Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>C(O)C>[CH2:8]([O:7][C:1]([CH:2]([C:3](=[O:4])[CH3:5])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(C)=O
Reaction time: 6 h
Yield: 95.4 %

Procedure:
In a four-necked flask equipped with a thermometer, dropping funnel and stirrer were placed 179 g (1.375 moles) of ethyl acetoacetate and 500 ml of ethanol, and then 31.5 g (1.375 moles) of sodium was added in portions thereto to form a solution. Then, a solution of 253.5 g (1.25 moles) of 4-chloromethylbiphenyl in 1000 ml of ethanol was added dropwise to the above solution at room temperature over a period of 2 hours. After completion of the addition, the resulting mixture was brought up to 65° C. and stirred at the temperature for 6 hours. After completion of the reaction ethanol was distilled off under reduced pressure, the residue obtained was extracted by addition of 1500 ml of toluene, and the organic layer was separated. The organic layer was washed with 10% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water in said order and then concentrated under reduced pressure to obtain 353.5 g of 4-(2-ethoxycarbonyl-3-oxobutyl)biphenyl as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[B:21]([OH:24])[OH:22]
Reactant: COB(OC)OC
Reactant: Clc1ccc(-c2ccc(Br)c(I)c2)cc1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: -75 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (8.00 g, 20.40 mmol) in a mixed solvent system of anhydrous diethyl ether (80 ml) and anhydrous tetrahydrofuran (80 ml) at −75° C. is added isopropylmagnesium bromide (31.60 ml, 15% in tetrahydrofuran) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 2 hours, then allowed to warm to −25° C. at which point trimethyl borate (3.15 g, 30.60 mmol) is added dropwise. After the addition is complete the reaction is allowed to warm to room temperature and stir overnight, followed by cooling in an ice-bath and acidification with 2M aqueous hydrochloric acid. The crude product is extracted with ethyl acetate (×3), and the organic fractions are combined, washed with brine, then dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate is evaporated in vacuo to give a solid which is further triturated with hexanes to afford 4-bromo-4′-chlorobiphenyl-3-yl-boronic acid (5.20 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:10]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[CH:1]1([CH2:6][C:7]2[N:11]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:10]3[CH:17]=[CH:18][C:19]([C:21]([Cl:32])=[O:23])=[CH:20][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)O)ccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)Cl)ccc21
Reaction time: 16 h
Yield: 100 %

Procedure:
To 8.00 g of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid in 100 ml of dichloromethane 0.1 ml of DMF and 4 ml of oxalyl chloride were added. The reaction was stirred at it for 16 h, then concentrated and co-distilled with toluene to obtain 8.45 g (100%) of the crude product as a brown solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26](C(OC(C)(C)C)=O)[C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][NH:26][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1

Procedure:
A solution of (2S,4S)-1-tert-butyl 2-methyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (24 mg) obtained in Step 6 above in methylene chloride (2.0 ml) and TFA (2.0 ml) was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (developing solvent: chloroform/methanol). The title compound was thus obtained as a light-yellow, amorphous substance (11.9 mg). Physical properties: m/z [M+H]+ 422.1
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22])/[C:5](=[O:11])[NH:6]2.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH2:70])=[N:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH:70][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:4]3\[C:5](=[O:11])[NH:6][C:7]4[C:3]\3=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=4)[NH:17][C:16]=2[CH3:18])=[O:20])=[N:63][CH:62]=1
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Reactant: Cc1cccc2c1/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2c1/C(=C/c1[nH]c(C)c(C(=O)NCCNc3ccc(C(=O)Nc4ccccc4N)cn3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
5-(4-Methyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (296 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (445 mg, 81%) as a yellow solid. LC-MS (m/z) 550 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][CH2:16]O.O>C1(C)C=CC=CC=1.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[CH2:16])=[N:3][CH:4]=1
Reactant: CCO
Reactant: Cc1ccc(Br)nc1
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: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 2-bromo-5-methyl-pyridine (1.7 g, 10 mmol), 2,4,6-trivinyl-cyclotriboroxanein (1.20 g, 5 mmol) and Na2CO3 (3.73 g, 35.2 mmol) in toluene (15 mL)/EtOH (10 mL)/H2O (5 mL) was added Pd(PPh3)4 (300 mg, 0.25 mmol) under N2. The mixture was stirred at 100° C. overnight. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography column (PE:EA=50:1) to afford 5-methyl-2-vinyl-pyridine (900 mg, 75.6%) as a yellow oil.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:53][C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (5.38 g) in anhydrous acetonitrile (70 ml), N,N'-carbonyldiimidazole (2.04 g) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (2.0 ml) and a solution of the compound (11.00 g), which had been obtained in (2), in anhydrous acetonitrile (35 ml) were added and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography (ethyl acetate-methanol) through a silica gel column, whereby the title target compound (10.09 g) was obtained as an amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])=[CH:22][C:23]=2[O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: CN(C)CCOc1ccc(N)c(Oc2ccccc2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN(C)C)cc2Oc2ccccc2)c1C(=O)OC
Yield: 76 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), 4-(2-dimethylamino-ethoxy)-2-phenoxy-phenylamine (1.9 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (60 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 2.2 g of the product, an orange solid, at 95:5 methylene chloride-methanol, in 76% yield; 1H NMR (CDCl3) δ 2.31 (s, 6H), 2.69 (t, J=5.6 Hz, 2H), 3.74 (s, 3H), 3.84 (s, 3H), 3.99 (t, J=5.6 Hz, 2H), 6.61 (d, J=2.6 Hz, 1H), 6.69 (dd, J=8.5 Hz, J=2.8 Hz, 1H), 6.86-6.90 (m, 2H), 6.98 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.01-7.07 (m, 1H), 7.11 (dd, J=8.6 Hz, J=1.1 Hz, 1H), 7.22-7.30 (m, 4H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(OCC)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:10][CH2:11][C:12]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:13]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CCCOC1CCCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(CCOC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolved in diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was diluted with diethyl ether (10 ml) and added dropwise into previous mixture. After addition the reaction mixture was extracted with water and the organic layer was dried with Na2SO4, filtered and evaporated. LC-MS: [M+1]=172.17.
Reaction SMILES: [CH3:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1>C(O)C.[Pd]>[NH2:21][C:20]1[C:2]([CH3:1])=[C:3]([CH:17]=[CH:18][CH:19]=1)[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6]1
Reactant: Cc1c(OC2CCN(C(=O)OC(C)(C)C)C2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1OC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
A mixture of t-butyl 3-(2-methyl-3-nitrophenoxy)pyrrolidin-1-Carboxylate (11.0 g, 34.2 mmol) and 10% Pd/C (0.55 g) in ethanol is hydrogenated (45 psi) at room temperature overnight. After filtering off the catalyst, the filtrate is concentrated to afford the title compound as an off-white solid, 9.98 g, mp 137° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Br[CH:2]([CH3:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:20]=[C:21]3[N:25]([C:2]=2[CH3:19])[CH:24]=[CH:23][S:22]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2nc3sccn3c2C)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (153 mg, 0.50 mmol) and 2-aminothiazole (50 mg, 0.50 mmol) in ethanol (1 mL) was heated to reflux for 12 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1 to 1:0) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)-5-methylimidazo[2,1-b][1,3]thiazole. 1H NMR (CDCl3, 500 MHz) δ 8.73 (m, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7.73 (dt, 1H), 7.52 (s, 1H), 7.35 (dd, 1H), 7.34 (dd, 1H), 7.22 (m, 1H), 6.86 (dd, 1H), 3.98 (s, 3H), 2.66 (s, 3H) ppm. MS (ESI) 322 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.42 g) in toluene (14 ml) warmed to 40° C. was added phosphorous tribromide (0.16 ml) and the mixture was then heated to 100° C. After heating for 6 hours the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.40 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12](=[O:17])[C:11]=1[C:18]#[N:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N>CO.[Ni]>[NH2:19][CH2:18][C:11]1[C:12](=[O:17])[NH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Reaction time: 15 h

Procedure:
To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.8 g, 13.7 mmol) in methanol (200 mL), Raney Ni and ammonia (20 mL) were added and reaction stirred under hydrogen balloon pressure for 15 h. On completion, reaction mixture was filtered through a celite bed and the filtrate concentrated to obtain 3-(aminomethyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2(1H)-one as an off white solid (3.2 g, 83.1%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH:38]([NH:41][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 69.4 %

Procedure:
3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5 carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (408 mg), 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg), HBTU (457 mg), and DIEA (350 uL) in DMF (3 mL).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>CO>[F:23][C:19]1[CH:18]=[C:17]([C:16]2[N:8]([C:5]3[N:6]=[N:7][C:2]([O:28][CH3:27])=[CH:3][CH:4]=3)[C:9]3[C:14]([N:15]=2)=[C:13]([N:24]([CH3:26])[CH3:25])[N:12]=[CH:11][N:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)c1ncnc2c1nc(-c1cccc(F)c1)n2-c1ccc(Cl)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2c(-c3cccc(F)c3)nc3c(N(C)C)ncnc32)nn1
Yield: 53.2 %

Procedure:
N-[9-(6-Chloro-3-pyridazinyl)-8-(3-fluorophenyl)-9H-6-purinyl ]-N,N-dimethylamine (50 mg, 0.18 mmol) in Example 54 was dissolved in 5 ml anhydrous methanol, and sodium methoxide (15 mg, 0.28 mmol) was added thereto and heated under reflux for 2 hours. The reaction solution was cooled, evaporated and suspended in water, and the precipitated solid were separated by filtration, to give the title compound (35 mg, 52%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1>O1CCCC1.C(=O)([O-])O.[Na+]>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:12]3[C:8]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc3c(c2)OCO3)c1
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
To a solution of 5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (200 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 64 mg) at room temperature and the mixture was stirred for 10 min. 15-Crown-5 (348 mg) was added dropwise, and the mixture was stirred for 5 min. 1,3-Benzodioxole-5-sulfonyl chloride (250 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→2:3) and crystallized from diethyl ether to give the title compound as colorless crystals (yield 250 mg, 64%).
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.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][NH:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][NH:26][CH2:27][CH:28]1[CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(CCNCC2CC2)c(Cl)c1
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCNCC2CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-chloro-4-[2-(cyclopropylmethylamino)ethyl]phenylamine. Yield: 15 mg (3.4% of theory); C22H19Cl2F3N2O (M=455.31); calc.: molecular ion peak (M+H)+: 455/457/459; found: molecular ion peak (M+H)+: 455/457/459; Rf value: 0.3 (Alox, petroleum ether/ethyl acetate (3:1)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
To a stirred solution of 3-methyl-4-phenoxynitrobenzene (2) (548 g, 2.39 moles, 1.0 eq.) in methanol (5 L) was added 10% Pd/C (100 g, 50% wet, 46.98 mmol, 0.02 eq.). Then the reaction mixture was stirred under a hydrogen atmosphere (60-80 psi) for 15-16 hours at room temperature in a 2 gallon Parr hydrogenator. The progress of the reaction was monitored by TLC (50% ethyl acetate in hexanes, sm Rf=0.69, pr Rf=0.47, UV visible). Then the reaction mixture was filtered through Celite, and the solid was washed with excess methanol. The filtrate was concentrated under reduced pressure to give 3-methyl-4-phenoxyaniline as a pale brown viscous liquid (451.0 9, 95%). The 3-methyl-4-phenoxyaniline was found to be pure by 1H and 13C NMR spectra, and used as such in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][N:3]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ncc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-chloro-5-iodopyrimidine (7.62 g), palladium(II) acetate (356 mg), tri(o-tolyl)phosphine (965 mg), and DMF (32 mL) was added ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (2.32 g).