Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:12]1[N:16]([CH3:17])[CH:15]=[N:14][C:13]=1[CH:18]=[O:19].CS(C)=O>C(OCC)(=O)C>[C:2]1([S:8]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][C:13]=2[CH:18]=[O:19])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(C=O)c1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1cnc(C=O)c1S(=O)(=O)c1ccccc1
Temperature: 180 °C
Yield: 61.2 %

Procedure:
A mixture of benzenesulfinic acid sodium salt (0.065 g), 5-bromo-1-methyl-1H-imidazole-4-carbaldehyde (0.037 g) and dimethyl sulfoxide (2.0 mL) was heated by microwave irradiation at 180° C. for 10 minutes. The mixture was treated with additional benzenesulfinic acid sodium salt (0.065 g), and heated by microwave irradiation at 180° C. for 40 minutes. The mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was triturated with cyclohexane to afford a yellow solid. The solid was collected by filtration, washed with cyclohexane and dried to afford the title compound (0.030 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[O:6][C:5](=[O:18])[CH:4]=1.[F:19][C:20]1[C:25]([C:26](Cl)=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=1[F:32]>>[CH2:14]([N:13]([CH2:16][CH3:17])[C:9]1[CH:8]=[C:7]2[C:12]([C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[C:24]([F:29])=[C:23]([F:30])[C:22]([F:31])=[C:21]([F:32])[C:20]=3[F:19])=[CH:4][C:5](=[O:18])[O:6]2)=[CH:11][CH:10]=1)[CH3:15]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CCN(CC)c1ccc2c(CN)cc(=O)oc2c1
Product: CCN(CC)c1ccc2c(CNC(=O)c3c(F)c(F)c(F)c(F)c3F)cc(=O)oc2c1

Procedure:
4-Aminomethyl-7-diethylaminocoumarin (50 mg, 0.2 mmol) is treated with pentafluorobenzoyl chloride (0.5 mL, 0.3 mmol) at 0° C. under dry argon protection, and worked up according to the procedure of Example 25. Compound 29 is obtained as an off-white solid (67 mg, yield: 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[Cl:38][C:11]1[C:10]2[CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH:28]([CH3:30])[CH3:29])=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:16]=[CH:15][C:14]=2[N:13]2[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CCC2CC(=O)O)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the enantiomer obtained during the resolution of Compound 6 by chiral HPLC (described as the enantiomer isolated and having the retention time of 6.7 min per the conditions reported in Example 1.2) (20 mg, 0.049 mmol) in DCM. (0.500 mL) was cooled to 0° C. NCS (6.60 mg, 0.049 mmol) was added and the reaction was allowed to continue at 0° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was diluted with DCM and washed with water (2×10 mL), then washed with sodium thiosulfate pentahydrate (aq) (2×10 mL), dried over MgSO4 and filtered by vacuum filtration. The filtrate was concentrated under reduced pressure to give an enantiomer of Compound 8 as a yellow solid (16.7 mg). LCMS m/z=439.8 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=5.94 Hz, 6H), 2.25-2.34 (m, 1H), 2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.29, 4.17 Hz, 1H), 3.63-3.73 (m, 1H), 3.96-4.04 (m, 1H), 4.12-4.19 (m, 1H), 4.76-4.83 (m, 1H), 5.07 (s, 2H), 6.86 (dd, J=8.84, 2.40 Hz, 1H), 6.96 (d, J=2.40 Hz, 1H), 7.28 (d, J=3.66 Hz, 1H), 7.30 (d, J=3.66 Hz, 1H), 7.72 (dd, J=8.72, 2.27 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.32 (bs, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccn1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), potassium carbonate (0.77 g), 2-(bromomethyl)pyridine hydrobromide (1.06 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)[CH3:31]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride (Aldrich) according to the method described in Example 1.1/d.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1
Reactant: CC=CCC1CC(=O)c2ccccc2S1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1CC(=O)c2ccccc2S1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 15 minutes through a solution, cooled to -70°, of 3 g of (RS)-2-(2-buten-1-yl)-4-thiochromanone in 100 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 50 ml of dichloromethane and, after the addition of 5 ml of water and 5 ml of trifluoroacetic acid, stirred at room temperature for 1 hour. The mixture was subsequently poured into 50 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 80 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There were obtained 2.8 g (99%) of 2-(2-oxoethyl)-4-thiochromanone as a yellow oil which was used in the next reaction without further recrystallization.
Reaction SMILES: C(O)(C)C.[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(N(CC)CC)C>[CH2:10]1[O:11][C:12]2[CH:13]=[CH:14][C:6]([CH2:5][NH:15][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][C:8]=2[O:9]1
Reactant: N#Cc1ccc2ncnc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89 %

Procedure:
15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of 4-chloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluting with ethyl acetate to give 200 mg of the title compound.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 ml of dichloromethane and cooled to 0° C. After addition of 8.16 mol(73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cncc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (846 mg, 5.9 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (2.46 g, 17.8 mmol) and 5-(bromomethyl)-1-methyl-1H-imidazole (1.56 g, 8.9 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration, washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{[(1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (589 mg, 42% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 3.61 (s, 314), 4.44 (s, 2H), 6.02 (s, 1H), 6.88 (s, 1H), 7.56 (s, 1H); LRMS (ES+) m/z 237 (100%, M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(CN2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and morpholine (0.65 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.66 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-(morpholinomethyl)-5-nitrobenzonitrile (0.87 g, 85%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1 H), 8.41 (br s, 1H), 8.01 (br s, 1H), 3.74 (br t, 4H, J=4.4 Hz), 3.64 (s, 2H), 2.48 (br t, 4H, J=4.4 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:8][C:4]1[CH:5]=[C:6]([O:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([F:9])[CH:11]=2)[N:7]=[CH:2][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Clc1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1F
Temperature: 50 °C
Reaction time: 13 h
Yield: 28.8 %

Procedure:
After dissolving 2,6-dichloropyrimidine (5.0 g) and 3-fluoro-4-nitrophenol (6.11 g) in 1-methyl-2-pyrrolidinone (25 ml) at room temperature under a nitrogen atmosphere, diisopropylethylamine (6.81 ml) was added and the mixture was stirred for 13 hours at 50° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The separated organic layer was washed with water, 1N aqueous sodium hydroxide, water, 10% aqueous potassium hydrogen sulfate and brine in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then ethyl acetate (25 ml) was added to the residue to precipitate crystals. The crystals were filtered and subjected to aeration drying to provide the title compound (2.61 g, 30%) as white crystals. The filtrate was concentrated under reduced pressure, and then diethyl ether (30 ml) was added to the resultant residue and the mixture was stirred. The precipitated crystals were filtered, washed with diethyl ether (5 ml×2) and subjected to aeration drying to provide the title compound (3.98 g, 44%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-cyclopentyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 124 mg, 3.1 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.193 mL, 3.1 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and used for next step reaction. [M+H] calc'd for C14H18ClFN4O, 313; found 313.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:15][C:16](=[O:36])[N:17]([CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:11]([O:15][C:16](=[O:36])[N:17]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)[OH:25])=[CH:20][N:19]=1)[CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C(O)c2c[nH]c3ncnc(Cl)c23)cn1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.121 g, 0.790 mmol), (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (77), 2.5 mL of N,N-dimethylformamide and cesium carbonate (0.751 g, 2.30 mmol) were combined in a round bottom flask. The reaction was stirred at room temperature for 6 days, then neutralized with 0.1 N aqueous hydrochloric acid, then extracted 3× with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated. The resulting material was purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (78, 0.023 g). MS (ESI) [M−H+]−=513.2, 515.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:24][C:25]([C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1)=[O:26].CCN(C(C)C)C(C)C.[CH2:45]([S:47](Cl)(=[O:49])=[O:48])[CH3:46]>C(O)(C(F)(F)F)=O>[CH2:45]([S:47]([N:15]1[CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:24][C:25]([C:27]4[N:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]5=[N:29][CH:28]=4)=[O:26])[CH:4]=3)[N:12]=2)[CH2:16]1)(=[O:49])=[O:48])[CH3:46]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl 3-(3-(4-fluoro-3-(imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F27) (14.4 mg, 0.03 mmol) was dissolved in TFA (0.5 mL) and stirred at room temperature for 10 minutes. Then TFA was removed under vacuum. The residue was dissolved in anhydrous dichloromethane (1 mL) and DIEA (13.0 mg, 0.10 mmol) and ethanesulfonyl chloride (5.8 mg, 0.045 mmol) were added. The reaction was stirred at room temperature for 10 minutes. The solvent was removed and the crude was purified by preparative HPLC to afford N-(5-(5-(1-(ethylsulfonyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (F28). 1H NMR (400 MHz, CDCl3) δ 9.50 (d, J=2 Hz, 1H), 9.09 (dd, J=2, 7.2 Hz, 1H), 8.21 (s, 1H), 7.87 (m, 1H), 7.79 (m, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.41 (m, 1H), 7.22 (dd, J=8.8, 10.4 Hz, 1H), 7.02 (dt, J=0.8, 6.8 Hz, 1H), 4.34 (m, 4H), 4.07 (m, 1H), 3.00 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). MS m/z 471.1 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I>C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([O:27][CH3:44])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-1-cyclopentyl-ethanol (24.8 mg, 0.041 mmol) in THF (0.2 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 8 mg, 0.2 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (30 μL, 0.5 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexanes) to afford the title compound (17 mg, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (t, J=8.09 Hz, 2H) 1.31-1.65 (m, 6H) 1.55 (s, 3H) 2.26-2.38 (m, 1H) 3.03 (s, 3H) 4.18 (s, 3H) 4.68-4.75 (m, J=16.18 Hz, 1H) 4.84 (d, J=16.18 Hz, 1H) 5.08 (d, J=17.84 Hz, 1H) 5.22 (d, J=17.43 Hz, 1H) 7.31 (d, J=8.71 Hz, 1H) 7.42-7.47 (m, 2H) 7.71 (s, 2H) 7.76 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.5 (M+1).
Reaction SMILES: [C:1]1(=[O:31])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])C(=O)C2=CC=CC=C12.O.NN.[CH2:35]([O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([N:46]=C=O)=[CH:42][CH:41]=1)=[O:39])[CH3:36]>CCO>[CH2:35]([O:37][C:38]([C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:1](=[O:31])[NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:44][CH:45]=1)=[O:39])[CH3:36]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=C(O)CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)NCCCN(CCCC(=O)O)C2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a solution of 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (137 mg, 0.32 mmol) in EtOH (5 ml) was added hydrazine monohydrate (63 μl, 1.3 mmol), and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under vacuum, and then water was added. The mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. To the filtrate was added 4-(ethoxycarbonyl)phenyl isocyanate (62 mg, 0.32 mmol), and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 17% methanol/chloroform to afford 4-[[3-[4-(ethoxycarbonyl)phenylureido]propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (25 mg, 16%): MS(ES+) m/e 482 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.80 (br, 1H), 7.91 (m, 3H), 7.61 (m, 3H), 7.21 (m, 1H), 7.12 (m, 2H), 4.70 (t, J=7.6 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.32 (m, 2H), 3.23 (m, 1H), 3.03-2.84 (m, 3H), 2.74 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 2.02-1.78 (m, 5H), 1.70 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH:27]=[CH:28][C:29]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:30][C:15]=2[S:14]1>C(O)C>[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:9])[C:16]2[CH:27]=[CH:28][C:29]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:30][C:15]=2[S:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ccccc1
Solvent: CCO
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ccccc1
Yield: 52.1 %

Procedure:
m-Chloroperbenzoic acid (0.6 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-phenylthioethyl)-6trifluoromethoxybenzothiazoline (1.3 g) in absolute ethanol (20 cc) cooled to 0.C. The reaction is continued for 3 hours at a temperature in the region of 20 C. The reaction medium is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) and the residue obtained purified by chromatography on a silica column with ethyl acetate as eluent. (RS)-2-Imino-3-(2-phenylsulphinylethyl)-6-trifluoromethoxybenzothiazoline (0.7 g) is obtained in the form of a yellowish oil, which is converted to a hydrochloride, m.p. 10 C.