Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[CH:28])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.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>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[C:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone (2aa) (5.5 g, 14.5 mmol), prop-2-ynyl-carbamic acid tert-butyl ester (2.5 g, 16 mmol), PdCl2(PPh3)2 (0.6 g, 0.9 mmol) and Cu(I)I (0.2 g, 0.9 mmol) were suspended in anhydrous CH2Cl2 (50 mL) and the mixture was sparged with nitrogen for 30 min. Diethylamine (8 mL) was added and the solution was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the resulting residue purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to afford 3aa (3.6 g, 61%) as a white solid, MS m/z=406 (M+H).
Reaction SMILES: [NH3:1].[F:2][C:3]([F:26])([F:25])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[CH2:21][O:20][C:19]3=[O:24])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O1CCCC1>CO>[F:25][C:3]([F:26])([F:2])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[O:20][CH2:21][C:22]([NH2:1])=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COC(=O)N1CCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 24 h

Procedure:
9.3 ml (64.82 mmol) of a solution of aqueous ammonia (7N) in methanol are added to a solution of 0.77 g (2.16 mmol) of 3-(2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione, obtained in step 3.3, in 10 ml of a 1/1 mixture of methanol and tetrahydrofuran. Stirring is continued at room temperature for 24 hours.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:6](Cl)[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[CH2:16]([C@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][CH2:8][C:7]2[CH:6]=[N:5][C:4]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)=[N:3][CH:2]=2)[CH2:15][CH2:14]1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1CC[C@H](CCc2c(Cl)nc(-c3ccc(F)c(F)c3)nc2Cl)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC[C@H]1CC[C@H](CCc2cnc(-c3ccc(F)c(F)c3)nc2)CC1
Yield: 67.2 %

Procedure:
This dichloropyrimidine compound (2.5 g) was then dissolved in ethyl alcohol (50 ml), followed by subjecting the solution to hydrogenation using 5% Pd/C (0.1 g) in the presence of triethylamine (1 ml), filtering off Pd/C catalyst after the absorption of hydrogen gas ceased, distilling off ethyl alcohol from the filtrate and recrystallizing a residue from ethyl acetate to obtain 5-[2'-(trans-4"-propylcyclohexyl)ethyl]-2-(3,4-difluorophenyl)pyrimidine (1.4 g).
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH3:6][C:7](=[CH2:10])[CH2:8][OH:9].CC(N=NC(C#N)(C)C)(C#N)C>C(O)(=O)C>[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=C(C)CO
Reactant: CCP(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Product: CCP(=O)(O)CC(C)CO
Yield: 92.1 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 114 g (1 mol) of 2-methyl-2-propen-1-ol are initially charged in 200 ml of glacial acetic acid in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% solution of AIBN in glacial acetic acid are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 153 g of ethyl-(2-methyl-3-hydroxypropyl) phosphinic acid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:10]=1[O:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][N:13]=1.[C:27](Cl)(=[O:30])[O:28][CH3:29]>O1CCCC1>[CH3:29][O:28][C:27]([N:14]1[C:15]([CH3:21])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:12]([O:11][C:10]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:9]=2[CH3:8])=[N:13]1)=[O:30]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1c(Oc2cccc(C)c2C)n[nH]c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Oc2cccc(C)c2C)nn(C(=O)OC)c1C

Procedure:
A mixture of 5.6 g of triethylamine, 13 g of 3-(2',3'-dimethylphenoxy)-5-methyl-4-methoxycarbonyl pyrazole and 100 ml of tetrahydrofuran is prepared, and, while stirring and cooling, 4.9 g of methyl chlorocarbonate is dripped in. After stirring for 16 hours, the precipitated hydrochloride is filtered off. The filtrate is concentrated and the residue is recrystallized from ethyl acetate. Melting point: 115° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][N:26]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccc(F)cc21
Yield: 67.1 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 210 mg of 6-fluoro-2,3-dihydro-1H-indole, and 194 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N, N-dimethylformamide. 184 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCCCCC>C1COCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl chloride in 200 ml of dry THF was added with vigorous shaking a solution of 13.76 g (80 mmol) of 4-bromoaniline in 300 ml of dry THF. The mixture was stood at room temperature for 2 h and then treated with 80 g of ice followed by 200 ml of hexane. The organic layer was separated and the aqueous layer was extracted with 2×50 ml of hexanes. The organic layers were combined and washed successively with 30 ml of water and 2×30 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by recrystallization from an ethyl acetate and hexanes mixture to give the title compound as colorless crystals. PMR (CDCl3): & 1.91 (3H, s), 2.23 (3H, s), 5.73 (1H, broad s), 7.38-7.55 (5H, m).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[CH2:11](Br)[C:12]#[CH:13].O=CC1C=CC(O)=C(OC)C=1>ClCCl>[CH3:8][O:7][C:5]([CH:4]1[CH2:9][CH2:10][N:1]([CH2:13][C:12]#[CH:11])[CH2:2][CH2:3]1)=[O:6]
Reactant: C#CCBr
Reactant: COC(=O)C1CCNCC1
Agent: COc1cc(C=O)ccc1O
Solvent: ClCCl
Product: C#CCN1CCC(C(=O)OC)CC1
Reaction time: 36 h

Procedure:
To a solution of methyl isonipecotate 3.5 g (24,4 mmol, 3.30 mL) in 100 mL dichloromethane was added TEA (1.5 eq, 36.6 mmol, 5.1 mL), propargyl bromide (3.0 eq, 73.2 mmol, 6.5 ml), at room temperature for 36 hrs. The reaction was quenched with 35 mL water to yield to provide a clear solution. The solution was extracted with dichloromethane 2×25 mL, dried with Na2SO4, and the solvent evaporated to provide a yellow oil. r.f. (40% EtOAc/Hexanes) 0.26 stains faint white with Vanillin, starting material r.f. 0.05 stains yellow with Vanillin. The product appeared pure after extraction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.ClC[C@@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:18][C:15]1([CH3:19])[O:16][C@H:17]([CH2:1][O:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[CH2:13][O:14]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2)O1

Procedure:
2 g (16.38 mmol) of p-methoxybenzaldehyde together with 3.7 g (24.57 mmol) of (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane and 15.8 g (114.64 mmol) of potassium carbonate are stirred in 10 ml of DMF at 130° C. overnight. The mixture is then added to water and extracted with methylene chloride. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 2.42 g (61% of theory) of the target compound.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH3:14])[N+:20]([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCC(Oc1ccccc1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CCCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.69 g of 2-phenoxyvaleric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Yield: 33.5 %

Procedure:
To a stirred suspension of 2-methyl-5-nitrophenol (2.0 g, 13 mmol) and sodium carbonate (1.94 g, 18.3 mmol) in acetone was added benzyl bromide (1.7 mL, 14 mmol). The mixture was heated to reflux for 24 h, cooled, filtered, and the solid washed with acetone. The filtrate and acetone washings were combined and concentrated in vacuo. Recrystallization from ether/hexanes gave 1.06 g (33%) of the title product as an off-white solid. MS-FD 243 m/e (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2
Reactant: COC(=O)CBr
Reactant: COc1cc2cc(N)c(OCc3ccccc3)cc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-amino-7-benzyloxy-3-methoxychromen-2-one (0.880 g, 2.96 mmol) and K2CO3 (0.820 g, 5.92 mmol) in DMF (50 mL) is added methyl bromoacetate (0.36 mL, 3.85 mmol). The mixture is stirred at 60° C. for 3 h. Additional methyl bromoacetate (0.14 mL) is added, and after 3 h, the mixture is allowed to cool to ambient temperature and poured into water and extracted with EtOAc. The organic layer is washed with water (3×), sat. NaCl, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using hexanes/EtOAc (7:1) to afford (7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-ylamino)-acetic acid methyl ester as a yellow solid: 1H NMR (CDCl3) δ 7.44-7.33 (m, 5H), 6.79 (s, 1H), 6.75 (s, 1H), 6.36 (s, 1H), 5.13 (s, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H); (M+H)+=370.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:13])[N:4]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]12
Reactant: Cn1c(=O)[nH]c2cccc(Cl)c2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c3cccc(Cl)c3c(=O)n(C)c12

Procedure:
M.p. 248°-254° C. by reaction between 3-methyl-5-chloro-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](Br)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[I-:37].[Na+]>CC(C)=O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([I:37])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(C)(CC)C(I)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 78.5 %

Procedure:
A solution of diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29) and sodium iodide (1.30 g) in acetone (15 ml) was allowed to stand for twenty hours at room temperature in the absence of light. It was then filtered through Hyflo Super-Cel, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-iodo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.85 g, m.p. 98°-100° C.). NMR (CDCl3): δ1.3(6H,t), 1.7-1.9(2H,m), 2.5-2.6(2H,m), 4.05(4H,m), 5.3(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 615.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33])[CH3:36]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A172) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:31]([O:33][C:34]([C@@:36]1([NH2:41])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:35])[CH3:32]>CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:41][C@:36]1([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 22.5 °C
Reaction time: 1.12 h

Procedure:
To a suspension of 138.8 g (600 mmol) of Boc-(2S,4R)-hydroxyproline in 890 mL of EtOAc was added 63.7 g (630 mmol) of NMM at 20-30° C. To this mixture 72.3 g (600 mmol) of pivaloyl chloride was added at 15-22° C. within 10-20 min followed by 50 mL of EtOAc. The mixture was stirred at 20-25° C. for 60-75 min. Then the emulsion of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 6 was added at a temperature of 20-30° C. within 5-30 min. The dosing funnel was rinsed with 20 mL DMF and 100 mL EtOAc. The reaction mixture was stirred for 4 h at 20-25° C. After complete conversion 450 mL of aqueous HCl (IN) was added. Phases were separated and the aqueous layer was extracted with 600 mL of EtOAc. The organic phase was washed with 200 mL of water, 400 mL of aqueous NaOH (2M) and 200 mL of water. The combined organic phases were concentrated to 400 mL under reduced pressure. To the residue 1500 mL of toluene was added and the mixture was concentrated to 1000 mL under reduced pressure. To the residue 720 mL of toluene was added to yield the (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a 12-13 wt % solution in toluene.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=[O:47].C(N(CC)C(C)C)(C)C>O1CCCC1.[I-].[K+]>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=3)[C:46]([OH:48])=[O:47])=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21a (1.6 g, 2.56 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), 3-mercaptobenzoic acid (390 mg, 2.53 mmol, 0.99 equiv), potassium iodide (21.2 mg, 0.13 mmol, 0.05 equiv), and N,N-diisopropylethylamine (660 mg, 5.12 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 40° C. in an oil bath. The reaction progress was monitored by TLC/LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 1.12 g (63%) of product as a yellow to green solid. 1H-NMR (400 MHz, CDCl3, ppm): δ 11.68(s, 1H), 9.75(s, 1H), 8.60-8.56(d, J=9.2 Hz, 1H), 8.00(s, 1H), 7.91(s, 3H), 7.88-7.81(m, 2H), 7.80-7.79(d, J=2.1 Hz, 1H), 7.66-7.65(d, J=2.4 Hz, 4H), 7.53-7.38(m, 2H), 7.33-7.25(m, 1H), 7.10-7.08(m, 1H), 4.20(s, 2H), 3.17(s, 4H), 1.69-1.54(m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: CCC(=O)N(CC)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: CCC(=O)N(CC)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Yield: 81.5 %

Procedure:
A mixture of 0.54 g of 3-amino-4-pyrazolecarbonitrile and 1.37 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylpropanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate. The mixture was then cooled and the solid collected, giving 1.3 g of the desired product, mp 161°-162° C.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:20][C:3]=1[CH:4]([OH:19])C1C=CC=C(NC(OC(C)(C)C)=O)C=1.C(OC1C=CC(C=O)=CC=1)C1C=CC=CC=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[C:28]1([CH2:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][CH:2]=[C:3]([CH:20]=2)[CH2:4][OH:19])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(O)c2cc(OCCCc3ccccc3)ccc2N)c1
Agent: N#C[Na]
Agent: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: OCc1cccc(OCCCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In methanol (12 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminophenyl)-5-(3-phenylpropyloxy)benzyl alcohol (0.7 g), 4-benzyloxybenzaldehyde (0.38 g) and acetic acid (0.1 g). To the solution was added cyano sodium borohydride (0.11 g). The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (50 ml) and water (100 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-(4-benzyloxybenzyl)-α-3-tert-butoxycarbonylaminomethylphenyl)-5-(3-phenylpropyloxy)benzyl alcohol as a yellow oily product (0.95 g).