Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:37][C:38]1([CH2:42][NH2:43])[CH2:41][O:40][CH2:39]1>>[CH3:22][NH:21][C:19](=[O:20])[C@:18]([CH3:33])([N:17]([CH3:34])[C:15](=[O:16])[C:14]1[CH:35]=[CH:36][C:11]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][NH:43][CH2:42][C:38]3([CH3:37])[CH2:41][O:40][CH2:39]3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:23]([NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[O:24]
Reactant: CC1(CN)COC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNCC3(C)COC3)cc2)cc1

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.15 g) as obtained in Example 16-(1) and [(3-methyloxetan-3-yl)methyl]amine (63 mg), (2S)-N,2-dimethyl-2-[methyl(4-{[4-({[(3-methyloxetan-3-yl)methyl]amino}methyl)phenyl]ethynyl}benzoyl)amino]-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) was obtained (0.13 g, 73%) in the same manner as in Example 16-(2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[N:5]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:21][CH3:22])[CH:15]=1)C(OC(C)(C)C)=O.C(Cl)[Cl:30]>>[ClH:30].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:21][CH3:22])[CH:15]=1
Reactant: ClCCl
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(OC)c1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)c(OC)c1
Product: Cl
Yield: 88.3 %

Procedure:
N-BOC-4-amino-3-methoxybenzoyl methionine methyl ester (0.71 g, 1.79 mmol) was taken up in CH2Cl2 (4 ml) and precipitated with 3-4M HCl/Et2O (12 ml). The precipitate was washed as usual with Et2O and dried overnight under vacuum to result in 0.55 g (88.3%) of reddish material. mp 176-177° C.; 1H NMR (CD3OD) 2.08 (3H, s), 2.21 (2H, m), 2.61 (2H, m), 3.74 (3H, s), 4.02 (3H, s), 4.79 (1H, m), 7.50 (1H, d, J=8.2 Hz), 7.57 (1H, d, J=4.1 Hz) 7.67 (1H, s); 13C NMR (CD3OD) 15.26, 31.34, 31.42, 52.95, 53.38, 57.12, 112.29, 121.43, 124.57, 124.77, 136.15, 153.67, 168.79, 173.81.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[O:27])=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (30.0 mg, 0.128 mmol) prepared in Process 3 of Example 12 in dichloromethane (3 mL) was added sequentially with 4-chlorophenyl isocyanate (19.7 mg, 0.128 mmol), triethylamine (19.4 mg, 0.192 mmol), DMAP (catalyst amount) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was filtered using celite, concentrated in vacuo, and the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (49.7 mg, 100%) was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1)([OH:3])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([NH:19][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([CH3:12])=[N:9][C:8]=3[CH:13]=2)=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc2cc(C(=O)Nc3ccccc3)ccc2o1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 594.6 %

Procedure:
5-Carboxy-2-methylbenzoxazole (2.0 g, 1.1 mmol) and phosphorous oxychloride (10 mL) were combined and heated at 100° C. for 1 hr. The reaction mixture was evaporated and the resulting oil was dissolved in 20 mL of acetonitrile and poured into a mixture of ice and water. The solid formed was collected, dissolved in 40 mL of acetonitrile and combined with aniline (2.0 g, 2.2 mmol). After stirring 45 min. the reaction mixture was poured into 500 mL of a mixture of ice and water. The resulting solid was collected and dried affording 1.65 g (58% yield) of 5-(Phenylcarbamoyl)-2-methylbenzoxazole, mp 137.5-139.0° C. Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10. Found: C, 71.16; H, 4.83; N, 10.96.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Br:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C.CC(C)([O-])C.[K+].C(OC(C1N(C(OC(C)(C)C)=O)CC2N(C3C=CC=CC=3)C(Br)=CC=2C1=O)=O)C.FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[C:4]([OH:3])=[C:6]2[CH:10]=[C:9]([Br:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[CH:18][N:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)cc(Br)n1-c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)C1C(=O)c2cc(Br)n(-c3ccccc3)c2CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ncc2c(cc(Br)n2-c2ccccc2)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-bromo-2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (390 mg, 0.767 mmol) was dissolved in tetrahydrofuran (5 mL) and then cooled with an acetone-dry ice bath. Potassium tert-butoxide in tetrahydrofuran (0.92 mL, 0.92 mmol, 1 M solution) was added; after addition, the reaction was stirred for 10 min at −78° C. The cold bath was removed and the reaction was stirred for another 30 min at room temperature (RT) before quenching with saturated ammonium chloride aqueous solution and extracting with ethyl acetate. The organic phase was subsequently washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and filtered, concentrated to give an oil containing crude intermediate 2-bromo-4-oxo-1-phenyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridine-5,6-dicarboxylic acid 6-tert-butyl ester 5-ethyl ester, which was then dissolved in dichloromethane (20 mL) at room temperature. Trifluoroacetic acid (5 mL) was added; the resulting reaction mixture was stirred overnight at room temperature before all solvents were removed. The residue was dissolved in dichloromethane and basified with triethylamine, then air was bubbled through the solution for 5 hours. The solvent was then removed, and the residue was purified with column to give the title compound. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.52 (s, 1H), 8.06 (s, 1H), 7.65-7.28 (m, 5H), 7.02 (s, 1H), 4.52 (q, 2H, J=7.4 Hz), 1.48 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(NS(=O)(=O)[O:33][CH2:34][C@@H:35]1[C@@H:42]2[C@@H:38]([O:39][C:40]([CH3:44])([CH3:43])[O:41]2)[C@H:37]([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=[N:47][CH:48]=[N:49][C:50]=3Cl)[O:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(O)C>[C@@H:3]1([N:2]([CH3:1])[C:50]2[N:49]=[CH:48][N:47]=[C:46]3[C:51]=2[N:52]=[CH:53][N:45]3[C@H:37]2[C@@H:38]3[O:39][C:40]([CH3:44])([CH3:43])[O:41][C@@H:42]3[C@@H:35]([CH2:34][OH:33])[O:36]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CCc2ccccc21
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21)[C@H]1CCc2ccccc21
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of (1S)-N-methylindan-1-amine (67.8 mg, 0.461 mmol), [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl tritylsulfamate (200 mg, 0.309 mmol) and DIPEA (0.160 mL, 0.919 mmol) in ethanol (3.0 mL) was heated at 150° C. for 600 s using microwave irradiation. The residue was purified via flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound as a brown oil (74.3 mg, 55%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH2:16]>C(O)C.[Pt]=O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: CC(=O)Cc1ccc(CO)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(Cc1ccc(CO)cc1)NCC(O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (1.64 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.23 g) in ethanol (80 ml) was refluxed 0.5 hours, cooled to ambient temperature, platinum oxide (0.1 g) added and the mixture hydrogenated at 75 psi and 50°-60° for 8 hours. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave the title compound as an oil which was finally obtained as a hard foam, (52:48 mixture of diastereoisomers) from ethyl acetate-benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[CH:10]=[CH2:11]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:11][CH:10]=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: C=CCBr
Product: C=CCOc1cccc(F)c1

Procedure:
3-fluoro-phenol was reacted with allyl bromide to form 3-fluoro-allyloxy-benzene with a refractive index of nD23 =1.4985 which was reacted with nitric acid to obtain 2-allyloxy-4-fluoro-nitro-benzene with a refractive index of nD23 =1.5432 which was reacted as in Example 1 to obtain 0-(4-nitro-3-allyloxy-phenyl)-hydroxylamine melting at 94°-95° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=S)=[N:6][CH:7]=1.CI.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][NH2:19]>CO>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[CH2:18][NH:19][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=1)=[NH:11]
Reactant: NC(=S)Nc1ccc(I)cn1
Reactant: COc1cccc(OC)c1CN
Solvent: CI
Solvent: CO
Product: COc1cccc(OC)c1CNC(=N)Nc1ccc(I)cn1
Temperature: 75 °C
Yield: 835.9 %

Procedure:
2.019 g (7.233 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 50 mL methanol, 0.60 mL (9.553 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated for 2.7 hr at 75° C. (oil bath temperature). The solvent was removed under vacuum, and the intermediate product was redissolved in 50 mL ethanol. 1.870 g (0.736 mmol) 2,6-dimethoxybenzylamine was added to the reaction mixture and heated for 2.25 hr at 90° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was dissolved in acetonitrile, and the product crystallized out with addition of water. The solid was suctioned off and washed with water. 2.698 g (6.152 mmol, 85%) N-(2,6-dimethoxybenzyl)-N′-(5-iodopyridin-2-yl)guanidine was isolated and used for further reaction.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:10]C)([NH:8][CH3:9])=O.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N:20]=[C:21]2[NH:25][CH2:24][CH2:23][NH:22]2)=[C:15]([Cl:26])[CH:14]=1.O1CCC[CH2:28]1>>[Cl:26][C:15]1[CH:14]=[C:13]([N:12]([CH3:28])[C:6]([NH:8][CH3:9])=[NH:10])[CH:18]=[C:17]([Cl:19])[C:16]=1[N:20]=[C:21]1[NH:25][CH2:24][CH2:23][NH:22]1
Reactant: C1CCOC1
Reactant: CNC(=O)NC
Reactant: Nc1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=N)N(C)c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Phosphoryl chloride (4.4 ml, 0.047 M) was added with cooling to dimethylurea (4 g, 0.045 M) in tetrahydrofuran (60 ml). After stirring at room temperature for 5 hours the mixture was added to 2-(4-amino-2,6-dichlorophenylimino) imidazolidine (3.0 g, 0.012 M) in tetrahydrofuran (60 ml). The mixture was refluxed for 18 hours and then evaporated to give an oily solid. The residue was extracted into 2 M HCl, washed with methylene chloride and then basified. Extraction of the alkaline mixture with methyl chloride yielded a gum on evaporation of the extract. The gum was taken up in ethanol and the required guanidino compound (300 mg) crystallised. The product was recrystallised as 2-[2,6-dichloro-4-(1,3-dimethylguanidino)phenylimino]imidazolidine dihydroiodide (MP 320° C.).
Reaction SMILES: C1(OP(N=[N+]=[N-])(=O)[O:9][C:10]2C=CC=CC=2)C=CC=CC=1.C([N:22](CC)CC)C.[S:27]1[CH:31]=[CH:30][C:29]([C:32]2(C(O)=O)[CH2:41][CH2:40][C:35]3([O:39][CH2:38][CH2:37][O:36]3)[CH2:34][CH2:33]2)=[CH:28]1>C1(OC)C=CC=CC=1>[N:22]([C:32]1([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH2:33][CH2:34][C:35]2([O:36][CH2:37][CH2:38][O:39]2)[CH2:40][CH2:41]1)=[C:10]=[O:9]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)C1(c2ccsc2)CCC2(CC1)OCCO2
Solvent: COc1ccccc1
Product: O=C=NC1(c2ccsc2)CCC2(CC1)OCCO2
Temperature: 95 °C
Yield: 41.1 %

Procedure:
Azidophosphoric acid diphenyl ester (15.4 g; 56 mmole) and triethylamine (5.66 g; 55 mmole) were added to 8-thiophen-3-yl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid (15 g; 56 mmole) dissolved in anisole (160 ml). The reaction mixture was heated for 2 hours to 90 to 100° C. On completion of the reaction (reaction monitored by thin layer chromatography), the mixture was purified by column chromatography (silica gel, 10% ethyl acetate in n-hexane). 6 g of 8-isocyanato-8-thiophen-3-yl-1,4-dioxa-spiro[4.5]decane were obtained (41%; colorless liquid).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[CH3:27][C:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH:9]=[CH:8][NH:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:33][CH:34]=1)([CH3:25])[CH3:26]
Reactant: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2cccc3cc(Oc4ncnc5[nH]ccc45)ccc23)cc1
Reaction time: 14 h

Procedure:
THF (1.3 mL) was added to 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoyl chloride (84.0 mg, 0.259 mmol) in a 10 mL round bottom flask, followed by 4-t-butyl aniline (62.4 mL, 0.389 mmol) and Hunig's base (45.1 μL, 0.259 mmol). The resulting solution was stirred for 14 h and then transferred to a 50 mL flask. To this solution was added ˜5 g of silica gel. The resulting slurry was concentrated by reduced pressure. The impregnated silica gel was loaded into a dry pack column cartridge and the crude mixture was purified through Biotage chromatography (Hex:EtOAc). The collected product was repurified through trituration with DCM. MS (ESI, pos. ion) m/z: 437.1 (M+1). Mass Calc'd for C18H15NO3: 436.51.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([Cl:10])=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)nc(Cl)c1Cl
Yield: 115.7 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.98 g (7.32 mmol) of N-chlorosuccinimide. The solution was poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.4 g (80%) of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:16])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:17](OC(C1C(O)=NC(CC)=NC=1)=O)[CH3:18].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(CC)nc1O
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 4-hydroxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (3 g, 13.377 mmol, prepared in an analogous manner as described for the preparation of 2-ethyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester, Dostert, P. et al. Eur. J. Med. Chem. 1982, 17, 437-444) in dimethylformamide (10 mL) was added slowly to the suspension of sodium hydride (800 mg, 60% in mineral oil, Aldrich) in dimethylformamide cooled to 0° C. After the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was stirred at room temperature for 4 h then quenched with saturated solution of ammonium chloride. It was extracted with ethyl acetate (2×). The organic extracts were washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (120 g of silica gel, eluting with a gradient of 5-60% ethyl acetate in hexane gave 4-ethoxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (1.12 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[S:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](=[O:29])[CH2:27]Br)=[CH:25][C:20]=2[N:19]=[N:18]1>>[S:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](=[O:29])[CH2:27][N:12]3[C:4]4=[N:3][C:2]([Cl:1])=[CH:7][C:6](=[O:8])[N:5]4[CH2:9][CH2:10][C@H:11]3[C:13]([F:14])([F:15])[F:16])=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: O=C(CBr)c1ccc2snnc2c1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc2snnc2c1

Procedure:
150 mg (0.59 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 167.25 mg (0.65 mmol) of 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone were used in the reaction. After purification by chromatography on silica gel (eluent: 90/10 DCM/MeOH), 210 mg of (8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:37][CH2:36][C:35]([O:34][CH3:33])=[O:38])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC(=O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(=O)OC)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (275 mg, 0.617 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and glycine methyl ester hydrochloride (120 mg, 0.956 mmol), WSCI.HCl (180 mg, 0.939 mmol) and 4-dimethylaminopyridine (150 mg, 1.23 mmol) were added, followed by stirring at room temperature for 2 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-60%) to afford the desired product (270 mg, yield 85%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29](S(C)(=O)=O)[N:28]=1.O>CN(C)C=O.C(O)(=O)C>[CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([O:15][C:29]1[N:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:27]([O:26][CH3:25])[N:28]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
3 g (10 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (comp. 1.1) are dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride is added. The mixture is stirred for 1 hour and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. The mixture is stirred at room temperature for 24 hours and then cautiously hydrolyzed with 10 ml of water, the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 ml of ethyl acetate, washed with water, dried over sodium sulfate and distilled to remove solvents. 10 ml of methyl t-butyl ether are added to the residue, and the precipitate is filtered off with suction. Drying results in 2.4 g of a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:9]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=O>O1CCOCC1>[NH2:7][C:8]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:9]=1[CH2:10][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1
Reactant: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a refluxing suspension of lithium aluminum hydride (16.1 g, 424 mmol, 3.50 equiv.) in dioxane (800 mL) was added a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (39.7 g, 121 mmol) in dioxane (250 mL) at such a rate that gas evolution was limited to a safe flow. Upon completion of the addition, the resulting suspension was heated at reflux for 4 h. The reaction was cooled to 0° C., and quenched by the cautious addition of 20% potassium hydroxide. Upon formation of a white, filterable precipitate, the solid was filtered through a course glass sintered funnel, and the eluent concentrated to give 36.3 g (96%) as a light yellow oil which was used without purification. Mass spec.: 314.29 (MH)+.