Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][C@@H:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:5]1.C([Li])CCC.[CH:23](=[O:25])[CH3:24]>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@@H:6]2[CH2:7][CH2:8][C@H:4]([C:3]#[C:2][CH:23]([OH:25])[CH3:24])[CH2:5]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(O[C@@H]2CC[C@H](C=C(Br)Br)C2)cc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)C#C[C@H]1CC[C@@H](Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1 -dibromo-2-{cis-3-(4-fluorophenoxy)cyclopentyl}ethene (6.12 g, 18 mmol) in dry THF (50 ml) at -78° C. under an argon atmosphere was added n-butyllithium (24.5 ml, 39 mmol, 1.6M n-hexane solution). The mixture was stirred for 0.5 h at the same temperature and then allowed to warm to room temperature over 1 h. The mixture was cooled to 0° C., a solution of dry acetaldehyde (1.76 g, 40 mmol) in dry THF (20 ml) added to the mixture and the whole stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (100 ml) and the whole extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography {SiO2, 250 g; hexane/ethyl acetate (4:1)} afforded 2.18 g (49%) of title compound as a yellow oil: 1H NMR δ7.05-6.92 (m, 2H), 6.86-6.77 (m, 2H), 4.78-4.62 (m, 1H), 4.60-4.48 (m, 1H), 2.81-2.65 (m, 1H), 2.52-2.36 (m, 1H), 2.12-1.81 (m, 5H), 1.65 (br.s, 1H), 1.45-1.40 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.C(OCC)(=O)C>[CH3:14][NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC#N
Product: CNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A stirred mixture of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (12.5 g), potassium carbonate (17.4 g) and iodomethane (22.5 g) in acetonitrile (150 ml) was heated at 80° C. for 3 hours. At this point, another portion of iodomethane (22.5 g) was added; the mixture was heated with stirring for another 2 hours. The mixture was then diluted with ethyl acetate (500 ml) and washed with water (150 ml). The organic layer was then dried over sodium sulphate, solvent removed under reduced pressure to give expected product 4-methylamino-6-chloro-3-nitro-pyridine-2-carbonitrile (13 g).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CCCC)CCCC)CCC.[CH:18]([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26])=[CH:19][CH3:20]>C(OCC)(=O)C>[Cl:4][C:1]([N:23]1[CH2:24][CH2:25][N:21]([CH:18]=[CH:19][CH3:20])[C:22]1=[O:26])=[O:2]
Reactant: CC=CN1CCNC1=O
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC=CN1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
First 6.3 pts. by wt. of phosgene and then 11.8 pts. by wt. of tri-n-butylamine are added to a suspension of 8.0 pts. by wt. of 1-propenyl-2-oxo-imidazolidine (prepared according to DAS (German Published Specification) No. 1,057,126) in 100 pts. by vol. of abs. ethyl acetate. The reaction mixture is stirred overnight and concentrated. The 1-chlorocarbonyl-2-oxo-3-propenyl-imidazolidine formed is used for Example 2 in a mixture with tributylammonium chloride. IR (liquid paraffin): 1,800 and 1,710 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@H:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:17][C@H:16]1[C:31](=[O:41])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1)=O)(C)(C)C>Cl.O1CCOCC1>[CH2:39]([C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:31]([C@@H:16]2[CH2:17][C@@H:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)[CH2:19][NH:15]2)=[O:41])=[CH:38][CH:37]=1)[CH3:40]
Reactant: CCc1ccc(NC(=O)[C@@H]2C[C@@H](Nc3ccc4cnccc4c3)CN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(NC(=O)[C@@H]2C[C@@H](Nc3ccc4cnccc4c3)CN2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4R)-2-(4-Ethyl-phenylcarbamoyl)-4-(isoquinolin-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate was dissolved in 4 N HCl in dioxane and stirred for 2 h at rt. Evaporation gave (2S,4R)-4-(Isoquinolin-6-ylamino)-pyrrolidine-2-carboxylic acid (4-ethyl-phenyl)-amide as the hydrochloride salt. Rt=1.05 min (Method A). Detected mass: 361.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[C:7]1([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>C1COCC1>[C:7]1([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cccnc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(N2CCN(Cc3cccnc3)CC2)cc1
Reaction time: 0.33 h

Procedure:
NaBH4 (1.50 g, 38.88 mmol, 1.2 equiv.) was slowly added over 20 minutes to a solution of acetic acid (glacial, 11.13 mL, 194.41 mmol, 6 equiv.) in anhydrous THF (50 mL) at 20° C. under a nitrogen blanket with stirring at 200 RPM. After aging for another 20 minutes, pre-dried molecular sieves (3A, 45 g) and additional anhydrous THF (20 mL) were added to the reaction mixture and the stirring rate was increased to 350 RPM. Ten minutes after addition of the sieves, 1-phenylpiperazine (4, 5.00 mL, 32.40 mmol, 1 eq.) and 3-pyridinecarboxaldehyde (2, 3.74 mL, 38.88 mmol, 1.2 equiv.) were added, and the mixture aged for another 30 minutes, at which point the reaction was 100% complete, as determined by monitoring the disappearance of 4 with HPLC. The molecular sieves were removed by filtration. The filtrate containing the product was quenched into brine and the pH adjusted to 7.5 to 8. The organic layer containing the product was separated and the aqueous layer discarded. The organic layer was then concentrated to dryness and the solids dissolved in hot hexanes. The desired product was then crystallized by slow cooling to 5–10° C. The resulting crystals were vacuum filtered while cold and washed with cold hexane (50 mL×2). The product was then dried under vacuum at 45° C. and 75 mm Hg pressure. The isolated yield of compound 6 (HPLC area 99.3%, mp 70.5–72.0° C.) was 90.7%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]=[O:11].CC(=CC)C.P([O-])(O)(O)=[O:18].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.C1COCC1.C(O)=O.O>[I:1][C:2]1[C:3]([C:10]([OH:18])=[O:11])=[C:4]([O:8][CH3:9])[N:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: COc1nccc(I)c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CC(C)(C)O
Product: COc1nccc(I)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (4.96 g, 18.9 mmol) in 22 mL tert.-butanol was added in this order 2-methyl-2-butene (30 mL of a 2 M solution in THF, 60 mmol), natriumdihydrogen-phosphate (5.7 g, 47.5 mmol), water (15 mL) and sodiumchlorite (3.9 g, 43 mmol). The mixture was stirred at ambient temperature for 1 hour, then poured on dilute aqueous formic acid. The mixture was extracted with ethyl acetate, the organic layer washed with water and brine and concentrated. The residue was dissolved in diisopropylether+dichloromethane (1+1) and extracted 3 times with half-concentrated aqueous NaOH solution. The combined aqueous layers were acidified with conc. HCl and extracted with ethyl acetate. The organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to give 3.462 g of the title compound as a white solid (67%). 1H NMR (500 MHz, CD3OD) δ 7.83 (d, J=5.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 3.94 (s, 3H);
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(Cl)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
(R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (13.3 g, 33.8 mmol) was dissolved in THF/H2O (20:1, 180 mL/9 mL), triphenylphosphine (36.0 g, 135 mmol) was added in portions. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure to the residue, which was purified on silica gel chromatography to afford (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (10.4 g, purity: HPLC=75%).
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C@H:13]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:12]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:31][C:27]1[NH:28][C:29](=[O:30])[C:24]2[S:23][C:22](=[O:32])[N:21]([C@H:13]3[C@H:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:15][C@@H:11]([CH2:10][OH:9])[O:12]3)[C:25]=2[N:26]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2N2CCCC2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)C[C@H]2N2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To a solution of compound [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32e, 250 mg, 0.54 mmol) in MeOH (8 mL) was added K2CO3 (138 mg, 1.0 mmol). After being stirred at room temperature for 5 hours, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 10.0 mg of 5-amino-3-[(2R,3R,55)-5-(hydroxymethyl)-3-pyrrolidin-1-yl-tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 32) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OCC(C)C)=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@H:9]1[CH2:10][C@@H:11]([C:13](=[O:15])[N:33]([O:34][CH3:35])[CH3:32])[CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To an ice cold solution of 1.74 g of cis-3-tert-butoxycarbonylmethyl-cyclobutanecarboxylic acid, 3 mL of N-methyl-piperidine, and 50 mL of dichloromethane was added 1.7 mL of isobutyl chloroformate drop-wise over 5 min. After an additional 5 min, 1.6 g of N-methyl-N-methoxy-amine hydrochloride was added and the mixture allowed to warm with stirring overnight. The resulting mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of water, 100 mL of 0.1 N HCl, 50 mL of saturated sodium carbonate and dried over magnesium sulfate. The solution was diluted with 50 mL of toluene and concentrated under reduced pressure. Drying under vacuum overnight gave 2.08 g of product as a colorless thick oil: MS (m+1)=258.3; 1H NMR (400 MHz, CDCl3) 3.62 (s, 3H), 3.16 (s, 3H), 2.35 (d, 2H), 2.0 (dd, 1H), 1.4 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH:34]1[CH:39]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:35]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:33][CH:34]([CH3:39])[CH3:35])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(OC(C)C)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
Compound 16 (650 mg, 1.34 mmol) and Argonaut PS-triphenylphosphine resin (4.02 mmol, 1.86 g) were placed under a dry nitrogen atmosphere in a flame-dried flask, and then dry THF (20 ml) was added. The flask was then cooled to 0° C. in an ice bath. Isopropanol (IPA) (0.20 ml, 2.68 mmol) was added followed by the dropwise addition of diethyl azodicarboxylate (DEAD) (0.366 ml, 2.0 mmol). The flask was removed from the ice bath and allowed to warm to ambient temperature. The reaction mixture was monitored for the disappearance of compound 16 by TLC. Upon consumption of 16, the solid supported material was filtered off. The crude reaction mixture was purified by flash chromatography using a 15 to 60% gradient of ethyl acetate in chloroform. Removal of the solvent afforded 460 mg (64.9%) of 27 as a white foam: MS (+)-ES [M+H]+ m/z 527. Rf=0.7 (75% Ethyl acetate -CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(OCC)(=O)C>CS(C)=O>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([Br:10])[CH:8]=1)[NH:1][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4]2
Reactant: Nc1c(Br)cc(Br)cc1C=O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Br)cc(Br)c2NC1C(F)(F)F
Temperature: 25 °C
Yield: 42.9 %

Procedure:
The 2-amino-3,5-dibromobenzaldehyde (6.50 g, 23.3 mmol), triethylamine (6.96 g, 69.9 mmol) and ethyl 4,4,4-trifluorocrotonate (7.85 g, 46.6 mmol) were mixed in dimethylsulfoxide (12.0 mL) at 90° C. for 48 h. The solution was cooled to room temperature and the solution poured into ethyl acetate (100 mL). The solution was extracted with saturated aqueous ammonium chloride (2×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The ethyl 6,8-dibromo-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (4.3 g, 10.0 mmol) was isolated as a yellow solid by flash silica chromatography (43% yield): MS m/z 428 (M−H, calcd 428).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13]C=O)[CH3:12].C(O)C.[OH-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH2:13])[CH3:12]
Reactant: CC(NC=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(N)c1ccc2ccccc2c1
Yield: 98.7 %

Procedure:
A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10 mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. The solution is cooled, poured into water and extracted with ether. The ether solution is dried with anhydrous potassium carbonate, filtered and concentrated to give the product (0.95 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH:13]=1)=O.Br[C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=1[S:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:29]([S:28][C:18]1[CH:19]=[C:20]([S:23][C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([S:3][C:2]([F:15])([F:14])[F:1])=[CH:13][C:9]=2[N:10]=1)[CH3:30]
Reactant: O=S(c1ccc2ocnc2c1)C(F)(F)F
Reactant: CCSc1cc(SC(F)(F)F)ccc1Br
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCSc1cc(SC(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)ccc2o1
Yield: 15.5 %

Procedure:
A mixture of 0.10 g of 5-trifluoromethylsulfinylbenzoxazole, 0.15 g of 1-bromo-2-ethylsulfanyl-4-trifluoromethylsulfanylbenzene, 0.01 g of palladium(II) acetate, 0.01 g of triphenylphosphine, 0.02 g of copper(II) acetate monohydrate, 0.13 g of potassium carbonate and 3 ml of toluene was stirred under heating and refluxing for 2 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate and then dried with anhydrous sodium sulfate. The residue obtained by concentrating the mixture under reduced pressure was applied to a silica gel column chromatography to obtain 0.03 g of 2-(2-ethylsulfanyl-4-trifluoromethylsulfanyl-phenyl)-5-trifluoromethylsulfanylbenzoxazole (hereinafter, referred to as Compound 19).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cccnc2n(C)c1=O

Procedure:
A stirred mixture of 5.2 g. (0.02 mole) of 4-chloro-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 2.0 g. (0.02 mole) of N-methylpiperazine and 2.12 g. (0.02 mole) of sodium carbonate was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 50 ml. of a 20% aqueous sodium carbonate solution and was extracted with 50 ml. of ether. The ether layer was dried over magnesium sulfate, filtered, diluted with a few ml. of ethanol and was acidified with a saturated ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethanol to afford 0.3 g. of product as the hydrochloride, hemihydrate, m.p. 231°-234° C. dec.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.Cl.[CH3:25][O:26][C:27]([C:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:25][O:26][C:27]([C:29]1([NH:35][C:19]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][Cl:13])=[CH:23][CH:22]=2)=[O:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
Under ice-cooling, 9.96 g (52 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 8.8 g (52 mmol) of 4-(chloromethyl)benzoic acid, 10 g (52 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 15 g (152 mmol) of triethylamine and 8.63 g (56 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 8.5 g (53%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12](/[CH:13]=[CH:14]/[O:15][CH3:16])=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][O:15][CH3:16])=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1/C=C/OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1CCOC
Yield: 99.4 %

Procedure:
According to Scheme 17 Step 3: To a mixture of (E)-ethyl 1-(4-methoxybenzyl)-5-(2-methoxyvinyl)-1H-pyrazole-4-carboxylate (1.58 mmol, 500 mg) in MeOH (7.9 mL) was hydrogenated in a H-Cube® with Pd/C under a 20 bar H2 atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to afford ethyl 1-(4-methoxybenzyl)-5-(2-methoxyethyl)-1H-pyrazole-4-carboxylate (1.57 mmol, 500 mg, 99%).
Reaction SMILES: NC1C=CC=CC=1.Cl[C:9]1[N:10]=[C:11](Cl)[C:12]2[N:17]=[C:16](Cl)[N:15]=[C:14](Cl)[C:13]=2[N:20]=1>C(Cl)(Cl)Cl>[N:17]1[C:12]2[CH:11]=[N:10][CH:9]=[N:20][C:13]=2[CH:14]=[N:15][CH:16]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Solvent: ClC(Cl)Cl
Solvent: Nc1ccccc1
Product: c1ncc2ncncc2n1
Yield: 199.2 %

Procedure:
8.7 mL (95 mmol) of aniline may be slowly added dropwise to a solution of 4 g (19 mmol) of 2,4,6,8-tetrachloropyrimidopyrimidine in 50 mL of chloroform in a water bath at about 0° C. The results of the reaction may be verified by thin layer chromatography (TLC). The reaction mixture may be washed with an aqueous ammonium chloride solution and extracted with chloroform. The organic layer may be separated, distilled under reduced pressure to remove the solvent, and dried in an oven to yield approximately 5 g of Compound 5a. Compound 5a may be a substantially pale yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCCN2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCN(CCOCC2CCNCC2)C1
Yield: 72.9 %

Procedure:
Tert-butyl 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine-1-carboxylate (5.28 g, 0.017 moles) was stirred at room temperature in TFA/DCM (1:1, 40 mL) for 1 hour. The solvent was removed at reduced pressure. The resulting residue was purified using an SCX column to afford 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (2.63 g). LCMS [M+H]+=213.2