Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:14]C)=[N:5][C:6]([CH3:13])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[CH:2].[ClH:16]>>[Cl:16][C:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]([CH3:13])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])=[CH2:2]
Reactant: Cl
Reactant: C#Cc1c(OC)nc(C)nc1C(F)(F)F
Product: C=C(Cl)c1c(C(F)(F)F)nc(C)[nH]c1=O
Temperature: 25 °C

Procedure:
5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) was added 6N-HCl (20 ml) with stirring and refluxed for 2 hr. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexanethyl acetate). The crude fraction was concentrated, and then washed with hexane to give 5-(1-chlorovinyl)-2-methyl-6-trifluoromethyl-3H-pyrimidin-4-one (1.62 g) as colorless crystalline solid, mp 164-166° C.
Reaction SMILES: [NH2:1][C:2]1[N:3](C)[CH2:4][N:5]=[CH:6][C:7]=1[CH:8]=O.C([O:13][C:14](=O)[CH2:15][C:16]#[N:17])C.N1CCCC[CH2:20]1>C(O)C>[C:16]([C:15]1[C:14]([OH:13])=[N:1][C:2]2[N:3]=[C:4]([CH3:20])[N:5]=[CH:6][C:7]=2[CH:8]=1)#[N:17]
Reactant: CN1CN=CC(C=O)=C1N
Reactant: CCOC(=O)CC#N
Reactant: C1CCNCC1
Solvent: CCO
Product: Cc1ncc2cc(C#N)c(O)nc2n1
Reaction time: 20 h
Yield: 50 %

Procedure:
A suspension of 3 g (22 mmol) of 4-amino-5-formyl-3-methylpyrimidine, 5 g (44 mmol) of ethylcyanoacetate and 850 mg (100 mmol) of piperidine in 20 ml of ethanol was stirred for 20 hours at 20°-25° C. The fine-particled solid formed was separated off, freed from solvent residues under reduced pressure and suspended twice in 20 ml of ethanol each time. The crude product was finally washed with diethyl ether. Yield: 50% (fine powder); mp.: >200° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:30])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][CH2:24]C1C=COC=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=C[C:32]=1/[CH:37]=[CH:38]/[C:39]([OH:41])=O.[CH3:42][C:43]1[N:48]=[C:47]([CH2:49][O:50][C:51]([NH:53][C@H:54]([C:58]([OH:60])=O)[CH:55]([CH3:57])[CH3:56])=[O:52])[CH:46]=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH2:49][O:50][C:51]([NH:53][C@H:54]([C:58]([NH:1][C@H:2]([C@@H:10]([OH:30])[CH2:11][C@H:12]([NH:20][C:21]([O:23][CH2:24][C:39]2[O:41][CH:32]=[CH:37][CH:38]=2)=[O:22])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:60])[CH:55]([CH3:56])[CH3:57])=[O:52])[N:48]=1
Reactant: Cc1cccc(COC(=O)N[C@H](C(=O)O)C(C)C)n1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1ccoc1
Reactant: O=C(O)/C=C/c1ccccn1
Product: Cc1cccc(COC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](Cc2ccccc2)NC(=O)OCc2ccco2)C(C)C)n1
Yield: 96 %

Procedure:
Using the procedure of Example 6I but replacing the resultant compound of Example 6H with (2S,3S,5S)-2-amino-5-(N((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing trans-3-(pyridinyl)acrylic acid with the resultant compound of Example 288 provided 92.9 mg (96%) of the desired compound as a white solid. 1H NMR (CDCl3) δ 0.73 (d, 3H), 0.87 (d, 3H), 1.64 (m, 2H), 2.13 (m, 1H), 2.50 (s, 3H), 2.76 (dd, 2H), 2.84 (d, 2H), 3.67 (m, 1H), 3.75 (m, 1H), 3.88 (m, 1H), 4.17 (m, 1H), 4.90 (s, 2H), 5.09 (br d, 1H), 5.15-5.22 (m, 3H), 6.31 (br d, 1H), 6.37 (s, 1H), 7.07-7.25 (m, 12H), 7.39 (m, 2H), 7.60 (t, 1H). Mass spectrum: (M+H)+ =657.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11](=S)=[S:12].Cl>C(Cl)Cl.O.C(O)C>[SH:12][C:11]1[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1cccnc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Sc1nc2ncccc2[nH]1
Reaction time: 1 h
Yield: 112.9 %

Procedure:
A solution of 2,3-diaminopyridine (10.0 g, 92 mmol), potassium hydroxide (6.8 g, 123 mmol)k, CS2 (9.4 g, 123 mmol), ethanol (100 mL), and water (20 mL) was stirred at reflux for 5 hours, then at ambient temperature overnight. Evaporation in vacuo gave a residue which was dissolved in CH2Cl2, acidified to pH 5 with 2N hydrochloric acid, and stirred for 1 hour. The resultant suspension was filtered to give 15.7 g of 2-mercaptoimidazopyridine as a brown solid. A solution of the 2-mercaptoimidazopyridine (4.23 g, 28 mmol) and geranyl chloride (4.8 g, 28 mmol) in methanol (40 mL) and 2N NaOH/H2O (40 mmol) was stirred in 16 hours at ambient temperature, evaporated, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. Flash chromatography (Merck Kieselgel, 5% MeOH/CH2Cl2) gave 2.0 g (25%) of 2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-imidazo[4,5-6]pyridine, 1.0 g of which was converted to its oxalate salt. m.p. 118°-121° C. NMR (DMSO-d6)δ8.20(d, J=5 Hz, 1H), 7.60(m, 2H), 5.40(d, J=7 Hz, 1H), 5.10(d, J=6 Hz, 1H), 4.00(d, J=6 Hz, 2H), 2.00(m, 4H), 1.70(s, 3H), 1.61(s, 3H), 1.60(s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)C>ClCCl>[CH3:11][C:8]1([CH3:12])[O:7][C@H:6]([C@H:5]2[N:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:3](=[O:21])[C@H:2]2[NH:1][C:29](=[O:30])[CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][O:9]1
Reactant: COc1ccc(N2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
A solution of (3S,4S)-3-amino-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphenyl)azetidin-2-one (12.21 g, 41.8mmol) in dichloromethane (160 ml) was cooled to 0° C. and treated sequentially with phenylacetyl chloride (6.1 ml, 46.1 mmol), then triethylamine (6.4 ml, 45.9 mmol). After stirring at 0° C. for 15min., the mixture was warmed to room temperature and stirred for a further 30 min. The reaction mixture was diluted with dichloromethane and washed twice with water, then brine, The organic layer was dried over magnesium sulphate, filtered and the solvent evaporated in vacuo to yield a solid. Trituration with diethyl ether yielded the title compound (16.16 g, 94%) as a white amorphous solid; [α]D 0.0° (c=1.00 DMF); νmax (KBr) 1757, 1661 and 1510 cm- ; δH (CDCl3) 1.16 (3H, s), 1.25 (3H, s), 3.62 (2H, s), 3.69-3.82 (2H, m), 3.76 (3H, s), 4.02 (1H, m), 4.36 (1H, dd, J 5.5, 4.0 Hz), 5.58 (1H, dd, J 9.4, 5.5 Hz), 6.56 (1H, d, J 9.4 Hz), 6.83 (2H, d, J 8.9 Hz) and 7.25-7.40 (7H, m); m/z (EI) 410 (5); (CI, +ve ion, ammonia) 411 (MH+).
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[CH:20]1[C:33]2[C:24](=[S+:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1.[CH:34]1[C:47]2[C:38](=[S+:39][C:40]3[C:45]([N:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[CH:36][CH:35]=1.C1[C:61]2C(=[S+]C3[C:59]([N:60]=2)=CC=CC=3)C=CC=1.[CH3:62][NH:63][CH3:64]>CO>[I-:2].[I-:2].[I-:2].[CH3:31][N:32]([CH3:33])[C:8]1[CH:7]=[CH:6][C:19]2[C:10]([CH:9]=1)=[S+:11][C:12]1[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:18]=2.[CH3:59][N:60]([C:36]1[CH:35]=[CH:34][C:47]2[C:38]([CH:37]=1)=[S+:39][C:40]1[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=1)[N:46]=2)[CH3:61].[CH3:62][N:63]([C:22]1[CH:21]=[CH:20][C:33]2[C:24]([CH:23]=1)=[S+:25][C:26]1[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=1)[N:32]=2)[CH3:64]
Reactant: CNC
Reactant: c1ccc2[s+]c3ccccc3nc2c1
Agent: [I-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc2nc3ccccc3[s+]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenothiazine-5-ium tetraiodide hydrate (0.417 g, 0.57 mmol) in methanol (10 ml) was stirred at room temperature and treated dropwise with a solution of dimethylamine (1.14 mmole) in methanol (2 ml). The mixture was stirred at room temperature for 3 hrs until the starting materials was consumed, as monitored by TLC (silica, CH3OH/TEA). The precipitate was filtered and washed with small amount of methanol, afforded a black solid, 0.30 g (84%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][C:37]4=[O:43])=[C:30]([CH:33]=[O:34])[N:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[N:31]=[C:30]([CH:33]=[O:34])[C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N+:39]([O-:6])([CH3:42])[CH2:38][C:37]4=[O:43])=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[N+](C)([O-])CC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chlorobenzoperoxoic acid (9.3 mg, 0.041 mmol) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Example 83, 20 mg, 0.039 mmol) in CHCl3 (0.1 ml) at 0° C. After stirring for 20 min, the mixture was warmed to room temperature and stirred for another 2 h. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3. The aqueous layer was back-extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a light purple solid.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[NH2:8][C@H:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10](O)=[O:11].CO>C1COCC1>[NH2:8][C@H:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][OH:11]
Reactant: N[C@@H](C(=O)O)c1cccs1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CO)c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
1.59 ml (3.18 mmol) of lithium borohydride (2 M in THF) were initially charged in 2.5 ml of dry THF, 0.80 ml (6.30 mmol) of chlorotrimethylsilane were added at RT and the mixture was stirred at RT for 5 min. Subsequently, 200 mg (1.27 mmol) of (2S)-amino(2-thienyl)acetic acid were added in portions and the reaction mixture was stirred at RT overnight. 2.5 ml of methanol were added dropwise to the reaction mixture, and the mixture was concentrated. The residue was admixed with 1.5 ml of a 20% aqueous potassium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. 173 mg of the target compound were obtained (90% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: Cc1ccc(C2(CN)CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ccc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (4,4-difluoro-1-(6-methylpyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=413.2, tR (minutes, Method D)=0.51
Reaction SMILES: [CH:1]1([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:22].C(=O)([O-])[O-].[Na+].[Na+].[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[C:31]([N:10]([CH2:9][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([Cl:22])=[O:20])=[CH:15][CH:16]=1)([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: O=C(O)Cc1ccc(NCC2CCCCCCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Cl)Cc1ccc(N(CC2CCCCCCC2)C(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(cyclooctylmethylamino)phenylacetic acid in 200 ml. warm chloroform is added a solution of 12 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g, carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 30 ml. Prevaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time ultimately to yield 4-(N-carbobenzyloxycyclooctylmethylamino)phenylacetyl chloride as a viscous, orange oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.[H][H].[Cl:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=1[C:19]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][N:24]2[CH:32]=[CH:33][CH:34]=[C:23]2[CH2:22]1)=[O:20]>CN(C)C=O.[Cl-].[Na+].O>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH:7]=[N:8][C:4]([CH3:3])=[N:5]2)[CH:15]=[CH:14][C:13]=1[C:19]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][N:24]2[CH:32]=[CH:33][CH:34]=[C:23]2[CH2:22]1)=[O:20]
Reactant: Cc1nc[nH]n1
Reactant: [H][H]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Temperature: 110 °C
Yield: 62 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.3 g) in dimethylformamide (50 ml) was added dropwise 3-methyl-1,2,4-triazole (0.45 g). After hydrogen gas evolution ceased, 2-chloro-4-fluorophenyl-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-methanone (1.70 g) was added and the reaction mixture was heated in a sand bath at 110° C. for 18 hours. The mixture was poured onto ice, diluted with brine, and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and the residue was triturated with diethyl ether to give 1.25 g of the title compound as colorless crystals, m.p. 191-193° C., MS m/z: 404.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:28][NH2:29])(=[O:27])[CH3:26]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:29]/[NH:28][C:25](=[O:27])[CH3:26])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CC(=O)NN
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: CC(=O)N/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 89.6 %

Procedure:
The title compound (30.5 mg, 82%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) and acetic acid hydrazide (23.0 mg, 0.28 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.83 (bs, 1H), 9.46 (s, 1H), 8.93 (dd, 1H), 8.40 (d, 1H), 8.19 (d, 1H), 7.81 (d, 1H), 7.53 (dd, 1H), 6.22 (s, 2H), 2.34, 2.14 (s, 6H). LCMS (method A): [MH]+=379, tR=2.07 min.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO>[CH:1]1([C:4]2[C:5]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C3CC3)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C3CC3)cc2c1
Yield: 96.7 %

Procedure:
Ethyl ester (154) (0.21 g, 0.45 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.19 g (96%) of the title compound (155) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.75-0.85 (m, 4H), 1.60-1.70 (m, 1H), 3.92 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.60 (d, J=8.6 Hz, 2H), 7.02 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.18-7.30 (m, 8H), 7.62 (d, J=15.9 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H). LCMS (APCI): m/z 437 (M+H)+, m/z 435 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>C1COCC1>[Br-:15].[C:18]([CH2:17][CH2:16][N:12]1[CH:13]=[CH:14][N+:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11]1)([OH:20])=[O:19]
Reactant: O=C(O)CCBr
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: O=C(O)CCn1cc[n+](-c2ccc([N+](=O)[O-])cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 0.756 mmol (0.250 g) 1-(4-nitrophenyl)imidazole and 0.756 mmol (0.115 g) 3-bromopropionic acid are dissolved in 5 ml THF and heated for 17 h to 90° C.
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[N:5]1.[OH2:13]>>[Cl-:1].[Mn+2:2].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[NH:5]1.[Cl-:1]
Reactant: O
Reactant: c1ccc2sncc2c1
Agent: [Mn+2]
Agent: [Cl-]
Product: O=c1[nH]sc2ccccc12
Yield: 77 %

Procedure:
To a solution of 1.26 g (0.01 mol) of anhydrous manganese chloride was added 4.5 g (0.03 mol) of 1,2-benzisothiazolin in 30 ml of water. The solution was concentrated to give a tan colored solid. The solid was thoroughly washed with dry acetone, filtered and dried at room temperature to yield 3.47 g (77%) of product, m.p.>250° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([CH3:30])[N:23]3[C:28]=2[C:27]([CH3:29])=[CH:26][CH:25]=[CH:24]3)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[CH3:30][C:22]1[N:23]2[C:28]([C:27]([CH3:29])=[CH:26][CH:25]=[CH:24]2)=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]2=[O:31])[CH:21]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (10 mg, 0.023 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (1.1 mg, 0.046 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 406.27 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(O)CCCCC.[C:12]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N#N>>[C:2]([O:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: Oc1cccc2ccccc12
Reactant: C=C(C)C
Agent: N#N
Solvent: CCCCCCO
Product: CC(C)(C)Oc1cccc2ccccc12

Procedure:
In a 200 ml autoclave, 300 mmol of isobutene, 50 mmol of 1-hexanol, 50 mmol of 1-naphthol and 300 mg of tin oxide/silicon dioxide/methylsilicon sesquioxide glass of composition 3 SnO2 : 97 SiO2 : 0 MeSiO1.5 were stirred at a pressure of 40 bar N2 and at a temperature of 140° C. for 16 h. Analysis of the product mixture by gas chromatography gave a yield of 1-naphthyl tert-butyl ether of 39.5% (based on 1-naphthol) as compared to a yield of 1-hexyl tert-butyl ether of 63.6% (based on 1-hexanol). In an analogous way, when the catalyst 1.5 Al2O3 : 97 SiO2 : 0 MeSiO1.5 was used, a yield of 1-naphthyl tert-butyl ether of 67.6% and a yield of 1-hexyl tert-butyl ether of 37.4% were achieved.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:22][CH:21]=1
Reactant: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(N3CCN(C)CC3)c3sccc3n2)cc1
Temperature: 200 °C

Procedure:
To a solution of 2-chloro-4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidine (0.11 g, 0.4 mmol) in pyridine (0.34 mL) in a microwave vial was added 4-methoxybenzylamine (0.55 mL, 4.2 mmol). The reaction mixture was heated to 200° C. in the microwave for 1 h, after which pyridine was removed under reduced pressure. The resultant residue was purified by FCC (2 M NH3 in MeOH/CH2Cl2) to yield (4-methoxy-benzyl)-[4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidin-2-yl]-amine. The intermediate was then dissolved in trifluoroacetic acid (2.5 mL) and heated at 60° C. for 1.5 h. After concentrating, the residue was purified by reverse-phase chromatography (acidic conditions) to afford the desired product as a TFA salt (30 mg). MS: 250.1. 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=5.6 Hz, 1H), 7.30 (d, J=5.6 Hz, 1H), 4.65-4.12 (m, 4H), 3.60-3.41 (m, 4H), 2.98 (s, 3H).