Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1([O:39][C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])[CH2:38][CH2:37][CH2:36]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([O:39][C:40]([N:42]2[CH2:47][CH2:46][N:45]([C:14](=[O:15])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:29]4[C:34]3=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:44][CH2:43]2)=[O:41])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
To a solution of 500 mg (S)-6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid in 7 ml DMF were added at 0° C. 172 mg piperazine-1-carboxylic acid cyclobutyl ester, 0.14 ml N-ethylmorpholine and 357 mg TOTU. After stirring for 3 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 726 mg.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH2:14][CH2:15][S:16]([O-:18])=[O:17].[Na+]>[Cu]I>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([S:16]([CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:19])(=[O:18])=[O:17])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: COC(=O)CCS(=O)[O-]
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Cu]I
Agent: [Na+]
Product: COC(=O)CCS(=O)(=O)c1ccc2cc[nH]c2c1
Temperature: 110 °C

Procedure:
6-bromo-1H-indole (3.0 g, 15.3 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (8.0 g, 45.9 mmol) and CuI (14.6 g, 77.0 mmol) were charged to a sealable flask. The flask was closed and degassed twice, and then dry DMSO (30 mL) was added and the reaction mixture degassed again before being heated at 110° C. in an oil bath overnight. The reaction mixture was cooled and diluted with ethyl acetate (300 mL). The mixture was filtered on a silica gel pad and eluted with ethyl acetate. The organic phase was concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate, then with DCM and methanol to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[C:10]#[CH:11])=[CH:4][CH:3]=1.I[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:12])[C:10]#[C:11][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)Nc1ccc(Cl)cc1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4-chlorophenyl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 80 mg (34.1% of theory); melting point: 153° C.-154° C.; C21H21ClN2O (M=352.86); calc.: molecular ion peak (M+H)+: 353/355; found: molecular ion peak (M+H)+: 353/355.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1Br)=[O:3].[C:12]([OH:15])(=[O:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][O:15][C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc(Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OCC(=O)c1ccc(Cl)cc1
Temperature: 4 °C
Yield: 90.1 %

Procedure:
To a cooled (4° C.) and stirred solution of 2-bromo-4-chloroacetophenone (5.0 g, 21.41 mmol) and glacial acetic acid (2.8 mL, 49.25 mmol) in acetonitrile was added triethylamine (6.1 mL, 44.97 mmol). The reaction mixture was warmed to room temperature, than refluxed for 3 hours. The reaction mixture was extracted with ether, acetate, washed with 1N hydrochloric acid, brine, dried, and concentrated to yield 4.1 g of acetic acid 2-(4-chlorophenyl)-2-oxo-ethyl ester.
Reaction SMILES: [C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[ClH:34].Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CN(C=O)C>[ClH:36].[ClH:34].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.5 %

Procedure:
(1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 3; 1.01 g, 3.0 mmol) was dissolved in DMF (10 mL). DIPEA (1.74 mL, 5.0 mmol) and, 4-(4-chlorophenyl)piperazine dihydrochloride (808 mg, 3.0 mmol) were added and the reaction mixture was stirred at room temperature for 14 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1M aq Na2CO3 solution (5×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 96:4 mixture of DCM:MeOH) followed by reverse phase column chromatography (gradient eluting with MeOH in water, 0-100%). The residue was dissolved in DCM (10 mL) and 2M HCl in Et2O (3 mL) was added. The reaction mixture was then concentrated in vacuo to give [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-chlorophenyl)piperazine-1-carboxylate dihydrochloride (468 mg, 39.5%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:35][CH:36]1[CH2:39][NH:38][CH2:37]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH:36]([F:35])[CH2:37]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: FC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(F)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-fluoro-azetidine hydrochloride in DMF. [α]D20=+19.7° (c=0.17, CHCl3), ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2(OCC[O:14]2)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)C>[CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC1CC1)C1(C)OCCO1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=NOC1CC1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 2-cyclopropyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(487 mg) in methylene chloride (0.8 ml) was added 90% trifluoroacetic acid (0.8 ml) under ice-cooling. The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in diethyl ether and washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(382 mg) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:20][C:21]1([F:67])[CH2:26][CH2:25][CH:24]([C:27]2[C:36]3[CH:35]([O:37]CC4C=CC(OC)=CC=4)[CH2:34][C:33]([CH3:48])([CH3:47])[CH2:32][C:31]=3[N:30]=[C:29]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[C:28]=2[CH:55]([F:66])[C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)[CH2:23][CH2:22]1>>[F:67][C:21]1([F:20])[CH2:26][CH2:25][CH:24]([C:27]2[C:36]3[CH:35]([OH:37])[CH2:34][C:33]([CH3:47])([CH3:48])[CH2:32][C:31]=3[N:30]=[C:29]([CH:49]3[CH2:54][CH2:53][N:52]([C:2]4[N:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=4)[CH2:51][CH2:50]3)[C:28]=2[CH:55]([F:66])[C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:64])([F:65])[F:63])=[CH:58][CH:57]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Agent: Clc1ncc(Br)cn1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(S(C)(=O)=O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(methylsulfonyl)pyrimidine, which was prepared by a method similar to that of Reference Example 14, instead of 5-bromo-2-chloropyrimidine, and from 49 mg (72 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 45 mg of the title compound was obtained as a white solid (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH:29]=O)[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH2:29][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Cl)c2)c1-c1nc2c(Br)cc(CN3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of (S)-7-Bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzimidazole-5-carbaldehyde (130 mg, 0.27 mmol) in methanol (60 mL) was added morpholine (0.2 mL, excess). The reaction mixture was stirred 1 h at room temperature. Then NaCNBH3 (1M THF solution, 1.35 mL, 1.35 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by prep. HPLC to yield the title compound (68 mg, 45%). 1H NMR (400 MHz, CD3OD) δ 7.83 (1H, s), 7.69 (1H, s), 7.68 (1H, s), 7.24–7.54 (4H, m), 6.30 (1H, d, J=7.6 Hz), 4.89–5.02 (1H, m), 4.50 (2H, s), 3.66–3.71 (4H, m), 3.17–3.43 (6H, m). LCMS (M+H)+ m/z 558 (t=1.41 min.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([N:10]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]3)=[C:8]([N+:24]([O-])=O)[CH:7]=[N:6]2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([NH:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48](O)=[O:49])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[F:47][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:40]=1[C:38]1[S:39][C:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[C:36]([C:48](=[O:49])[NH:24][C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:9]=2[N:10]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]2)[N:37]=1
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 77 %

Procedure:
Following the procedure for Example 517 starting with (R)-N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (136 mg, 77%). 1H-NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.41-7.36 (m, 1H), 7.10-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.25-4.10 (m, 1H), 3.90-3.83 (m, 2H), 3.43-3.31 (m, 2H), 3.30-3.15 (m, 2H), 2.25-2.05 (m, 2H), 2.03-1.70 (m, 4H), 1.57 (s, 9H) 1.35-1.20 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CO.CN1C(=O)N(C)CCC1.C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CN1CCNCC1
Agent: [Ni]
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)CC1

Procedure:
136.4 mg (0.50 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d] pyrimidine and 67 μl of N-methylpiperazine in 5 ml of methanol, 15 ml of DMPU and 63 μl of acetic acid are hydrogenated at 50° C. in the presence of 30 mg of Raney nickel. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in ethyl acetate and satd NaHCO3 solution. The aqueous phase separated off is extracted twice with ethyl acetate; the organic phases are washed with satd NaHCO3 solution, 4 times with water and brine, dried over Na2SO4 and evaporated. Column chromatography (SiO2, CH2Cl2/methanol=7:2) and stirring in diethyl ether yields 4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=7.4; TLC-Rf=0.16 (CH2Cl2/methanol=7:3); FAB-MS: (M+H)+=357.
Reaction SMILES: B(F)(F)F.[CH:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1.[CH3:11][C:12]([CH3:14])=[O:13]>CCOCC>[CH:5]1([C:8](=[O:10])[CH2:11][C:12](=[O:13])[CH3:14])[CH2:7][CH2:6]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)CC(=O)C1CC1

Procedure:
Boron trifluoride gas is introduced for one hour at 40° C. into a mixture of 191 g of cyclopropanecarboxylic acid and 45 g of acetone. There is formed a black oily product, which is diluted with 800 ml of ether. The ether phase is then washed 4 times with 300 ml of water each time, and, with ice cooling, 30% sodium hydroxide solution is finally added until the pH value is ~9. The ether layer is separated, and the aqueous phase is extracted three times with 300 ml of ether each time. The ether phases are collected, dried over sodium sulfate, purified with active charcoal, filtered, and concentrated by evaporation. The oil which remains is purified by chromatography through a silica gel column with ether/hexane (1:3) as the eluant. The yield after removal of the solvent by evaporation is 22 g of the title compound as light-coloured oil; refractive index nD24 : 1.488.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC([O-])=O.[OH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[N:17]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:18]=[N:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1>C(Cl)Cl>[CH3:25][O:24][C:22]1[CH:21]=[C:20]2[C:15]([C:16](=[O:34])[N:17]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])[CH:18]=[N:19]2)=[C:14]([O:13][CH:55]2[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]2)[CH:23]=1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (1.7 g) in methylene chloride (5 ml) was added to a stirred mixture of 5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.5 g), triphenylphosphine (1.9 g), 4-hydroxy-1-methylpiperidine (0.675 g) and methylene chloride (20 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 7-methoxy-5-(N-methylpiperidin-4-yloxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.75 g); NMR Spectrum: (CDCl3): 1.2 (s, 9H), 2.05 (br s, 41, 2.3 (s, 3H), 2.3-2.42 (m, 2H), 2.7-2.8 (m, 2H), 3.9 (s, 3H), 4.48 (m, 1H), 5.9 (s, 2H), 6.5 (d, 1H), 6.71 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: CC(=O)OCc1cc2cc(OCc3ccccc3)ccc2n1Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from [5-(benzyloxy)-1H-indol-2-yl]methyl acetate and 4-tert-butylbenzyl bromide in substantially the same manner, as described in step 3 of Example 4. The product was obtained as a white solid; mp: 132-133° C. Mass spectrum (ESI, [M+H]+) m/z 442. 1H NMR (400MHz, DMSO-d6) δ 7.45 (d, 2H, J=7.33 Hz), 7.38 (t, 2H, J=7.33 Hz), 7.32-7.27 (m, 4H), 7.16 (d, 1H, J=2.30 Hz), 6.88-6.84 (m, 3H), 6.53 (s, 1H), 5.36 (s, 2H), 5.18 (s, 2H), 5.08 (s, 2H), 1.77 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: [NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([OH:5])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:5]
Reactant: CC(=O)NCC(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)NCCC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ac-Gly-OH a (3.77 g, 32.2 mmol) and triethylamine (6.7 mL, 48.1 mmol) were dissolved in 160 mL THF and cooled to −10° C., and isobutylchloroformate (5.02 g, 38.6 mmol) was added. The mixture was stirred at −10° C. for 1 hr. H-beta-Ala-OBzl.PTSA e (11.26 g, 32.0 mmol) and triethylamine (6.7 mL, 48.1 mmol) was dissolved in 160 mL THF, and added into mix anhydride solution. The reaction mixture was stirred at room temperature overnight. The salt was filtrated off and THF was removed in vacuum. The residue obtained was purified by column chromatography using ethyl acetate and heptane as eluent to obtain 5.95 g Ac-Gly-beta-Ala-OBzl f.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:37]([O:36][C:34]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:10]=1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(CO)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 56.5 %

Procedure:
Methyl 2,6-di(bis(tert-butoxycarbonyl)amino)pyrimidine-4-carboxylate Crude methyl 2,6-diaminopyrimidine-4-carboxylate (2.52 g, 15 mmol) was suspended in dry tetrahydrofuran (200 ml) then treated sequentially with di-tert-butyl dicarbonate (19.6 g, 90 mmol), triethylamine (16.7 ml, 120 mmol), and 4-dimethylaminopyridine (0.092 g, 0.75 mmol). This mixture was refluxed gently for 16 h, evaporated, dissolved in diethyl ether, washed with water and brine, dried and evaporated to give a dark red gum. This residue was purified by flash chromatography, eluting with 0–18% ethyl acetate in petroleum ether, to give the title compound as an off-white foam (4.58 g, 54%); m/z (APCI+) 569 [MH]+ 100%.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:14])[CH:12]2[CH:7]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][CH2:4]1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>O1CCCC1>[Si:15]([O:14][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]2[CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCCC2C(O)CCCC12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCC2C(O)CCCC12
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A suspension of 0.45 gm (12 mmole) of sodium hydride dispersion (60%) in 75 mL of tetrahydrofuran was treated with 2.0 gm (12 mmole) of 1,5-decalindiol in an inert atmosphere. This mixture was stirred overnight at about 56° C. then cooled to room temperature and 1.8 gm (12 mmole) of t-butyldimethylsilyl chloride added. The mixture was stirred at room temperature for 4 days then 200 mL of diethyl ether added followed by washing the resulting mixture with 10% aqueous potassium carbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography on 40 microns silica gel to give 5-(t-butyldimethylsilyloxy)-1 -hydroxydecalin as a clear, colorless oil. Satisfactory ir, cmr and pmr spectra were obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([NH2:10])[N:4]=1.[C:11]([O-:14])(=O)[CH3:12].[Na+].ClCC=O>O>[CH3:1][S:2][C:3]1[NH:8][C:7]2[C:12]([N:10]=[CH:5][CH:6]=2)=[C:11]([OH:14])[N:4]=1
Reactant: CSc1nc(N)cc(O)n1
Reactant: CC(=O)[O-]
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: CSc1nc(O)c2nccc-2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-(Methylthio)4-hydroxy-6-aminopyrimidine (3.1) (40 g) and sodium acetate (40 g, 2 eq.) were mixed with water (600 ml) and the slurry heated to 80° C. with vigorous stirring. To the mixture was then added chloroacetaldehyde (50 wt. % in water, 40 g, 1 eq.), slowly over 10 mins. The mixture turned yellow in colour and the solid mostly dissolved, before a new solid precipitated. After a further 30 mins, the mixture was allowed to cool overnight, then the solid was collected by filtration, washed well with water and then with acetone. Dried under vacuum at 50° C. to give (3.2), 8.7 g. δH (300MHz, DMSO-db); 2.49 (3H, s, SCH3), 6.33 (1H, m, H7), 6.89 (1H, m, H8), 11.74 and 12.03 (2×broad s, D2O exch.) ppm.