Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:18]([CH3:19])=[C:17]([C:20]#[N:21])[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]=1[F:22])=O.[C:23]([NH2:26])(=[S:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:20]([C:17]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([F:22])=[C:5]([C:3]2[N:26]=[C:23]([CH3:24])[S:25][CH:2]=2)[C:18]=1[CH3:19])#[N:21]
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CC(N)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C(=O)N(C)C)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 65.1 %

Procedure:
Under nitrogen atmosphere, a toluene (100 ml) suspension of 6-bromoacetyl-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-128) (3.80 g, 10.3 mmol), thioacetamide (931 mg, 12.4 mmol) and cesium carbonate (4.36 g, 13.4 mmol) was stirred at 100° C. for 45 minutes. After cooling, the reaction liquid was filtered through Celite, the obtained filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica, gel column chromatography, and the eluate with n-hexane/ethyl acetate (1:1, v/v) gave the entitled compound (2.31 g, 65%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13](/[C:12](=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)/[C:11]([O:17][CH2:18][CH3:19])=[O:16])(=[O:14])[CH3:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzaldehyde (2 g, 15.3 mmol), ethyl acetoacetate (1.98 g, 15.3 mmol), piperidine (65 mg, 0.76 mmol), and p-toluenesulfonic acid (131 mg, 0.76 mmol) in toluene (100 ml) is stirred under an argon atmosphere at reflux for 72 hours in a flask equipped with a Dean-Stark trap. The crude reaction mixture is concentrated in vacuo to afford an oil which is chromatographed over silica gel with cyclohexane/ethyl acetate 20:1 as eluent.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C=Cl.[O-2].[O-2].[Mn+4]>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:14]=12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCc1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.7 %

Procedure:
[7-(Dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (3.0 g, 8.74 mmol) was dissolved in methylene chlorine (175 mL). Manganese dioxide (8.0 g, 92 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The slurry was filtered through diatomaceous earth to remove the catalyst, and the filtrate was concentrated to a dark oil. Purification by Biotage chromatography (10-30% ethyl acetate in hexanes) provided 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (1.78 g, 60%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ4.89 (4H, s), 7.06-7.12 (2H, m), 7.27-7.38 (10H, m), 7.93 (1H, d, J=5.7 Hz), 8.74 (1H, br s), 9.77 (1H, s).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:17])[CH:12]([CH:14]([CH3:16])[CH3:15])[NH2:13].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(OCC)(=O)C>C(Cl)Cl>[CH3:18][S:19]([NH:13][CH:12]([CH:14]([CH3:16])[CH3:15])[C:11]([O:10][CH3:9])=[O:17])(=[O:21])=[O:20]
Reactant: COC(=O)C(N)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NS(C)(=O)=O)C(C)C
Reaction time: 8 h

Procedure:
Triethylamine (6.7 ml) is added to a solution of DL-valine methyl ester hydrochloride (3.35 g, Reference compound No. 45-1) in methylene chloride (70 ml). The mixture is cooled with ice, methanesulfonyl chloride (1.9 ml) is added to the mixture, and the whole is stirred overnight. Ethyl acetate is added to the reaction mixture, the whole is washed with 0.1 N hydrochloric acid and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (4.00 g).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:13]([CH:14]2[CH2:16][C:15]2([Br:18])[Br:17])=[CH:12][N:11]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:10]=1>O1CCCC1>[Br:18][C:15]1([Br:17])[CH2:16][CH:14]1[C:13]1[CH:9]=[N:10][N:11]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:28])([F:29])[F:27])=[CH:21][C:20]=2[Cl:30])[CH:12]=1
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyl nitrite (0.12 ml) was added dropwise to a stirred, ice-cooled solution of the title compound of Example 8 (0.25 g) in tetrahydrofuran (5 ml). The reaction mixture was then allowed to warm to room temperature, stirred for 1 hour, heated under reflux for 30 minutes, allowed to cool and partitioned between ether and water. The aqueous phase was separated and extracted with ether, then the combined ether solutions washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel, using a mixture of hexane:ethyl acetate (9:1) as eluant, furnished the title compound as a colourless oil. δ (CDCl3): 1.85 (t,1H), 2.20 (dd,1H), 2.80 (dd,1H), 7.45 (s,1H), 7.75 (s,2H), 7.78 (s,1H). MS (thermospray): M/Z [M+H] 476.7; C13H7Br2Cl2F3N2 +H requires 476.84.
Reaction SMILES: [CH2:1]([Sn:5]([C:14]#[CH:15])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[N:16]([CH2:19][CH2:20][CH2:21][OH:22])=[N+:17]=[N-:18]>C1(C)C=CC=CC=1>[CH2:10]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]1[N:18]=[N:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: [N-]=[N+]=NCCCO
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Temperature: 110 °C
Yield: 77 %

Procedure:
A solution of tributylstannylethyne (1.47 g, 4.67 mmol) and 3-azidopropan-1-ol (450 mg, 4.4 mmol) in PhMe (15 mL) was heated at 80° C. under nitrogen for 3 days. Another 0.5 eq. of Tributylstannylethyne was added, and the resulting mixture was heated at 110° C. for 5 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO system: acetone/heptane=0-30%) to give the desired product as a colorless oil, 1.42 g, 77% yield. 1H NMR (CDCl3, 400 MHz): δ=7.48 (s, 1H), 4.57 (d, J=6.6 Hz, 2H), 3.63-3.67 (m, 2H), 2.11-2.17 (m, 2H), 1.95 (br s, 1H), 1.54-1.58 (m, 6H), 1.33-1.37 (m, 6H), 1.10-1.14 (m, 6H), 0.89 (t, J=7.3 Hz, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:18][CH:19]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(CCCC(=O)O)nc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(CCCC(=O)O)nc2)cc1
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of 4-methoxybenzenesulphonyl chloride (2.06 g) and 4-(5-aminopyrid-2-yl)butanoic acid (1.8 g) in pyridine (15 ml) was allowed to stand at room temperature for 18 hours. The solvent was removed and the residue was dissolved in water and treated with dilute hydrochloric acid to give a solution at pH 4.5. The resulting precipitate was collected and recrystallised from ethanol to give the title compound (1.96 g) as prisms. m.p. 129°-130° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH:14]([CH3:16])[O:13][CH:12]([CH3:17])[CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=[O:8].C[C:19]([N:21](C)C)=O>CP(C)[C-]1C=CC=C1.[C-]1(P(C)C)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH3:17][C@H:12]1[O:13][C@@H:14]([CH3:16])[CH2:15][N:10]([C:5]2[CH:4]=[CH:3][C:2]([C:19]#[N:21])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:11]1
Reactant: CC1CN(c2ccc(Br)cc2C=O)CC(C)O1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CP(C)[c-]1cccc1
Product: C[C@@H]1CN(c2ccc(C#N)cc2C=O)C[C@H](C)O1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-2-(2,6-dimethylmorpholin-4-yl)benzaldehyde (0.298 g, 1.00 mmol), 1,1′-bis(dimethylphosphino)ferrocene [dppf] (0.022 g, 0.040 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3] (0.018 g, 0.020 mmol), zinc dust (0.008 g, 0.12 mmol) and zinc cyanide (0.070 g, 0.60 mmol) in dimethylacetamide (2 mL) is heated 120° C. for 4 h. The reaction mixture is cooled and partitioned between dilute ammonium hydroxide and ethyl acetate. The phases are separated. The organic layer is extracted with an additional portion of ethyl acetate. The combined organic layers are dried (NaSO4) and then concentrated. The resulting residue is purified by silica gel chromatography using ethyl acetate-methylene chloride-heptane (0.5:4.0:5.5) as the eluent to afford, 172 mg (70%) of the cyano aldehyde. 1H NMR (400 MHz, CDCl3) δ 10.05, 7.97, 7.64, 7.01, 3.92–3.79, 3.14, 2.70, 1.17.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH:20]([O:23]C1C=CC=C2C=1NC=C2)([CH3:22])[CH3:21]>>[CH:20]([O:23][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)([CH3:22])[CH3:21]
Reactant: CC(C)Oc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC(C)Oc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-isopropoxy-1H-indole.
Reaction SMILES: [CH2:1]([N:3]([CH2:43][CH3:44])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]([CH2:26][C@H:27]([OH:42])[C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH2:34][N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[C:32]=2[CH:41]=1)C(=O)OC(C)(C)C)[CH3:17])=[O:5])[CH3:2].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:43]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH:18][CH2:26][C@H:27]([OH:42])[C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][CH2:34][N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[C:32]=2[CH:41]=1)[CH3:17])=[O:5])[CH3:44]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N(C[C@H](O)c3ccc4c(c3)N(S(C)(=O)=O)CCO4)C(=O)OC(C)(C)C)c[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc4c(c3)N(S(C)(=O)=O)CCO4)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
To a solution of tert-butyl [2-(7-diethylcarbamoyl-1H-indol-3-yl)-(1R)-1-methylethyl]-[(2R)-2-hydroxy-2-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethyl]carbamate (48.4 mg, 0.077 mmol) in methylene chloride (3 mL) is added trifluoroacetic acid (250 μL) under nitrogen atmosphere, and the mixture is stirred at room temperature for 18 hours, and to the mixture is added trifluoroacetic acid (1 mL). The mixture is stirred at room temperature for 3 hours, and thereto are added trifluoroacetic acid (1 mL) and thioanisole (50 μL). The mixture is stirred at room temperature for one hour. The pH value of the reaction solution is adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is distilled off. The residue is dissolved in chloroform:methanol (2:1, 75 mL), and the insoluble materials are removed by filtration. The solvent is removed by distillation, and the crude product is purified by preparative TLC (a saturated ammonia solution in chloroform) and prepartive HPLC (trifluoroacetic acid-acetonitrile-water) to give the desired 3-{(2R)-2-[(2R)-2-hydroxy-2-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamino]propyl}-1H-indole-7-carboxylic acid diethylamide trifluoroacetate (6.6 mg, 0.0103 mmol, yield: 13%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:14][CH3:15])=[CH:8]/[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:14][CH3:15])=[CH:8]/[CH2:9][CH2:10][C:11]([O:13][CH2:21][CH3:22])=[O:12])[S:5][CH:6]=1
Reactant: CCO
Reactant: CC/C(=C\CCC(=O)O)c1cc(Br)cs1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC/C=C(\CC)c1cc(Br)cs1

Procedure:
16.6 g (57 mmol) of (E)-5-(4-bromo-2-thienyl)-4-heptenoic acid are dissolved in 150 mL of absolute ethanol and 1 mL of concentrated sulphuric acid is added. The mixture is refluxed for 2 hours and then cooled. After the usual treatment and chromatography on silica gel, the desired product is obtained in the form of a yellow oil (m=14.1 g; Y=77%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[N:13]=1.P(=O)(O)(O)O.N>>[NH2:18][C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[N:11][C:5]([OH:7])=[CH:4][C:3]=2[CH2:2][Cl:1])[N:13]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC(=O)CC(=O)CCl
Agent: N
Agent: O=P(O)(O)O
Product: Nc1ccc2c(CCl)cc(O)nc2n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
32.9 g (0.2 mol) of ethyl 4-chloroacetoacetate is dripped into a suspension of 21.8 g (0.2 mol) of 2,6-diaminopyridine in 100 ml of 85% strength phosphoric acid. The reaction mixture is stirred for 3 hours at 90° C., cooled and poured into ice water, followed by neutralization with concentrated aqueous ammonia solution. The precipitate is suction filtered, stirred into water again and finally boiled with acetonitrile. 22.8 g (54%) of the title compound is obtained; m.p.: >280° C.
Reaction SMILES: [CH:1]1(C2(CCC3C=CC(C(O)C)=C(F)C=3)OC(=O)C(CC3N=C4N=C(C)C=C(C)N4N=3)=C(O)C2)CCCC1.N1C=CC=CC=1S[C:45](=[O:54])[C:46]1[CH:51]=[CH:50][C:49]([Br:52])=[CH:48][C:47]=1[Cl:53].N1C=CC=CC=1SC(=O)C1C=CC(Br)=CC=1F>>[Br:52][C:49]1[CH:50]=[CH:51][C:46]([C:45](=[O:54])[CH3:1])=[C:47]([Cl:53])[CH:48]=1
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C(C)O)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Agent: O=C(Sc1ccccn1)c1ccc(Br)cc1F
Product: CC(=O)c1ccc(Br)cc1Cl

Procedure:
The title compound was prepared analogously to Step 2 from Example X(X): 6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one where 4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (described in step 1 below) was substituted in place of 4-Bromo-2-fluoro-thiobenzoic acid S-pyridin-2-yl ester. 1H NMR (CDCl3) δ2.64 (s, 3H), 7.46-7.48 (m, 2H), 7.61 (s, 1H). ESIMS (MH+): 234.1
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:2]1([C:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCC(O)C#Cc1ccccc1
Temperature: 85 °C
Yield: 114.6 %

Procedure:
To a degassed solution of iodobenzene (0.110 mL, 0.980 mmol), bis(triphenylphosphine)palladium(II) chloride (41.3 mg, 0.059 mmol), copper(I) iodide (9.34 mg, 0.049 mmol), and diisopropylamine (0.559 mL, 3.92 mmol) in N,N-dimethylformamide (6 mL) was added pent-1-yn-3-ol (124 mg, 1.47 mmol). The reaction mixture was heated to 85° C. for 6 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with a 10% aqueous solution of lithium chloride (10 mL), washed with a 2M aqueous ammonium hydroxide (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/1) afforded 1-Phenylpent-1-yn-3-ol (180 mg). The compound had an HPLC ret. time=2.74 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH:12]=[CH2:13])(=[O:11])=[O:10])=[C:4]([CH3:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([O:8][S:9]([CH:12]=[CH2:13])(=[O:11])=[O:10])=[C:4]([CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: C=CS(=O)(=O)Oc1ccc(Cl)cc1C
Agent: O=S(=O)(O)O
Product: C=CS(=O)(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Compound 105 (33.2 g, 142 mmol) was dissolved in cold concentrated sulphuric acid (70 ml) and 98% nitric acid (9.8 g) was added drop wise while cooling to keep the temperature below 10° C. The mixture was stirred for one hour at about 5° C. The mixture was added to ice water and extracted three times with ethyl acetate. The organic phase was washed twice with brine, dried with sodium sulphate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>>[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(OC(C)=O)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(acetyloxy)benzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 4-(3-hydroxypropyl)benzonitrile (13 g, 0.081 mol; see step (iii) above) and triphenylphosphine (42.3 g, 0.16 mol) in DCM (150 mL) was added, dropwise at 0-5° C., a solution of CBr4 (53.5 g, 0.16 mol) in DCM (100 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the product was purified by column chromatography over silica gel, using petroleum ether in ethyl acetate as eluent, to yield 12.5 g (69%) of the sub-title compound as a yellow liquid.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:26][OH:27])[CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7]1)=[O:5])C.CC(C)([O-])C.[K+].[OH-].[Na+]>C1(C)C=CC=CC=1>[O:27]1[CH2:14][CH:13]([O:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]2)[CH2:26]1
Reactant: CCOC(=O)[C@H]1CC[C@H](OC(CO)COS(=O)(=O)c2ccc(C)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)[C@H]1CC[C@H](OC2COC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis/trans-4-[1-hydroxymethyl-2-(toluene-4-sulfonyloxy)-ethoxy]-cyclohexanecarboxylic acid ethyl ester (3:7) (0.46 g, 1.2 mmol) in toluene (11.5 ml) was added potassium tert-butoxide (0.14 g, 1.3 mmol). The reaction mixture was heated at reflux for 20 h. After cooling to room temperature the mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous hydrogen chloride solution (30 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (12 ml) and 2 M aqueous sodium hydroxide solution (5.7 ml, 12 mmol). After stirring at room temperature for 16 h the mixture was partitioned between tert-butyl methyl ether (30 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The organic layer was extracted with one 50-ml portion of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified by addition of concentrated hydrochloric acid solution and crushed ice (50 g) and extracted with three 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.12 g, 50%) as off-white solid. MS m/e: 199 (M+H+)
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:7]1=[O:29])C.O.[OH-].[Li+].Cl>O.CO>[C:25]([O:24][C:22]([N:17]([CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH2:16][CH2:15][CH2:14][NH:13][C:8]1[C:7](=[O:29])[N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:11]([Cl:12])=[CH:10][N:9]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)Cn1c(Cl)cnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCNc1ncc(Cl)n(CC(=O)O)c1=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-6-chloro-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (0.22 g, 0.50 mmol) and lithium hydroxide monohydrate (27 mg, 0.65 mmol) in water (0.65 ml) and methanol (3 ml) was stirred at room temperature for 1.5 h. hydrochloric acid solution (1N, 0.65 ml) was added and the reaction mixture was stirred at room temperature for 5 min. Concentration from methanol gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-6-chloro-2-oxo-2H-pyrazin-1-yl}-acetic acid; 1H NMR (CD3OD, 400 MHz) δ 6.90 (s, 1H), 4.90 (s, 2H), 3.34 (m, 4H), 3.11 (d, 2H, J=6.8 Hz), 1.88 (m, 2H), 1.45 (s, 9H), 0.99 (m, 1H), 0.49 (m, 2H), 0.22 (m, 2H).