dropwise via syringe. The resulting solution was stirred at room temperature for 4 hr. The mixture was cooled to -20° C. and 1-iodopropane (6.09 mL, 62.5 mmol) was added dropwise via syringe in 10 min. After being stirred at room temperature for 14 hr and refluxed for 4 hr, the mixture was quenched with 200 mL of water, concentrated in vacuo to remove THF and extracted with ether. The organic layer was washed with water, dried (MgSO4) and concentrated. The crude product was washed with hexane to give 11.07 g of the title compound: mp 48.5-49.5° C.; 1H NMR (CDCl3): 6.13 (2 H, s), 3.80 (3 H, s), 3.79 (6 H, s), 2.52 (2 h, m), 1.44 (2 H, sex, J=7.5 Hz), 0.91 (3 H, t, J=7.5 Hz).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[NH3:7].[NH2:8][C:9]1[N:10]=[N:11][C:12]([Br:15])=[CH:13][N:14]=1>>[NH2:8][C:9]1[N:10]=[N:11][C:12]([Br:15])=[C:13]([NH2:7])[N:14]=1
Reactant: N
Reactant: Nc1ncc(Br)nn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1nnc(Br)c(N)n1
Temperature: -33 °C

Procedure:
A solution of 6.0 grams (0.038 mole) of potassium permanganate in about 300 mL of liquid ammonia (-33° C.) is stirred, and 5.3 grams (0.030 mole) of 3-amino-6-bromo-1,2,4-triazine is added portionwise. Upon completion of addition, the reaction mixture is maintained at -33° C. for 15 minutes. Ammonia is then evaporated and the residue is extracted with about 150 mL of hot 1-methylethanol. The solution is concentrated under reduced pressure, yielding 3,5-diamino-6-bromo-1,2,4-triazine.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1.Br[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:5][CH2:6][N:7]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH2:8][CH2:9]2)[CH2:3]1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CN1CC2(CCNCC2)c2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC2(CCN(Cc3ccc(C(=O)O)cc3)CC2)c2ccccc21
Yield: 142.5 %

Procedure:
A mixed solution of 1-methylspiro[indolin-3,4′-piperidine] (1.0 g) synthesized according to a method described in [WO 2011/046851 pamphlet, (preparation 15)], 4-(bromomethyl)benzoic acid (1.08 g), and N,N-diisopropylethylamine (2.61 mL) in ethanol (20 mL) was heated and refluxed for 2 hours. To the resultant reaction mixture, N,N-diisopropylethylamine (1.04 mL) was further added, and the resultant reaction mixture was heated and refluxed for 2 hours. The reaction solution was left to reach room temperature, and from the reaction solution, the solvent was distilled off under reduced pressure to obtain a mixture (2.37 g) containing the subject compound. The resultant mixture was used in the next reaction without further purification.