Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.67 mmol) in anhydrous tetrahydrofuran (10 mL) was added to sodium hydride (60% in mineral oil, 215 mg, 5.34 mmol) gradually, and the resulting mixture was stirred at room temperature for 1 h. 2-Chloro-5-nitropyridine (425 mg, 2.68 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h, then quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to afford (S)-3-(5-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown oil (800 mg, 98% yield). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(c2ccc(C)cc2)c2c(S(=O)(=O)NC(C)C)[nH]c3ccccc23)cc1
Yield: 74.6 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-dimethylbenzhydrol (0.96 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.44 g (yield: 75%) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[O:34][N:33]=1>C(O)(C)(C)C>[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[CH:36]=[C:35]([C:37]5[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=5)[O:34][N:33]=4)[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4cc(-c5ccc(C(F)(F)F)cc5)on4)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol hydrochloride (50 mg) in t-butanol at room temperature was added triethylamine (60 μl), and the mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole (26 mg), and the mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of methanol, and purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to afford 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinyl]propan-2-ol, a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].ClCCl.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:20]([O:15][CH2:14][C@H:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Cl:1])[OH:16])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a solution of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (4E) (0.920 g, 3.89 mmol) in pyridine (5.0 mL)/dichloromethane (15.0 mL) was added pivaloyl chloride (0.574 mL, 4.67 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction was incomplete and additional pivaloyl chloride (0.574 mL, 4.67 mmol) was added. After stirring for 1 h, the reaction mixture was quenched with 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 4F as a colorless oil (1.139 g). LCMS-ESI+ (m/z): [M—O]+ calcd for C18H21ClO2: 304.80. Found: 303.0, 305.0.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15]/[C:16](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])[CH:40]=O.O>O1CCCC1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])/[CH:40]=[CH:15]/[C:16](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)/C=C(/CP(=O)(OCC)OCC)c1ccccc1
Reactant: COc1ccc(OC)c(C(=O)C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/C=C/C(=O)c1cc(OC)ccc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
1.32 g (11.8 mmol) of potassium tert-butoxide and 30 ml of tetrahydrofuran are mixed together at 25° C. A solution of 3.85 g (11.8 mmol) of ethyl (E)-4-(diethoxyphosphoryl)-3-phenylbut-2-enoate in 30 ml of tetrahydrofuran is then added dropwise. A solution of 3 g (15.4 mmol) of (2,5-dimethoxyphenyl)-2-oxoacetaldehyde dissolved in 30 ml of tetrahydrofuran is added dropwise, at 25° C. The mixture is stirred for 16 hours at 25° C. It is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off under reduced pressure. The 4 g of product obtained are purified by flash chromatography (80/20 heptane/ethyl acetate) (yellow oil: 0.46 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:28]3[C:22]([CH3:21])=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1OC
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC

Procedure:
The compound was synthesized according to the procedure K using 7-chloro-2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C)C=O>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CSc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(methylthio)acetophenone 1 g) and sodium hydride (60%; 288 mg) in N,N-dimethylformamide (7 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled to 0° C., and diethyl oxalate (0.98 ml) was added dropwise to the mixture. The resulting mixture was stirred at ambient temperature for 3 hours, poured into ice-water and acidified with dilute hydrochloric acid. The precipitates were filtered, washed with water, and dried under reduced pressure to give a pale brown powder of ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (1.6 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]1([C:22]#[C:23][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cnc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cnc(C#Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a round bottom flask was added 2-bromo-5-formylthiazole (3.83 g, 19.9 mmol, purchased from Frontier Scientific, Inc.), THF (100 mL) and triethylamine (20 mL). To the solution was successively added CuI (228 mg, 1.20 mmol), PdCl2(PPh3)2 (420 mg, 0.60 mmol) and a solution of phenylacetylene (2.24 g, 21.9 mmol) in THF (20 mL) over a period of about 5 minutes. The reaction was then stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, the residue transferred to a 1.0-L separatory funnel with EtOAc (200 mL) and saturated aqueous sodium bicarbonate (300 mL) and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (2×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient ranging from 5% to 50% EtOAc in hexanes to afford the titled compound, 2-phenylethynyl-thiazole-5-carbaldehyde, (3.94 g, 93%) as an orange solid.
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].[CH3:21]I>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH3:21])[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: CI
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Agent: [K]
Solvent: CN(C)C=O
Product: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 40 ml of dimethylformamide were added 5.0 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 1) and 11.9 g of methyl iodide; the mixture was stirred at room temperature for 16 hours. The mixture was then poured into 150 g of ice water and extracted with benzene. The benzene extract was washed with ice water and then dried over potassium carbonate. After removing the benzene, the residue was chromatographed through a column of silica gel (eluent, ethyl acetate), giving 2.7 g of Compound 2, mp 137° - 142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 65.6 %

Procedure:
4-Bromo-2-chloro-1-methylbenzene (CAS 89794-02-5, 30 g, 0.15 mol) and N-bromosuccinimide (26 g, 0.15 mol) were mixed in CCl4 (300 mL). Azobis(2-methylpropionitrile) (˜0.3 g) was added in portions under vigorous stirring and refluxing. The mixture was refluxed for 30 min and cooled. The precipitate was filtered off and discarded. The filtrate was evaporated. The residue was distilled at 1 mmHg, bp 75° C. to give the title compound (28 g, 65%). 1H NMR data (CDCl3): δ 7.57 (d, J=1.9 Hz, 1H ArH), 7.39 (dd, 1H, J1=1.9 Hz, J2=8.1 Hz, ArH), 7.31 (d, 1H, J=1.9 Hz, ArH), 4.53 (s, 2H, ArCH2).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:7][C:8]1([Cl:12])[CH:1]2[CH:2]([CH2:3][CH2:4][CH:5]=[CH:6]2)[C:9]1=[O:10]
Reactant: C1=CCCC=C1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1C2CCC=CC2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
A mixture of 238 g of cyclohexadiene and 245 g of dichloroacetyl chloride in 2 litres of diethyl ether under nitrogen was refluxed while adding 220 g of triethylamine dropwise over a period of 3 hours. The mixture was then stirred at room temperature for 20 hours and filtered. The filtrate was washed with brine, 1 N hydrochloric acid, saturated sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue distilled to give 224 g of 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, the compound of formula (4).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Br:9]Br>CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(C=O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(C=O)cc1Br
Reaction time: 48 h
Yield: 67.9 %

Procedure:
A solution of 5-methylthiophene-2-carbaldehyde (10 g, 79 mmol) in 30 ml of AcOH was added over a 7-hour period, with a syringe pump, to a stirring mixture of bromine (4.9 ml, 95 mmol) and 30 ml of AcOH, while the reaction was kept in the dark. The reaction was allowed to stir for 2 days and then poured slowly in 600 ml of 2M sodium carbonate. The mixture was stirred for 1 hour and extracted (3×) with ether. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, loaded unto silica and purified by column chromatography on silica gel using a gradient of 5 to 25% EtOAc in hexanes to give 4-bromo-5-methylthiophene-2-carbaldehyde (11 g, 68% yield) as yellow solid. MP 58° C. as reported in literature.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH3:39]>O1CCCC1>[CH3:39]/[C:38](/[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])=[CH:8]/[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCCCCCCCO
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCCCCC/C(C)=C\CCCC(=O)O
Yield: 107 %

Procedure:
164.6 g (0.37 mol) of (4-carboxybutyl)triphenylphosphonium bromide were suspended in 700 ml of tetrahydrofuran. 101 g (0.9 mol) of potassium t-butylate in 150 ml of tetrahydrofuran were added and then 68 g (0.36 mol) of 11-hydroxy-2-undecanone in 50 ml of tetrahydrofuran were added After usual working up there were obtained 98 g of crude 5Z-6-methylpentadec-5-enoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: COc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 27.9 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 298 mg of 4-methoxyindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 107 mg of 2-[2-(4-methoxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a salmon pink powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:24]#[N:25].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl chloride (0.66 g) in N,N-dimethylformamide (20 mL) was added potassium cyanide (0.40 g), and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-3/1) to give [4-(2-Benzyloxybenzyl)phenyl]-acetonitrile (0.54 g).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([CH:35]=3)[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([CH:35]=3)[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(CCc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To ethyl 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate 52 (0.6 mmol) is added THF (3 mL), MeOH (2 mL) and 3M lithium hydroxide (7.3 mmol). The reaction mixture is stirred at rt for 6 h until complete as detected by LCMS. Subsequently, the organic solvents are evaporated and the reaction mixture is diluted with water (10 mL) then neutralized with 3M HCl (7.3 mmol). The resulting precipitate is filtered, washed with water and air dried. The crude precipitate is purified by preparative LCMS to yield 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylic acid F2 as white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.69 (s, 1H), 8.79 (s, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.60 (bd, J=8.0 Hz, 1H), 7.56 (bs, 1H), 7.46 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 3.19 (m, 1H), 2.96 (m, 2H), 2.27 (s, 3H), 2.10 (m, 2H), 1.75 (m, 2H). MS (m/z) (M+1)+: 483.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([C:18]2[C:19]3[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=3[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:17])=[CH:12][CH:11]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:10]2[N:15]=[CH:14][C:13]([C:16]([C:18]3[C:19]4[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=4[S:21][C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(Cl)nc2)cc1
Reactant: OCCN1CCCC1
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)nc2)cc1
Temperature: 25 °C
Yield: 160.6 %

Procedure:
A solution of 0.50 mL (4.30 mmol) of 1-(2-hydroxyethyl)pyrrolidine in 10 mL of xylenes was treated with 50 mg (2.20 mmol) of Na. The mixture was heated to 50° C. until all the Na had disappeared, cooled to room temperature, and then treated with a solution of 420 mg (1.10 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) in 5 mL of xylenes. The reaction was heated to 50° C. for 2 h and was evaporated in vacuo. The residue was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 810 mg of a yellow solid. Purification by radial chromatography (SiO2; gradient of 1-5% MeOH in CH2Cl2) gave 525 mg (1.09 mmol; 99%) of the title compound as an amber oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[CH:3][CH:2]=1.[N:15]1[CH:16]=[C:17](B(O)O)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.CCO.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[C:17]([C:10]2[CH:9]=[C:8]([NH:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12
Reactant: OB(O)c1cnc2ccccn12
Reactant: Brc1cccc(Nc2ccccc2)c1
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: CCO
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cccc(-c3cnc4ccccn34)c2)cc1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
To 3-Bromodiphenylamine (0.16 g, 0.6 mmol) was added imidazo[1,2-a]pyridine-3-ylboronic acid (0.1 g, 0.6 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 5 mol %), EtOH (0.5 ml), toluene (0.5 ml) and 2M Na2CO3 (0.9 ml). The reaction mixture was heated at 80° C. for 6 h, before being allowed to cool and then partitioned between EtOAc and H2O. The organic fraction was separated, washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography (20%-100% EtOAc/hexane) to afford the product (4 mg). MS: [M+H]+ 286.
Reaction SMILES: [CH:1]([N:4]([CH:25]=[CH:26][CH3:27])[C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]=[N:11][C:10]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:9][C:8]2=1)=[CH:2][CH3:3].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C=O)C>[Cl:34][CH2:33][CH2:32][CH2:31][N:14]1[C:13]2[CH:12]=[N:11][C:10]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([N:4]([CH:1]=[CH:2][CH3:3])[CH:25]=[CH:26][CH3:27])[CH:6]=2
Reactant: CC=CN(C=CC)c1ccc2[nH]c3cnc(-c4nc(CC)no4)cc3c2c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CN(C=CC)c1ccc2c(c1)c1cc(-c3nc(CC)no3)ncc1n2CCCCl
Yield: 28 %

Procedure:
The compound was synthesized by mixing (Compound 18) (1 g, 2.8 mmol), NaH (50% in oil) (0.075 g, 3.1 mmol) and 1-bromo-3-chloropropane (0.44 g, 3.1 mmol) in DMF in the same manner as illustrated in example 3 to give the title compound (0.35 g, 28%).