Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[N:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14](Cl)(=[N:21][OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:15]1([C:14]2[N:12]([NH2:13])[C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:22][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: NN=C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: NN1C(c2ccccc2)=NOC12CCCC2
Temperature: 25 °C
Yield: 50341.3 %

Procedure:
A round bottom flask was charged with a solution of 20 g of K2CO3 in 50 mL of water and cooled in an ice bath. Cyclopentylidene-hydrazine (7.9 g, 80 mmol) in 25 mL of CH2Cl2 was added, followed by a drop-wise addition of benzohydroximoyl chloride (5 g, 0.032 mmol) in 25 mL of CH2Cl2 over a period of 15 minutes. The mixture was stirred for several days, and allowed to warm to room temperature. Water (50 mL) and CH2Cl2 (50 mL) were added and the phases were separated. The organic layer was washed twice with 50 mL of water, dried over MgSO4, and filtered. The solvent was removed in vacuo, leaving 9 g of a waxy solid. Crystallization from ethyl acetate/hexane provided 3.5 g (50%) of 3-phenyl-1-oxa-2,4-diaza-spiro[4.4]non-2-en-4-ylamine after drying. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.72 ((m, 2H), 7.46 (m, 3H), 3.54 (s, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.85 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]3[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=3[C:17]=2[CH2:29][CH2:30][CH3:31])=[C:9]([CH2:34][CH2:35][CH3:36])[C:8]=1[O:37][CH3:38])=O.O.[NH2:41]N.Cl.C(OCC)(=O)C>CO>[CH3:38][O:37][C:8]1[C:9]([CH2:34][CH2:35][CH3:36])=[C:10]([CH:32]=[CH:33][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:41]=1)[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:19]2[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=2[C:17]=1[CH2:29][CH2:30][CH3:31]
Reactant: NN
Reactant: CCCc1c(OCCCOc2ccc(C(=O)/C=C\N(C)C)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(-c3cc[nH]n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2

Procedure:
The crude compound from Example 5 was stirred in 4.0 ml of methanol/1.0 ml water with 0.1 ml hydrazine hydrate at reflux for 2.0 hours. The reaction mixture was poured into 1N hydrochloric acid/ethyl acetate, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. Flash chromatography of the concentrate on silica gel using 5:1 to 2:1 hexane/ethyl acetate (1% acetic acid) as eluant gave the product, melting point 156°-158° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]C(O)=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].N1CCCCC1>O>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.00 g (28 mmol) of 4-diethylaminobenzaldehyde, 5.62 g (31 mmol) of 4-nitrophenylacetic acid, 2.40 g (28 mmol) of piperidine, and 100 mL of xylenes was heated with stirring at reflux for 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, and the residue was cooled to 3 0° C. Red crystals separated which were collected and then recrystallized from isopropanol/pyridine. Yield: 4.05 g (48%), mp 179-181 (lit2 182°-182.5° C.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([C:16]([NH2:18])=[NH:17])([CH3:15])[CH3:14].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[NH:18][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2ccc(Br)cc2)c[nH]1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.18 (s, 1H) 1.42 (s, 9H). MS (ES+) m/e 279/281 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@@H:14]1[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@@H:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Yield: 88.1 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.07 g, 10.0 mmol) was stirred in refluxing absolute ethanol (40 mL) under nitrogen to achieve partial dissolution. To this stirred mixture was added a solution of freshly prepared (1S,4R)-4-amino-2-cyclopentene-1-methanol (PCT Application 9204015.3, 1.57 g, 12.5 mmol as 90%) in ethanol (15 mL) followed by triethylamine (3.5 mL, 25 mmol, freshly distilled from calcium hydride). After 14 hours of reflux, the resulting dark solution was cooled and 1 N sodium hydroxide (10 mL) was added. The volatiles were evaporated in vacuo. The residual tan solid foam was dissolved in 5% methanol-ethyl acectate, and the solution was washed through a silica gel pad to give the title compound as an off-white solid (2.50 g, 88%), after evaporation of solvents. Recrystallization of the solid from ethyl acetate-methanol (20:1) gave the title compound (Via) as fine white crystals (2.29 g, 81%), m.p. 177-178° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6) δ: 8.99 and 8.58 (s and d, J=11.1 Hz, total 1, amide NH), 8.11 and 7.80 (s and d, J=11.1 Hz, total 1, amide CH), 6.77 and 6.61 (two d, J=8.0 Hz) overlapping 6.60 and 6.48 (two br s, total 3, NH and NH2), 5.85 and 5.70 (two m, 1 each, CH═CH), 5.15-5.00 (m, 1, NCH), 4.71 (t, J=5.1, 1, OH), 3.45-3.30 (m overlapping H2O, OCH2), 2.80-2.65 (m, 1, CH), 2.45-2.25 and 1.45-1.30 (both m, 1 each, CH2); [α]20589+21.2°, [α]20578+22.2°, [α]20546+25.2°, [α]20436+41.4°, [α]20365+48.3° (c 0.50, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]([C:10]3[CH2:16][CH:15]4[N:17](C)[CH:12]([CH2:13][CH2:14]4)[CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.[Cl:21]C(OC(Cl)=O)C.CO>C1(C)C=CC=CC=1>[ClH:21].[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]([C:10]3[CH2:16][CH:15]4[NH:17][CH:12]([CH2:13][CH2:14]4)[CH:11]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C3=CC4CCC(C3)N4C)cc2c1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2sc(C3=CC4CCC(C3)N4)cc2c1
Product: Cl
Reaction time: 1 h

Procedure:
3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene (2.28 g, 7.99 mmol) was solved in toluene (25 ml). 1-Chloroethylchloroformate (2.28 g, 15.97 mmol) was added at room-temperature. The mixture was stirred at room-temperature for 1 hour and was then stirred at reflux for 15 hours. Methanol (20 ml) was added followed by reflux for 2 hours. The mixture was cooled on an ice-bath. The product crystallized and was washed with ethanol and diethylether. The product was recrystallised from ethanol as hydrochloric acid salt, yield 0.37 g (15%). The mother liquor was evaporated, converted to the free base by adding aqueous ammonia and extraction with dichloromethane followed by chromatographic purification using dichloromethane, methanol and aqueous ammonia (9:1+1%). Yield 0.30 g (14%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>>[CH2:13]([NH:15][C:16]([N:7]1[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]1)=[O:17])[CH3:14]
Reactant: CCN=C=O
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Product: CCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O

Procedure:
Using the same conditions as in Example 4, 17 parts of 2,2,7,7 -tetramethyl-1,4-diazacycloheptan-5-one and 8 parts of ethylisocyanate afforded an almost colourless oil which was distilled in vacuo to yield 20 parts of 4-ethylcarbamoyl-2,2,7,7-tetramethyl-1,4diazacycloheptan-5-one of boiling point 103° - 107°C at 1mm pressure. This material gave the following elemental analysis by weight:
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)CCC.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[N:18]=[CH:19][S:20][CH:21]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Temperature: 110 °C
Yield: 45.3 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.15 g, 0.66 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.066 mmol) and then purged with N2 (g) inlet prior to addition of 4-(tributylstannyl)thiazole (0.42 g, 1.13 mmol), dioxane (1.2 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (71 mgs, 45%) Retention time (min)=1.656, method [4], MS (ESI) 238.0 (M+H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>O.ClCCl>[CH3:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:51][CH2:52]1
Reactant: Cc1cccc(-c2ccc(CN3CCNCC3)c(C)c2)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (160 mg, 0.540 mmol, 0.30 equiv), dichloromethane (20 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (302 mg, 1.80 mmol, 1.00 equiv) and N,N-diisopropylethylamine (441 mg, 3.41 mmol, 1.90 equiv) were added. The resulting solution was stirred for 2 h at room temperature. 1-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine (500 mg, 1.78 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (50 mL), extracted with dichloromethane (3×40 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (250 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 141 mg (16% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. 1H NMR 400 MHz (CDCl3) δ 7.30-7.42 (m, 6H), 7.18 (d, J=7.2 Hz, 1H), 5.76-5.82 (m, 1H), 3.55-3.58 (m, 6H), 2.45-2.53 (m, 10H). LCMS (ESI, m/z): 475 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:19]=[CH:18][C:17]2[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=2)[N:11]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:8][C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[C:12]2[C:17]=1[CH:18]=[N:19][C:10]([Cl:9])=[N:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2cnc(Cl)nc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)c2cnc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Solid NBS (1 eq) was added to a stirred solution of 2-chloroquinazolin-8-ol (1 eq) (See example 1 for synthesis) in NMP at 0° C. under argon. After stirring at 0° C. for 30 min, LCMS showed that the reaction was complete. The formation of both 5-bromo (Major) and 7-bromo (Minor) isomers along with 5,7 dibromo product was observed. The reaction mixture was diluted with ethyl acetate and washed with satd. sodium bicarbonate, water and brine. Dried, filtered and concentrated. The crude was purified by flash chromatography (3-5% EtOAc/Hexane) to provide 5-bromo-2-chloroquinazolin-8-ol as a white solid in 60% yield. ES/MS m/z 259.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[C:9]([O:13][CH2:14][CH2:15][CH2:16]N3CCCC3=O)=[N:10][S:11][N:12]=2)[CH2:3]1.CN1CCC=[C:26]([C:30]2C(OCCN3C(=O)CO[CH-]3)=NSN=2)[CH2:25]1.CN1CCC=C(C2C(OCCCN3CCCC3)=N[S:54]N=2)C1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[C:9]([O:13][CH2:14][CH2:15][C:16]3[S:54][CH:25]=[CH:26][CH:30]=3)=[N:10][S:11][N:12]=2)[CH2:3]1
Reactant: CN1CCC=C(c2nsnc2OCCCN2CCCC2)C1
Reactant: CN1CCC=C(c2nsnc2OCCCN2CCCC2=O)C1
Reactant: CN1CCC=C(c2nsnc2OCCN2[CH-]OCC2=O)C1
Product: CN1CCC=C(c2nsnc2OCCc2cccs2)C1

Procedure:
1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4yl)pyrid 1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4yl)pyrid 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4yl)pyridine; 1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-thiadiazol -4-yl)pyridine; 1,2,5,6-Tetrahydro- 1-methyl-3-(3-(2-(2-pyrrolidon- 1-yl)- 1-ethoxy)- 1,2,5thi adiaz o 1-4- y 1 )p yri din e; 1,2,5,6-Tetrahydro- 1-methyl-3-(3-(2-(2-oxazolidon-3-yl)- 1-ethoxy)- 1,2,5thiadiazo 1-4- yl )p yri dine; 1,2,5,6-Tetrahydro- 1-methyl-3-(3-(3-(1-pyrrolidyl)- 1-propoxy)- 1,2,5-thiadiazol- -yl)pyridine; or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH:17]=[CH2:18])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:14][C:28](=[O:30])[CH3:29])([CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of tert-butyl-4-(but-3-en-1-yl)-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, purified by flash chromatography to provide the title compound 16C as colorless oil (3.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NNC(=O)CC2)cc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(C2=NNC(=O)CC2)cc1OCC1CO1
Yield: 77 %

Procedure:
A mixture of powdered 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone (5.0 g, 0.024 mole), epichlorohydrin (19.3 ml, 0.24 mole), and piperidine (0.2 ml) was heated on a steam bath for 1 hour. Evaporation of the solution under reduced pressure gave an oil which was dissolved in a small volume of dichloromethane and stirred with dilute sodium hydroxide solution (15 ml). The organic phase was washed with water, dried, and evaporated to an oil which under reduced pressure gave a solid, 6.2 g, 98%. Trituration with ethanol-ether gave crude 6-[3-(2,3-epoxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone 4.81 g, 76%, m.p. 128°-132°C. Purification, by recrystallisation from ethanol, or by column chromatography (silica, chloroform) gave the pure epoxide, m.p. 140°-142.5°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCN1CCOc2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2 mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydrous sodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to yield the title compounds as liquid mass (2.6 g, 47%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([Si:19]([CH3:21])([CH3:20])[O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 2,2-dimethyl-propane-1,3-diol (5.0 g, 48 mmol) in DCM (20 mL) was added triethylamine (14.6 g, 144.3 mmol) and tert-butyl-chloro-dimethyl-silane (7.2 g, 48.1 mmol). The solution was stirred overnight at room temperature. The reaction mixture was then washed with water (×3) and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (6.1 g, 58%): 1H NMR (CDCl3, 400 MHz) delta 0.04 (s, 6H), 0.86 (s, 6H), 0.87 (s, 9H), 2.94 (s, 1H), 3.43 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[I:16]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:16])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)cc1I
Temperature: 50 °C

Procedure:
To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50° C. for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1N NaOH the title compound (11) was collected by filtration as a brown solid in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:13])=[CH:6][CH:5]=1.[H][H]>CO.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Yield: 100.8 %

Procedure:
A mixture of 4-{(E)-3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propenyl}-benzoic acid methyl ester (287 mg, 731 μmol) in methanol (12.2 mL) at 25° C. was treated with platinum (IV) oxide (8.3 mg, 36.5 μmol). The reaction was stirred under a balloon of hydrogen gas at 25° C. for 18 h. At this time, the reaction was filtered through a pad of Celite® to remove the catalyst. The Celite® was rinsed with a 10% solution of methanol/methylene chloride (2×30 mL). The filtrate was concentrated in vacuo to afford 4-{3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propyl}-benzoic acid methyl ester (291 mg, quant.) as a dark green solid. The material was used without further purification.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:17])[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)([F:9])[F:8])C>CO.O.O>[Br:16][C:12]1[CH:11]=[C:10]([C:7]([F:8])([F:9])[C:6]([OH:17])=[O:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(F)(F)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(F)(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Lithium hydroxide (0.13 g, 3.12 mmol) is added to a solution of (3-bromo-phenyl)-difluoro-acetic acid ethyl ester (0.29 g, 1.04 mmol) in methanol/water (8 mL, 3:1) and the reaction mixture is stirred overnight at room temperature. The mixture is diluted with water and volatiles are removed in vacuo. The aqueous is extracted once with diethyl ether, acidified to pH 2, and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and concentrated in vacuo to afford (3-bromo-phenyl)-difluoro-acetic acid (250 mg), which is used in the next step without further purification. LCMS: RT=2.26 minutes; MS: 249, 251(M−H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:32]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)c1ccccc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@H](C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC)c1ccccc1
Yield: 50.8 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-2-phenylacetamide (Compound IV-26) 63 mg (0.15 mmol) to obtain the title compound 22 mg (25%).