Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][C@@H:14]([OH:17])[C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18]I>CN(C=O)C>[C:1]([N:8]1[CH2:16][CH2:15][C@@H:14]([O:17][CH3:18])[C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](OC)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of 500 mg (2.05 mmol) of N-BOC-3(R)-hydroxy-(L)-proline, methyl ester and 1.7 g (12.2 mmol) of MeI in 10 mL of DMF was added 473 mg (2.05 mmol) of Ag2O. The mixture was stirred for 18 h and was then filtered through a pad of celite and concentrated. The crude residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL), saturated NaHCO3 (2×10 mL), brine (1×10 mL), dried anhydrous MgSO4, and concentrated to give 500 mg of N-BOC-3(R)-methoxy-(L)-proline, methyl ester as a light yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>CC(C)=O>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]([CH3:11])[O:13][CH3:14])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4,6-Trichloro-1,3,5-triazine (XVIII) (30 g, 163 mmol) was dissolved in acetone (300 mL), and N,O-dimethylhydroxylamine hydrochloride (15.8 g, 163 mmol) and DIPEA (42 g, 326 mmol) were added and the mixture then stirred at 0° C. for 1 h. The solution was concentrated and the residue was treated with EtOAc (750 mL), washed with water (100 mL), and the organic layer was dried with Na2SO4. The volatiles were removed in vacuo and the residue was purified by flash column chromatography (pet ether/ethyl acetate=50/1 to 10/1) to yield the desired product, N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXX), as a white solid (25 g, 73% yield). LCMS (ESI) m/z=210 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][OH:25]>C(O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([CH2:23][CH2:24][OH:25])[N:18]=[N:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: OCCBr
Reactant: COc1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Solvent: CCCO
Product: COc1ccc(COc2ccc(-c3nnnn3CCO)cc2)cc1

Procedure:
To 30 ml of n-propanol are added 10-2 mole of 5-[4-(4-methoxy benzyloxy) phenyl] tetrazole and 10-2 mole of 2-bromo ethanol. The mixture is heated to reflux for 25 hours. The solvent is evaporated and the residue taken up in 100 ml of hot ether. The etherated solution is washed with 0.5N NaOH, then with water. After drying on sodium sulfate, the etherated phase is concentrated. The compound of code number 42 is obtained after recrystallization in methanol. The recrystallization solvent is concentrated and the residue is subjected to chromatography on a silica column (eluent:ethyl acetate/petroleum ether:1/4) whereby the compound of code number 51 is isolated.
Reaction SMILES: O[CH:2]([C:14]([OH:16])=[O:15])[NH:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:17]([SH:20])([CH3:19])[CH3:18].OS(O)(=O)=O>C(O)(=O)C>[CH:17]([S:20][CH:2]([C:14]([OH:16])=[O:15])[NH:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:19])[CH3:18]
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Reactant: CC(C)S
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
α-hydroxy-N-benzyloxycarbonylglycine 22A (5.57 g, 0.027 mol) of Example 1 was stirred with isopropylmercaptan (8.29 g, 0.11 mol) in glacial acetic acid (26.5 mL) at 0° C. Conc H2SO4 (0.27 mL) was added and the mixture stirred for 2 days at room temperature. The mixture was then poured into ice and the organic layer extracted with ethyl acetate. The ethyl acetate solution was washed with water, 5% NaHCO3, dried over MgSO4, solvent removed to give 22B in 94% yield. This was used without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH2:16]>>[C:15]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:14]
Reactant: C=C(C)CC(C)(C)C
Reactant: c1ccc2[nH]nnc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)CC(C)(C)n1nnc2ccccc21
Temperature: 130 °C
Reaction time: 11 h

Procedure:
To benzotriazole (100 g.) melted, heated to 130° C. and stirred there was added aluminum chloride (0.1 g.) and the addition of diisobutylene drop by drop was begun. As the reaction mixture was cooled to 100° C. by refluxing olefin, addition was discontinued until consumption by alkylation allowed the temperature to rise to 120° C. where addition was resumed. This procedure was continued for 11 hrs. during which a total of 90 g. of diisobutylene was added. The reaction mixture was cooled, treated with water, extracted with benzene and filtered to remove solids. The benzene portion was separated, dried and stripped of solvent by rotary evaporation. The product N-tert-octylbenzotriazole was obtained as a tan semi-solid residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[CH2:15]([C:17]1[O:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:16].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]([NH:22][C:20]1[O:21][C:17]([CH2:15][CH3:16])=[N:18][N:19]=1)=[O:14]
Reactant: CCc1nnc(N)o1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(NC(=O)c2ccc(S(C)(=O)=O)cc2Cl)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
415 mg (1.77 mmol) of 2-chloro-4-(methylsulfonyl)benzenecarboxylic acid and 200 mg (1.77 mmol) of 5-ethyl-1,3,4-oxadiazol-2-amine are dissolved at RT in 9 ml of CH2Cl2. Then 1.68 g (2.64 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.246 ml (1.77 mmol) of triethylamine, 43 mg (0.35 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at RT for 48 h and then washed twice with 4 ml each time of water, and purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 41 mg (6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1C(F)(F)F
Yield: 54.9 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (116 mg, 55%). MS (ISP) 423.3 [(M+H)+]; mp 177° C.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]([NH2:25])=[S:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>C(O)C.O1CCOCC1>[S:24]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:25]=[C:23]1[NH:22][C:12]1[CH:13]=[CH:14][C:15]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:10]([O:9][CH3:8])[CH:11]=1
Reactant: O=C1CCCC1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 40 mg (0.33 mmol) 2-chlorocyclopentanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1.5 ml) and dioxane (1.5 ml). The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 41 mg (42%) (5,6-dihydro-4H-cyclopentathiazol-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 327.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.25 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.01 (s, 1H), 3.78 (s, 3H), 2.78 (br t, 2H), 2.67 (br t, 2H), 2.35 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ncc[nH]2)cc1
Product: O=[N+]([O-])c1ccc(-c2nccn2Cc2ccccc2)cc1

Procedure:
Prepared from 4-(imidazol-2-yl)-nitrobenzene and benzyl bromide
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([NH:15][CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1.[OH-].[K+].I[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([N:15]([CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1
Reactant: CCCI
Reactant: CCCNc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)c1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
To a solution containing 0.2 g (0.74 mmol) of 5-(2,4-dimethylphenyl)-3-methyl-2-propylaminopyrimidin-4(3H)-one in 5 ml of tetrahydrofuran under a nitrogen atmosphere was added 0.12 g (2.2 mmol) of potassium hydroxide followed by 0.38 g (2.2 mmol) of 1-iodopropane. The reaction was allowed to stir at room temperature for 12 h, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 30% ethyl acetate/dichloromethane gave 0.15 g (65%) of product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1RS,2SR)-2-[(benzylamino)methyl]-1-(3-chloro-4-fluorophenyl)propane-1,3-diol (the above-mentioned crude product) in THF (170 ml) were added tert-butylchlorodimethylsilane (5.38 g), triethylamine (7.1 ml) and 4-(dimethylamino)pyridine (415 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (14.1 g).
Reaction SMILES: [F:1][C:2]([C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13](O)[N:8]2[N:7]=1)([F:5])[CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:19][C:13]1[N:8]2[N:7]=[C:6]([C:2]([F:5])([F:1])[CH2:3][CH3:4])[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(F)(F)c1nc2nc(C)cc(O)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(F)(F)c1nc2nc(C)cc(Cl)n2n1

Procedure:
A suspension of Intermediate 6 (0.660 g, 2.89 mmol) in phosphorus oxychloride (ALDRICH, 0.404 mL, 43.4 mmol) was heated under reflux for 2 h, the starting material dissolving during the process. The mixture was slowly added to a mixture of water and ice. The resulting solution was neutralized with solid Na2CO3 and extracted with DCM (25 mL). The aqueous layer was further extracted with DCM (2×5 mL) and the combined organic layers were washed with water (20 mL); then with brine (20 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 40:60%) to afford Intermediate 7 as a pale yellow solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].N1CC[C@H]([OH:29])C1.Cl>CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][C@H:21]([OH:29])[CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CC[C@H](O)C3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using (S)-pyrrolidin-3-ol instead of pyrrolidine for Step 1 and a hydrogen chloride solution in methanol (1.25 M) for Step 2. MS (ES+) (M+H) 306.1; LCMS retention time: 0.26 minutes (Method M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][CH2:17][OH:18])[CH2:11]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH:12]([CH2:16][CH2:17][OH:18])[CH2:11]2)[N:3]=1
Reactant: OCCC1CNCCO1
Reactant: O=Cc1nccc(Cl)n1
Product: OCCC1CN(Cc2nccc(Cl)n2)CCO1

Procedure:
The title compound was prepared as described in Example 106, Step 1 with 4-chloropyrimidine-2-carbaldehyde (110 mg, 0.84 mmol) and 2-morpholin-2-ylethanol (100 mg, 0.70 mmol) as starting materials.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][OH:12].[NH:13]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14]2)=[C:3]([CH2:11][OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2CO)C1

Procedure:
(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 307.40 (C16H25N3O3); MS (ESI): 308 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.CCN(C(C)C)C(C)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>C(Cl)Cl>[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-(piperidin-3-yl)ethanone (53, 2.6 g, 20 mmol) in DCM (100 ml) at room temperature was added DIEA (5.2 ml, 30 mmol). A solution of Cbz-Cl (4.4 ml, 30 mmol) in DCM (20 ml) was added dropwise over 2 hrs. The mixture was stirred at room temperature for 17 hrs, washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give the benzyl 3-acetylpiperidine-1-carboxylate (54) which was used in the next step without further purification. LC-MS for C15H19NO3 calcd: 261; found: 262.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:28])[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].O>C(N(CC)CC)C.[Cu]I>[Cl:28][C:4]1[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=[C:2]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:3]=1
Reactant: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C#CC(C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of 0.15 g of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(isopropoxyimino)ethyl]-2-(trifluoromethyl)benzamide and 0.05 g of 3,3-dimethyl-1-butyne in 3 ml of triethylamine, 0.04 g of copper(I) iodide and 0.02 g of dichlorobistriphenylphosphine palladium(II) were added, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 10 ml of water and extracted with ethyl acetate (20 ml×1). The resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:5 to 2:4) as the eluent to obtain 0.15 g of the desired product as a yellow resinous substance.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:31])=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl.C(N(CC)CC)C>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[C:20]([CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc(=O)[nH]c2)c1C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (40 mg, 0.09 mmol) in dioxane (1 mL) was added 4M HCl and the reaction was stirred at 90° C. for 3 hours. To the mixture at room temperature, 0.5 mL of triethyl amine was added and the reaction was concentrated under reduced pressure. The crude residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (50-100%). ESI-MS m/z calc. 439.4. found 440.3 (M+1)+. Retention times: 1.53 minutes. H NMR (400 MHz, DMSO) 8.79 (s, 1H), 7.76 (s, 1H), 7.56-7.53 (m, 2H), 7.44-7.32 (m, 3H), 6.35 (d, J=9.4 Hz, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 1.50-1.48 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([O:10][C:11]([CH2:13][S+](C)C)=[O:12])[CH3:9]>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:3][C@H:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:12])[CH3:9]
Reactant: CCOC(=O)C[S+](C)C
Reactant: C=CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: 22 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Ethyl acrylate (99%, 270 g, 1.4 eq.) was added to a solution of 2 (282 g, 1.91 mol) in CHCl3 (1500 mL) at 5° C. Cooling was removed and the reaction was stirred at 22° C. for 12 h. Evaporation of the solvent and excess acrylate left an orange oil, which was vacuum distilled (bp 70-75° C./1 mm) to produce 3 (286 g, 80.6%) as a clear thick oil. 1H NMR (250 MHz, CDCl3) δ4.15 (q, J=7.1, 4H); 2.16 (dd, J=7.5, 5.7, 2H); 1.41 (dd, J=7.5, 5.7, 2H); 0.88 (t, J=7.1, 6H). 13C NMR (62.5 MHz, CDCl3) δ 171.69; 60.96; 22.26; 15.18; 14.08.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1.O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[CH3:20][N:7]([CH3:6])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:26]=[O:27]
Reactant: CN(C)CCCc1c[nH]c2c1CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Yield: 50 %

Procedure:
Phosphorus oxychloride (9.2 g, 0.06 mol) was slowly added to 12 ml of dimethylformamid at 0° C. with stirring and the mixture stirred for 30 minutes. Dimethyl-[3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-amine ( 6.2 g, 0.03 mol) was dissolved in 10 ml of dimethylformamide and added to the mixture. The reaction was stirred for 2 hours at room temperature. The stirred mixture was cooled in an ice bath and water was slowly added followed by 10 N sodium hydroxide solution until pH was 10. The mixture was stirred at room temperature for 45 minutes and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (3.5 g, 50% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1CN
Solvent: c1ccncc1
Product: CC(=O)NCc1sccc1C

Procedure:
2-Aminomethyl-3-methylthiophene (H. D. Hartough, et al., J. Am. Chem. Soc., 70, 4018 [1948]) is dissolved in pyridine and treated with excess acetic anhydride overnight. The solvent is removed under reduced pressure, the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid and sodium bicarbonate solution. The organic extract is dried over magnesium sulfate and evaporated to yield the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]=1.Br.C(N(CC)CC)C>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (420 mg, 1.5 mmol) and 2-amino-5-iodopyridine (330 mg, 1.5 mmol) in ethanol (6.7 mL) containing hydrobromic acid (48%, 84 μL, 0.75 mmol) and triethylamine (105 μL, 0.75 mmol) was heated under reflux under argon overnight. After cooling to room temperature, the mixture was evaporated and poured onto hydrochloric acid (0.5 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (170 mg, 28%) which was obtained as a light yellow solid. MS: m/e=402.1 [M+H]+.