Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>CN(C)C=O.C(OCC)(=O)C>[BrH:11].[Br:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Br)cnc1N
Reactant: Clc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: N=c1c(C(N)=O)cc(Br)cn1Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To a solution of 2-amino-5-bromonicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-chlorobenzylbromide (0.17 g), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (0.05 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][C:14]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:38]N(C)C=O.[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:5]([O:12][C:13]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][C:14]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:38][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:43][CH3:49])=[O:24])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCOC(=O)CCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Yield: 82 %

Procedure:
4.6 g (40 mmol) of thionyl chloride dissolved in 12 ml of anhydrous toluene were dropwise added to a suspension of 9.0 g (20 mmol) of 6-{N-[2,5-di(benzyloxy)benzoyl]amino}hexanoic acid (compound of Example 3) in 60 ml of anhydrous toluene and 0.93 g (13 mmol) of anhydrous dimethylformamide at room temperature during 5 minutes stirring. The reaction mixture was stirred at 50° C. for 1 hour then evaporated under reduced pressure to dryness at a temperature below 50° C. The residue obtained was thoroughly triturated with ether, filtered to obtain 7.68 g (82%) of the aimed product, m.p.: 90°-94° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C([O-])(=O)C.[K+]>CCO.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:24]=[C:25]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(-c2cc(C3OCCO3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.200 g, 12.66 mmol), 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (3.165 g, 14.86 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (514.9 mg, 0.7272 mmol), and potassium acetate (4.180 g, 42.59 mmol) were suspended in EtOH (50 mL) and water (10 mL) and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (80° C.), and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, poured into water (125 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter with about 3 inches of silica gel, 40:1 DCM/2N ammonia in MeOH). The fractions with product were collected, concentrated, and washed repeatedly with hexanes and dried to give 6-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g), which was used for the next step. MS (ESI pos. ion) m/z 386 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[N:17][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[N:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Trifluoroacetic acid (0.13 mL) was added to a solution of {2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic acid ethyl ester (Example 64-(1); 19.4 mg, 0.030 mmol) in dichloromethane (0.74 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (15.0 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:39]
Reactant: O=C=Nc1ccccc1F
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 1-fluoro-2-isocyanato-benzene to yield 1-(2-fluoro-phenyl)-3-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea. LC/MS at 254 nm; [M+H] 521; Rt 3.641 min.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[OH-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>O>[CH3:6][C@H:3]([CH2:2][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:4][OH:5]
Reactant: COc1ccccc1S
Reactant: C[C@@H](CO)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1SC[C@@H](C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
2.2 ml (0.021 mol) of 3-bromo-2-(S)-methyl-1-propanol are introduced into a round-bottomed flask kept under an inert atmosphere. 20 ml of an aqueous sodium hydroxide solution (1N) are added dropwise, followed by 2.3 ml (0.019 mol) of 2-methoxythiophenol. The mixture is brought to 90° C. for 4 hours and is then cooled to ambient temperature. 50 ml of water are then added and the mixture is extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol=99:1). 4 g (0.019 mol) of the title compound (XXb-1) are recovered in the form of a colorless oil.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.CC([O-:21])(C)C.[K+]>>[Br:12][CH2:13][CH2:14][CH2:15][O:21][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:2]=[N:3]2
Reactant: BrCCCBr
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc2ccccc2n1
Agent: [K+]
Product: BrCCCOc1cccc2ncccc12

Procedure:
Following the same procedure as in Example 1-(a), reaction and treatment were carried out using 1.0 g of -hyroxyquinoline, 2.1 g of 1,3-dibromopropane and 0.78 g of t-BuOK as a base, in order to obtain 0.65 g of 5-(3-bromopropoxy)quinoline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)#[N:2].[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(O)(=O)C.ClC(Cl)C.C([BH3-])#N.[Na+]>CO>[C:26]([O:25][C:24](=[O:30])[NH:23][CH2:22][CH2:21][NH:20][CH:16]1[CH2:17][CH2:18][N:13]([C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25 (535 mg, 1.99 mmol), 1 (335 mg, 2.09 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol(2 mL)/dichloroethane(1 mL) was treated with sodium cyanoborohydride (130 mg, 2.06 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (26).
Reaction SMILES: O[CH2:2][CH2:3]CC1NC=CN=1.[C:10]([NH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]=[C:22]([F:44])[N:23]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=1)=[O:15])(=[O:12])[CH3:11]>>[F:44][C:22]1[N:23]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[C:20]([CH2:19][CH2:18][CH2:17][O:16][C:14](=[O:15])[NH:13][C:10]2[O:12][CH:2]=[CH:3][CH:11]=2)[N:21]=1
Reactant: CC(=O)NC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: OCCCc1ncc[nH]1
Product: O=C(Nc1ccco1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A suspension of 2-furoamide in 1,2-dichloroethane was treated with oxalyl chloride; 2-furoylisocyanate was isolated by distillation. This product was reacted with the hydroxypropylimidazole, as for the starting material of Example 12, to give 2-fluoro-4-[3-(fur-2-yl)carbamoyloxypropyl]-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.82 (m, 2H); 2.47 (t, 2H); 4.07 (t, 2H); 6.3 (s, 1H); 6.64 (m, 1H); 7.0-7.45 (m, 15H); 7.5 (m, 1H); 7.91 (m, 1H); 10.1 (br, 1H).
Reaction SMILES: ClC1C=C(I)C=CC=1N.[C:10]([O:14][C:15]([NH:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]2CC2)=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:33]([O:37]C(N[C@H](C1C=CC(OCCOC2CCCCO2)=CC=1)C(O)=O)=O)([CH3:36])([CH3:35])[CH3:34].C1(CBr)CC1>>[C:10]([O:14][C:15]([NH:17][C@H:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC2CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: BrCC1CC1
Agent: Nc1ccc(I)cc1Cl
Product: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that 2-chloro-4-iodoaniline was used in place of 2-chloro-4-bromoaniline in step 1 and (R)-tert-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid was prepared by a similar method as described for the preparation of (R)-tert-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid in example 48 except that cyclopropylmethyl bromide was used in place of 2-(2-bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:34])[CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.17 mmol) of the compound from Example 43 were introduced into 10 ml of dichloromethane at 0° C., 42.3 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 54 mg (79% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: C1COC2CNCC2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2OCCOC2C1
Temperature: 60 °C
Yield: 25 %

Procedure:
A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), K2CO3 (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60° C. for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a grayish-white solid (230 mg, 25.00%), HPLC: 99.11%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, J=3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=3.5 Hz), 4.22 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.[CH3:15][C:16](=O)[C:17](=O)[CH3:18]>O>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[C:17]([CH3:18])[C:16]([CH3:15])=[N:1]1
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Reactant: CC(=O)C(C)=O
Solvent: O
Product: Cc1nc2ccc3nc(O)c(O)nc3c2nc1C
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 10 ml water was at 50° C. added a solution of 0,45 g (5,2 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50o for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,4 g (64%) 2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 7.27 (1H,d), 6.93 (1H,d), 2.07 (6H,s).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)[C:10]1=[O:31])=O)(C)(C)C.[BH4-].[Li+].N>C1COCC1>[OH:5][CH2:6][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH2:16]2)[C:10]1=[O:31]
Reactant: CC(C)(C)OC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Yield: 99.5 %

Procedure:
A solution of benzyl 4-[3-(tert-butoxycarbonylmethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.60 g) obtained in Example 35a) and lithium borohydride (0.091 g) in THF (15 mL) was refluxed for 5 hours. The reaction mixture was allowed to stand at room temperature and poured into an aqueous saturated ammonia solution under ice-cooling. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=95/5) to obtain the title compound (0.50 g, 99%) as a colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:3][CH2:6][CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(F)CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(F)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of thionyl chloride of 8.99 g (0.08 mol) was introduced at 20-25° C. into a dry 50 ml round-bottomed flask under a nitrogen atmosphere. Ethyl 3-hydroxy-2-fluoropropionate (10.0 g, 0.07 mol) were subsequently metered in in 1 h and the mixture was subsequently stirred at ambient temperature for a further 2 h. An amount of toluene of 3.98 g (0.04 mol), together with 0.286 g of pyridine (5 mol %), were introduced into a second round-bottomed flask with an Anschutz head and the mixture was heated to 80° C., The mixture from the 1st round-bottomed flask was added dropwise to the preheated solution in 1 h at 75-85° C. Solvents were distilled off under reduced pressure and the residue was subsequently finely distilled at 120° C. and 10 mbar. 4.1 g of distillate were obtained as a colorless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][C:16]([C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=[CH:24][C:23]=4[NH:33]C(=O)OC(C)(C)C)=[O:20])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][C:16]([C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=[CH:24][C:23]=4[NH2:33])=[O:20])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:41][CH:42]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1cnc(N2CCN(Cc3ccc(C#N)cc3)CC2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CN2CCN(c3ncc(C(=O)Nc4cc(-c5cccs5)ccc4N)s3)CC2)cc1
Yield: 58.7 %

Procedure:
A solution of compound 340 (96 mg, 0.16 mmol) in 1:1 DCM/TFA (6 mL) was stirred at room temperature for 1 hour. The mixture was concentrated and purified by flash chromatography using EtOAc as an eluent, to afford the title compound 341 (47 mg, 59% yield). 1H NMR: (400.2 MHz, CD3OD) δ (ppm): 7.95 (br.s, 1H), 7.75 (m, 1H), 7.68 (m, 2H), 7.53 (t, 1H, J=7.6 Hz), 7.42 (s, 1H), 7.33 (d, 1H, J=8.2 Hz), 7.20 (m, 2H), 7.00 (m, 1H), 6.87 (d, 1H, J=8.3 Hz), 3.72 (s, 2H), 3.60 (m, 4H), 2.68 (m, 4H). MS: calc: 500.1; found: 501.2 (M+H)
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH3:14])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH:20](OC)=[O:21].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:13]([O:12][C:3]1[C:2]([CH:20]=[O:21])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[CH:5][N:4]=1)[CH3:14]
Reactant: COC=O
Reactant: CCOc1ncnc(C(F)(F)F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ncnc(C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 81.5 %

Procedure:
A solution of 5.76 g (21.3 mmoles) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine dissolved in 250 ml of THF was cooled to −78° C. Thereto was dropwise added 22.6 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 36.1 mmoles). The mixture was stirred for 40 minutes. Thereto was added 2.7 g (45.1 mmoles) of methyl formate. The resulting mixture was stirred for 1.5 hours to give rise to a reaction. After the completion of the reaction, an aqueous ammonium chloride solution was added. The mixture was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 3.82 g (yield: 81.6%) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:24][C:21]3[N:22]=[CH:23][N:19]([CH2:18][C:17]4[CH:25]=[C:26]([F:29])[C:27]([F:28])=[C:15]([F:14])[CH:16]=4)[N:20]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cc(F)c(F)c(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,4,5-trifluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2cc[nH]c2c1

Procedure:
A yellow solution of 5.2 g. 6-nitroindole in 150 ml. ethyl acetate was added to 1.25 g. of pre-reduced 10% w/w palladium-on-charcoal in 50 ml. ethyl acetate. The mixture was shaken under 3.45 bar hydrogen overnight and then filtered through diatomaceous earth. The residue was washed with 150 ml. hot chloroform and the combined colourless filtrate and washings were evaporated to give a quantitative yield of 6-aminoindole as a dark oil; NMR: 3.5 (br s, 2H, NH2), 6.4 (m, 1H, H3), 6.5 (m, 2H, H5 +H7), 7.0 (dd, 1H, H2), 7.4 (d, 1H, H4), 7.8 (br, 1H, NH).