Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.CN(C([O:26][N:27]1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NO>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([NH:27][OH:26])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1cccc(-c2ccc(O)cc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(-c2ccc(O)cc2)c1)NO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
70 mg (0.29 mmol) of E-3-(4′-hydroxybiphenyl-3-yl)-acrylic acid were dissolved under nitrogen in 3 ml of DMF, then 109 mg (0.29 mmol) of HBTU and 100 μL (0.57 mmol) of DIPEA were added at 0° C. After 5 min hydroxylamine hydrochloride (20 mg, 0.29 mmol) was added and the mixture was stirred at 0° C. for 10 min., then at room temperature for 4 h. DMF was removed under reduced pressure and the residue was washed with water to obtain, after filtration, 73 mg of a crude product. Purification by flash chromatography on KH2PO4 buffered silicagel using as eluent CH2Cl2/MeOH 95:5 afforded 24 mg of the title compound as a white solid. M.p. 127-128° C. Rf=0.26 (Merck silica gel 60F254, CH2Cl2:/MeOH 90:10)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 44, 400 mg, 1.19 mmol), DMAP (365 mg, 2.97 mmol, 2.5 eq), diisopropylethylamine (0.7 mL, 2.97 mmol) and EDCl (700 mg, 2.97 mmol) in dichloromethane (10 mL) was allowed to stir for 10 minutes at room temperature under nitrogen. Methane sulphonamide (400 mg, 3.57 mmol) was added in one portion and the reaction mixture left to stir for 16 hours. The reaction was quenched with 6N HCl (20 mL) and the organic layer removed. The DCM layer was extracted into 1N NaOH (30 mL) and the organic layer discarded. The aqueous phase was adjusted to pH 5 using acetic acid and extracted into ethyl acetate (2×30 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the title compound as a white solid (168 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][Br:10])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)cnc1Cl
Yield: 48 %

Procedure:
A suspension of 2-chloro-3-fluoro-5-methylpyridine (5.1 g, 35 mmol), N-bromosuccinimide (6.1 g, 35 mmol) and benzolyperoxide (0.16 g, 0.66 mmol) in carbon tetrachloride (100 mL) was refluxed overnight. Upon cooling down, the solid was filtered off and the filtrate was concentrated and loaded onto a silica gel column eluted with 5% EtOAc in hexane to give 3.77 g of the desired 2-chloro-3-fluoro-5-bromomethylpyridine as colorless oil in 48% yield. GC-MS calcd. for C6H4BrClFN: 224.46. Found: 224.
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]1[C:17]([OH:18])=[C:16]2[C:12]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[O:14][CH2:15]2)=[CH:11][N:10]=1.[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])([O-:28])=[O:27].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:18][C:17]1[C:16]2[CH2:15][O:14][C@H:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:12]=2[CH:11]=[N:10][C:9]=1[CH3:8])=[O:34])([O-:28])=[O:27]
Reactant: O=C(O)CCCO[N+](=O)[O-]
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ncc2c(c1OC(=O)CCCO[N+](=O)[O-])CO[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methylmorpholine (90 μL, 0.82 mmol) was added to a stirred solution of (R)-(−)-cicletanine (48 mg, 0.18 mmol), 4-(nitrooxy)butanoic acid (27 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (1.8 mL). The solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by HPLC reverse phase (C-18) cluting with acetonitrile/water with 0.05% TFA to afford the title compound as a colorless oil. LC-MS: m/z 392.9 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[CH2:22](Cl)[CH2:23][Cl:24]>>[C:1]1([C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([CH2:22][CH2:23][Cl:24])[C:8]#[N:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(c1ccccc1)c1cccnc1
Reactant: ClCCCl
Solvent: c1ccccc1
Product: N#CC(CCCl)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 19.3 parts of α-phenyl-3-pyridylacetonitrile in 140 parts by volume of dry benzene is treated with 4 parts of soda amide and the mixture is refluxed with stirring for 1 hour. The mixture is cooled to room temperature and ethylene dichloride 17.2 parts is added. The mixture is stirred and refluxed for 4 hours, cooled, washed with water and dried. Removal of solvent and isolation provides 2-phenyl-2-(3-pyridyl)-4-chlorobutyronitrile. Following the procedure set out in Example 9, 8.9 parts of 4-hydroxy-4-phenylpiperidine are reacted in 400 parts by volume of ethylene glycol monoethyl ether at reflux for 18 hours to provide 2-phenyl-2-(3-pyridyl)-4-(4-hydroxy-4-phenyl)piperidinobutyronitrile. Also following the procedures in Example 9 the latter compound is converted to 5-1-(phenyl)-1-(3-pyridyl)-3-[4-(4-hydroxy-4-phenyl)piperidino]propyl-1H-tetrazole and in turn to 5-1-(phenyl)-1-(3-pyridyl)-3-[4-(4-hydroxy-4-phenyl)piperidino]propyl-1,3,4-oxadiazole having the following structural formula ##STR46##
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]5[CH2:54][CH2:53][CH2:52][CH2:51]5)=[O:11])[CH:24]=4)=[CH:27][C:28]=3[F:48])=[O:34])[CH2:37][CH2:36]2)=[O:47])=[CH:45][CH:44]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCCC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was added pyrrolidine (0.100 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (17.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[NH:6][C:5]2([CH2:26][N+:27]([O-])=O)[C:22]([F:25])([F:24])[F:23].[Cl-].[NH4+].O>CO.[Fe]>[NH2:27][CH2:26][C:5]1([C:22]([F:24])([F:25])[F:23])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:7](=[O:21])[NH:6]1
Reactant: COc1ccc(CN2C(=O)NC(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2C(=O)NC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (1.0 g, 2.1 mmol), iron (294 mg, 5.3 mmol) and ammonium chloride (562 mg, 10.5 mmol) were stirred in methanol (5 mL) and water (5 mL) and the resulting solution was heated overnight under reflux. After the reaction solution was cooled to room temperature, methanol (10 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the resulting solid was removed by filtration, the mother liquid was concentrated, and the residue was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (958 mg, quant.) was obtained as a colorless foamy solid.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[O:7][C:6]([CH:8]([CH2:10][C:11]#[CH:12])O)=[CH:5][CH:4]=1.[OH-].[Na+].[Cl-].[Na+]>C([O-])(=O)C.[Na+].C(O)(=O)C>[CH2:10]([CH:8]1[C:3]([OH:7])([CH3:2])[CH:4]=[CH:5][C:6]1=[O:1])[C:11]#[CH:12]
Reactant: C#CCC(O)c1ccc(C)o1
Reactant: O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (1600 ml), anhydrous sodium acetate (0.4 g) and 5-methyl-2-furylpropargylcarbinol (20 g) were charged, and the temperature was elevated to reflux. The pH value was adjusted to 4.5 with an aqueous 0.5 N acetic acid solution, and the mixture was stirred under reflux for 13 hours while maintaining a pH value of 4.0 to 5.0 by the addition of an aqueous 1/3 N NaOH solution. Then, the reaction mixture was cooled to 40° C., neutralized with an aqueous 1/3 N NaOH solution and, after addition of sodium chloride (300 g), extracted with methyl isobutyl ketone (400 ml) five times. From the extract, methyl isobutyl ketone was removed by distillation at 60° c. under reduced pressure to give an oily substance (16 g), which was subjected to distillation under reduced pressure to obtain 2-propargyl-3-hydroxy-3-methyl-4-cyclopentenone (14.8 g). Yield, 74%. B.P., 115°-132° C./0.1 mmHg. nD25 1.5124. C13NMR spectrum (CDCl3, internal standard TMS, δ ppm, 22.6 MHz): 206.2 (1-C); 167.8 (5-C); 130.7 (4-C); 82.0 (--CH2 -C≡CH); 78.5 (3-C); 70.6 (--CH2 --C≡CH); 57.0 (2-C); 23.4 (--CH3); 14.7 (--CH2 --C≡CH).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH:21]1[N:25]=[CH:24][N:23]([C:26](N2C=NC=C2)=[O:27])[CH:22]=1>C1COCC1.CCOC(C)=O>[N:23]1([C:26]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:27])[CH:22]=[CH:21][N:25]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)n2ccnc2)C1
Temperature: 50 °C
Yield: 64.5 %

Procedure:
To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (360 mg, 1.9 mmol) in THF (8 mL) was added triethylamine (253 mg, 349 μL, 2.5 mmol) followed by the addition of CDI (374 mg, 2.3 mmol) portionwise. The reaction mixture was heated at 50° C. for 3 h, cooled to room temperature and diluted with EtOAc. The organic layer was washed with 1 M HCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via silica gel column chromatography using 20 to 100% EtOAc in hexanes to obtain (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl 1H-imidazole-1-carboxylate (345 mg, 64%). 1HNMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.09 (s, 1H), 4.46 (s, 1H), 3.66 (dd, J=33.8, 10.7 Hz, 1H), 3.56-3.29 (m, 2H), 2.25 (s, 1H), 2.04-1.87 (m, 2H), 1.48 (t, J=4.0 Hz, 9H). LC/MS m/z 282.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNc1nc2cc(OC(=O)C(C)(C)C)ccc2c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 3 (100 mg, 0.3 mmol) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (100 mg, 0.8 mmol) and pivaloyl chloride (37 μl, 0.3 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water to wash the organic layer, which was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1(v/v)) and crystallized from hexane to give 105 mg (yield: 80.0%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: NC1C=CC([Cl:11])=C(C=1)C(O)=O.Cl.C(Cl)(=O)C1C=CC=NC=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)=[CH:28][C:24]=1[C:25](O)=[O:26].S(Cl)(Cl)=O>C1COCC1.ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)=[CH:28][C:24]=1[C:25]([Cl:11])=[O:26]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccnc1
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(C(=O)Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (1.71 g, 10 mmol) and TEA (6.96 mL, 50 mmol) in THF (50 mL) was added nicotinoyl chloride hydrochloride (1.78 g, 10 mmol) solid portion-wise. After 1 h stirring at room temperature, product was isolated through filtration as a white solid. The solid was washed with water and dried (1.85 g, 67%). The solid, 2-chloro-5-(nicotinamido)benzoic acid (1.0 g, 3.62 mmol) was suspended in dichloromethane (50 mL) and treated with thionyl chloride (1.57 mL, 36.2 mmol) at reflux for 6 hr. The reaction mixture was evaporated, and the residue was dissolved in hexane-ethyl acetate mixture (100 mL, 6:4) and quickly filtered through a short silica plug. On evaporation of solvent, the title compound was obtained as a white solid (873 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[CH:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(c1nnnn1C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Yield: 90.9 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol (8.25 g, 0.025 mole) [prepared in Step B] and 100 mg of p-toluene sulfonic acid monohydrate in xylene (60 mL) was heated to reflux with a Dean & Stark water collecting apparatus for a period of 12 hours. The reaction mixture was washed with 1N NaOH (10 mL) while it was warm and with water (100 mL). Concentration of the organic layer gave off-white crystals of product. This was purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; m.p.=146°-147° C.
Reaction SMILES: BrBr.[O:3]=[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])[CH3:5].C(=O)(O)[O-].[Na+].[Br:27]C(CCN1C(=O)C2N(C)C=NC=2N(C)C1=O)C(=O)C>CO.O>[Br:27][CH2:5][C:4](=[O:3])[CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: CC(=O)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(=O)C(Br)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCC(=O)CBr)c(=O)n2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.93 Grams (0.031 moles) of bromine were added to a solution of 7.3 g (0.0276 moles) of compound (a) in 100 ml of methanol, at 10° C. After stirring for 15 hours at room temperature, the reaction mixture volume was concentrated to 30 ml under reduced pressure, then 60 ml of water, and 3 drops of conc. sulphuric acid were added. The mixture was stirred at room temperature for 4 hours, in order to hydrolyze any dimethylketals formed by reaction with methanol. After dilution with 50 ml of water, the pH of the mixture was adjusted to 8-9, by addition of a 10% sodium bicarbonate aqueous solution, the mixture was extracted with 3×50 ml of methylene chloride, washed with water, dried on anhydrous sodium sulfate, filtered and evaporated under vacuum. 8.3 Grams of compound were obtained, which, by TLC and NMR analysis, showed to be impure by the presence of the 1-(3-bromo-2-keto-5-pentyl)-3,7-dimethylxanthine regioisomer. The crude compound was directly used for the next step.
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19](=O)[CH3:20].C(O)(=O)C.C([BH3-])#N.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH2:19]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:2][CH2:3]1)[CH3:20]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCCN(CC)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol), acetaldehyde (0.701 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00 mmol) in tetrahydrofuran (30 mL), methanol (3 mL) was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was cooled and extra amount of acetaldehyde (2.146 mL, 38 mmol) and sodium triacetoxyborohydride (1.060 g, 5.00 mmol) were added. The reaction was stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in 2N HCl (5 ml) and methanol (20 ml). The solution of crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford ethyl 4-(4-ethyl-1,4-diazepan-1-yl)benzoate (0.526 g, 76%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: COc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OCCN2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To 4-[2-(3-methoxy-4-nitro-phenoxy)ethyl]morpholine (Intermediate 48; 16.97 g, 60 mmol, 1 eq) in ethanol (120 mL) was added 10% palladium on charcoal (850 mg, 5% wt). The reaction was stirred at room temperature for 19 hours. After filtering off the palladium residues the solvent was evaporated under reduced pressure. The product was dissolved in ethyl acetate (100 ml) and extracted twice with 2M HCl. The aqueous layers were combined, washed with ethyl acetate then basified by the addition of 2N NaOH. The basic layer was re-acidified and captured onto mp-TsOH resin. After washing several times with methanol the product was released using 10% ammonia in methanol. After evaporation in vacuo the title compound was obtained as a dark brown oil. (14.5 g, 89%)
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=O)C.[BH4-].[Na+]>C1COCC1.CCO>[CH3:18][O:17][C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]2[O:6][C:5]([CH2:4][OH:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(OC)c2oc(CO)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Compound 39 (460 mg, 2.23 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). NaBH4 (102 mg, 2.68 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1 h. Solvents were evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (1:1) to give 41 (388 mg, 82%) as a white solid. m/z=209.08 (M+H). 1H NMR (500 MHz, CDCl3): δ: 6.62 (1H, s, H-3), 6.60 (1H, s, H-6), 6.46 (1H, s, H-4), 4.76 (2H, s, 2-CH2), 3.99 (3H, s, OMe), 3.85 (3H, s, OMe). 13C NMR (500 MHz, CDCl3): δ: 157.23 (C-5), 156.72 (C-1), 145.36 (C-7), 139.50 (C1a), 129.38 (C4a), 104.62 (C-3), 96.96 (C-6), 94.58 (C-4), 57.98 (2-CH2), 55.95 (OMe), 55.83 (OMe).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cnn(C)c2)on1
Reaction time: 24 h
Yield: 13.8 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 12 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H), 4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d, 1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).