Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc(F)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(F)c1Cl
Reaction time: 8 h

Procedure:
A solution of 2-chloro-3-fluorobenzoic acid (0.098 g) and carbonyldiimidazole (0.091 g), in N,N-dimethylformamide (3.0 ml) was stirred for 2.5 hours at room temperature. 1-Adamantanemethylamine (0.1 ml) was then added and stirring continued overnight. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid and the organic layer was separated, washed with 10% aqueous sodium hydroxide, water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was subsequently concentrated under reduced pressure to yield the tire compound as a white solid (0.138 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][Mg]Cl>O1CCCC1.[Cl-].[Na+].O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])([CH3:36])[CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-{4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (210 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. was added methylmagnesium chloride in tetrahydrofuran (3 M, 0.43 ml, 1.29 mmol) dropwise. After stirring for 2 h at 0° C., the reaction mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (220 mg, 100%): LC/MS m/e calcd for C29H29FN2O3S [M+H]+ 505.63, observed 505.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:16](OC)(OC)OC.[NH2:23][CH2:24][CH:25]=O>C(COC)OC.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[N:11]1[CH:25]=[CH:24][N:23]=[CH:16]1
Reactant: Nc1ccccc1Cc1ccccc1Cl
Reactant: COC(OC)OC
Reactant: NCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COCCOC
Product: Clc1ccccc1Cc1ccccc1-n1ccnc1

Procedure:
In the manner given in Example 1, α-(0-chlorophenyl)-0-toluidine is reacted first with trimethyl orthoformate; the resulting product is reacted with aminoacetaldehyde, dimethyl acetal, and the resulting product of this reaction is heated with titanium tetrachloride in monoglyme to give 1-[α-(0-chlorophenyl)-0-tolyl]imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(OC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)cc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of compound 55 (25.0 g, 89.4 mmol) in THF (100 mL), H2O (100 mL) and MeOH (100 mL) was added aq. 5 N NaOH dropwise at 0° C. The mixture was stirred at room temperature for 1 hour. Conc. HCl was added to the mixture to acidify and the mixture was extracted with EtOAc (500 mL×2). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the crude acid 56 (22.6 g, 96%) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3](I)([F:5])[F:4].C1([Mg]Br)C=CC=CC=1.[Br:20][CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24].C(O)(=O)C>C(OCC)C.O>[Br:20][CH2:21][C:22]([OH:27])([C:3]([F:5])([F:4])[C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(CBr)C(F)(F)F
Agent: Br[Mg]c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: OC(CBr)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Heptafluoropropyl iodide (5 g, 16.9 mmole) was stirred in dry diethyl ether (20 ml) at -78° C. Phenylmagnesium bromide (10 ml of a 1.88M solution in ether) was then added dropwise, keeping the temperature below -65° C. When the addition was complete, the reaction mixture was stirred at -20° C. for one hour. It was then cooled to -78° C. and 3-bromo-1,1,1-trifluoropropanone (4.87 g, 18.0 mmole) in dry diethylether (20 ml) was added dropwise, keeping the temperature below -65° C. When the addition was complete, the mixture was stirred at between -20° and -50° C. for four hours. Glacial acetic acid (3 ml) in diethyl ether (5 ml) was then added slowly, followed by water (15 ml). The mixture was then allowed to warm to 5° C. and the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 2-bromomethyl-decafluoropentan-2-ol (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[ClH:1].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: c1ccc2c(c1)CCNC2
Product: Cl
Product: Fc1cccc2c(N3CCc4ccccc4C3)ccnc12

Procedure:
The title compound, MS: m/e=279.2 (M+H+), was prepared from 4-chloro-8-fluoroquinoline and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and water (125 ml) is stirred at about 80° C. for 24 hours. Excess 2-chloroacrylonitrile is distilled off by raising the external temperature to about 130° C. The mixture is cooled to about 95° C. and the product is crystallized by seeding. After cooling to about 40° C., the suspension is treated with cyclohexane (50 ml) and brought to about 20° C., and stirred for about 2 hours. The product is isolated by filtration, washed with cyclohexane (75 ml) and then with water and dried in vacuo at about 60° C. Yield: 43.13 g=98%.
Reaction SMILES: CO[C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9][C:8]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 70 %

Procedure:
In an analogous procedure to Example 651, part c, 1-methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (456.46, 70% yield) as a beige foam. 1H-NMR (CDCl3) δ 7.92 (m, 2H), 7.27 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.40 (m, 2H), 3.90 (m, 1H), 3.72 (s, 3H), 3.24 (m, 4H), 2.81 (M, 4H), 2.66 (m, 1H), 2.49 (m, 1H), 2.22 (m, 2H), 2.08 (m, 2H), 1.36 (m, 6H). LC/MS (ESI+)=591 (M+H).
Reaction SMILES: C([CH:3](O)[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)C.S([O-])(O)(=O)=O.[Na+].[C:20]1(C=CC(O)=CC=1)O.C(=O)([O-])O.[Na+].[CH3:33][OH:34]>>[CH3:33][O:34][CH2:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH2:8][CH3:20])[CH:5]=1
Reactant: CO
Reactant: CCC(O)c1ccc(O)c(OC)c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CCOc1cc(COC)ccc1O
Temperature: 50 °C
Yield: 56.3 %

Procedure:
100 g of ethylvanillyl alcohol (4-hydroxy-3-ethoxybenzyl alcohol) are dissolved in 200 ml of methanol. The solution is treated with 10 g of sodium hydrogen sulphate and a knife tip of hydroquinone. The mixture is firstly heated to 50° C. for 2 minutes and left to cool again to room temperature. The methanolic solution is now poured into 85 ml of a saturated sodium hydrogen carbonate solution. The methyl alcohol is distilled off in vacuo, the residue is taken up in toluene, the organic solution is washed neutral with water and evaporated. The residue (95.5 g) is fractionally distilled. There are obtained 61.1 g of chemically and olfactorily pure 4-hydroxy-3-ethoxybenzyl methyl ether; b.p.=77° C./0.03 mmHg; d420 =1.1084; nD20 =1.529.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccc(F)cc3)c1)N2
Yield: 42.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) and pyridine (90 mg, 1.14 mmol) in dichloromethane (6 mL) was added 4-fluoro-benzenesulfonyl chloride (120 mg, 0.62 mmol) under nitrogen. The resultant mixture was stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 100 mg of 4-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 42%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][CH2:62][NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:63][CH2:62][CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
351 mg (0.63 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.63 mmol) 2-(Tritylsulfanyl)ethanamine, 0.11 ml (0.63 mmol) N,N-diisopropylethyl-amine and 238 mg (0.63 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 98 mg (0.110 mmol, 16% of theory) of the desired product.
Reaction SMILES: [CH:1]([OH:3])=O.N#N.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:38])[C:24]=1[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[CH2:29][NH:28][N:27]=1.C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:38])[C:24]=1[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[CH2:29][N:28]([CH:1]=[O:3])[N:27]=1
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=CO
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C=O)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of formic acid (0.123 ml, 3.255 mmoles) in dry THF (40 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.53 g, 3.255 mmoles) and the mixture was left to stand for 1 hour. Then 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, was portionwise added. After 6.5 hours another portion of a mixture of formic acid/carbonyldiimidazole (about ⅓ of the previous one) was added and the mixture was stirred at room temperature for 1 hour, then left to stand overnight. The mixture was poured into water/ice, THF was evaporated, and the solution was extracted more times with CH2Cl2. The organic phase was washed with KHSO4, then with NaHCO3 and with water, anhydrified and concentrated. The residue was crystallised from acetonitrile (40 ml) to give 1 g of the title compound (yield: 92.6%). m.p.: 165-167° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:11][CH:12]=[CH:13][C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:10])=[CH:4][C:3]=1[CH2:20][CH:21](O)C.P(Cl)(Cl)(Cl)=O.N1C=CC=C[CH:30]=1>>[CH3:19][C:16]([CH3:17])([CH3:18])[C:15]#[C:14]/[CH:13]=[CH:12]/[CH2:11][N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([CH3:21])=[CH2:30])[CH:4]=1)[CH3:10]
Reactant: CC(O)Cc1cc(CN(C)CC=CC#CC(C)(C)C)ccc1F
Reactant: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cc(CN(C)C/C=C/C#CC(C)(C)C)ccc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
Compound 29 (0.55 g; 1.73 mmol) and phosphorus oxychloride (1.33 g; 8.65 mmol) were dissolved in pyridine (25 ml). The solution was stirred for 3 hours at 110° C., and left to cool to room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.17 g of the target compound (yield: 32.8%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[O:12]=[C:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.[CH2:19]=O>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:19][N:17]1[CH2:16][CH2:15][NH:14][C:13](=[O:12])[CH2:18]1
Reactant: O=C1CNCCN1
Reactant: O=C1COc2cc(O)ccc21
Reactant: C=O
Solvent: CCO
Product: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.750 g, 5.00 mmol) in ethanol (5 mL) was added with 2-oxopiperazine (0.500 g, 5.00 mmol), and 37% aqueous formaldehyde (0.406 g, 5.00 mmol) at room temperature. The mixture was stirred overnight at room temperature, and then added with 37% aqueous formaldehyde (0.406 g, 5.00 mmol) at room temperature, and the mixture was refluxed for 4 hours by heating. The reaction mixture was cooled to room temperature, and then subjected to suction filtration to obtain 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-methyl]piperazin-2-one (0.631 g, 48%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][CH:14]([C:18](O)=[O:19])[CH2:13]1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1>ClCCl.ClCCl.CO>[Cl:2][C:3]1[C:4]([CH2:9][NH:10][C:18]([CH:14]2[CH2:15][C:16](=[O:17])[N:12]([CH3:11])[CH2:13]2)=[O:19])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: CN1CC(C(=O)O)CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CC(C(=O)NCc2nccnc2Cl)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
(3-Chloropyrazin-2-yl)methanamine hydrochloride (content 77%, 1.634 g, 6.99 mmol) and 1-methyl-5-oxopyrrolidine-3-carboxylic acid (1.000 g, 6.99 mmol) were suspended in dichloromethane (20 ml) and the reaction mixture was cooled to 0° C. under an argon atmosphere. N,N-diisopropylethylamine (3.05 ml, 17.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (1.474 g, 7.69 mmol) and 1-hydroxy-7-azabenzotriazole (0.476 g, 3.50 mmol) were added and the reaction mixture was stirred at room temperature overnight. Reaction was worked up by evaporting the solvents and a dark brown oil was obtained. This crude product was submitted to column chromatography (silica gel; dichloromethane/methanol 96/4) to yield impure material that was further purified by column chromatography (silica gel; dichloromethane/methanol 99/1) to give N-((3-chloropyrazin-2-yl)methyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (1.24 g).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:31])[C@@H:22]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:23]>C(OCC)(=O)C.O>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][C@H:22]([C:21]1([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])[CH2:8][O:31]1)[CH3:23]
Reactant: C[S+](C)(C)=O
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 15 °C
Yield: 76.1 %

Procedure:
To dimethyl sulfoxide (5 ml) was added 60% sodium hydride in oil (85 mg), to which was added trimethyl sulfoxonium iodide (0.49 g) with stirring at about 15° C., and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (1.2 ml) of (2S)-2',4'-difluoro-2-(3,4,5,6-tetrahydro- 2H-pyran-2-yloxy)propiophenone (0.50 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture were added water (10 ml) and ethyl acetate (50 ml), and the resultant mixture was shaken. The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) twice, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=10:1) to afford 2-[(1S)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (0.40 g) as a pale yellow oily product.
Reaction SMILES: CC(C)([O-:4])C.[K+].[CH3:7][S:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[CH2:20]([O:19][C:23](=[O:4])/[CH:22]=[CH:15]/[C:14]1[CH:17]=[CH:18][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Potassium tert-butoxide (10.96 g, 98 mmol) in tetrahydrofuran (60 ml) was added portionwise to a solution of triethyl phosphonoacetate (21.91 g, 98 mmol) in tetrahydrofuran (150 ml). The reaction mixture was stirred for 40 min at room temp. A solution of 4-(methylsulfonyl)benzaldehyde (Acros no.: 42490-0025; 10.0 g, 54 mmol) in tetrahydrofuran (60 ml) was added dropwise. The reaction mixture was stirred for 1 h at room temp. It was diluted with ethyl acetate (500 ml) and washed with 1 N hydrochloric acid (300 ml): The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by crystallization from ethyl acetate/heptane to give 4.3 g of (E)-3-(4-(methylsulfonyl)phenyl)acrylic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) and 3-aminophenol (3.28 g, 30.1 mmol) in N,N-dimethylformamide (30 ml) was added potassium carbonate (6.23 g, 45.2 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate (150 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=20/80→70/30) and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (5.09 g, 66%) as a yellow powder.