Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([NH2:13])([CH2:11][CH3:12])[CH3:10].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]([CH2:11][CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCC(C)N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(C)Nc1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine and 3.13 mL (31.0 mmol) sec-butylamin are added to 12 mL ACN. The reaction mixture is stirred at 120° C. for 2 h, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: ClCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4ccccn4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 2-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A5 pure as a yellow solid (27 mg, 47%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.51 (m, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H), 7.60 (t, 1H), 7.36 (m, 1H), 7.13 (t, 1H), 5.40 (m, 1H), 3.65 (m, 2H), 3.07 (s, 3H), 2.72 (m, 2H), 2.45 (m, 2H), 2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 484.5 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]([NH:22][NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=O)=O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:20]4[S:39][C:24]([CH:26]5[CH2:28][CH2:27]5)=[N:23][N:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1nc2n(c1C(=O)NNC(=O)C1CC1)C1CC(C1)c1ccc(Br)cc1-2
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2n(c1-c1nnc(C3CC3)s1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 25 °C

Procedure:
Methyl 10-bromo-3-(2-(cyclopropanecarbonyl)hydrazinecarbonyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was dissolved in toluene (0.56 mL) and treated with Lawesson's reagent (1.3 equiv., 29.8 mg, 0.07359 mmol). The reaction was heated to reflux until judged complete by LC/MS analysis. The solution was cooled to room temperature. Water was added and the solution was extracted 2× with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated in vacuo. The crude material was carried forward without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:10]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5]1.[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:29])[O:1][CH2:2][CH2:3][CH:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(CCO)C2
Solvent: c1ccncc1
Product: CCOC(=O)COc1cccc2c1CCC(CCOC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 36.4 %

Procedure:
A mixture of ethyl [5,6,7,8-tetrahydro-6-(2-hydroxyethyl)-1-naphthyloxy]acetate (50 mg), N,N-diphenylcarbamoyl chloride (50 mg), and pyridine (32 mg) was stirred at 100° C. for 1 hour and 40 minutes, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed successively with water, aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford 2-[5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl]ethyl N,N-diphenylcarbamate (31 mg) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10](OCCOC)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COCCOn1nc(-c2ccc(F)cc2)c2cc(N)ccc21
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-(2-methoxyethoxy)-1H-indazole-5-ylamine (115 mg, 0.36 mmol) in dioxane (5 mL) was added 4-fluorophenyl isocyanate (50 μL, 0.44 mmol). The reaction was stirred overnight at room temperature. It was then filtered and the solid dried in a vaxuum oven. The solid was then taken up in 6N HCl (10 mL) and methanol (10 mL) and heated to 80° C. for 2 hours. The reaction was then cooled to room temperature and quenched with NaHCO3 (100 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined and dried with magnesium sulfate (MgSO4) and concentrated to a solid to afford the title compound (25 mg, 19% yield). 1H NMR (CDCl3) δ 13.1 (br s, 1H), 9.32 (s, 2H), 8.28 (s, 1H), 7.94 (dd, 2H), 7.52 (d, 1H), 7.48 (dd, 2H), 7.38 (t, 2H), 7.33 (dd, 1H), 7.11 (t, 2H); ES-MS (m/z) 364 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25](NC)[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrC1C=C(C2C=[C:46]([C:48]([OH:51])(C)[CH3:49])N=C(C3C=CC=CN=3)C=2)C=NC=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]4[CH:26]=[C:25]([CH2:46][CH:48]([OH:51])[CH3:49])[N:24]=[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:22]=4)[CH:18]=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Product: CC(O)Cc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
is prepared analogously to (5″-[1-(1-Isopropyl-piperidin-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.175) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with 2-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (Example 2.80; step2)
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:19])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.C1COCC1.O.[OH-].[K+].OO>C1COCC1>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:19])[CH2:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: CC1=CO[C@@H]2O[C@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@H]2[C@@H](C)CO[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of anhydrodihydroartemisinin (AHA) (2.08 g, 7.8 mmol) in THF (20 ml), was dropwise added a solution of BH3/THF complex in THF soln. (1 M; 14 ml) with ice-cooling. After being stirred at room temperature for 1 h, the mixture was treated with THF-water (1:1; 4 ml), followed by a mixture of aq. KOH (10%; 10 ml) and aq. H2O2 (50%; 4 ml).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11]Br)[CH:3]=1.[OH:13][CH2:14][C:15]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:11][O:13][CH2:14][C:15]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc([N+](=O)[O-])c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-nitrobenzene (2.12 g, 7.21 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.75 g, 6.0 mmol) were combined in dimethylformamide (18 mL) and cooled to 0° C. The reaction was treated with sodium hydride (288 mg, 12.0 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.4 g (38%). 1H-NMR (CDCl3, 500 MHz) δ 8.20 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 7.33-7.38 (m, 4H), 4.37 (s, 2H), 3.75-3.78 (m, 2H), 3.43 (s, 2H), 3.00-3.04 (m, 2H), 2.20-2.22 (m, 2H), 1.82-1.87 (m, 2H), 1.42 (s, 9H). Mass spec.: 507.10 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([CH:30]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1)=[O:8].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:52])[O:42][C:43]1[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=1[CH3:51]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:52])[O:42][C:43]2[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=2[CH3:51])=[CH:30][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(OC(=O)Nc2ccc(C)c(C(=O)Nc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 16×100 mm vial was charged with 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.100 g, 0.24 mmol), 4-(dimethylamino)pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 mL), and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl carbonochloridate (0.048 g, 0.24 mmol) in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at room temperature for 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford mesityl 4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenylcarbamate 47 as a bright yellow solid. MS m/z found 580 [MH+]; calc. for C33H37N7O3=579.69.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:15])=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[Si:16]([O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[C:3]([CH3:15])=[N:4]2)[CH2:9][CH2:10]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nn([C@H]2CC[C@H](O)CC2)c(C)c1I
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c(C)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)cyclohexanol (206.0 mg, 0.6434 mmol), tert-butyldimethylsilyl chloride (0.194 g, 1.29 mmol), 4-dimethylaminopyridine (20 mg, 0.1 mmol), imidazole (131 mg, 1.93 mmol) and DCM (4 mL, 60 mmol) was stirred at rt for 20 min. The material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 3% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=435.14 (100) [MH+]. HPLC: tR=2.26 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.[C:24]([Si:28]([O:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]=[C:39]=[O:40])[CH2:34][CH2:33]1)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:24]([Si:28]([CH3:30])([CH3:29])[O:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:39]2=[O:40])[CH2:34][CH2:33]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxy-phenyl)amine (1.0 g, 3.52 mmol) (from Example 1d supra) in tetrahydrofuran (50 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.7 mL, 4.22 mmol) (Aldrich). After stirring at −78° C. for 20 minutes, tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane (1.1 g, 4.22 mmol) (from Example 17b supra) was added. The mixture was stirred at −70° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.61 g, 34%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH2:8]([C:5]1[N:4]=[C:3]([CH2:2][N:1]=[CH:12][N:13]([CH3:15])[CH3:14])[O:7][N:6]=1)[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCc1noc(CN)n1
Product: CCc1noc(CN=CN(C)C)n1
Yield: 74.8 %

Procedure:
A mixture of 26 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 30 ml of dimethylformamide dimethylacetal is heated for 6 1/2 hours to 80° C. (bath temperature). Subsequently, 16 ml of methanol is removed by distillation and the resultant product is purified by bulb tube distillation, thus obtaining 27.9 g (74.8%) of an oil having a boiling point of 130-150° C. (0.05 torr); nD20 :1.4924.
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH3:9][C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: Cc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-methyl-1,3-thiazole hydrobromide (19.4 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (2.47 g, 12.6 mmol) in absolute ethanol (100 mL) was added triethylamine (8.00 mL, 57.4 mmol). The mixture was stirred at room temperature for 2 days. The solid material was removed by filtration and washed with diethyl ether (100 mL). The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×50 mL). The solid residue was treated with water (100 mL), and the mixture was stirred for 30 minutes. The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and then dried in vacuo to afford 2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (1.76 g, 45%); 1H NMR (500 MHz, DMSO-d6): δ 2.39 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 8.86 (s, 1H); M+308.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
Molten zinc chloride (0.22 g), trimethylhydroquinone (2.47 g) and anhydrous dioxane (10 cc) are introduced into a 250 cc reactor. The mixture is heated to 40°-45° C. and a solution of 1,7,11,15-tetrachloro-3,7,11,15-tetramethyl-hexadec-2-ene (6.8 g) in dioxane (7 cc) is then added over the course of 20 minutes. Stirring is continued for 1 hour 30 minutes. The reaction mixture is poured into an aqueous solution (50 cc) of ammonium chloride (100 g/liter). The batch is extracted with ethyl acetate (twice 50 cc) and the organic phases are then dried over magnesium sulphate. After filtration and evaporation of the solvent, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyltridecyl)-chroman-6-ol is obtained in a yield of 43.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][C:13]([CH2:18][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[OH:20])([CH3:17])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:28][CH3:29]>>[CH2:28]([O:20][CH:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][C:13]1([CH3:17])[CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:29]
Reactant: CCI
Reactant: CC1(CC(O)c2ccccc2)CCc2c(cnn2-c2ccc(F)cc2)C1
Product: CCOC(CC1(C)CCc2c(cnn2-c2ccc(F)cc2)C1)c1ccccc1

Procedure:
Using a procedure analogous to Example 35, the alcohols from Examples 117 and 118 were reacted with iodoethane to give Examples 119 and 120, respectively. MS found: (M+H)+=379.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=O)=[O:5])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNCC1
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:28]=[O:29])C.O>C1COCC1>[CH:28]([C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: Cc1cc(C)c2c(c1C)OCC2c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(-c3cccc(C=O)c3)coc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 203 (1.77 g, 5.57 mmol) in THF (20 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 4.18 mL, 6.68 mmol) under argon atmosphere at −78° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise DMF (0.86 mL, 11.14 mmol) at the same temperature, and the mixture was stirred for 30 minutes, and then was warmed to room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure to give 1.48 g (yield is quantitative) of the title compound. Oily matter.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f6) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18].CS(O[CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:45]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:46][C@H:47]([OH:59])[C:48]2[C:56]3[S:55][C:54](=[O:57])[NH:53][C:52]=3[C:51]([OH:58])=[CH:50][CH:49]=2)=[CH:40][CH:39]=1)(=O)=O>C(#N)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[CH:40][C:41]([CH2:44][N:45]([CH2:46][C@H:47]([OH:59])[C:48]4[C:56]5[S:55][C:54](=[O:57])[NH:53][C:52]=5[C:51]([OH:58])=[CH:50][CH:49]=4)[C:60](=[O:61])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:42][CH:43]=3)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2nc4ccccc4s2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.22 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream foam. Yield 0.34 g.