Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 59.3 %

Procedure:
A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (1.50 g, 3.91 mmol), 1-bromododecane (1.41 ml, 5.87 mmol) and potassium carbonate (811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.28 g (yield: 59.3%)
Reaction SMILES: [H-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[CH:3]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[O:6][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2C=O)c([N+](=O)[O-])c1
Temperature: 103 °C

Procedure:
Sodium hydride (3.09 g) was added in portions to a stirred solution of salicylaldehyde (14.3 g) in N,N-dimethylformamide (180 mL) under nitrogen. To the resulting dark solution was added methyl 4-chloro-3-nitrobenzoate (23.0 g) and N,N-dimethylformamide (50 mL), and the reaction was heated at 103° C. for 2.75 hours. The reaction was evaporated under vacuum, and the resulting oily mixture was partitioned between chloroform and water. The layers were separated, and the chloroform layer was washed with 1 M NaOH, water, and brine, dried over magnesium sulfate, and evaporated under vacuum to a yellow solid. Recrystalization from methanol yielded the title compound as light yellow crystals Mp: 109°-110° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=[N:13][C:14]=1[OH:15]>N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=[N:13][C:14]=1[OH:15])=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ncnc(O)c1O
Solvent: c1ccncc1
Product: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Temperature: 40 °C

Procedure:
Pivaloyl chloride 1.1 eq. was added to a solution of the product of Step 2 in pyridine, and the mixture was heated to 40° C. for 10 minutes. HPLC showed the complete conversion of starting material. The reaction mixture was concentrated, the resulting oil was diluted with ethyl acetate and washed with 1 N HCl solution. The title product was obtained as a brown solid after evaporation of the organic phase and trituration with diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:46][CH2:47][CH2:48][O:49][CH3:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[NH:35]1[C:36]2[C:32](=[CH:31][C:30]([NH:29][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:46][CH2:47][CH2:48][O:49][CH3:50])[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a suspension of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.321 g, 0.47 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The resulting mixture was stirred at RT for 1.5 h, upon which it was concentrated in vacuo and the residue purified by preparative HPLC (10-35-90 method) to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide trifluoroacetate salt (0.141 g, 0.202 mmol, 43% over two steps). MS 584 (M+1). HPLC retention time 4.40 mins.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])(=O)C.[Cs+].CS(C)=O>C(OCC)(=O)C.[Cu]>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:9][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([NH2:23])=[N:13]2)[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Reactant: N#Cc1cccnc1Cl
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2nc(N)c3cccnc32)C1
Temperature: 100 °C

Procedure:
Tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4 g, 19.87 mmol), 2-chloro-3-cyanopyridine (3 g, 21.65 mmol), cesium acetate (14 g, 72.9 mmol), and copper powder (0.126 g, 1.987 mmol) were placed under nitrogen. Dry dimethylsulfoxide (20 mL) was added and the mixture stirred at 100° C. After 1 hour the mixture was cooled and diluted with ethyl acetate (300 mL). The mixture was filtered through a pad of celite and the filtrate washed with 10% saturated sodium bicarbonate (500 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (10% (2 N ammonia in methanol) in dichloromethane) gave the desired tert-butyl(trans-3-(3-amino-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (2.72 g, 8.97 mmol, 45.1% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Ni]
Solvent: CO
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Yield: 103.4 %

Procedure:
To a stirred solution of N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (3.0 g) in methanol (100 mL) was added activated nickel (0.3 g). Hydrogen was added to the reaction mixture at atmospheric pressure till the starting material disappeared. The solid was filtered off and the filtrate was concentrated to give the N-(5-amino-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (2.8 g).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[CH3:16][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of cyclobutanol (1 g, 13.9 mmol) in pyridine (20 mL) was added p-toluenesulfonyl chloride (2.9 g, 15.3 mmol) and the solution stirred at room temperature for 4 hours. Aqueous HCl was then added, and the solution extracted with ethyl acetate (×3). The combined organic layers were washed successively with saturated aqueous copper(II) sulfate (×3) and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using flash column chromatography on silica gel (gradient of 0% to 5% ethyl acetate in petrol) to give cyclobutyl 4-methylbenzenesulfonate (2.05 g, 9.07 mmol, 65%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH:20]=[CH:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:22](=[O:24])[CH:21]=[CH:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:17])[F:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: COc1ccccc1CN
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)C=CC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This is the compound of Example 1. It can be prepared also by the following synthesis method: a mixture of 0.493 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid, 0.137 g of 2-methoxy-benzylamine, 0.21 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.134 g of 4-dimethylaminopyridine and 10 ml of methylene chloride is stirred at room temperature under argon for 16 hours and then concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 1:1). In this way the title compound is obtained in the form of a colourless amorphous solid. 1H-NMR, 200 MHz, CDCl3, delta (ppm): 7.3-7.0(m, 4H), 6.95-6.7(m, 5H), 6.0(s,1H), 5.77(d, 1H), 5.0(b, 1H), 4.5(d, 2H), 3.85(s, 3H), 2.9-2.6(m, 5H), 1.3(bs, 9H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](Cl)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].N1C=CC=CC=1>CC(C)=O>[C:1]([O:9][CH2:10][C:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Reactant: O=C1CCCN1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(OCC(=O)N1CCCC1=O)c1ccccc1
Yield: 64.7 %

Procedure:
A mixture of (benzoyloxy)acetyl chloride (1.98 g, 0.01 mole), pyrrolidone (0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) in acetone (10 ml) was refluxed for 3 h. The cooled mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and the solution washed with a 2% aqueous solution of sodium bicarbonate, 2M hydrochloric acid and water. After drying over anhydrous sulphate, the organic phase was evaporated under reduced pressure to give a residue which crystallized by addition of ether. Recrystallization from ether-petroleum ether yielded 1.6 g (65%) of the title compound. Mp 83°-84° C.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:22][CH2:23][C:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[C@@:24]1([O:32][C:2]([NH:1][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=3)=[N:22][CH2:23]1)[CH2:25]2
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cc1nc(N=C=S)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ccc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 6-isothiocyanato-2-methylnicotinonitrile (0.25 g, 1.43 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.5 mL, 3.666 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.33 g, 1.46 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.67 mL, 4.28 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile (0.09 g, 0.3 mmol, 21% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.11 (s, 1 H), 7.87 (d, J=7.93 Hz, 2 H), 6.69 (s, 1 H), 3.89 (d, J=10.38 Hz, 2 H), 3.63 (d, J=10.38 Hz, 3 H), 3.00 (s, 5 H), 2.72-2.80 (m, 4 H), 2.64-2.69 (m, 5 H), 2.60 (s, 7 H), 2.00 (d, J=2.14 Hz, 3 H), 1.91 (s, 1 H), 1.87 (s, 2 H), 1.58 (s, 5 H), 1.42-1.50 (m, 2 H). MS (LC/MS) R.T.=0.48; [M+H]+=298.13.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N-]=C=O.[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12>>[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[O:12])[CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccc3c(c2)CCC3)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using 5-indanyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 386 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].[OH-].[Na+]>ClCCl.O>[O:17]1[CH2:13][CH2:14][N:15]=[C:16]1[NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: NC1CCCc2cccnc21
Reactant: O=C=NCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: c1cnc2c(c1)CCCC2NC1=NCCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 5,6,7,8-tetrahydroquinolin-8-amine (Intermediate 17) (3.0 mmol) in dichloromethane (10 mL) was added chloroethylisocyanate (3.3 mmol). The solution was stirred at room temperature for 1.5 hour. The solvent was removed under vacuum gave a crude material, which was refluxed in H2O (60 mL) for 1 hour. After cooling to room temperature, the reaction was basified with NaOH (pH 14), extracted in Ethyl acetate (3×50 mL). The pooled organic layers were washed with brine and dried over magnesium sulphate to give 747. (4,5-Dihydro-oxazol-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 747 as a solid.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]\[C:6]1[S:14][C:13]2[C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([F:30])[CH:17]=3)[CH:10]=[N:9][C:8]=2[CH:7]=1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[S:14][C:13]2[C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([F:30])[CH:17]=3)[CH:10]=[N:9][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCO/C=C\c1cc2ncn(-c3ccc(OCCN4CCCC4)c(F)c3)c(=O)c2s1
Agent: [Pd]
Solvent: CO
Product: CCOCCc1cc2ncn(-c3ccc(OCCN4CCCC4)c(F)c3)c(=O)c2s1

Procedure:
Palladium on carbon (40 mg) was added to a solution of 6-((Z)-2-ethoxyvinyl)-3-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (73 mg) in methanol (4 mL), and the mixture was hydrogenated until starting material was no longer present. The mixture was filtered and the filtrate was concentrated. The product with the molecular weight of 431.53 (C22H26FN3O3S) was obtained in this way; MS (ESI): 432 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([Mg]Br)=[CH:21][CH3:22]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:14]([OH:15])[CH:20]=[CH:21][CH3:22])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C[Mg]Br
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC=CC(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Analogously to the procedure of example II, starting from 3.00 g (11.66 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 60 ml of THF and 37.8 ml (18.66 mmol) of a 0.5 M 1-propenylmagnesium bromide solution in THF at −78° C., 1.95 g (56%) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-buten-1-ol are obtained as an E/Z mixture.
Reaction SMILES: [C:1]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:8]1[CH:23]1[CH2:25][CH2:24]1)([O:3]C)=[O:2].[OH-].[Na+].CO>O>[C:1]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:8]1[CH:23]1[CH2:25][CH2:24]1)([OH:3])=[O:2]
Reactant: COC(=O)CCn1c(C2CC2)c(Cc2cccnc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCn1c(C2CC2)c(Cc2cccnc2)c2ccccc21
Yield: 57.4 %

Procedure:
A mixture of 1-(2-carbomethoxyethyl)-2-cyclopropyl-3-(3-pyridylmethyl)indole (1.0 g), sodium hydroxide (0.18 g), methanol (1 ml) and water (10 ml) was heated under reflux for six hours. The resulting solution was evaporated to dryness and the residue was dissolved in a small volume of water. Acidification with acetic acid gave a solid which was filtered off, washed with water, dried and crystallised from isopropanol/petrol (b.p. 60°-80°) to give 1-(2-carboxyethyl)-2-cyclopropyl-3-(3-pyridylmethyl)indole (0.55 g), m.p. 159°-160°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:13]=1[C:14](Cl)=[O:15].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[C:13]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNC(=O)c2c(C)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-methoxyphenyl)methanamine (264 g, 2.4 mol, 1.eq) in DCM (1800 mL), a solution of 2-chloro-6-methylbenzoyl chloride (340) in DCM (150 mL) was added dropwise while keeping the reaction temperature between 25° C. to 40° C. The resulting mixture was stirred at RT for 2 h, and then water (600 mL) was added. The organic layer was separated, washed with water (2×300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was slurried in petroleum ether (300 mL) and stirred at RT for 30 min. The solid was collected by filtration and further dried in vacuo to afford N-(4-methoxybenzyl)-2-chloro-6-methylbenzamide (341).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:36])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2.5 hrs with a stream of nitrogen bubbling through it. The n-propylamine (2.06 g, 0.0348 mole) was added dropwise and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere overnight. The tetrahydrofuran was evaporated and the residue was triturated with water. The solid was collected and dried under high vacuum at 50° C. overnight. The solid was dissolved in isopropyl alcohol, filtered, diluted with water, and placed in the freezer overnight. The crystalline precipitate was collected by filtration, washed with water, and dried at 50° C. under high vacuum overnight to give 3.6 g (63%), m.p. 220°-21° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][N:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].CS(O[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])(=O)=O.O>C1COCC1>[F:39][C:32]1[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:12]1[CH:13]=[CH:14][N:15]=[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)[C:11]1=[O:16]
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Reactant: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-isopropyl-1-piperazinyl)-2(1H)-pyrazinone (0.58 g, 2.6 mmol; from Step 2) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Example 54, Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temperature, HPLC showed only 25% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.18 g of the crude product as a yellow oil. Purification by chromatography on silica gel (eluent: 2.5% MeOH in CHCl3+NH3 (g)) gave the title compound as a colourless oil, which solidified upon cooling. Yield: 120 mg (14%). HPLC purity: 99%. MS m/z 397 (M+H)+. HRMS m/z calcd for C19H23F3N4O2 (M)+ 396.1773, found 396.1771.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[N+:17]([C:12]1[C:13]([OH:15])=[N:14][C:9]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: Oc1cc(O)nc(SCc2ccccc2)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(SCc2ccccc2)nc1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The product of example 2, step (a) (2 g) was added to a mixture of glacial acetic acid (50 ml) and concentrated nitric acid (20 ml) and the reaction mixture heated to 50° C. A further 28 g of the product of step (a) was added in portions over 2 hours whilst maintaining the reaction temperature between 50 and 60° C. After stirring the reaction mixture for a further 1 hour at 50° C. it was poured onto crushed ice and the subtitled product isolated by filtration as a yellow solid (12.3 g).