Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH:19]([OH:21])[CH2:18][CH:17]4[C:22](O)=[O:23])[N:15]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[F:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[NH:5][N:6]=[C:7]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]4[C:22]([NH:35][C:32]4[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:23])[N:15]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)C1CC(O)CN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](O)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
To a solution of 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol) in DMF (3 mL) was added 6-fluoropyridin-3-amine (121 mg, 1.08 mmol), HATU (246 mg, 0.648 mmol) and DIPEA (0.16 mL, 0.864 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (4×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide (10 mg). Compound No. 10a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m, 4H), 3.75-3.91 (m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H), 7.99 (s, 1H), 8.19 (s, 1H). Compound No. 10b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m, 4H), 3.75-3.91 (m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H), 7.99 (s, 1H), 8.19 (s, 1H). Separation by chiral HPLC provided additional diastereomers 10c and 10d.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].Cl.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20].C(N(CC)CC)C>CO>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:3]([OH:4])=[CH:2][C:1]([C:7]([O:9][CH3:10])=[O:8])=[N:20]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl acetylenedicarboxylate (87.4 g, 757 mmol) was added to a solution of 2-fluoro-phenylhydrazine hydrochloride (100 g, 615 mmol) in methanol (1 l) at 0° C. Then triethylamine (125 g, 1.23 mol) was added slowly during 60 min. The solution was stirred for 16 h at room temperature, the solvent then removed under reduced pressure and the residue dissolved in EA (500 ml). After washing with aqueous hydrochloric acid (500 ml), the solvent was removed under reduced pressure. The title compound was obtained as an almost white solid in quantitative yield.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[F:9][CH2:8][C:7]1[C:2]([O:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][N:19]=[C:18]3[NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ccc(N)n1
Reactant: FCc1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncccc4CF)cc23)n1

Procedure:
The compound of Example 125 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-fluoromethylpyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]1([CH:42]=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[N:18]([CH2:42][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=CC1CCCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCCC3)c3cc4c(cc32)COC4)n1

Procedure:
To a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195 mmol) dichloroethane (5 mL), add cyclopentanecarbaldehyde (0.780 mmol) along with a catalytic amount of acetic acid. Add sodium triacetoxyborohydride (0.975 mmol) and stir at room temperature overnight. Quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (5 mL). Dry the organic portion, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-35%) to afford the title compound as a colorless foam. MS (ES+): 595.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]1([CH3:33])[CH2:18][CH2:17][CH2:16][CH:15]1[NH:19][C:20](=[O:32])[O:21][C@@H:22]1[CH2:27][C@H:26]([CH3:28])[CH2:25][CH2:24][C@H:23]1[CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:33][C@:14]1([NH:13][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:32])[O:21][C@@H:22]1[CH2:27][C@H:26]([CH3:28])[CH2:25][CH2:24][C@H:23]1[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 0.816 ml, 6.61 mmol), (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 2.00 g, 6.01 mmol) and DIPEA (3.15 ml, 18.02 mmol) in DMSO (10 mL) was subjected to microwave irradiation at 140° C. for 5 hours. The reaction was diluted with ethyl acetate (100 ml) and a saturated solution of sodium bicarbonate (50 m). The organics were washed with water (40 ml), brine (40 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)[CH3:5].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C(C)CCBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: COc1cccc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
The 3-(3-methoxyphenyl)butyltriphenylphosphonium bromide is prepared by refluxing a mixture of 1-bromo-3-(3-methoxyphenyl)butane (19.09 g., 78.5 mmoles) and triphenyl phosphine (20.5 g., 78.5 mmoles) in xylene (60 ml.) for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The filter cake is washed with ether and dried in a vacuum desicator to give the product.
Reaction SMILES: C(O[C:4]([CH:6]([C:8]1[NH:9][C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][C:11]=2[N:26]=1)C)=O)C.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[NH:37][CH3:38].[CH3:39]N1C(=O)N(C)CCC1.C1C=CC=CC=1>CCOCC>[CH2:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]2[NH:9][C:8]([CH:6]([C:38]3[N:37]([CH3:39])[C:29]4[CH:30]=[C:31]([C:32]([OH:34])=[O:33])[CH:35]=[CH:36][C:28]=4[N:27]=3)[CH3:4])=[N:26][C:11]=2[CH2:12]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CNc1cc(C(=O)O)ccc1N
Reactant: CCOC(=O)C(C)c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2
Reactant: CN1CCCN(C)C1=O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2ccc(C(=O)O)cc2n1C
Temperature: 185 °C
Yield: 58 %

Procedure:
A mixture comprising benzyl 2-(1-ethoxycarbonylethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3-(N-methylamino)benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) was degassed briefly on a vacuum line, heated heated at 185° C. under nitrogen for 4 hours, cooled and combined with an equivalent volume of benzene. Ether was then added to the mixture to give a precipitate. The precipitate was isolated by filtration, dried briefly on a vacuum line and further purified by a reprecipitation from hot ethanol/water. The precipitate was isolated recovered by filtration and dried to provided 2-[1-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carboxylic acid (4.73 g, 58%); 1H-NMR (300 MHz, DMSO-d6) d ppm: 12.70 (br s, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J=8.3 Hz), 7.64 (d, 1H, J=8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q, 1H, J=5.2 Hz), 4.32 (br s, 2H), 3.78 (s, 3H), 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J=5.2 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(=O)OCC>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:16][CH2:17][N:12]([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:13][CH2:14]1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)nicotinonitrile (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.75 (m, 4H) 3.68 (m, 4H) 4.07 (s, 2H) 6.94 (m, 1H) 7.56 (m, 1H) 8.08 (dd, J=7.80, 2.03 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.42 (dd, J=4.75, 1.70 Hz, 1H) 8.60 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 337 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[SH:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[CH2:20]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][S:22][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1)[CH3:21]
Reactant: Sc1ncccn1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCSc1ncccn1
Yield: 80.1 %

Procedure:
Using the general method of Example 20 Part A, 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.30 mmol) was reacted with 2-mercaptopyrimidine (0.59 g, 5.3 mmol) to provide 1.0 g of 2-ethyl-1-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, m.p. 182-185° C.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[F:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=1.CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:3])[C:18]([N:19]([CH3:21])[CH3:20])=[O:22])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=1
Reactant: CN(C)C=O
Reactant: CN(C)C(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N(C)CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
Sodium hydride (55% in oil) (396 mg, 9.1 mmol) was added, while being cooled with ice, to a DMF solution (9 ml) of 2.0 g of 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (7.0 mmol) and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.735 ml, 11.8 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and extraction with ethyl acetate was performed. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=9:1→6:1). The purified product was concentrated under reduced pressure to thereby obtain 0.83 g of oily pale yellow 1-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethylurea (yield: 40%).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=O)C.C1COCC1.O.[OH-].[Li+]>O>[Cl:14][C:13]1[C:8]2[C@H:7]([CH3:15])[CH2:6][CH:5]([OH:4])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC(O)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (11.86 g, 52.33 mmol) in 2:1 THF:H2O (270 mL) was cooled to 0° C. and treated with lithium hydroxide hydrate (3.95 g, 94.2 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was concentrated and diluted with water and acidified with 6N HCl to a pH of 6. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried MgSO4, filtered, and concentrated. The crude residue was chromatographed (Biotage 65) eluting with 30-50% EtOAc/hexane to give (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9]#[C:10][C:11]([CH3:18])([O:13][Si](C)(C)C)[CH3:12])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[C:9]#[C:10][C:11]([OH:13])([CH3:12])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(C)(C#CC(=O)c1ccc(Cl)cc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#CC(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.7 g, 12.50 mmol) in DCM (20 mL) was added PTSA (2.87 g, 15.01 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-one (2.40 g) as a pale red oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.CN(C)C=O.[C:19]([C:23]1[C:24]([CH:30]=[CH2:31])=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:23]1[C:24]([CH:30]=[CH2:31])=[C:25]([NH:29][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: C=Cc1c(N)cccc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1c(NC(=O)c2cn(C)nc2C(F)(F)F)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
197 mg (1,01 mmol) 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and 135 mg (1,07 mmol) oxalylic acid chloride are dissolved in 8 ml methylenechloride. The solution is stirred for 3 hours at room temperature in the presence of a catalytic amount of dimethylformamide (DMF). After this the solution is slowly added to a solution consisting of 180 mg (1,01 mmol) 3-tert-butyl-2-vinyl-phenylamine, 155 mg (1,52 mmol) triethylamine and 7 ml methylenechloride. The resulting reaction mixture is then stirred at room temperature for 16 hours. After removal of the solvent in a water jet vacuum, the residue is purified by flash chromatography over silicagel (eluent: hexane/ethylacetate 2:1). This gives 0,27 g 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-tert-butyl-2-vinylphenyl)amide in the form of a colourless solid (m.p. 118-119° C.; 76% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=O)(C)(C)C.[Cl:17][CH:18]([CH:22](OCC)OCC)[C:19](=O)[CH3:20]>CC(O)=O>[Cl:17][C:18]1[C:19]([CH3:20])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[CH2:9][NH:8][CH2:15][C:14]3=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CCOC(OCC)C(Cl)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2cc1Cl)CNC3
Yield: 31.5 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5.8 g; 25.9 mmol; 1 eq.) and 3-chloro-4,4-diethoxy-butan-2-one (5.6 g; 25.9 mmol; 1 eq.) in AcOH (26 mL) was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was poured onto sat. aq. NaHCO3 and the formed precipitate was filtered off and dried. Purification by column chromatography (30% EA in heptane) afforded the title compound (1.7 g, 22%) as a white solid. 1H NMR (DMSO-d6) δ 9.48 (s, 1H), 4.62-4.54 (m, 4H), 2.60-2.57 (m, 3H), 1.48 (s, 9H). HPLC (max plot) 97.0%, Rt 3.93 min. UPLC/MS: (MS+) 309.3 ([M+H]+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=[CH:14][N:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCC3(CC2)OCCO3)ccn1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (895 μL, 6.98 mmol) and 2-chloro-4-fluoropyridine (1.01 g, 7.68 mmol) in dioxane (15 mL) was added N,N-diisopropylethylamine (1.83 mL, 10.5 mmol). Argon was bubbled through the reaction mixture for 5 minutes before it was heated to 120° C. in microwave for 3 hours. After evaporation, purification by chromatography (silica gel, 20 g, 30 to 10% ethyl acetate in heptane) afforded the title compound (1.3 g, 73%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:32].[Na+]>CC(C)=O.O.O.[Ru](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([C:29]([OH:32])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2CO)cc1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)cc1
Reaction time: 0.67 h
Yield: 102.4 %

Procedure:
Ruthenium (IV) oxide hydrate (238 mg) was added to a solution of (2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine (5.3 g) in acetone (50 ml) and H2O (20 ml), followed by addition of sodium periodate (5.1 g) with cooling on an ice bath. After stirring at the same temperature for 40 minutes, the reaction was quenched with 2-propanol (50 ml). Insoluble matter was removed by filtration through a celite pad, and the filtrate was washed with acetone and AcOEt. The filtrate and combined washings were concentrated in vacuo, and the residue was partitioned by dissolving same in 5% aqueous sodium bisulfite and AcOEt. The organic layer was washed with saturated NaCl solution, dried over MgS04, and concentrated in vacuo to give 5.6 g of (2R,5R)-4-(tert-butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine-2-carboxylic acid as an amorphous powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].C1(N)CC1.C1(C2C=CC([N+]([O-])=[O:23])=C(C=2)N)CCCC=1.[N+:25]([C:28]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][C:29]=1[NH2:30])([O-])=O>>[NH2:25][C:28]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][C:29]=1[NH:30][C:1]([NH:2][CH:3]1[CH2:5][CH2:4]1)=[O:23]
Reactant: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Reactant: Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Reactant: CCCNC
Agent: NC1CC1
Product: Nc1ccc(-c2cccs2)cc1NC(=O)NC1CC1

Procedure:
1-(2-amino-5-(thiophen-2-yl)phenyl)-3-cyclopropylurea (100) was prepared by substituting N-methylpropan-1-amine in Scheme 25 with cyclopropanamine and by substituting 5-(cyclopent-1-en-1-yl)-2-nitroaniline in Scheme 25 with 2-nitro-5-(thiophen-2-yl)aniline. ESI+ MS: m/z 273 ([M]+), 1H NMR (500 MHz, d6-DMSO): δ 7.62 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=4.5 Hz, 1H), 7.18 (d, J=3.0 Hz, 1H), 7.11 (dd, J=2.0, 8.0 Hz, 1H), 7.03 (dd, J=3.5, 4.5 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 4.90 (s, 2H), 2.58-2.50 (m, 1H), 0.65-0.61 (m, 2H), 0.45-0.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([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:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirred suspension of crude 2-tert.-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol (33.5 mmol) and caesium carbonate (25.1 g, 77.1 mmol) in dry acetone is added ethyl bromoacetate (5.6 ml, 50.3 mmol). The reaction mixture is stirred at rt overnight and then filtered over a small plug of Celite. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (hexane/EtOAc 5:1) to afford pure sub-title compound as yellow oil (8.45 g) in 70% yield (over two steps). tR (LC-2) 2.46 min; ESI-MS (positive ion): m/z 381.54 [M+Na]+ (calcd 358.43 for C20H26N2O4).
Reaction SMILES: [C:1]12(CC(O)=O)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:19])C=CC=CC=1.[CH2:29]([N:31]([CH2:34]C)CC)C>C1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH:6]2[CH2:29][N:31]=[C:34]=[O:19]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC12CCC(CC1)C2
Solvent: c1ccccc1
Product: O=C=NCC1CC2CCC1C2

Procedure:
The reaction of 2-norbornylacetic acid and diphenylphosphoryl azide in a solution of triethylamine and benzene provided a solution comprising 2-norbornylmethyl isocyanate (I.R.: 2270 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-(2-norbornylmethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 1.