Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 65 %

Procedure:
As described for Example 1j, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using 4-methoxyphenylboronic acid instead of phenylboronic acid, to the title compound (90 mg, 65%) which was obtained as a white solid. MS (ESI): m/e=386.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.[CH2:26]=O>C(O)C>[N:17]1([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([Si:13]([CH3:15])([CH3:14])[CH3:16])=[C:6]([CH:12]=2)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CCNC(=O)c1cc(N)ccc1[Si](C)(C)C
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=O
Solvent: CCO
Product: CCNC(=O)c1cc(NCn2nnc3ccccc32)ccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of the compound of Example 217 (0.29 g, 1.2 mmol) and benzotriazole (0.143 g, 1.2 mmol) in absolute ethanol (5 mL) at RT was added 37% aq formaldehyde (0.090 mL, 1.2 mmol). An aliquot was induced to precipitate by cooling and addition of a small amount of water. The precipitate was added back into the reaction which was stirred at RT overnight and cooled in a refrigerator for 6 h. The resultant mixture was filtered and dried under vacuum (P2O5) to afford 5-[(1H-benzotriazol-1-ylmethyl)amino]-N-ethyl-2-(trimethylsilyl)benzamide as a white solid (0.308 g, 70%). m.p. 207°-208° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]4=[CH:26][O:25][N:23]=[C:20]4[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nocc4c3O2)cc1
Reaction time: 48 h

Procedure:
19.7 g (87.4 mmole) of stannous chloride dihydrate was added to a solution of 6.62 g (17.5 mmole) of (2R)-(8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate in 400 mL of 1:1 tetrahydrofuran/methanol followed by the addition of 23.8 g (0.17 mole) of sodium acetate trihydrate. The mixture was stirred under nitrogen for a period of 48 hours. The solvent was removed in vacuo and replaced with an equal amount of methylene chloride and the solution was washed with 400 mL portions of saturated aqueous sodium bicarbonate and saturated brine and dried over magnesium sulfate. After the solution was filtered and concentrated in vacuum, the crude oil obtained was column chromatographed on silica gel with methylene chloride as eluant and the product fractions were combined and evaporated in vacuum to give 4.47 g (71%) of the (R)-enantiomer of the title compound as a light yellow solid, m.p.109-110° C.
Reaction SMILES: [C:1]([C:5]1[C:6](O)=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+].CC[OH:27]>O>[CH2:15]([O:27][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCO
Reactant: CC(C)(C)c1cccc(C(=O)O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 3-t-butylhydroxybenzoic acid (2.00 g, 10.3 mmol), benzyl bromide (6.12 mL, 52.5 mmol), KOH (3.47 g, 61.8 mmol), EtOH (60 mL), and water (6 mL) was heated at 100° C. for 48 h under nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOH (100 mL) and water (100 mL), then stirred with KOH (3.47 g, 61.8 mmol) at 100° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water (400 mL) and extracted with EtOAc (200 mL). The aqueous layer was acidified with 1 N HCl (10 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo to provide 4-(benzyloxy)-3-tert-butylbenzoic acid (2.36 g, 81%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.80 (br s, 1H), 8.08 (s, 1H), 8.07-7.94 (m, 1H), 7.45-7.34 (m, 5H), 6.99-6.96 (m, 1H), 5.20 (s, 2H), 1.42 (s, 9H); MS found: (M+H)+=285.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH3:10])[N:12]=2)=[N:3][CH:4]=1
Reactant: Cn1ccc(N)n1
Reactant: COc1ccc(Br)nc1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccn(C)n2)nc1
Temperature: 80 °C
Yield: 55 %

Procedure:
2-Bromo-5-methoxy-pyridine (0.97 mmol), sodium-tert.-butylate (1.5 eq.), and 1-methyl-1H-pyrazole-3-amine (1.3 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (5 mg) in degassed dioxane (1 ml) is added and the reaction is heated for 20 hours at 110° C. The reaction is quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Methoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A24”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as colorless powder in a yield of 55%; HPLC (method C): 1.09 min; LC-MS (method A): 0.73 min, 205.0 (M+H+);
Reaction SMILES: [C:1]([C:3]12[O:19][CH:18]1[CH2:17][CH:16]([C:20]([CH3:31])=[CH:21][C:22]1[N:23]=[C:24]([CH2:27][N:28]=[N+]=[N-])[S:25][CH:26]=1)[O:15][C:14](=[O:32])[CH2:13][CH:12]([OH:33])[C:11]([CH3:35])([CH3:34])[C:10](=[O:36])[CH:9]([CH3:37])[CH:8]([OH:38])[CH:7]([CH3:39])[CH2:6][CH2:5][CH2:4]2)#[N:2].CP(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]12[O:19][CH:18]1[CH2:17][CH:16]([C:20]([CH3:31])=[CH:21][C:22]1[N:23]=[C:24]([CH2:27][NH2:28])[S:25][CH:26]=1)[O:15][C:14](=[O:32])[CH2:13][CH:12]([OH:33])[C:11]([CH3:34])([CH3:35])[C:10](=[O:36])[CH:9]([CH3:37])[CH:8]([OH:38])[CH:7]([CH3:39])[CH2:6][CH2:5][CH2:4]2)#[N:2]
Reactant: CC(=Cc1csc(CN=[N+]=[N-])n1)C1CC2OC2(C#N)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C#N)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a stirred solution of the compound prepared in Example 5 (117 mg, 0.21 mmol) in tetrahydrofuran (2 mL) under argon was added trimethylphosphine (231 mL, 0.23 mmol, 1M in tetrahydrofuran) and the reaction was stirred at room temperature for 1 hour, then quenched with ammonium hydroxide (325 mL, 28% in water). The mixture was stirred for an additional 30 min. The volatiles were removed in vacuo and the crude material was purified (SiO2, ethyl acetate, then 1–10% MeOH/CHCl3 gradient elution). The material obtained was dissolved in ethyl acetate (20 mL) and washed twice with 20 mL portions of saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate and dried in vacuo to provide the title compound (100.5 mg, 89%) as a white solid. MS (ESI+): 534.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](Cl)(Cl)=[S:12]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]=[C:11]=[S:12])([O-:3])=[O:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccccc1N=C=S

Procedure:
To 200 ml of benzene were added 22 g of 2-nitroaniline and 6.6 ml of thiophosgene. The mixture was refluxed for 2 hours. After cooling, the resulting crystals were removed by filtration and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate/n-hexane=0/1→1/10) to obtain 8.0 g of 2-nitrophenyl isothiocyanate.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[N:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)s1
Temperature: 80 °C
Yield: 72.1 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-benzyl piperazine 14b (211 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15b (229 mg, 72.7%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(OCC)(=O)C.[P:33]([O:40]CC)([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])(=[O:10])=[O:9]
Reactant: CCOP(OCC)OCC
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12)OCC
Yield: 25 %

Procedure:
A solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (240 mg) in triethyl phosphite (5 mL) was stirred at 100° C. for 1 hr. The reaction mixture was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (67 mg, yield 25%) as a pale-yellow amorphous. M+1=526.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([Cl:18])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[ClH:18].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:20])[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1nc(Cl)c2sccc2n1
Reactant: CNc1ccccc1
Solvent: CCOCC
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2sccc2n1
Product: Cl

Procedure:
2-(4-Fluoro-2-methylphenylamino)-4-chlorothieno-[3,2-d]pyrimidine (1.5 g, 0.0051 mol) and N-methylaniline were heated in an oil bath at 150° for 1 hour. Addition of diethyl ether gave a solid which was collected by filtration and dried, (1.85 g). Recrystallization from ethanol gave the title compound, (0.75 g), m.p. 242°-244°.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]([O:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:17])[CH3:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:21]2[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([O:18][CH:15]([CH3:17])[CH3:16])[CH:20]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: CC(C)Oc1cc(-c2nnc(N)nc2-c2ccccc2)ccc1O
Yield: 18.6 %

Procedure:
4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol (0.450 g, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.9 g, 7.52 mmol) and 3-isopropoxy-4-hydroxyphenylboronic acid pinacol ester (2.5 g, 9.02 mmol) according to the general procedure of Example 1.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:15][C@H:14]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Reactant: Clc1ccccn1
Product: C[C@@H](COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1

Procedure:
The resulting oily substance containing (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was reacted with 2-chloropyridine in the same manner as described in Example 1 to give (S)-(+)-2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Ic1ccc2nccn2c1
Solvent: CC(=O)O
Product: Brc1cnc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture comprising 6-iodo-imidazo[1,2-a]pyridine (1 eq, 95 mmol, 23.3 g) in acetic acid (220 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 95 mmol, 4.8 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered. The resulting solid is suspended in DCM (1% MeOH) (500 ml) and washed with 4N sodium hydroxide (100 ml). When the solid dissolves, the organic layer is separated, dried (MgSO4) and evaporated to give a beige solid; [M+H]+323 (325).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]([CH2:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=O)=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1.O>CC(C)=O>[CH3:18][O:17][C:15]([C:13]1[NH:19][C:4]2[C:5]([CH:12]=1)=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:16]
Reactant: COC(=O)C(=O)Cc1c(CCCO)cc(Cl)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(CCCO)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 3-chloro-5-(3-hydroxypropyl)-6-methoxalylmethylnitrobenzene (19.91 g, 0.063 mol) in acetone (300 mL) was added dropwise a mixture of 20% TiCl3 (340 g, 0.441 mol), water (300 mL), and acetone (300 mL) at room temperature over a period of 30 min. The mixture was stirred for 30 min at room temperature and extracted with AcOEt. The extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 1:2 hexane/toluene to give 11.39 g of the title compound (68%): 1H NMR (CDCl3) δ8.96 (bs, 1H), 7.27 (s, 1H), 7.26 (d, 1H, J=1.7 Hz), 6.97 (d, 1H, J=1.7 Hz), 3.95 (s, 3H), 3.71 (t, 2H, J=6.3 Hz), 2.98 (t, 2H, J=7.8 Hz), 2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1.Cl>ClCCl.CO>[ClH:1].[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:14](=[O:16])[C:13]#[C:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Cl:1])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1
Reactant: CCCN(CCOc1ccc(N)cc1OC)CC1CC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCN(CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.66 mmol) of 4-[2-(cyclopropylmethylpropylamino)ethoxy]-3-methoxyphenylamine. Yield: 180 mg (59% of theory); melting point: 185° C.-188° C.; C26H28ClF3N2O3 (M=508.96)*HCl; calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].[OH-].[Na+]>N1C=CC=CC=1.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cccc(Br)c1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A solution of imidazole (2.66 g, 39.1 mmol) and triethylamine (Et3N) 8.03 g, 79.4 mmol) in pyridine at 0° C. is treated with 3-bromobenzoyl chloride (17.5 g, 79.9 mmol), stirred for 5 min, allowed to warm to room temperature for 45 min, treated with an aqueous sodium hydroxide solution (7.5 N, 20 mL, 150 mmol), heated at reflux temperature for 2 h, cooled to room temperature, diluted with water, further cooled with an ice bath for 1 h and filtered. The filtercake is washed with water and dried under vacuum at 50° C. overnight to afford the title compound as a light tan solid, 4.89 g (50% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 10.58 (br s, 1H), 8.73 (t, J=1.8 Hz, 1H), 8.61 (dt, J=7.8, 1.2 Hz, 1H), 7.75-7.72 (m, 1H), 7.42-7.38 (m, 2H), 7.32 (s, 1H); ESI MS m/z 250 [C10H7BrN2O+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:45]=[O:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:50]>ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:50])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (52 mg, 0.0839 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of methanol. Sodium borohydride solution (9.52 mg, 0.252 mmol) in water (0.5 mL) and methanol (1.0 mL) was added in drops. The mixture was stirred at room temperature for 1 hr. LC/MS showed a clean desired product. The mixture was evaporated to dryness and extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to give a pure desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (51 mg, 98% yield). LC/MS clacd for C34H32FN7O4 (m/e) 621.25, obsd 622.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 3.59-3.77 (m, 8H), 4.37 (br. s., 2H), 6.59 (br. s., 1H), 7.43 (d, J=8.6 Hz, 2H), 7.48 (dd, J=7.8, 1.3 Hz, 1H), 7.54-7.61 (m, 4H), 7.66 (t, J=8.1 Hz, 1H), 7.81 (dd, J=8.1, 1.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:28])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH3:33]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[N:20]([CH3:33])[CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:28])=[CH:4][C:3]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)nc1=O
Yield: 14.3 %

Procedure:
The same procedure as E141 from 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (60 mg, 0.126 mmol), DIPEA (0.044 mL, 0.253 mmol) and MeI (0.012 mL, 0.190 mmol) in DCM (2 mL), except that the reaction time was 3 h, to afford the title compound (11 mg, 0.018 mmol, 14.44% yield). LCMS: rt=3.62 min, [M+H+]=489
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C:27](O)=[O:28]>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17]
Reactant: COc1ccccc1CCC(=O)O
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: COc1ccccc1CCC(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 62 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3-(2-methoxyphenyl) propionic acid in 62% yield following procedure 1. The product was crystallized from acetonitrile. 96% Purity by LC/MS (TIC, DAD), Mass-spec [M+H+]=371, 1H NMR (MeOH-d4): 2.62 t, 7.5 Hz (2H), 2.97 t, 7.5 Hz (2H), 3.74 s (3H, OMe), 6.40 s (1H), 6.81 t, 7 Hz (1H), 6.88 d, 8 Hz (1H), 7.03 t, 8 Hz (1H), 7.10–7.14 m (2H), 7.17 t, 8 Hz (1H), 7.27 t, 7 Hz (1H), 7.33 td, 7.5, 1 Hz (1H), 7.40 d, 8 Hz (1H), 7.54 d, 8 Hz (1H), 7.57 dd, 7.1 Hz (1H), 7.76 d, 8 Hz (1H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>CS(C)=O.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:2])[CH2:16][O:17]2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2 mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl)ethanone (2 g, 14.47 mmol, 1 equiv.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The progress of the reaction was checked by TLC and the reaction mixture was poured in 100 mL water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×150 mL), followed by brine. The organic layer was dried over sodium sulfate and evaporated to dryness to yield a brown oil (2.2 g). 1H NMR (d6-acetone) was consistent with the structure. Product Rf 0.8 (ethyl acetate:hexane 10:90)