Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1COCC1>[F:13][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1F
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(F)c(N)cc2C(F)(F)F)CC1
Temperature: 120 °C

Procedure:
To a microwave reaction tube was added 4-bromo-2-fluoro-5-(trifluoromethyl)aniline (256 mg, 1.0 mmol), 1-methylpiperazine (300 mg, 3 mmol) Pd2(dba)3 (91.5 mg, 0.1 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg, 0.2 mmol), NaOtBu (144 mg, 1.5 mmol) and THF (3 mL). After the reaction tube was degassed and filled with N2, the tube was heated to 120° C. in a microwave reactor for 40 min. The mixture was then poured into saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient MeOH/CH2Cl2, 0˜10%) to provide 2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline as a white solid. ESMS m/z 278.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2C[CH2:21][CH2:20][CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H]([O:73][C:74]3[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.OC1C=NC=CC=1>C1COCC1>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@@H:20]([O:73][C:74]3[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](Oc3cccnc3)CN2C(c2ccccc2)c2ccccc2)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: Oc1cccnc1
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3cccnc3)CN2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Step 13 (A): (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)oxazolidin-2-one. To a solution of triphenylphosphine (54 mg, 0.206 mmol) in THF (2.5 mL) at rt was added DEAD (0.0324 mL, 0.206 mmol). After 1 min, a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation K, 80 mg, 0.172 mmol) in THF (2.5 mL) was added. After 2 min, 3-hydroxypyridine (16.4 mg, 0.172 mmol) was added and the mixture was stirred at rt for 3.5 h. pH 7 buffer was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-100% ethyl acetate/hexane) gave the title compound: HPLC retention time: 1.39 min (method A). MS (ESI) (M+H)+ 542.18.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:27](O)([CH3:29])[CH3:28])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH:26]=1>O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:17][C:13]3[C:12]([C:27]([CH3:29])=[CH2:28])=[CH:11][C:10]([OH:9])=[CH:26][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 2-[5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole-7-yl]propan-2-ol (114 mg, 0.36 mmol) and the reaction was stirred for 2 h. The mixture was cooled to room temperature, dissolved in water and extracted with EtOAc. The organic layers were combined and washed with HCl (1N), water then brine and dried over MgSO4. Evaporation and purification by flash chromatography (50%-60% EtOAc/petroleum ether) gave (40 mg, 41% yield) of the product as a light red-brown solid, m.p. 225-228° C.; MS m/e 268 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=2)[N:17]=1>C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=2)[N:17]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-Methyl-4-nitrophenethylamine (0.39 g, 2.15 mmole) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1 mmole) were heated at reflux temperature in ethanol (30 ml) for 6 hours. The solvent was then evaporated and the residue diluted with 2M hydrochloric acid and extracted with methylene chloride. The aqueous layer was basified with aqueous sodium carbonate (to pH ~12) and extracted three times with methylene chloride. These latter organic extracts were combined, dried (MgSO4) and evaporated giving an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give a solid which was recrystallised from ethanol to give the title compound, yield 0.21 g, m.p. 104°-105°.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:12][C@H](C)C2C=CC=CC=2)[CH3:11])=[CH:5][CH:4]=1>[Pd].CO>[ClH:1].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([NH2:12])[CH3:11])=[CH:7][CH:8]=1
Reactant: C[C@H](Cc1ccc(O)cc1)N[C@H](C)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H](N)Cc1ccc(O)cc1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
A hastalloy autoclave was charged with (2R)-1-(4-hydroxyphenyl)-2-(N-[(R)-a-methylbenzyl])amino propane hydrochloride (72.3 g, 248 mmol), 5% Pd/C (16.0 g, wetted with 100 mL of EtOH), and MeOH (400 mL). The autoclave was pressurized to 50 psi H2 and heated to 50° C. for 6 h with vigorous stirring. After cooling, purging with nitrogen and filtering the mixture, the filtrate was concentrated on a rotary evaporator under vacuum. The resulting oily foam was dissolved in a minimal amount of MeOH and was triturated by addition of EtOAc. The solid was filtered, and another crop of solid which precipitated from the filtrate was also collected. The combined solids were dried in a 45° C. vacuum oven overnight to yield 34.2 g (73%) of a white solid. MP 160° C. [dec]. MS(FD+) m/z 151 (92%).
Reaction SMILES: C([NH:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:53](=[O:54])[N:32]3[C:33]([C:37]([O:39]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:55]1(OC)C=CC=C[CH:56]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:25][C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:53](=[O:54])[N:32]3[C:33]([C:37]([OH:39])=[O:38])=[C:34]([CH:55]=[CH2:56])[CH2:35][S:36][C@H:31]23)=[O:28])=[N:23][N:22]=1
Reactant: O=C(Cc1nnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3nnc(N)s3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-cephem-4-carboxylate (2.6 g) in methylene chloride (30 ml) and anisole (2.1 g) was added trifluoroacetic acid (7.6 g) under ice-cooling, followed by stirring at ambient temperature for 1.5 hours. The reaction mixture was poured into diisopropyl ether (300 ml), and the precipitates were collected by filtration and suspended in water (40 ml). After adjusting to pH 7 with 10% aqueous sodium hydroxide, the aqueous solution was washed with ethyl acetate and then adjusted to pH 5 with 10% hydrochloric acid. The organic solvent included in the resultant aqueous solution was completely removed by evaporation, and the resultant aqueous solution was adjusted to pH 4 with dilute acetic acid, which was chromatographed on a non-ionic adsorption resin "Diaion HP-20" (50 ml). After washing with water, elution was carried out with 30% isopropyl alcohol, and the fractions containing a desired compound were collected and then concentrated under reduced pressure. The concentrate was lyophilized to obtain 7-[2-(5-amino-1,3,4-thiadiazol-2yl)-acetamido]-3-vinyl-3-cephem4- carboxylic acid (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH2:20])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][C:28](=[O:30])[CH3:29])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl-methyl]-1H-imidazol-2-ylamine (1.0 g, 3.2 mmol) in THF (32 ml) was treated at rt with triethylamine (0.33 g, 3.2 mmol) and acetyl chloride (0.25 g, 3.2 mmol). The mixture was stirred at rt for 2 h, filtered and the organic phase was evaporated to dryness. After chromatography [silica, elution with gradient CH2Cl2 to 50% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] the title compound (0.19 g, 17%) was isolated as a light brown solid. Mp. >236° C. dec.(AcOEt), MS: m/e=350 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15]([OH:17])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OCCCN(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=C\c1ccc(OCCCN(C)C)cc1)C(=O)O

Procedure:
2 b) The ester from 2 a) was hydrolyzed in accordance with a standard method (sodium hydroxide in methanol). E-3-[4-(3-Dimethylamino-propoxy)phenyl)-2-methyl-propenoic acid was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[N:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]1)[CH3:2].[Cl:25][C:26]1[C:39]([N:40]=[C:41]=S)=[C:38]([Cl:43])[CH:37]=[CH:36][C:27]=1[CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CC(C)N=C=NC(C)C>CC#N>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[N:11]=[C:41]([NH:40][C:39]3[C:38]([Cl:43])=[CH:37][CH:36]=[C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=3[Cl:25])[N:12]([CH3:13])[C:8]2=[N:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:21])[F:22])[CH2:16][CH2:15]1)=[O:24])[CH3:2]
Reactant: CCOC(=O)c1cc(N)c(NC)nc1N1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2nc1N1CCC(C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
A mixture of 6-methylamino-5-amino-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid ethylester (2.80 g, 7.92 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (2.76 g, 8.72 mmol) and MeCN (60 mL) is stirred overnight, concentrated and triturated with MeCN and Et2O. The resulting solid is diluted with 60 mL MeCN and DIC (1.06 mL, 6.8 mmol) is added and it is stirred for 3 h at 60° C. The crude mixture is concentrated, diluted with EtOAc, washed with water, dried with Na2SO4, filtered, concentrated and purified by flash chromatography (silica; PE:EtOAc 3:1->1:1). Yield: 4.04 g. HPLC Rt=1.56 min (method D). MS m/z: 629 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C1Cc2c(F)cc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)cc(F)c2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 74.8 %

Procedure:
To the mixture of 6-chloro-4-fluoroindolin-2-one (Natrochem, 85% purity) (1.1 g, 5.0 mmol) and 3-chloro-2-fluorobenzaldehyde (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was added piperidine (1.7 g, 20 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, washed with cold methanol, dried to give the first batch of desired product (1.22 g). The filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-35% EtOAc in hexanes) to give the second batch of desired product (0.32 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.54 g, 94%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[S:10])=[N:5][C:4]=1[C:22]1[CH:31]=[CH:30][C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=1)[CH3:2].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]2[N:5]([S:10][C:9](=[N:11][S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[N:8]=2)[C:4]=1[C:22]1[CH:31]=[CH:30][C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=1)[CH3:2]
Reactant: CCc1sc(NC(=S)NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc2c(c1)CCCC2
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1sc2nc(=NS(=O)(=O)c3ccc(C)cc3)sn2c1-c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a mixture of 1-[5-ethyl-4-(5,6,7,8-tetrahydro-2-naphthyl)-2-thiazolyl]-3-(4-methylphenyl)sulfonyl-2-thiourea (1.40 g) and chloroform (10 ml), sulfuryl chloride (420 mg) was added. After being stirred at room temperature for 2 hours, the reaction mixture was concentrated; the residue was treated with ethanol, and the resulting crystal was collected by filtration and recrystallized from dichloromethane-ethanol to yield 5-ethyl-2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazole (1.00 g, yield 72%) as a colorless needle.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:19][CH3:20])[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCC(NCc1ccccc1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
3-Benzyl-2-(1-benzylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 42, 23.1 mg, 0.062 mmol) in CHCl3 (5 mL) was treated with benzoylchloride (28.8 μL, 0.248 mmol) and Et3N (23.0 μL, 0.166 mmol), then stirred for 18 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (22 mg, 83%) as a colorless film: LC/MS 87% at 3.72 min (ESI+) 477 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[CH:18]=[O:19].CC(=CC)C.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>O.C(O)(C)(C)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]([OH:26])=[O:19]
Reactant: [O-][Cl+][O-]
Reactant: CCCCCOc1cc(C=O)c(Br)c2ccccc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCOc1cc(C(=O)O)c(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 76.5 %

Procedure:
1-Bromo-4-pentyloxynaphthalene-2-carbaldehyde (0.77 g, 2.4 mmol), t-butanol (4.8 ml) and 2-methyl-2-butene (1.71 ml, 16.1 mmol) were mixed, and a solution prepared by mixing sodium chlorite (360 mg, 3.12 mmol), sodium dihydrogenphosphate (374 mg, 3.12 mmol) and water (2.4 ml) was added dropwise. The mixture was stirred at room temperature for 16.5 hours. A 1N aqueous sodium hydroxide solution (5 ml) was added, and t-butanol was evaporated under reduced pressure. Conc. hydrochloric acid was added to make the mixture acidic. Saturated saturated brine (5 ml) was added, and the aqueous layer was extracted 3 times with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 1-bromo-4-pentyloxynaphthalene-2-carboxylic acid (619 mg, 76%) as pale-yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:31][CH3:32])=[C:28]([CH3:30])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:32][O:31][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[CH3:30]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.05 g, 4.63 mmol) was dissolved in TFA/CH2Cl2 (1/2) and stirred at rt for 1 h. The reaction mixture was concentrated under vacuum, the residue was diluted with CH2Cl2, the organic layer washed with NaOH 1N then brine, dried over Na2SO4, filtered and evaporated to give 6-(6-methoxy-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CDCl3, 298K) δ ppm 2.20-2.30 (m, 2 H), 2.22 (s, 3 H), 3.00-3.06 (t, 2 H), 3.09-3.18 (m, 1 H), 3.22-3.37 (m, 3 H), 3.45-3.50 (t, 2 H), 3.95 (s 3 H), 4.10 (s, 2 H), 4.20-4.65 (br.s 1 H), 5.63-5.69 (m, 1 H), 7.21-7.252 (m, 1 H), 7.70-7.74 (m, 1 H), 8.60 (s, 1 H). LCMS: [M+H]+=341.9, Rt(7)=0.61 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]1([CH3:22])C=CC=C[CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH:22]2[CH2:16][CH2:17]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: Cc1c(Cl)ncnc1C1CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4,6-dichloro-5-methylpyrimidine (1 g, 6.13 mmol) in toluene (38.2 ml) was added potassium cyclopropyl(trifluoro)borate (0.999 g, 6.75 mmol), di(1-adamantyl)-n-butylphosphine (0.066 g, 0.184 mmol), palladium(II) acetate (0.028 g, 0.123 mmol), cesium carbonate (6.00 g, 18.40 mmol) and the reaction mixture stirred under argon at 100° C. for 24 hours. The reaction mixture was washed with water and extracted with ethyl acetate (3×25 mL). The organic layers were collected, dried under magnesium sulphate and evaporated under reduced pressure. Crude residues were purified by Si SP4 column chromatography eluting with a gradient of 0-15% ethyl acetate-isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (491 mg);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[Cl:44][C:45]1[CH:46]=[C:47]([N:52]=[C:53]=[O:54])[CH:48]=[CH:49][C:50]=1[Cl:51]>C1(C)C=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:53]([NH:52][C:47]4[CH:48]=[CH:49][C:50]([Cl:51])=[C:45]([Cl:44])[CH:46]=4)=[O:54])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 24 h

Procedure:
To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.