Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](O)=[O:18].C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[NH:9][C:17](=[O:18])[CH:12]3[CH2:13][O:14][CH2:15][CH2:16][N:11]3[C:6]=2[N:7]=1
Reactant: Nc1c(Cl)nc(Cl)nc1Cl
Reactant: O=C(O)C1COCCN1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Temperature: 75 °C
Yield: 36.7 %

Procedure:
A round-bottom flask was charged with 2,4,6-trichloropyrimidin-5-amine (982 mg, 4.95 mmol), morpholine-3-carboxylic acid (649 mg, 4.95 mmol) and triethylamine (2.78 mL, 19.79 mmol) in ethanol (20 mL). The mixture was heated at 75° C. for 3 days then diluted with water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and dried in vacuo to give 500 mg of crude 2,4-dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one which was used without further purification. MS [M+H] Found 275.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:12])(=[O:11])/[C:5](=[C:7](\[CH:9]=O)/[Cl:8])/Cl.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18]>CO>[C:4]([C:5]1[C:7]([Cl:8])=[CH:9][N:19]=[CH:17][N:18]=1)([OH:12])=[O:11]
Reactant: N=CN
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ncncc1Cl
Yield: 35.1 %

Procedure:
Sodium methoxide (162 g) is added to a solution of mucochloric acid (169 g) and formamidine acetate (208 g) in methanol (3 liters) over the course of 20 minutes, and the reaction mixture is heated for 1 hour at 35°-40° C., and then for one and a half hours under reflux. The solvent is removed and water (500 cc) is added to the residue. The aqueous mixture is extracted with ethyl acetate (2 liters). The aqueous phase is brought to pH 1 by the addition of concentrated hydrochloric acid, and the aqueous phase is extracted with ethyl acetate (5 liters). The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness. The residue is washed with diethyl ether (300 cc) and then with diisopropyl ether (600 cc). 4-Carboxy-5-chloropyrimidine (55.6 g), melting at 190° C., is obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[NH2:27]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:27][N:23]2[CH2:24][CH2:25][CH2:26][C@H:22]2[CH2:21][O:20][CH3:19])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Reactant: COC[C@@H]1CCCN1N
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and (S)-2-methoxymethyl-pyrrolidin-1-yl amine as starting materials (CAN 59983-39-0); MS (ESI) 396.4 (M+Na)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57](Cl)=[O:58])=[CH:48]1.C(N(CC)CC)C>O1CCCC1>[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:58])=[CH:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 2-indol-3-yl-2-oxoacetyl chloride (0.103 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 774 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate (3.40 g, 10.5 mmol) in a solution of ammonia in MeOH (7N, 20 mL) was heated in sealed vessel at 80° C. for 5 h. The reaction mixture was cooled down and concentrated in vacuo. The residue was dried in high vacuum and used for the next step without further purification. LC/MS RT=1.30 min (5 min method). Mass calculated for, M+H 303.17, observed 318.19.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)C.[OH-].[Na+]>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(C#Cc2ccc(NC(C)=O)nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoate (0.68 mmol) in 5 ml of ethanol is cooled to 0° C. To this solution is dropped in 3 ml of 1M NaOH. The hydrolysis is stirred at this temperature for 2 h and r.t. for 3 h. The solvent (ethanol) is evaporated, and more water is added to dissolve the solid. The clear solution is washed with ether twice and then titrated with 2M HCl to pH 6. The precipitate is filtered, washed with water and ether, and dried to afford the product. The filtrate (pH 6) was extracted with DCM, dried, and evaporated to obtain additional amount of the hydrolyzed product.
Reaction SMILES: [CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])C.[Li+].[Li][CH2:10]CCC.C(NC(C)C)(C)C.C[C:22]1[O:26][N:25]=[CH:24][CH:23]=1.NOC1CCCCC=1.[ClH:35]>C1COCC1.CO>[ClH:35].[NH2:25][C:24]1[N:4]2[C:5]([CH2:6][CH2:10][CH2:3][CH2:1]2)=[CH:7][C:22](=[O:26])[CH:23]=1
Reactant: Cc1ccno1
Reactant: CC(C)[N-]C(C)C
Reactant: [Li]CCCC
Agent: Cl
Agent: NOC1=CCCCC1
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(=O)cc2n1CCCC2
Reaction time: 20 h
Yield: 29 %

Procedure:
To a solution of lithium diisopropylamide (LDA), prepared from n-BuLi (64.5 ml, 0.1M) and diisopropylamine (10.1 g, 14 ml, 0.1M) in dry THF (100 ml) was added under N2 at -10° C. 5-methylisoxazole (4.2 g, 4.1 ml, 0.05M). The resultant yellow suspension was stirred (mechanical stirrer) at -10° C. for 1 hr before 1-aza-2-methoxy-1-cyclohexene (5.6 g, 0.05M) was added dropwise. A light yellow precipitate was immediately formed. The mixture was allowed to warm to ambient over a period of 20 hr. MeOH (40 ml) was slowly added and the resulting reddish solution was stirred at ambient for 2 hr. The solvents were evaporated in vacuo, and the residual oil was flash column chromatographed on silica gel (EM-60) with 30% MeOH in CH2Cl2 as the eluent to give the desired free base. The HCl salt was then prepared by adding conc HCl to a solution of the free base in methanol. Recrystallization from MeOH/ether gave the title compound (2.9 g, 29%). TLC (30% MeOH in CH2Cl2); Rf=0.53. IR (KBr), cm-1, 3330, 3180, 3030, 2950.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[CH3:27][NH2:28].Cl>O.O1CCOCC1>[CH3:27][NH:28][C:13]([C:6]1[NH:7][C:8]2[C:3]([C:4](=[N:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:5]=1)=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[O:15]
Reactant: CN
Reactant: COC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 18 h

Procedure:
Combine 5,7-dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.0 g, 2.4 mmol) and 40% methylamine in water (25 mL) and dioxane (50 mL). Stopper and stir for 18 hours. Evaporate in vacuo to give a yellow oil. Dissolve the oil in water (15 mL) and add 1M hydrochloric acid solution (15 mL). Stir for 15 minutes and then filter to obtain a solid. Rinse the solid with 1M hydrochloric acid solution and water. Recrystallize from acetonitrile/water to give the title compound as a solid: mp; 196°-197° C. Elem. Anal. calculated for C17H13Cl2N3O3S.H2O: C, 47.68; H, 3.53; N, 9.81. Found: C, 47.55; H, 3.42; N, 9.78.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].[O:24]1CCCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([OH:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: O=C(OCc1ccccc1)N1CCN(O)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a mixture of oil 1-benzyloxycarbonyl-4-ethoxycarbonyl-piperazine (30 g) in tetrahydrofuran (200 ml) was added lithiumborohydride (2.7 g) and stirred at 60° C. for 5 hours. To quench thc mixture, added methanol, dilute hydrochloric acid and then concentrated hydrochloric acid. Diluted with diethylether and resulting suspension washed with water (×2) dilute sodiumbicarbonate then brine, dried (MgSO4) and evaporated to give as a colourless oil oil 1-benzyloxycarbonyl-4-hydroxy-piperazine (23 g) which was used directly in the next step without further purification or characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:26].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[O:26]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41](=[S:47])/[N:42]=[CH:43]/[N:44](C)C)[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.NOS(O)(=O)=O>CO.CCO>[CH2:7]([O:14][N:15]([C@H:28]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]2[S:47][N:44]=[CH:43][N:42]=2)[CH2:30][CH2:29]1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)/C=N/C(=S)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of pyridine (320 mg, 4.0 mmol) in CH3OH (10 mL) was added to a mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-((E)-(dimethylamino)methylenecarbamothioyl)piperidine-1-carboxylate (1.2 g, 2.0 mmol) in EtOH (20 mL), followed by addition of (aminooxy)sulfonic acid (270 mg, 2.4 mmol). The mixture was stirred at rt for 2 hrs. The solvent was removed, and the residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (520 mg, 48%) as a yellow solid. ESI-MS (EI+, m/z): 598 [M+Na]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][CH2:17][N:18]([CH2:26][CH:27]2[CH2:29][CH2:28]2)C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.[ClH:51]>C(OCC)C>[ClH:51].[ClH:51].[ClH:51].[ClH:51].[CH:27]1([CH2:26][NH:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13]/[CH:12]=[CH:11]/[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N(C/C=C/CN(CCCN(CC1CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCN(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C(=C/CNCCCNCC1CC1)\CNCCCNCC1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.5 g (2.116 mmol) of (E)-1,14-di-cyclopropylmethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 23 ml of 3N methanolic hydrochloric acid is stirred for 5 h at room temperature, and then 20 ml of diethyl ether are added. Working up analogously to Example 1 yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ0.33-0.38(m,4H); 0.65-0.71 (m,4H); 1.00-1.14(m,2H); 2.05-2.16(m,4H); 2.96(d,4H); 3.13-3.19(m,8H); 3.77(d,4H); 6.04-6.07(m,2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O>[C:3]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[F:22])[CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)C1CNc2ccccc2C1=O
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cn(Cc2ccccc2F)c2ccccc2c1=O
Yield: 37.9 %

Procedure:
Compound 4u was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.4 mmol) of sodium hydride (60%), 75 mg (0.31 mmol) of 3-benzoyl-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 74 mg (0.40 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 42 mg of a colorless solid 4u: LC-MSD, m/z for C23H16FNO2, [M+H]+=358.4, [M+2H]+=359.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time =2.291 min; 1H NMR (400 MHz, CDCl3/HCl): δ 5.42 (s, 2H), 7.00-7.20 (m, 3H), 7.28-7.46 (m, 5H), 7.51 (t, 1H), 7.61 (t, 1H), 7.78-7.86 (m, 2H), 8.32 (d, 1H), 8.46 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:19][C:20](=[O:41])[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:28][C:29]4[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([C:39]#[N:40])=[CH:32][C:30]=4[N:31]=3)=[CH:23][CH:22]=2)[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C(=O)([O-])[O-].[K+].[K+]>>[C:39]([C:33]1[CH:34]=[C:35]([CH:36]([CH3:38])[CH3:37])[C:29]2[O:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:15]([O:17][CH3:18])=[O:16])=[O:41])=[CH:26][CH:25]=3)=[N:31][C:30]=2[CH:32]=1)#[N:40]
Reactant: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 40-ml scintillation vial was added tert-butyl-4-(1-{[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (150 mg, 0.268 mmol) and 2 ml of a TFA-water solution [95:5]. The reaction was stirred for 16 h at room temperature and then poured into 5 g of crushed ice and basified with potassium carbonate. The product was extracted with dichloromethane (4×3 ml), and the combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to provide the title compound as an off-white solid. The crude product was used without further purification in the next step. Mass spectrum (ESI) 461.57 (M+1). 1H NMR (600 MHz, CDCl3): δ8.27 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.92 (d, J=1.1 Hz, 1H), 7.57 (s, 1H), 4.6 (d, J=7.1 Hz, 1H), 3.71 (s, 3H), 3.43 (m, 1H), 3.23 (m, 2H), 2.84 (m, 2H), 2.2 (m, 1H), 1.88 (d, J=13.8 Hz, 2H), 1.51 (m, 2H), 1.40 (d, J=6.8, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].CS([C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]([NH2:22])=[N:19][C:18]=2[CH3:23])[CH:14]=[C:13]([CH3:24])[N:12]=1)=O>CN1C(=O)CCC1>[NH2:22][C:20]1[S:21][C:17]([C:15]2[CH:14]=[C:13]([CH3:24])[N:12]=[C:11]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:16]=2)=[C:18]([CH3:23])[N:19]=1
Reactant: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Reactant: CNCCN(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2sc(N)nc2C)nc(N(C)CCN(C)C)n1
Temperature: 70 °C

Procedure:
N,N,N′-Trimethyl-ethane-1,2-diamine (0.62 g, 6.16 mmol) is added to a stirred solution of 5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AD, 0.33 g, 1.23 mmol) in NMP (15 ml). The reaction is heated at 70° C. for 18 hours then the solvent is removed in vacuo. The residue is purified by reverse phase chromatography (C18 Jones Flashmaster™ chromatographic system, gradient elution conditions MeCN/H2O) to give the titled product.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]([CH3:29])[CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]([CH3:29])[CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1CNc2cccc(O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2cccc(O)c21
Yield: 55.4 %

Procedure:
(±)-2-{2-[4-Hydroxy-3-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is prepared by following the procedure described in example 1c using 0.70 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.44 g of 4-hydroxy-3-methylindoline (reference example 3c), and 0.68 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.65 ml of pyridine and 15 ml of N,N-dimethylformamide. 0.55 g of (±)-2-{2-[4-hydroxy-3-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a bright pink powder, the characteristics of which are the following:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18](B4OC(C)(C)C(C)(C)O4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1[C:30]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:31][N:32]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:33]=1>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:32]1[CH:33]=[C:29]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[C:30]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:31]1
Reactant: CN(C)CCn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)OC1(C)C
Product: CN(C)CCn1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 2-[4-bromo-3-(4-nitrophenyl)-1H-pyrazol-1-yl]-N,N-dimethylethanamine provided the title compound. ESMS [M+H]+: 517.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=[C:5]([NH2:13])[N:4]=1.Br[CH2:15][C:16](=O)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CCOCC>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]2[CH:15]=[C:16]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[N:13]=[C:5]2[N:4]=1
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: COc1nc(N)nc2c1CCCC2
Solvent: CCOCC
Product: COc1nc2nc(C(=O)c3ccccc3)cn2c2c1CCCC2

Procedure:
A solution of 20 g of 4-methoxy-5,6,7,8-tetrahydro-2-quinazolinamine, 28.6 g of 3-bromo-1-phenyl-propane- 1,2-dione and 400 ml of ether was stirred overnight at room temperature and was filtered. The 29.5 g of 4-methoxy-1-(3-phenyl-2,3-dioxopropyl)-5,6,7,8-tetrahydro-2-quinazolinium bromide were washed with ether and suspended in methanol. The suspension was refluxed for 2 hours and the solution was evaporated to dryness under reduced pressure. The residue was shaken with a mixture of aqueous potassium carbonate and chloroform and the decanted organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ethanol and filtered to obtain 18 g of (5-methoxy-6,7,8,9-tetrahydroimidazo[1,2-a]quinazolin-2-yl-phenylmethanone in the form of pale yellow crystals melting at 234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1>[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:27][C:26]3([F:29])[F:28])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(=CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cn(C(CC2CC2(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 240 mg (purity 78%, 404 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2,2-difluorocyclopropyl)prop-2-enoate (diastereomer mixture) were admixed with 30 ml of a “Hot Stryker's” reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reaction mixture was stirred at RT for 2 h, and 20 ml of saturated aqueous ammonium chloride solution were then added. The phases were separated and the aqueous phase was extracted three times with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 g silica cartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 216 mg (quant.)