Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:56])[N:18]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]4[C:45](=[CH:46][CH:47]=3)[CH2:44][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[N:28](COCC[Si](C)(C)C)[C:27]3=[O:43])[CH2:25]4)[C:17](=[O:48])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@@:9]2([CH3:56])[N:18]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]4[C:45](=[CH:46][CH:47]=3)[CH2:44][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]3=[O:43])[CH2:25]4)[C:17](=[O:48])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(C/C=C/c2ccc3c(c2)CC2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1C/C=C/c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reaction time: 24 h

Procedure:
tert-Butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-9-[(2E)-3-(2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)prop-2-en-1-yl]-6,9-diazaspiro[4.5]decane-6-carboxylate from Step A above (0.2276 g, 0.290 mmol) was dissolved in DCM (5 mL). To this solution was added 1 mL of TFA. The reaction was stirred for 24 hours, then concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and to this solution was added 1N NaOH (2.90 ml, 2.90 mmol), and ethylenediamine (0.078 ml, 1.160 mmol). The reaction was stirred for ½ hour at RT, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, then the aqueous layer was washed 3×20 mL with ethyl acetate. The combined organic layers were washed with brine. Dried over Magnesium sulfate, filtered and concentrated in vacuo to yield the title compound. Diastereomer separation was accomplished using a Chiralcel OJ column, eluting with CO2:MeOH—70:30. Two peaks were isolated. Peak 1 MS: m/z=555 (M+1) HRMS: m/z=555.2569 (M+1); calculated m/z=555.2566 (M+1) for C33H32F2N4O2, and Peak 2 MS: m/z=555 (M+1)HRMS: m/z=555.2569 (M+1); calculated m/z=555.2566 (M+1) for C33H33F2N4O2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.Cl[C:60]([O:62][CH3:63])=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:60]([O:62][CH3:63])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by methyl chloroformate (0.009 g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 440.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:15][C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4].NC1C=C(C)C=C(C)N=1.C(O)(=O)CC.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:3]([C:5]1[N:15]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH:41]=[CH:40][CH2:39]3)=[CH:36][CH:37]=2)[C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC=CC1
Agent: Cc1cc(C)nc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OC)CC=CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.885 g, 22.1 mmol) in 50 ml of DMF at 0° C. was added a solution of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (3.57 g, 20 mmol, prepared from 2-amino-4,6-dimethylpyridine by nitration, hydrogenolysis to the diamine and condensation with propionic acid and polyphosphoric acid, as described in EP 400974 A2) in 10 ml of DMF dropwise and the reaction mixture was warmed to room temperature. After 20 minutes the reaction was cooled to 0° C. and a solution of the product of Step 4, above, (5 g, 17 mmol) in 10 ml of DMF was added dropwise. The reaction was then allowed to warm to room temperature and stirred overnight then the DMF was removed in vacuo. The residue was taken up in water and extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution, dried with MgSO4, filtered, evaporated and chromatographed on silica gel with a gradient elution from 5:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to yield 5.8 g of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=394.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:14][CH3:15].C(N(CC)CC)C.C(Cl)(Cl)[Cl:28].CCCCCC>>[Cl:28][C:12]1[CH:11]=[C:18]([NH:19][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH:17]=[CH:16][C:13]=1[O:14][CH3:15]
Reactant: ClC(Cl)Cl
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1Cl
Yield: 22 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine (0.29 g, 1.58 mmol) in 1:1 chloroform-hexane (10 mL) was added 3-chloro-p-anisidine (0.5 g, 3.1 mmol) at 25° C. with stirring. To this was added triethylamine (0.22 mL, 1.59 mmol) at 25° C. and the mixture was heated and refluxed for 7 hours under nitrogen atmosphere. The mixture was then concentrated under vacuum, diluted with cold water (30 mL) and extracted with ethyl acetate (2×60 mL). The organic layers were collected, combined, washed with brine (30 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude product thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to afford the desired compound. Yield: 22%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][OH:11].CCN(C(C)C)C(C)C.Cl[C:22](OCC)=[O:23]>C1COCC1>[O:23]=[C:22]1[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][O:11]1
Reactant: N#Cc1ccc(N)c(CO)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 mmol of 4-Amino-3-hydroxymethyl-benzonitrile were dissolved in THF. 1.2 eq. of DIPEA were added and the reaction cooled to 0° C. 3.5 eq of ethyl chloroformate were added dropwise and the reaction warmed to rt and stirred for another 15 min. The crude material was extracted form etyhlacetate and sat. NaHCO3. After separation, and drying of the organic layer the solvent was evaporated and the crude taken up in toluene. 2.5 ml of DBU were added and the reaction mixture refluxed for 4 h. The organic layer was extracted with water and the organic layer separated and reduced resulting in a yellow oil. Crude material was not further characterized.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].Cl.[O:10]1[CH2:14][CH:13]([OH:15])[CH2:12][NH:11]1>CN(C=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:15][CH:13]1[CH2:14][O:10][NH:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CNOC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CNOC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
tert-Butyl-dimethyl-chlorosilane (0.5 g, 3.21 mmol) was added to a stirred solution of isoxazolidin-4-ol hydrochloride (0.40 g, 3.18 mmol) in DMF (3 mL). The mixture was left to stir at ambient temperature for 2.5 hours before the solvent was evaporated and the resultant residue partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was separated and washed with water (3×20 mL) then brine (20 mL), dried (MgSO4), filtered and evaporated to provide the desired product as a colourless oil (0.62 g, 96%). 1H NMR (CDCl3, 400 MHz) 5.52 (s, 1H), 4.60-4.65 (m, 1H), 3.45-3.62 (m, 1H), 3.80-4.05 (m, 1H), 2.80-3.05 (m, 2H), 0.80 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:31]([C:32]([NH2:34])=[O:33])[C:30]([OH:36])=[CH:29][CH:28]=1>>[C:32]([C:31]1[CH:35]=[C:27]([CH:28]=[CH:29][C:30]=1[OH:36])[O:26][CH2:25][CH2:24][NH:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([CH3:21])[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:16]=2)=[CH:10][CH:11]=1)(=[O:33])[NH2:34]
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN)cc1
Reactant: NC(=O)c1cc(OCCBr)ccc1O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g of 1-amino-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol and 0.82 g of 5-(2-bromoethoxy)-salicylamide is stirred for 1 hour in an oil bath at a temperature of 100°. The melt is then extracted by boiling with 30 ml of isopropanol. The filtered solution is concentrated to 15 ml, cooled and the crystals that are precipitated are filtered off. Recrystallisation from methanol yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 195°-197°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.O=[C:13]([CH2:19][C:20](=O)[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C.O>[CH2:17]([O:16][C:14]([C:13]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=[C:20]([CH3:21])[CH:19]=1)=[O:15])[CH3:18].[CH2:17]([O:16][C:14]([C:13]1[CH:19]=[C:20]([CH3:21])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)=[O:15])[CH3:18]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc(OC)cc2)n1
Product: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylhydrazine hydrochloride (6.05 g, 34.8 mmol) and ethyl 2,4-dioxovalerate (4.45 mL, 31.6 mmol) were stirred overnight at 80° C. in ethanol (80 mL). After the solution was allowed to cool to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 1 N HCl, and saturated sodium bicarbonate. Concentration and SiO2 chromatography with 20-30% ethyl acetate/hexanes gave 3.1 g of the title compound along with 2.9 g of 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.C(O[B:17]([O:22][CH:23]([CH3:25])C)[O:18][CH:19]([CH3:21])C)(C)C.[Li]CCCC.[C:31]1([N:37](CCO)CCO)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:11][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([B:17]2[O:18][CH2:19][CH2:21][N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:23][O:22]2)[N:7]=1)([CH3:12])[C:9]#[N:10]
Reactant: OCCN(CCO)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C#N)c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(B2OCCN(c3ccccc3)CCO2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A stirred solution of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (1 g, 4.44 mmol) and triisopropylborate (1.23 ml, 5.33 mmol) in tetrahydrofuran (10 ml) was cooled down to −75° C. A 2.5 M solution of n-BuLi in hexanes (2.31 ml, 5.77 mmol) was added at such a rate that the temperature did not exceed −67° C. After complete addition, the reaction was allowed to warm to room temperature and was stirred at this temperature for 16 hours. After this time, a solution of N-phenyldiethanolamine (805 mg, 4.44 mmol) in THF (8 ml) was added and the resulting mixture was heated at reflux for 4 hours. The mixture was concentrated in vacuo, diluted with isopropanol (18 ml) and refluxed for 1 hour. The reaction mixture was cooled down to room temperature and stirred for 18 hours. The newly formed solid was filtered off and dried under vacuo at 40° C. to afford the title compound as a white solid (880 mg, 59% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A suspension of 4-hydroxycarbostyril (1.5g; 0.0093 mole) in glacial acetic acid (10 ml) was well stirred during the addition of concentrated nitric acid (2.5 ml d, 1.42) and the mixture shaken at 95° C for a few minutes until dissolution was complete. The deep red solution soon deposited yellow crystals which after cooling were filtered off and washed with acetic acid and then ethanol. Drying in vacuo over phosphorus pentoxide afforded analytically pure 3-nitro compound m.p. 216° C (decomp) (Found C, 52.74; H, 3.14; N, 13.57; C9H6N2O4 required; C, 52.44; H, 2.93; N, 13.59%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)CCC>C(#N)C.[Pd](Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccs4)cc3CC[C@@H]12
Yield: 33.1 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mg of bis(triphenylphosphene) palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was flushed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp 193°-195°. FDMS 311.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:34])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:34])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.04 g), diisopropylethylamine (4.34 ml), phosphoryl chloride (1.02 ml) and 1,2-dichloroethane (60 ml) was stirred and heated to 80° C. for 2 hours. The mixture was evaporated to give 7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34].C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccncc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.90 g, 1.65 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.49 g, 0.83 mmol), and N,N-diisopropylethylamine (2.1 mL, 11.6 mmol) in acetronitrile (14 mL). Heat to reflux. After 48 hour, add sodium carbonate and stir. After 1 hour, dilute the reaction mixture with dichloromethane, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia and then 50% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Dissolve the residue in dichloromethane, extract with a saturated aqueous sodium bicarbonate solution, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.39 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([O:35][CH3:36])[C:27]=1[O:28][CH2:29][CH:30](OC)OC)[C:21](=[NH:24])[NH:22]O.[NH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[N:22]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:24]=2)[CH:25]=[C:26]([O:35][CH3:36])[C:27]=1[O:28][CH2:29][CH2:30][NH:37][CH2:38][C:39]([OH:41])=[O:40]
Reactant: CCOC(=O)CN
Reactant: COc1cc(C(=N)NO)cc(Cl)c1OCC(OC)OC
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Product: COc1cc(-c2nc(-c3cc(Cl)c(OCCNCC(=O)O)c(OC)c3)no2)cc(C2CCCC2)n1

Procedure:
The title compound is prepared starting from 2-cyclopentyl-6-methoxy-isonicotinic acid, 3-chloro-4-(2,2-dimethoxyethoxy)-N-hydroxy-5-methoxybenzimidamide and ethyl glycinate in analogy to Example 43 and 1 (saponification); LC-MS: tR=0.88 min, [M+H]+=503.11.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1>[C:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (300 mg, 1.01 mmol) in tetrahydrofuran (15 ml) was added benzoyl chloride (145 mg, 1.03 mmol) and triethylamine (101 mg, 1.00 mmol) and the mixture was stirred at room temperature overnight. After reaction, the reaction mixture was filterated and evaporated under reduced pressure to a residue, which was cromatographed to afford 2-benzamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (279 mg, 69% yield): mp 147°-147.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10](C(F)(F)F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:15]C1C=C(Cl)C=CC=1C(O)=O.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2,4-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)=[O:25]
Reactant: O=C(NCCCCNc1nc(Cl)ncc1Br)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)NCCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 21 h

Procedure:
A solution of 568 mg (1.32 mmol) of N-[4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butyl]-3-nitro-benzamide in 15 ml of THF is mixed at room temperature with 9 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 21 hours, the batch is made basic with 2N NaOH solution, mixed with ethyl acetate and filtered on Celite. The filter cake is rewashed with ethyl acetate. The organic phase of the filtrate is filtered through a Whatman filter and concentrated by evaporation. 447 mg (1.12 mmol, corresponding to 85% of theory) of the product is obtained.