Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]CC2C=CC(Cl)=CC=2F)=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C[S-].[Na+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Cc2cc(Cl)ccc2O)n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 75.6 %

Procedure:
A mixture of ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}-phenyl)methyl]-2-pyridinecarboxylate (453 mg), sodium thiomethoxide (370 mg) and dimethylformamide (5 ml) was stirred at 100° C. for 2.5 hours. After cooling water (30 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The aqueous layer was acidified with conc. hydrochloric acid and extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was washed with water and recrystallised from ether to afford the title compound (208 mg, 76%) as a pale buff solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22](O)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][CH2:26][CH2:27][OH:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:25][CH2:26][CH2:27][OH:28])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1csc(C(=O)NCCO)c1)nn2C1CCCC1

Procedure:
A solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (90.0 mg) obtained in Step A of Example 155, 2-aminoethanol (0.024 mL), EDCI hydrochloride (75.0 mg) and HOBt (53.1 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (67.3 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:11]([C:9]3[S:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=4[CH:8]=3)=[O:13])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: N#Cc1ccc2sc(C(=O)O)cc2c1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: N#Cc1ccc2sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2c1

Procedure:
In a similar manner to Referential Example 12 except for the use of 5-cyanobenzothiophen-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: C(O[C:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(OCC)C.CCCCCC>O1CCCC1.[Cu](Cl)Cl>[C:11]([C:5]1([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[CH:12]
Reactant: C1CCNCC1
Reactant: C#CC1(OC(C)=O)CCCCC1
Agent: Cl[Cu]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C#CC1(N2CCCCC2)CCCCC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
7.0 g of 1-acetoxy-1-ethynylcyclohexane (Production Example 17) was dissolved in 140 ml of tetrahydrofuran, and after 20.8 ml of piperidine was added dropwise thereto at room temperature, 208 mg of copper chloride (I) was added to the resulting yellow transparent solution. The resulting mixture was stirred in an oil bath at 95° C. for 2 hours. The reaction mixture was left to stand to cool to room temperature, 200 ml of diethyl ether was added thereto and extracted with 100 ml of an aqueous 2 N hydrochloric solution twice. After addition of about 200 ml of ice to the resultant acidic solution, sodium hydroxide was added to the solution until the solution became basic (pH=10). The solution was extracted with 100 ml of dichloromethane twice. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, to give a brown solid. To the solid was added hexane and washed, and the solid was collected by filtration, to give 700 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[C:14](N)(=[S:16])[CH3:15].O>S1(CCCC1)(=O)=O>[CH3:15][C:14]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: CC(N)=S
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Cc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 10.13 g of 2,4-dinitrochlorobenzene and 15 g of thioacetamide in 50 ml of sulpholane was heated to 100° C. and stirred at this temperature for 1 hour. After cooling, the mixture was clarified. 200 ml of water were added to the filtrate. The solid was filtered off with suction, washed with water and dried.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.Cl.CCOC(C)=O>C(O)(=O)C.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:3](=[O:16])[CH2:4][C:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)CC(=O)CCc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC(CCc2ccc(F)cc2)=NN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(4-fluoro-phenyl)-3-oxo-pentanoic acid methyl ester (0.43 g) in acetic acid (5 mL) in a sealable tube was added 4-fluorophenylhydrazine.HCl (0.31 g). The reaction vessel was sealed and immersed into an oil bath at 100° C. for 18 hours. The reaction vessel was cooled to ambient temperature, opened and the contents were poured onto a mixture of EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and dried over sodium sulfate. Filtration and evaporation of the volatiles in vacuo afforded a crude crystalline material. The crude product was washed with ether to afford the desired 2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-2,4-dihydro-pyrazol-3-one (0.37 g) as a beige crystalline solid. MS (ESI+): 301.1 [M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[CH2:53](Br)[C:54]#[CH:55]>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH2:55][C:54]#[CH:53])[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: C#CCBr
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCC(C2(CNC(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 40 %

Procedure:
Following the procedure analogous to that used in reaction (10), the compound from Example 29 was reacted with propargyl bromide to provide the title compound (8.5 mg, 40%). MS found: (M+H)+=554.4.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN.[C:17]([BH3-])#[N:18].[Na+]>CO.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 45.9 %

Procedure:
To a solution of 1-BOC-4-piperidone (3.5 g, 17.5 mmol) in methanol (10 mL) was added a solution of 2M methylamine in methanol (13 mL, 26 mmol). The reaction mixture was stirred for 16 hours and then sodium cyanoborohydride (1.1 g, 17.5 mmol) was added. After stirring for 2 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography using 10% methanol in dichloromethane as the eluent to yield 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 46%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH-:12].[Na+]>>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: [Na+]
Product: Oc1cccc(C(F)(F)F)n1
Temperature: 150 °C
Yield: 79.7 %

Procedure:
2-Chloro-6-trifluoromethylpyridine (8.05 g at 98% strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100 psi. The pressure was released and the reactor heated to 150° C. Sodium hydroxide solution (9.823% strength; 40.1 g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150° C. for a further 4 hours. The mixture was cooled, unreacted 2-chloro-6-trifluoromethylpyridine extracted with methylene chloride, and the aqueous phase acidified with hydrochloric acid and filtered to afford 2-hydroxy-6-trifluoromethylpyridine (5.615 g; 93% strength; 73% isolated yield). Further product was obtained by extraction of the filtrates with methylene chloride.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: NCCCCCO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCCCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 77.5 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.38 g of 5-(4-nitro-3-methylphenylamino)pentan-1-ol (17) were obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[CH2:32]([CH:39]1[CH2:43][N:42]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[C:41](=[O:50])[NH:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O:51]1CCC[CH2:52]1>>[CH2:32]([CH:39]1[CH2:43][N:42]([CH:44]2[CH2:49][CH2:48][N:47]([C:52]([NH:1][C@@H:2]3[N:8]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=4[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]3=[O:24])=[O:51])[CH2:46][CH2:45]2)[C:41](=[O:50])[NH:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C1CCOC1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1NC(Cc2ccccc2)CN1C1CCNCC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2CC(Cc3ccccc3)NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (23 mg, 0.069 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (0.009 μL, 0.069 mmol) were added to a solution of p-nitrophenylchloroformate (14 mg, 0.069 mmol) in tetrahydrofuran (15 mL) at 0 oC. After 1 h, 4-benzyl-1-piperidin-4-ylimidazolidin-2-one (18 mg, 0.069 mmol) and additional triethylamine (0.027 mL, 0.207 mmol) were added and the reaction warmed to ambient temperature. After 16 h, the reaction was concentrated and partitioned between ethyl acetate and 1 N sodium hydroxide solution. The organics were washed with water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane=9% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (30 mg). MS 619.6 (M+1)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]([NH2:29])=O)=[CH:14]3)=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27](=[S:39])[NH2:29])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 99.4 %

Procedure:
To a solution of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.45 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.6 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.5 g, yield 99%) as a yellow amorphous solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C@H:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[C@H:31]1([NH:41][C:6]([C:3]2[CH2:2][O:1][CH2:5][CH:4]=2)=[O:8])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: O=C(O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCc2ccccc21)C1=CCOC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0° C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS (M+H, 242).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)c(Cl)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 17.5 %

Procedure:
To a solution of 1-(3-chloro-4-fluorophenyl)-2-phenylethanone (Intermediate 17) (65 mg, 0.26 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (51.6 mg, 0.26 mmol), and urea (47.6 mg, 0.78 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 44 (22 mg, yield 17.4%). 1H NMR (DMSO-d6 300 MHz): δ 10.28 (s, 1H), 8.83 (s, 1H), 7.57 (s, 1H), 7.43 (m, 2H), 7.28 (t, J=9.0 Hz, 1H), 7.17-7.04 (m, 5H), 6.87 (d, J=6.3 Hz, 2H), 5.25 (d, J=2.4 Hz, 1H), 4.04 (m, 2H), 1.32 (t, J=6.9 Hz, 3H); MS (ESI): m/z 483.9[M+1]+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][S:20]([Cl:23])(=[O:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C=C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 29 %

Procedure:
1,1-Diphenylethene (11.3 mmol, 2 ml) was added to a solution of DMF (22.7 mmol, 1.75 ml) and sulfuryl chloride (19.3 mmol, 1.55 ml) at 0° C. The reaction was heated to 90° C. for 4 hr, then cooled to ambient temperature and poured into ice (500 ml). The aqueous layer was extracted with EtOAc (2×100 ml). Then the organic was dried (MgSO4) filtered and concentrated. Flash chromatography (5% EtOAc/hexane) provided 0.92 g (29% yield) of light yellow crystals.
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[OH:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:29]=[CH:30]C(O)=O.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:30]=[CH:29]/[C:28]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:26]([OH:25])[CH:27]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: COc1ccc(C=CC(=O)O)cc1O
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 3-Hydroxy-4-methoxycinnamic acid (predominantly trans) (0.070 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18f (0.01 g, 8%) as a yellow solid: mp 215–218° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 9.13 (s, 1 H), 8.73 (dd, J=4.1, 1.4, 1 H), 8.36 (dd, J=8.5, 1.4, 1 H), 8.17 (bs, 1 H), 7.57 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.25 (d, J=2.0, 1 H), 7.20 (dd, J=8.4, 2.0, 1 H), 6.99 (d, J=8.1, 1 H), 6.96 (d, J=15.0, 1 H), 4.54 (dd, J=10.5, 9.4, 1 H), 4.44 (dd, J=11.1, 2.6, 1 H), 4.00 (dd, J=11.2, 3.3, 1 H),3.88 (dd, J=11.1, 7.5, 1 H), 3.83 (s, 3H). C22H1935ClN2O4 requires M+H 411.1112. Found (FAB) 411.1127.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH:21]([C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)([CH3:23])[CH3:22]
Reactant: C#CCCc1nc2cccc(C(C)C)c2o1
Reactant: Brc1ccccn1
Product: CC(C)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 μmol, 6%) of 7-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:22](=[O:24])=[O:23].O>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[C:22]([OH:24])=[O:23])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1C(=O)O
Yield: 76.1 %

Procedure:
400 ml (600 mmol) of tert.butyllithium (1.5M in pentane) were added dropwise within 1 hour to a solution, cooled to -70°, of 57.2 g (250 mmol) of N-(tert.butoxycarbonyl)-3,4-difluoroaniline in 500 ml of tetrahydrofuran. Subsequently, 160 g of dry ice were added in small portions to the yellow suspension, the mixture was left to warm to 0° and 400 ml of water were added dropwise. The tetrahydrofuran and the pentane were distilled off and the aqueous phase was washed twice with ether and subsequently adjusted to pH=1 with conc. hydrochloric acid. The acidic aqueous phase was extracted three times with methylene chloride; the organic phase was dried over sodium sulfate, filtered and evaporated. The beige solid obtained was recrystallized from ethylene chloride and there were obtained 52 g (76%) of 2-(tert.-butoxycarbonyl)amino-5,6-difluorobenzoic acid as colourless needles of m.p. 159.5°-160.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][C:24]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)(=[O:31])=[O:30])([CH2:26][OH:27])[CH3:25]>>[OH:22][CH2:23][C:24]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)[CH:37]=1)(=[O:31])=[O:30])([CH2:26][OH:27])[CH3:25]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (81 mg, 0.25 mmol) (example B.4) according to general procedure II. Obtained as a yellow solid (68 mg, 50%). MS (ISP) 538.0 [(M+H)+]; mp 204–206° C.