Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][C@@:16]1([OH:32])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30].[CH:34]1([C:37](OC2C([2H])([2H])C([2H])([2H])C3C(=CC=C(F)C=3)C2(CCN(CCCC2NC3C=CC=CC=3N=2)C)C(C)C)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([O:32][C@:16]2([CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH3:33])[CH2:25][C:24]([F:27])([F:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=3)[C@@H:17]2[CH:29]([CH3:31])[CH3:30])=[O:38])[CH2:36][CH2:35]1
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1
Reactant: [2H]C1([2H])c2cc(F)ccc2C(CCN(C)CCCc2nc3ccccc3[nH]2)(C(C)C)C(OC(=O)C2CC2)C1([2H])[2H]
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@@]1(CCN(C)CCCc1nc2ccccc2[nH]1)OC(=O)C1CC1

Procedure:
Compound 304 is prepared from 35d in a manner analogous to that of Example 6 for compound 704a.
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[CH:24][N:25]=1>>[N:1]1([CH2:5][C@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[N:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[CH:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cncc2c(O)ncnc12
Product: NC(=O)c1cncc2c(N[C@@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 19 was prepared following general synthetic scheme 7 wherein (R)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine was reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to give the title compound as an off-white solid. LC-MS [451 (M+1)], 1H NMR (400 MHz, Chloroform-d) δ 10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d, 1H), 3.25 (dq, 4H), 3.05-2.89 (m, 2H), 2.14 (p, 2H).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)=O)[CH2:7]1)=[O:5])C.[OH-].[Li+:26].C1COCC1>O>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@:6]([CH3:24])([C:4]([O-:5])=[O:3])[CH2:7]1.[Li+:26]
Reactant: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]1(C(=O)[O-])CCCN(C[C@H]2COc3ccccc3O2)C1
Yield: 74.2 %

Procedure:
(S)-1-((R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (512 mg, 1.60 mmol), 1 M lithium hydroxide (4.81 ml, 4.81 mmol) and THF:H2O solution (9:1) (5 ml) were heated under microwaves at 100° C. for 26 h. The mixture was filtered and evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc and the aqueous phase was evaporated to dryness to give 353 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([OH:11])([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][CH2:2][CH2:3][C:4]([OH:11])([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH3:20])=[CH:15][CH:14]=1
Reactant: C=CCC(O)(CC=C)CCCl
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CC=C)CCN[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-chloro-ethyl)-hepta-1,6-dien-4-ol (7.87 g), (S)-1-(4-bromo-phenyl)-ethylamine (13.52 g), K2CO3 (9.34 g), KI (8.23 g), and acetonitrile (150 mL) is stirred at reflux temperature overnight. After cooling to room temperature, the mixture is concentrated under reduced pressure and water is added to the residue. The resulting mixture is extracted with ethyl acetate (3×), and the combined extracts are washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to afford the title compound as an oil. Yield: 8.36 g (55% of theory); Mass spectrum (ESI+): m/z=338/340 (Br) [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH2:20][CH3:21])(C)(C)C.P(=O)(O)(O)O>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH2:20][CH3:21]
Reactant: CC[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CC[C@H]1Oc2ccccc2NC(=O)[C@H]1N
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield by reaction of 460 mg (1.50 mmol) ((6R,7S)-6-ethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester with 2.23 g (22.5 mmol) ortho phosphoric acid in 4 ml tetrahydrofurane, MS m/e (%): 207.1 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][CH3:17])[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: COc1ccccc1N
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3OC)nc21
Temperature: 175 °C
Yield: 34 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (140 mg, 0.59 mmol) and 500 μL of 2-methoxyaniline was heated at 175° C. for 20 minutes. The reaction mixture was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from ethyl acetate and hexane provided 60 mg (34%) of 8-ethyl-2-(2-methoxyphenyl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 126-128° C.
Reaction SMILES: [C:1]([C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]([F:24])([F:23])[F:22])[C:5]=1[C:25]#[N:26])(=O)[NH2:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([C:1]#[N:2])=[C:5]([C:25]#[N:26])[C:6]([C:21]([F:23])([F:24])[F:22])=[N:7]1
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Reaction time: 3 h

Procedure:
5-Carbamoyl-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.57 g) was heated to 200° C. with phosphorus pentoxide (2.82 g) with stirring. After 3 hours, the cooled product was treated with ice, and extracted with dichloromethane (3×50 ml). The organic solution was washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a solid. Recrystallization from hexane gave 1-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dicyano-3-trifluoromethyl-pyrazole in the form of white crystals (1.8 g), m.p. 8 0° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[C:7]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]>[Pd].C(O)C>[O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[C:7]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(C#Cc3ccccc3)cc2c2cc[nH]c12
Agent: [Pd]
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(CCc3ccccc3)cc2c2cc[nH]c12
Reaction time: 24 h
Yield: 27.7 %

Procedure:
10 mg of palladium on charcoal is added to a suspension of 14 mg (0.04 mmol) of 4-oxo-8-phenylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of ethanol and the mixture is placed under a hydrogen atmosphere for 24 hours. The raw reaction product is then filtered on celite, and the filtrate is evaporated. The residue is triturated with methanol to give 4 mg (28%) of 4-oxo-8-phenethyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[H][H]>[Ni].C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c(Br)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCOCC2)c(Br)c1

Procedure:
A reaction mixture of 220 mg (0.66 mmol) of 4-[2-(2-bromo-4-nitrophenoxy)ethyl]morpholine and 100 mg Raney nickel in 50 mL of ethyl acetate is hydrogenated at ambient temperature and 3 bar hydrogen. The catalyst is suction filtered and the filtrate is evaporated down. The purification is carried out by column chromatography on aluminum oxide (eluant: petroleum ether/ethyl acetate (1:1)). Yield: 100 mg (50% of theory); C12H17BrN2O2 (M=301.18); calc.: molecular ion peak (M+H)+: 301/303 (Br); found: molecular ion peak (M+H)+: 301/303 (Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6](=[O:8])(=[O:7])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([O-:14])=[O:13].[Na+].ClCBr.C(N(C(C)C)CC)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:15])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: CC1(C)[C@H](C(=O)[O-])N2C(=O)C[C@H]2S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClCBr
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
The tetrabutylammonium salt of sulbactam (53 g of an oil) was prepared from sulbactam sodium salt (20.0 g, 0.078 mol) and tetrabutylammonium hydrogen sulfate (33.2 g) according to the method of Example 1. The entire 53 g batch was taken into 1280 ml of chlorobromomethane containing 1.70 ml (0.0098 mol) of diisopropylethylamine. After 5 hours, the reaction mixture was extracted with 3×100 ml of water. By optical rotation assay, the first, second and third extracts contained 5.7%, 1.1% and 0.3% of recovered sulbactam. The organic layer was stripped to a volume of 300 ml, and the BrCH2Cl displaced with 2×500 ml of ethyl acetate to a final volume of 275 ml, diluted with 100 ml fresh ethyl acetate, extracted 1×275 ml H2O, 1×275 ml saturated Na2SO4, 1×275 H2O and 1×275 ml brine, dried over 20 g MgSO 4, stirred with 4 g of activated carbon for 30 minutes, and filtered over diatomaceous earth with 100 ml of ethyl acetate wash. The filtrate and wash liquor were combined, stripped to 100 ml, cooled to 0°-5° C., diluted dropwise with 90 ml of hexane, maintaining 0°-5° C. (leading to an oil), warmed back to ambient temperature (causing the oil to form crystals), diluted dropwise over 1.5 hours with 150 ml of additional hexane, cooled and granulated at 0°-5° C. for 1 hour, and title product recovered in two crops (the second following evaporation of the mother liquor and trituration with hexane), 13.8 g and 4.7 g, both melting at 89°-95° C., a yield of 84% uncorrected, a yield of 80% corrected for purity by hplc.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25](O)=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:23][CH2:24][C:25]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1Cl

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(3-chloro-4-methoxyphenyl)propionic acid (215 mg; 1 mmol) as described in method 2; yield: 0.071 g (20.1%); MS m/z: 355.4/357.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06-3.08 (m, 2H); 3.24-3.27 (m, 2H); 3.80 (s, 3H); 7.04-7.06 (m, 1H); 7.21-7.23 (m, 1H); 7.39 (br s, 1H); 7.87-7.89 (m, 1H); 7.94-7.96 (m, 1H); 8.25 (br s, 1H); 8.92 (s, 1H); HPLC (METHOD [A]): rt 12.55 min (95.7%)
Reaction SMILES: [C:1]1([C:7]2[C:8](I)=[C:9]3[CH2:14][CH2:13][CH2:12][N:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:17]1[CH:22]=[C:21]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:11][N:10]3[CH2:12][CH2:13][CH2:14][C:9]=23)[CH:20]=[CH:19][N:18]=1
Reactant: Ic1c(-c2ccccc2)nn2c1CCC2
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(-c2c(-c3ccccc3)nn3c2CCC3)ccn1
Temperature: 60 °C
Yield: 56.4 %

Procedure:
A mixture of 1.00 g (3.22 mmol) of 2-(phenyl)-3-iodo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 1.80 g (8.06 mmol) of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 2.63 g (8.06 mmol) of Cs2CO3 and 526 mg (0.65 mmol) of Pd(dppf)Cl2 in 8 ml of THF is heated under argon at 60° C. for 16 h. 20 ml of water are added, and the reaction mixture is extracted with 3×50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 507 mg (57%) of the desired product; log P(HCOOH): 2.53; 1H-NMR (DMSO-d6): 8.10 (d, 1H), 7.40 (m, 5H), 7.07 (d, 1H), 6.85 (s, 1H), 4.19 (dd, 2H), 3.11 (dd, 2H), 2.62 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10]([CH:9]=[N:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(C=Nc2ccc(F)cc2)CCN1Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 0.70 g of 1-(4-fluorophenyliminomethyl)-2-nitroiminoimidazolidine, 0.45 g of 2-chloro-5-chloromethylpyridine, 0.77 g of potassium carbonate and 5 ml of dimethylsulfoxide were agitated at 70° C. for 1 hour. The reaction mixture was, as it is, subjected to purification by column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to give 0.45 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(4-fluorophenyliminomethyl)imidazolidine.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:20][CH3:21])=[CH:25][CH:24]=1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(Br)cc1)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
0.40 g (1.39 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 8.0 ml of ethanol, and 514 mg (2.78 mmol, 2.0 equivalents) of 4-bromobenzaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.707 g (3.34 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred for 22 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH (manufactured by FujiSilysia Chemical Ltd.), n-hexane:ethyl acetate=3:1), thereby obtaining 0.508 g of 4-{[(4-bromobenzyl)-(4-dipropylaminobutyl)amino]methyl}benzonitrile (15) as a light yellow oily substance (yield: 80.0%). [HPLC: 96.2% (HPLC measurement conditions B)]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:22]([CH3:23])[C:18]([S:17][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)=[C:19]([CH3:20])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Reactant: Nc1cc(O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (0.36 g), 3-(4-chlorophenylsulfanyl)pentane-2,4-dione (0.61 g) and p-toluenesulfonic acid monohydrate (0.040 g) was heated at 140° C. for 10 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford title compound as a brown oil, 0.050 g.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:20])=O.N>C(Cl)(Cl)Cl>[Cl:20][CH2:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Temperature: 0 °C

Procedure:
38 g of 4,5-Dimethyl-2-(4-(2-propyl)-phenyl)-oxazole 3-oxide are dissolved in 200 ml of chloroform, 16.4 ml of phosphorus oxychloride are added and the mixture is heated under reflux for 30 minutes. The reaction mixture is cooled to 0° C., a slightly alkaline pH is established using ammonia and the mixture is extracted three times with in each case 500 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 10.3 g of 4-chloromethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole as a colorless solid. C14H16CINO (249.74), MS(ESI): 250 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[OH:16].[Br:17][CH2:18][CH:19](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:17][CH2:18][CH:19]1[O:16][C:4]2[CH:5]=[C:6]([S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: O=S(=O)(c1ccc(CO)c(O)c1)C(F)(F)F
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Temperature: 50 °C
Yield: 87 %

Procedure:
Preparation according to Preparation 9. 2-(hydroxymethyl)-5-[(trifluoromethyl)sulfonyl]phenol (2.7 g, 10.5 mmol), 2-bromo-1,1-dimethoxyethane (3.0 ml, 25.4 mmol), conc. H2SO4 (1.0 ml), THF (20 ml). Heating at 50° C. for 6 h. Additional 2-bromo-1,1-dimethoxyethane (5×0.5 ml, 21.1 mmol) and conc. H2SO4 (3×1.0 ml) were added during the reaction. Purification by flash column chromatography gave the title compound (3.3 g). MS m/z (rel. intensity, 70 eV) 362 (M+, 5), 360 (M+, 5), 267 (bp), 238 (64), 141 (52), 77 (55).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([O:28]C)=[O:27])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([OH:28])=[O:27])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
To a solution of methyl 1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5naphthyridine-3-carboxylate (0.65 g, 1.62 mmol) in THF (20 mL) was added sodium hydroxide (16.2 mL, 1 N) and the solution was heated to 80° C. and after 1.5 hours the reaction was completed. The reaction was allowed to cool and then the THF was removed leaving the product in water. The water was acidified with 1N HCl to adjust the pH to 3 and the resulting crude solids were collected by vacuum filtration and taken on as is.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]O>OS(O)(=O)=O.C(Cl)(Cl)Cl>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(S)cc1
Yield: 97.7 %

Procedure:
To a solution of 4-mercapto benzoic acid (5 g, 32.4 mmol) in methanol (25 mL) was added catalytic H2SO4 (1-2 drops) and refluxed for 5-6 h. TLC (mobile phase-10% methanol in chloroform Rf. S.M.—0.2, product—0.6) shows absence of starting material and formation of product; the methanol was distilled off in vacuo and the residue was diluted with ethyl acetate. The organic layer was washed with water (2×25 mL) followed by 10% aq. sodium bicarbonate solution. The organic layer was dried over Na2SO4 and concentrated in vacuo to obtained the product as an off-white solid (Yield-5 g).
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:13]1([N:19]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NNc1ccccc1
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 95 °C
Yield: 61.3 %

Procedure:
A mixture of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.93 g, 16 mmol) and phenylhydrazine (1.947 g, 18 mmol) in EtOH (15 mL) was heated at 95° C. for 8 hours. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as a yellow solid (2.23 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.51 (m, 5H), 5.87 (s, 1H), 3.93 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.