Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:19][CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:35])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH2:20][CH3:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)COCCCCBr
Product: CCN(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 5,6-diphenyl-2-(ethylamino)pyrazine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH:30][C:40](=[O:41])[N:39]([CH3:43])[CH3:38])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and dimethylcarbamoyl chloride (20 μL, 0.222 mmol) are combined and stirred at room temperature for 16 h. Concentrate the crude reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (64 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:3]([CH:28]=[O:29])=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])=[N:16][CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:30]B(O)O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:28]([C:3]1[C:2]([CH3:30])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])=[N:16][CH:17]=1)=[O:29]
Reactant: CB(O)O
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2C=O)cn1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-(3-chloro-2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (150 mg, 0.35 mmol), methylboronic acid (31 mg, 0.53 mmol), Pd(dppf)Cl2 (34 mg, 0.05 mmol) and K3Pa4hydrate (322 mg, 1.40 mmol) were dissolved in 1,4-dioxane (2 mL) and the resulting mixture was heated to 90° C. After 10 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cn1
Yield: 33 %

Procedure:
The titled compound (yield=33%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 2-methoxypyrimidin-5-yl boronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.49 (d, J=5.05 Hz, 2H) 4.01 (s, 3H) 4.78 (t, J=5.31 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 8.10 (d, J=8.59 Hz, 2H) 8.16 (d, J=8.59 Hz, 1H) 8.22-8.29 (m, 1H) 9.33 (s, 2H) 13.02 (s, 1H); ESI-MS: m/z 436.0 (M+H)+.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13]([CH:15]1[CH2:20][C:19]([C:36]#[N:37])([C:21]2[C:29]3[C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[O:26][C:25]=3[C:24]([O:34][CH3:35])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16]1=O)=O>CO>[CH3:35][O:34][C:24]1[C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[C:21]([C:19]2([C:36]#[N:37])[CH2:18][CH2:17][C:16]3[N:10]=[CH:8][NH:9][C:13](=[O:12])[C:15]=3[CH2:20]2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a stirred solution of sodium methoxide (185.3 mg, 3.5 mmol) in 10 ml of methanol was added formamidine acetate (290 mg, 2.78 mmol) and the compound obtained in example 1. The reaction mass was allowed to stir at 60-70° C. for 18 hrs under nitrogen atmosphere. Most of the methanol was evaporated under vacuum and residue was purified by column chromatography to get 200 mg (67.3% yields) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1.O>CN(C)C=O>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC1CCN(CCCCl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(CCCSc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
Dissolve 8.50 g (55 mmol) of 4-nitrothiophenol in 40 mL of dimethylformamide and make basic with 13.7 mL of 4N potassium hydroxide. Add 10.60 g (60 mmol) of N-[3-chloropropyl]-4-methylpiperidine and heat this solution to 100° C. for 3 h. After this time cool the reaction to room temperature. Add 200 mL of water and extract with 2×150 mL of methylene chloride. Acidify the combined organic extracts to pH=1 with 1N hydrochloric acid and extract with 4×150 mL of water. Neutralize the combined aqueous extracts with saturated sodium bicarbonate solution and extract with 3×200 mL of methylene chloride. Dry the organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH2:3][CH2:2][CH2:1]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCCC(Br)c2ccccc21
Yield: 53.3 %

Procedure:
1-Benzosuberone (960 mg, 6.0 mmol), N-bromosuccinic acid imide (1.1 g, 6.3 mmol) and azobisisobutyronitrile (99 mg, 0.60 mmol) were stirred overnight at 80° C. in carbon tetrachloride (8 ml). The reaction solution was mixed with chloroform (60 ml), washed with saturated sodium bicarbonate aqueous solution and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 770 mg (3.2 mmol, 54%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].[Cl:12][C:13]1[C:18]([NH2:19])=[C:17](Cl)[N:16]=[CH:15][N:14]=1>C(O)C>[NH2:19][C:18]1[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])=[N:16][CH:15]=[N:14][C:13]=1[Cl:12]
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (16.9 g, 45.1 mmol) and 4,6-dichloropyrimidin-5-amine (5.7 g, 35 mmol) in ethanol (45 mL) was evenly distributed amongst three tubes and subjected to microwave conditions (CEM apparatus, 300 W max, 150° C. max, 250 psi max, 3 min ramp, 30 min hold) to afford brown solutions; HPLC/LC MS indicated conversion to the desired product. The three reaction mixtures were combined and concentrated in vacuo to afford the crude title compound as a dark brown oil, which was concentrated from toluene (2×30 mL) and carried on without purification: MS (ESI+) for C10H15ClN4O3 m/z 275.0 (M+H)+; MS (ESI−) for C10H15ClN4O3 m/z 273.0 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:34])C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH2:20][S:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:34])[N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(CSc2ccccc2)ns1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(CS(=O)c2ccccc2)ns1

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-N-(3-(phenylthiomethyl)-1,2,4-thiadiazol-5-yl)pyridin-3-amine (Example 470) (250 mg, 0.56 mmol), peracetic acid (32% wt/v, 132 μL, 0.56 mmol in DCM (3 mL) was stirred at rt for 2 h. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by preparative HPLC to give Example 471. (M+H)+=465; 1H NMR (400 MHz, DMSO d6) δ ppm 1.29 (s, 9 H), 4.33 (d, J=13.13 Hz, 1 H), 4.42 (d, J=13.13 Hz, 1 H), 6.91 (td, J=7.84, 1.51 Hz, 1 H), 7.08 (dd, J=7.84, 4.80, 1H), 7.16 (dt, J=7.58, 1.52, 1H), 7.22 (td, J=7.32, 1.76, 1H), 7.41 (dd, J=7.83, 1.52 Hz, 1 H), 7.5-7.7 (m, 5H), 7.75 (dd, J=4.80, 1.51 Hz, 1 H), 8.45 (dd, J=7.83, 1.51 Hz, 1H), 10.84 (s, 1 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccccc3F)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(2-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.49 g of 4,5-bis(4-methoxyphenyl)-2-(2-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:13]=1[NH2:14].C(N(C(C)C)CC)(C)C>CC(O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:12]([CH3:11])=[C:13]([NH:14][C:6]2[C:5]([O:9][CH3:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(C(C)(C)C)cc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A solution of 2,4-dichloro-5-methoxypyrimidine (200 mg, 1.12 mmol), 2-methyl-5-t-butylaniline (192 mg, 1.17 mmol) and diisopropylethylamine (1.5 mL) in 2-propanol (1.5 mL) was heated at 120° C. for 17 h in an oil bath. The mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, EtOAc/Hexane, 0%-100%) to afford the product as a solid (166 mg, 48.6%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[N:20]=[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:18]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([O:16][CH2:14][CH3:15])[N:18]=[C:19]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:27]2)[N:20]=1)[CH3:25]
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: CCOc1cc(OCC)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 115.5 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.2 g), 1-(4,6-diethoxypyrimidin-2-yl)piperazine (1.7 g) and potassium carbonate (1.3 g) in dimethylformamide (20 ml) was stirred at 80° C. for 4.5 hr. The reaction mixture was poured into water(150 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.9 g). The obtained brown oil was purified by silica gel column chromatography to give a pale-yellow oil (2.4 g). The obtained pale-yellow oil was crystallized from ethyl acetate/hexane (2:1, 30 ml) to give the title compound (1.7 g) as white crystals, m.p.=119-120° C.
Reaction SMILES: O[C:2]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH2:22]2)([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10]1)C1C=CC=CC=1.[C:28]1(C)[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[CH:15]([N:11]1[CH2:12][CH2:13][O:14][CH:9]([CH2:2][O:18][C:19]2[CH:20]=[C:21]3[C:25]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH2:22]3)=[CH:26][CH:27]=2)[CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCOC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C)N1CCOC(COc2ccc3c(c2)CC=C3c2ccccc2)C1
Yield: 70.2 %

Procedure:
In 50 ml. of xylene was dissolved 1.5 g. of 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4-isopropylmorpholine and after adding to the solution 5 mg. of p-toluenesulfonic acid, the mixture was refluxed for 8 hours. Thereafter, xylene was distilled off under reduced pressure and the residue was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and eluted using ethyl acetate as the eluent. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 200 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 1.0 g. (yield 70.2%) of 4isopropyl-2-(3-phenyl-6-indenyloxymethyl)morpholine. The citrate of the product had a melting point of 107°-109° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](=[S:9])[NH2:8])=[CH:5][CH:4]=1.CO[CH:16](OC)[CH2:17]Br>Cl.C(O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:9][CH:16]=[CH:17][N:8]=2)=[CH:5][CH:4]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2nccs2)cc1
Yield: 60 %

Procedure:
A stirred solution of 5.0 grams (0.024 mole) of 4-trifluoromethylbenzthioamide, 4.4 grams (0.026 mole) of bromoacetaldehyde dimethyl acetal, and 4 drops of concentrated hydrochloric acid in 50 ml of ethanol was heated at reflux for 18 hours. After this time the reaction mixture was subjected to column chromatography on silica gel. Elution was accomplished using 20% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of 2-(4-trifluoromethylphenyl)thiazole. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:30]=[N:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-n1cc(CBr)cn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cnn(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
27 mg (0.09 mmol) of the compound from Example 5A were dissolved in 2 ml of acetonitrile, and 58 mg (0.18 mmol) of cesium carbonate and 24 mg (0.09 mmol) of the compound from Example 43A were added. The mixture was stirred at 65° C. for 2 h and then at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 25 mg (56% of theory) of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([CH2:24][NH2:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[NH2:25][CH2:24][C:23]1[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=[CH:21][N:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3CN)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nccnc2CN)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(3-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (190 mg, 0.532 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.111 g, 2.66 mmol). The resulting solution was stirred at room temperature overnight. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl. The resulting mixture was concentrated and the residue was purified by prep HPLC. The title compound was obtained (100 mg, 57%) as a white solid. 1H NMR (CD3OD) δ8.30 (d, 1H), 8.07 (d, 1H), 7.21 (d, 1H), 7.09 (d, 1H), 5.66 (dd, 1H), 4.47 (s, 2H), 3.14 (dd, 1H), 2.37 (s, 3H), 2.30 (dd, 1H). MS calcd for (C15H16BN3O5+H)+: 330. MS found: (M+H)+=330.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15].C(O)C>C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:15][NH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[O:4]
Reactant: CCOC(=O)NN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)NNC(=O)c1ccccc1N
Yield: 66.8 %

Procedure:
A mixture of 16.3 g of isatoic anhydride, 10.4 g of ethyl carbazate and 50 ml of ethanol was heated to reflux for 3 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 14.9 g of N-(2-aminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula:
Reaction SMILES: [C:1]([NH:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38](C)[CH:39]=O>O>[CH3:37][N:38]([CH:1]=[N:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccn2cc(CCc3ccc4nc(N=CN(C)C)oc4c3)nc2c1

Procedure:
2-Acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (2.20 g) was added in small portions to a solution of phosphorous oxychloride (1.79 ml) in N,N-dimethylformamide (20 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was diluted with water (200 ml) and stirred for an additional 30 minutes. The mixture was made alkaline with aqueous potassium carbonate and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give dark brown amorphous powder. The crude material was chromatographed on silica gel by eluting with chloroform-methanol (50:1, V/V), followed by recrystallization from a mixture of methanol and diisopropyl]ether to give 2-dimethylaminomethyleneamino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.31 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]=[C:16]=[O:17].O>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CN=C=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl (3R)-3-aminopyrrolidine-1-carboxylate 6-2 (1.813 g, 9.73 mmol) was dissolved in 10 mL CH2Cl2. A solution of methylisocyanate (0.555 g, 9.73 mmol) in 10 mL CH2Cl2 was added. The solution was stirred for 3.5 hours. 50 mL H2O was added and the precipitate was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford tert-butyl (3R)-3-{[(methylamino)carbonyl]amino}pyrrolidine-1-carboxylate 6-3 as a white semi-solid. Free base: 1H NMR (DMSO-d6) δ 6.15 (bs, 1H), 5.63 (bd, 1H, J=4.22 Hz), 4.02 (m, 1H), 3.42-3.34 (m, 1H), 3.28-3.19 (m, 2H), 2.93-2.98 (m, 1H), 2.53 (d, 3H, J=4.58 Hz), 1.99-1.93 (m, 1H), 1.68-1.63 (m, 1H), 1.39 (s, 9H).