Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[C:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]([O:27][C:25]([N:32]1[CH2:37][CH2:36][CH:35]([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:34][CH2:33]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)CC1
Yield: 47.7 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), 1-Boc-4-piperidinol (0.11 g, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.11 mmol) and DMF (1 ml) gave the title compound (70 mg, 46%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:19])([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6](=[O:20])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:19])([CH3:18])[C:11]([OH:13])=[O:12])[C:6](=[O:20])[C:5]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OC(C)(C)C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Yield: 79.2 %

Procedure:
A mixture of tert butyl 2-(2,3-dihydro-6-methoxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.6 g) and trifluoroacetic acid (2.05 g) was stirred in dichloromethane for 20 hours at 35° C. A further addition of trifluoroacetic acid (0.82 g) was made and the solution heated under reflux for 24 hours. The cooled mixture was diluted (dichloromethane) and extracted (sodium carbonate solution). The aqueous extract was acidified (2 M hydrochloric acid solution), extracted (ethyl acetate), dried (magnesium sulphate) and evaporated. The residue was dissolved in ethyl acetate and evaporated (three times) redissolved in hexane and evaporated to give 2-(2,3-dihydro-6-methoxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (1.74 g) as a white solid, m.p. 135-138° C.
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[CH:1]1([CH:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:10][CH2:11]2)[CH3:5])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C1CCNCC1)C1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 91.4 %

Procedure:
Dissolve racemic 4-(1-cyclopropylethyl)-piperidine (1.75 g, 11.42 mmol) and N,N-dimethyl-4-pyridinamine (139.5 mg, 1.14 mmol) in pyridine (15 mL) and dichloromethane (30 mL). Add N-(benzyloxycarbonyloxy)succinimide (3.70 g, 14.84 mmol) and stir the solution for 4 hours. Pour the reaction mixture into 5N HCl and extract twice with EtOAc. Wash the organic extracts with sodium bicarbonate, followed by brine; dry over sodium sulfate; filter; collect the filtrate; and concentrate under reduced pressure. Purify the crude material on a silica gel flash column chromatography using a gradient of 0-20% EtOAc in hexane to give the title compound (3.0 g, 91%) as a clear oil. MS (m/z): 288 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CS(C)=O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[N:19]=[N:20][N:21]=[C:2]1[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc2c(c1)c(-c1ccccc1)nc1nnnn12
Temperature: 100 °C
Yield: 96.7 %

Procedure:
The starting material may be prepared as follows: To a solution of 1.92 g of 2,6-dichloro-4-phenylquinazoline in 30 ml of dimethylsulfoxide was added 0.91 g of sodium azide. The mixture was heated at 100° C. for 1 hour with stirring and then poured into ice-water. The resulting precipitate was collected by filtration, washed with water and dried to give 1.9 g of 7-chloro-5-phenyltetrazolo[1,5-a]quinazoline. Recrystallization from chloroform-ethanol gave pale yellow needles, m.p. 209° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][C@@:56]([F:62])([C:59](O)=[O:60])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[F:62][C@@:56]1([C:59](=[O:60])[NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH2:57][CH2:58][N:54]([C:52]([O:51][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:53])[CH2:55]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Yield: 37.9 %

Procedure:
According to the general procedure D, from #86 (300 mg, 0.45 mmol, 1 eq.), #169 (106 mg, 0.45 mmol, 1 eq.), dichloromethane (10 mL), HATU (194 mg, 0.54 mmol, 1.2 eq.) and diisopropylethylamine (117 mg, 0.9 mmol, 2 eq.) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method P) to afford #193 (149 mg, 37%) as a white solid. HPLC (Protocol X): m/z 873.4 [M+H+], retention time=3.34 minutes (purity=98%).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:10]O)[C:4]=2[CH:3]=[CH:2]1.CC(C[AlH]CC(C)C)C.[F-].[Na+].O>C(Cl)Cl>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:10][C:4]=2[CH:3]=[CH:2]1
Reactant: ON=C1CCCc2[nH]ccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1cc2c([nH]1)CCCCN2
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one oxime (1.2 g, 7.7 mmol) in DCM (anhydrous, 250 mL) was added DIBAL-H (1M solution in DCM, 35 mL) at 0° C. under nitrogen. After 2 hours, NaF (7 g) was added followed by water (2.24 g). After 20 mins, the reaction was filtered through celite and the solvent was removed to give 350 mg of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine as a brown oil
Reaction SMILES: [NH2:1][C:2]([C:27]1[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=1)([C:21]1[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[OH-].N.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:27]4[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([N:1]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[C:21]4[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=4)[CH:4]=3)[NH:9][C:8](=[O:13])[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: COc1ccc(C=O)cc1
Agent: N
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of the title compound of example 42 (11.89 g, 25.03 mmol) in acetic acid (75 ml) was added p-anisaldehyde (6.09 ml, 60.06 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 4 hours after which time it was cooled to 0° C. 10 ml of ammonia hydroxide was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (1:99:0.1 to 5:95:0.1) as eluents to afford the title compound of Example 43A as a white solid (11.58 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(Cl)c2)N1
Yield: 79.9 %

Procedure:
Analogous to the procedure described for Example 1A, Step B, 5-[4-(3-chloro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (1.9 g, 7.15 mmol) was reduced with NaBH4 (135 mg, 3.57 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[4-(3-chloro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.53 g). 1H NMR (CDCl3) δ7.22 (m, 3H), 7.07 (m, 1H), 6.51 (d, 1H), 3.82 (m, 1H), 3.66 (m, 1H), 2.77 (m, 1H), 2.66 (m, 1H), 2.33-2.19 (m, 3H), 2.04 (d, 1H), 1.74-1.45 (m, 5H); MS 268.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][OH:17])=[CH:5][CH:4]=1)[NH2:2].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[CH:11]([C:16]1[N:8]2[CH:7]=[C:6]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1)([CH3:12])[CH3:10]
Reactant: NNc1ccc(Oc2ccccc2CO)cn1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)OCc1ccccc1Oc1ccc2nnc(C(C)C)n2c1
Temperature: 105 °C
Yield: 77 %

Procedure:
A mixture of {2-(6-hydrazino-pyridin-3-yloxy)-phenyl]-methanol (231 mg, 1 mmol) and isobutyryl chloride (938 μL, 9 mmol) was heated at 105° C. for 3 hours. The reaction was cooled to ambient temperature and quenched with saturated NaHCO3. The aqueous was extracted with ethyl acetate and the organics combined, dried over sodium sulfate, and concentrated in vacuo to an oil. The residue was purified by flash chromatography (eluting with 2% methanol/ethyl acetate) to give the title compound (136 mg, 39% for two steps).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:2]=[CH2:3].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:27]([CH2:29][OH:30])[CH:28]=1>>[OH:30][CH2:29][C:27]1[CH:28]=[C:23]([NH:22][C:8]2[N:7]=[C:6]3[N:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]3=[CH:10][N:9]=2)[CH:24]=[CH:25][C:26]=1[N:31]1[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(CO)c3)nc2n1-c1ccccn1

Procedure:
10 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 29-1 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:44])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:20][CH:19]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.O.CO>[OH-].[K+]>[C:40]([O:39][C:37]([CH:19]1[CH2:20][CH:21]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:44])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)NCC(C)C)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1F
Yield: 16.2 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 4.2 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(isobutylcarbamoyl)pyrrolidine-2-carboxylate in a mixture of 6.8 cm3 of a normal aqueous potassium hydroxide solution, 30 cm3 of distilled water and 140 cm3 of methanol. After treatment, there is obtained 0.65 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-isobutylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 160° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][Cl:9])[CH2:3][CH2:4][CH3:5].[N-:10]=[N+:11]=[N-:12].[Na+].[OH-].[Na+]>CN(C=O)C.CCOCC>[ClH:9].[CH2:2]([NH:6][CH2:7][CH2:8][N:10]=[N+:11]=[N-:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNCCCl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCNCCN=[N+]=[N-]
Yield: 68.8 %

Procedure:
7.0 g of 2-butylamino-ethyl chloride hydrochloride (Org. Synth. IV 1963, 333) are stirred together with 7.9 g of sodium azide in 50 ml of DMF at 500. After cooling, 82 ml of 1N sodium hydroxide solution are added dropwise. The mixture is taken up in 700 ml of ether, washed with water and, after drying the ether phase, treated with 25 ml of hydrochloric acid (5 molar in dioxane). After evaporating the ether phase, the residue is suspended in ether. The crystals are filtered and washed with ether. There are obtained 5 g of 2-butylamino-ethyl azide hydrochloride, Rf=0.14.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:14])=[C:6]([C:10]([OH:13])=[CH:11][CH:12]=1)[C:7]([OH:9])=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:34][C:35]1[C:40]([CH2:41][NH:42][CH2:43][CH2:44][OH:45])=[C:39]([CH3:46])[CH:38]=[C:37]([CH3:47])[N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[C:40]([CH2:41][N:42]([CH2:43][CH2:44][OH:45])[C:7](=[O:9])[C:6]2[C:10]([OH:13])=[CH:11][CH:12]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[CH3:14])=[C:39]([CH3:46])[CH:38]=[C:37]([CH3:47])[N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Reactant: CCOc1ccc(O)c(C(=O)O)c1C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(O)c(C(=O)N(CCO)Cc2c(C)cc(C)nc2OCc2ccccc2)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of 3-ethoxy-6-hydroxy-2-methylbenzoic acid (114d, 0.168 g, 0.856 mmol) in THF (4.0 mL) was added 1,1′-carbonyldiimidazole (0.155 g, 0.91 mmol), and the reaction was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, and 2-({[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}amino)ethanol (Cpd KK, 330 mg, 1.10 mmol) was added. Heating was then continued at 60° C. for 16 hour. The reaction mixture was cooled to room temperature, and 10M NaOH (0.3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and was then poured into ethyl acetate and washed with 1M KH2PO4 and water. The organic layer was concentrated and purified by column chromatography (0-80% ethyl acetate/dichloromethane) to give N-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-3-ethoxy-6-hydroxy-N-(2-hydroxyethyl)-2-methylbenzamide (114e, 0.274 g, 69% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.CN.[CH:28]([N:31](CC)C(C)C)(C)C>C1COCC1>[CH3:28][NH:31][C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (36 mg, 0.09 mmol) in 1 mL THF was added methylamine (2 M in THF, 0.13 mL, 0.26 mmol), followed by N,N-diisopropylethylamine (12 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The resulting crude title compound was used in the next step without further purification. HPLC/MS: retention time=4.06 min, [M+H]30 =386.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:32])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(#N)C>[O:25]([C:24]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCCOc1ccc2[nH]c(=O)ccc2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of water (50 ml) and acetonitrile (50 ml) are added 6-(3-aminopropoxy)carbostyril hydrochloride (5.0 g) and potassium carbonate (3.4 g) at room temperature. The mixture is stirred at room temperature for 2 hours, and cooled to -5° C. To the mixture is added dropwise phenyl chlorocarbonate (3.9 g) while the temperature of the mixture is kept below 0° C. The mixture is stirred at the same temperature for 1 hour, and thereto is added water (100 ml), and then the mixture is further stirred for 0.5 hour. The precipitated crystals are collected by filtration, and washed successively with water and acetone to give 6-(3-phenoxycarbonylaminopropoxy)carbostyril (6.0 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][Si:16](Cl)([Cl:18])[CH3:17].C([Li])CCC>>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([Si:16]([Cl:18])([CH2:15][Cl:14])[CH3:17])=[CH:3][CH:4]=1
Reactant: C[Si](Cl)(Cl)CCl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Product: C[Si](Cl)(CCl)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound can be prepared by reaction of equimolar quantities of 4-bromobiphenyl, chloromethyldichloro(methyl)silane, and n-butyllithium according to the procedure of Example 3.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1([CH3:32])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:41])=[O:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(S(C)(=O)=O)cn3)cc2)COC1(C)C
Reaction time: 0.67 h
Yield: 114.5 %

Procedure:
To a stirred solution of (4S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfinyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (227 mg) in dichloromethane (5 ml) was added m-CPBA (155 mg) and stirring was continued at RT for 40 min. The reaction mixture was then diluted with aq. Na2SO3 solution and extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo to give (S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfonyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (269 mg, 70% purity, 94% yield) as a brown oil. MS (ISP): 477.4 ([M+H]+), 421.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3n2c(=O)c1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Acetoxy-10-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethyl]-4-oxo-4,10-dihydro-benzo[4,5]imidazo[1,2-α]pyrimidine-2-carboxylic acid methyl ester (33 mg, 0.064 mmol) was treated with trifluoroacetic acid (0.20 mL) and stirred for one hour at room temperature. After this time, the mixture was concentrated and the crude residue was the desired product (27 mg, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32]CC)=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:38]>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([NH2:38])=[O:32])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 24 h

Procedure:
To a solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (0.5 g) in tetrahydrofuran (5 ml) was added NH3 (5 ml, 4N methanol solution). After being stirred for 24 hours, the solvent was removed. The residue was purified by chromatography on silica gel to give (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetamide (220 mg).
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[S:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:16]=2[N:17]=1>ClCCCl>[Cl:23][C:18]1[C:16]2[N:17]=[C:13]([S:3][CH3:4])[S:14][C:15]=2[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CSSC
Reactant: Nc1nc2c(Cl)cc(Cl)cc2s1
Agent: CC(C)(C)ON=O
Solvent: ClCCCl
Product: CSc1nc2c(Cl)cc(Cl)cc2s1
Reaction time: 16 h

Procedure:
43.7 g (0.47 mol) of dimethyl disulfide and 154.5 g (1.5 mol) of tert-butyl nitrite were added to a solution of 34 g (0.16 mol) of 2-amino-4,6-dichlorobenzothiazole in 1 liter of 1,2-dichloroethane. Stirring was carried out for 16 hours, followed by washing with water and 10% strength sodium hydroxide solution, drying over magnesium sulfate and evaporating down.