Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([OH:21])=O)[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([NH:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:21])[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1c[nH]c(C(=O)O)c1)C2
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1cc(CCC2CNc3nc(N)nc(O)c3C2)c[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6yl)ethyl]pyrrole-2-carboxylic acid (152 mg, 0.5 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (98 mg, 0.55 mmol), and 4-methylmorpholine (0.066 mL, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. Dimethyl L-glutamate hydrochloride (0.116 g, 0.55 mmol) and 4-methylmorpholine (0.066 mL, 0.6 mmol) were sequentially added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue chromatographed using chloroform:methanol (9:1) to give dimethyl N-{4-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrol-2-ylcarbonyl}-L-glutamate (152 mg, 66%) as a white solid, mp 151-153° C.: 1H N (CDCl3 /1 drop CD3OD) δ 10.20 (br s, 1H), 7.27 (s, 1H, J=7.9 Hz), 6.70 (s, 1H), 6.82 (s, 1H), 5.83 (br s, 2H), 5.38 (br s, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.42 (br d, 1H, J=10.1 Hz), 3.05 (m, 1H), 2.76 (dd, 1H, J=15.0, 4.4 Hz), 2.65 (m, 2H), 2.56 (m, 2H), 2.36 (m, 1H), 2.14 (m, 2H), 1.91 (m, 1H), 1.68 (m, 2H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
Benzyl alcohol (682 mg, 6.3 mmol), 18 crown ether (2.5 g, 9.4 mmol) and KOH (637 mg, 11.3 mmol) were added to a solution of 2-chloro-5-nitro-pyridine (1 g, 6.3 mmol) in toluene (15 mL) and the reaction mixture was maintained at 80° C. for 2 hours, then diluted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using neutral alumina (2% ethyl acetate in hexane) to afford 410 mg (28%) of 2-benzyloxy-5-nitro-pyridine. LCMS: 231.07 (M+1)+, 98.4%
Reaction SMILES: [C:1]([PH:5](=[O:13])[CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([P:5](=[O:13])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCOC(OCC)[PH](=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(Cc1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Tertiary-butyl(diethoxymethyl)phosphine oxide (2.5 g), (0.012 mol) is dissolved in 35 ml of dry tetrahydrofuran and cooled to -78° C. under an argon atmosphere. To this stirred solution is added 9.0 ml of n-butyl lithium (1.6M solution in hexane) and the mixture is stirred at -78° C. for 10 minutes. After this time, a solution of 2.47 g (0.014 mol) of benzyl bromide in 15 ml of dry tetrahydrofuran is added, and the reaction mixture is allowed to warm to room temperature. After stirring for 3 hours at room temperature, 10 ml of saturated ammonium chloride solution is added and the product is extracted into diethyl ether (2×100 ml). The combined organic extracts are dried and evaporated under reduced pressure to give a crude product. This is purified by chromatography on silica, using ethyl acetate as eluent, to give tertiary-butyl(benzyl)(diethoxymethyl) phosphine oxide as a colourless oil.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1.C(O)C>[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:33]1([CH2:38][CH2:39][C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][N:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-cyclopentylpropanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 46%).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:19]([Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH2:20][CH2:21][CH3:22]
Reactant: OC1CCC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC1CCC1
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a solution of 2.3 g of cyclobutanol in 60 mL of dry THF was added 624 mg of 98% sodium hydride. After stirring 2 h, 5.6 g of iodomethyl tributyltin (prepared as described by Seitz et al 1983 Synthetic Comm. 13 129) was added and the reaction mixture was stirred at room temperature for 48 h, and then poured onto water and extracted with hexanes. The extracts were washed with brine, dried and evaporated to a crude product that was purified by flash chromatography (hexanes then 67% ethyl acetate/hexanes eluents) to afford 1.64 g of tributyl (cyclobutyloxymethyl)tin as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH:22]=O)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH2:22][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(C=O)n(C)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CN3CCCC3)n(C)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To solution of methyl 5-ethyl-6-(5-formyl-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (49.4 mg, 0.14 mmol) in dichloroethane (1.5 mL) was added pyrrolidine (20 μL, 0.24 mmol) followed by AcOH (15 μL, 0.25 mmol). After stirring at room temperature for 10 min NaBH(OAc)3 (60 mg, 0.28 mmol) was added. Reaction was stirred at room temperature overnight and then quenched with NaHCO3 solution (aqueous saturated, 5 mL). Product was extracted with DCM (3×7 mL). Organic phase was dried over Na2SO4 and solvent was concentrated. Product was purified by column chromatography (MeOH/DCM, 0-5% gradient). Methyl 5-ethyl-2-methoxy-6-(6-methyl-5-(pyrrolidin-1-ylmethyl)-6H-thieno[2,3-b]pyrrol-2-yl)nicotinate (49.7 mg) was obtained in 86% yield. LC-MS 343.1 [M-71+H]+, RT 1.00 min.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19](F)=[O:20])([F:18])[F:17])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].S(=O)(=O)(O)[OH:23]>>[C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19]([OH:23])=[O:20])([F:17])[F:18])([F:13])[F:12])([F:9])[F:10])([F:6])[F:7])([F:3])([F:2])[F:4]
Reactant: O=S(=O)(O)O
Reactant: O=C(F)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 28-g portion of the CF3CF2CF2CF2OCH2CF2COF obtained was hydrolyzed by gradually pouring the same into dilute sulfuric acid with stirring. The product was washed several times with dilute sulfuric acid and distilled under reduced pressure to give 25.7 g of pure CF3CF2CF2CF2OCH2CF2COOH. The CF3CF2CF2CF2OCH2CF2COOH obtained had a boiling point of 75.5° C. at a pressure of 1.3×103 Pa. A 3.0-g portion of the CF3CF2CF2CF2OCH2CF2COOH obtained was neutralized with an aqueous solution of sodium hydroxide, and the product was dried to give the desired compound. A 0.2% (by mass) aqueous solution of this CF3CF2CF2CF2OCH2CF2COONa had a surface tension of 63.4 mN/m. A 2.0% (by mass) aqueous solution thereof had a surface tension of 37.5 mN/m.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=[O:8])C.Cl[C:17]1C=C(C=C(Cl)N=1)C(O)=O.C(NC)C>>[CH2:13]([C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N:3]([CH2:14][CH3:15])[CH3:1])[N:12]=1)[C:7]([OH:9])=[O:8])[CH3:17]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Agent: CCNC
Product: CCc1cc(C(=O)O)cc(N(C)CC)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid starting from 2,6-dichloro-isonicotinic acid and N-ethyl-N-methylamine; LC-MS: tR=0.56 min, [M+1]+=209.09; 1H NMR (D6-DMSO): δ 1.16 (t, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H), 2.95 (q, J=7.5 Hz, 2H), 3.57 (s, 3H), 3.76 (q, J=6.8 Hz, 2H), 6.98 (s, 1H), 7.23 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:28][O:27][C:25]([CH2:24][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:10]2[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:20][CH2:19][C:11]1=2)=[O:26]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (450 mg, 1.65 mmol) was dissolved in DMF (7 mL) and stirred at room temperature. The vessel was flushed with argon and sodium hydride (67.0 mg, 1.65 mmol) was added. After 30 minutes, methyl bromoacetate (253 mg, 1.65 mmol) in DMF (2 mL) was added and the mixture stirred overnight. The solvent was removed in vacuo and the residue partitioned between brine (20 mL) and ethyl acetate (2×40 mL). Combined organics were dried (sodium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-40% ethyl acetate/isohexane). This gave tert-butyl 5-methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a pale yellow foam (387 mg, 68%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.C(OC(=O)NC1CC(=O)OC1OCCC1C=CC=CC=1)C=C.[C:41]1([CH2:47][CH2:48][CH2:49]O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:16]=[CH2:17]
Reactant: OCCCc1ccccc1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Agent: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCc1ccccc1
Yield: 32 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using 3-phenylpropanol to afford 1.15 grams (32% yield) of the title compound as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 1.82-2.05 (m, 2H), 2.38 (dd, 1H), 2.68 (m, 2H), 2.82 (dd, 1H), 3.55-3.65 (m, 1H), 3.82-3.92 (m, 1H), 4.48-4.72 (m, 3H), 5.12-5.59 (m, 3H), 5.82-6.03 (m, 1H), 7.11-7.45 (m, 5H). Analytical HPLC: 9.08 min. LC-MS (ES+): m/e=320.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>>[OH:68][C@@H:67]([CH3:69])[C:66]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH:17]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[N:15]=5)[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:4]1)=[O:70]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CNC5)c4)cc2OCC3)n(C(C)C)n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CN(C(=O)[C@H](C)O)C5)c4)cc2OCC3)n(C(C)C)n1

Procedure:
8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was coupled with DIPEA, HATU, and L-lactic acid to give 228. MS(ESI+) 503.2. 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=1.7, 1H), 8.37 (d, J=8.4, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.42 (dd, J=8.4, 1.7, 1H), 7.32 (d, J=1.7, 1H), 5.92-5.74 (m, 1H), 5.34-5.25 (m, 1H), 5.21 (t, J=5.5, 1H), 4.84-4.66 (m, 1H), 4.60-4.53 (m, 1H), 4.52 (s, 4H), 4.40-4.31 (m, 1H), 4.26-4.09 (m, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H), 1.22 (d, J=6.7, 3H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[OH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:64]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[CH:3][CH:4]=2)[N:9]([CH3:12])[C:8](=[O:13])[C:7]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2ccc(Br)cc21
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(N3CCCCC3)cc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A solution of tert-butyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (205 mg, 498 mop, Pd2dba3.CHCl3 (52 mg, 50 μmol), X-Phos (48 mg, 100 μmol) and piperidine (123 μl, 1246 μmol) in 1,4-dioxane (5 ml) was treated with sodium tert-butoxide (192 mg, 1994 μmol). The reaction was stirred at 80° C. in a sealed tube. After 15 hours, the solution was cooled to 23° C., adsorped onto silica gel, concentrated in vacuo and purified by silica gel chromatography (eluant: 5% methanol/dichloromethane, followed by 5% methanol/dichloromethane+1% AcOH), affording an yellow solid which was 83% pure. The impure solid was purified by RP HPLC (0-100% MeCN/water+1% TFA, 10 min), affording 83 mg (46%) of the product as an yellow solid.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90]CC)[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[CH3:96])[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:78])([F:79])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:90])([OH:93])[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[CH3:96])[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(C)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(C)c1
Yield: 99.8 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methylbenzyl)phosphonate (Compound 33B, 345 mg, 510 μmol) to afford 330 mg of the title compound (99.8%). 1H NMR (400 MHz, CD3OD) δ 8.71-8.96 (m, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.34 (s, 1H), 7.22-7.28 (m, 2H), 4.32 (t, J=6.8 Hz, 2H), 3.88 (t, J=7.0 Hz, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.06 (d, J=21.9 Hz, 2H), 2.98 (s, 3H), 2.23 (s, 3H), 2.11 (t, J=6.3 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H). MS (ESI): m/z=649.65 [M+H]+. UPLC: tR=1.06 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][NH:2][CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].[C:18](Cl)(Cl)=[O:19].N1C=CC=CC=1>O.COCCOC>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:15][C:18](=[O:19])[N:2]([CH3:1])[CH2:3][N:4]=2)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: CNCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: c1ccncc1
Product: CN1CN=C(c2ccc([N+](=O)[O-])cc2)OC1=O
Reaction time: 2 h

Procedure:
A suspension of 24.6 g (0.1 mole) of N-(methylaminomethyl)-4-nitro-benzamide in 300 ml of water is neutralised at 0°-25°C with 50 ml of 2 normal sodium hydroxide solution (0.1 mole). The neutralised product is filtered off and dried in vacuo. It is then taken up in 150 ml of 1,2-dimethoxyethane and this solution is treated at 0°-25°C over the course of 1 hour with 9.9 g (0.1 mole) of phosgene in 150 ml of 1,2-dimethoxyethane. A solution of 15.8 g (0.2 mole) of pyridine in 150 ml of 1,2-dimethoxyethane is then added over the course of a further hour. Stirring of the reaction mixture is continued for 2 hours and then it is refluxed for 5 hours. After the reaction mixture has cooled, the precipitate which has formed is collected by filtration, the residue is dissolved in methylene chloride and washed first with sodium bicarbonate solution and then with water and dried. The solvent is evaporated and the residue is recrystallised from ethyl acetate to yield 6-(4-nitro-phenyl)-3-methyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one with a melting point of 153°-154°C (compound 2).
Reaction SMILES: C(N(CC)[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:16]([O:18]C)=O)=O)C.[BH4-].[Na+].[CH3:24][OH:25]>O1CCCC1>[CH2:12]([N:13]([CH2:14][CH3:6])[C:24]([CH2:4][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][CH2:16][OH:18])=[O:25])[CH3:11]
Reactant: CO
Reactant: CCN(CC)C(=O)c1cccc2c(CC(=O)OC)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cc1cccc2c(CCO)c[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a solution of methyl (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetate (1.87 g, 6.48 mmol) in tetrahydrofuran (30 mL) are added sodium borohydride (1.35 g, 35.7 mmol) and methanol (5 mL) under nitrogen atmosphere, and the mixture is stirred at room temperature for 24 hours, and then refluxed for 4 hours. The mixture is cooled to room temperature, and methanol is added to the reaction solution. The solvent is evaporated, and the residue is separated into water and chloroform. The organic layer is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→ethyl acetate ethyl acetate:methanol=5:1) to give N,N-diethyl-3-(2-hydroxyethyl)-1H-indole-7-carboxyamide (1.56 g, 5.99 mmol, yield: 92%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=O)[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:44][O:45][NH3+:46]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=[N:46][O:45][CH3:44])[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: CC(C)(C)CC1CC(C#CC(=O)C(CCCOCc2ccccc2)CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C#CC1CC(CC(C)(C)C)C1)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
tert-Butyl 3-(3-benzyloxypropyl)-6-[3-(2,2-dimethylpropyl)cyclobutyl]-4-oxo-5-hexynoate (3.44 g) and methanol (35 mL) were mixed. To the mixture were added sodium sulfate (2.15 g), pyridine (3.5 mL) and O-methylhydroxylammonium chloride (1.26 g). The mixture was stirred at RT overnight. The mixture was then filtered, and the filtrate was concentrated in vacuo. To the resultant residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue was added silica gel (5 g), and the mixture was stirred at RT for 10 min. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (3.38 g) as a crude product.
Reaction SMILES: Br[CH:2]([CH:6](Br)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[Cl:13])[C:3]([O-:5])=[O:4].BrC(CBr)C([O-])=O>>[Cl:13][CH:8]1[CH:7]([C:6]#[C:2][C:3]([OH:5])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C([O-])C(Br)C(Br)C1CCCCC1Cl
Agent: O=C([O-])C(Br)CBr
Product: O=C(O)C#CC1CCCCC1Cl

Procedure:
When α,β-dibromo-β-(3-chloro-4-cyclohexyl)propionate in the above example is replaced by the α,β-dibromopropionate of Example 26, then the corresponding propiolic acid is prepared.