Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:30])[CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:31]([O:30][CH:10]([CH:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:12])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(C)C(COCc1ccccc1)OC(C)=O
Yield: 95.7 %

Procedure:
In chloroform, 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol, 26.34 g of acetic anhydride and 10.42 g of triethylamine were heated under reflux for 17 hours. The reaction mixture was treated in a conventional manner and purified by silica gel column chromatography to give 4.56 g of 2-acetyloxy-1-benzyloxy-3-hexadecyloxybutane.
Reaction SMILES: C([Mg]Cl)(C)C.CON(C)[C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11].[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:23]1=2.Cl>C1COCC1.O>[O:22]1[C:23]2[CH:31]=[CH:30][C:29]([C@@H:9]([OH:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:11])=[CH:28][C:24]=2[O:25][CH2:26][CH2:27]1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccc2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol) was added to a suspension of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) keeping the temperature below −10° C. (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. 1N HCl (300 mL) was cooled on ice bath to +10° C., the reaction mixture was poured into the acidic water solution and extracted with TBME=tert-butyl methyl ether. The ether phases were washed with water, brine and dried (Na2SO4). Filtration and evaporation of solvents afforded a crude product as a slightly yellow oil that was purified by flash chromatography using TBME:Heptane=1:2 as eluent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[CH3:11][C:12]([S@:15](/[N:17]=[CH:18]/[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])([CH3:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:18]([NH:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1(c2ccc3ccccc3c2)CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)NC(CCC1OCCCO1)C1(c2ccc3ccccc3c2)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A flame dried flask under N2 was charged with anhydrous Et2O (3 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 6.78 mL, 3.39 mmol) and cooled to −78° C. (R,E)-2-methyl-N-((1-(naphthalen-2-yl)cyclohexyl)methylene)propane-2-sulfinamide (524 mg, 1.54 mmol) in anhydrous Et2O (3 mL) was added dropwise and the solution was stirred at −78° C. for 1 h, then allowed to warm to RT overnight. After 20 h sat'd aqueous Na2SO4 solution (4 mL) was added and the suspension was filtered, dried (Na2SO4), filtered and concentrated. Purification on the Biotage with a 25M column and an ethyl acetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100% EtOAc for 5 CV) gave the title compound (581 mg, 83%) as a clear oil. HPLC (JPK method) Rt=2.61 min; 1H NMR (400 MHz, CDCl3) 7.85-7.80 (m, 4H), 7.53 (d, J=8.8 Hz, 1H), 7.48-7.45 (m, 2H), 4.38 (t, J=5.13 Hz, 1H), 4.10-3.99 (m, 2H), 3.77-3.62 (m, 2H), 3.25 (d, J=8.8 Hz, 1H), 3.15-3.10 (m, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.51 (d, J=11.7 Hz, 1H), 2.03-1.90 (m, 2H), 1.64-1.59 (m, 4H), 1.49-1.42 (m, 2H), 1.31-1.23 (m, 4H), 1.12 (s, 9H), 0.87-0.83 (m, 1H); 13C NMR (100 MHz, CDCl3) 138.5, 133.6, 132.0, 128.2, 128.1, 127.5, 126.9, 126.2, 126.0, 102.1, 67.0, 66.7, 57.0, 46.4, 35.0, 34.8, 32.8, 26.2 (d), 25.9, 23.3, 22.6, 22.2; LC-MS 10.4 min, (M+1)+458 @10.6 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].Br[C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C>[CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:41]4[CH:42]=[N:43][CH:44]=[N:45][CH:46]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc2C)cc1
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cncnc4)cc3)oc2C)cc1
Temperature: 86 °C
Reaction time: 0.33 h

Procedure:
A 50 mL flask was charged with 2-methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionic acid ethyl ester (198 mg, 0.371 mmol), 5-bromopyrimidine (54 mg, 338 mmol), and 5 mL of isopropanol. The flask was purged with N2 three times. After 20 min, palladium acetate (3.0 mg, 0.04 mmol) and triphenylphosphine (3.5 mg, 0.04 mmol) were added. Following addition of a solution of sodium carbonate (43 mg in 1 mL H2O), the mixture was heated to 86° C. for 4 h. The solvent was removed under reduced pressure and the remaining residue taken up in CH2Cl2 (25 mL) and extracted with 0.5 N NaOH (25 mL). The aqueous layer was back extracted with an additional 25 mL CH2Cl2 and the organic layers combined. The organic layer was washed with 1 N NaOH (25 mL) and H2O (25 mL) and then dried and concentrated in vacuo. Flash chromatography provided the desired product. 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 9.20 (s, 2H), 8.16 (d, 2H), 7.65 (d, 2H), 6.88 (d, 2H), 6.75 (d, 2H), 4.21 (q, 2H), 4.20 (t, 2H), 3.00 (t, 2H), 2.39 (s, 3H), 1.48 (s, 6H), 1.21 (t, 3H); MS (EI) 4.88.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(F)c3)nc2n(CC)c1=O
Yield: 48.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3 -diethyluracil and 2.79 g (15.2 mmol) of 3,4-difluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.12 g (yield 49%) of Compound 116 as gray plates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:34])([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:34])([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 48.3 %

Procedure:
Following General Procedure I, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-2-methylpropylcarbamate (600 mg, 1.3 mmol) was reacted with NBS (330 mg, 1.9 mmol) to afford the desired product (350 mg, 51%) as a yellow solid: ESI MS m/z 557 [C27H29BrN2O4S+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([F:14])[C:7]=1[C:15](O)([CH3:20])[C:16]([F:19])([F:18])[F:17].N1C=CC=CC=1>>[Cl:3][C:15]([C:7]1[C:6]([F:5])=[CH:11][C:10]([O:12][CH3:13])=[CH:9][C:8]=1[F:14])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(F)c(C(C)(Cl)C(F)(F)F)c(F)c1
Yield: 94 %

Procedure:
A thionyl chloride (25 ml) solution of 2-(2,6-difluoro-4-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (8.7 g, 34.1 mmol) and pyridine (26 mg, 0.34 mmol) was stirred at 70° C. for 3 hours. Then, the reaction was concentrated in vacuo and diluted with water. The product was extracted with hexane and the organic layer was dried over sodium sulfate, filtered and concentrated to furnish 8.84 g (94% yield) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of bis(4-chlorophenyl)methanol (2.0 g) in dichloromethane (20 ml) was added oxalylchloride (1 ml). The mixture was stirred for 4 hours and the solvent was removed in vacuo. The residue was dissolved in n-hexane (20 ml) and filtered off. The solvent was removed in vacuo to give colorless oil of bis(4-chlorophenyl)methyl chloride (2.15 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH2:25]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (89.3 mg, 0.5 mmol), 2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.86 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H), 2.57 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@H](O)Cc3ccccc3)c2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to CH2Cl2 (8.0 mL). This mixture was added to 1-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(R)-propanol (381 mg, 0.80 mmol) in a 25 mL round-bottom flask with magnetic stirrer under N2. After stirring at room temperature overnight, the solution was concentrated in vacuo, the residue was diluted with water, and the solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product (250 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm particle size; UV detection at 254 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, methanol; 40-70% B in A in 6 min). The product-containing eluate was partially concentrated under reduced pressure to remove MeOH. The residual solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. Concentration gave the free amine (130 mg, 43%) as a white solid. LC-MS (ESI) m/z 375 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([OH:11])[CH:10]=1)=[O:5])C.CCO.O.[OH-].[Li+]>O>[OH:11][N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]1
Reactant: CCOC(=O)c1cn(O)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
1-Hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol) and EtOH (25 mL) were combined with a pre-dissolved solution of lithium hydroxide monohydrate (1.6 g, 38.2 mmol) and water (10 mL), and stirred at room temperature for 4 hours. The mixture was partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuum to yield the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(OC)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
81 mg (64%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(4-methoxyphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 110 °C
Yield: 87.4 %

Procedure:
A mixture of 2-bromo-5-nitro pyridine (300 mg, 1.48 mmol) and pyrrolidine (313 mg, 4.41 mmol) in toluene (5 mL) was heated at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, poured onto ice-water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 5-nitro-2-pyrrolidin-1-yl-pyridine (250 mg, 88%) as a solid.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+].CCN(C(C)C)C(C)C.Br[CH2:48][CH2:49][O:50][CH3:51]>C(Cl)Cl>[CH3:51][O:50][CH2:49][CH2:48][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:19][CH2:20]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (200 mg, 0.45 mmol, 1.00 equiv) in DCM (10 mL) was added hydrogen chloride (conc., 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, extracted with DCM (40 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in DMF (5 mL) and DIEA (333 mg, 2.58 mmol, 6.00 equiv) and 1-bromo-2-methoxyethane (598 mg, 4.30 mmol, 10.00 equiv) were added. Stirring was continued for 2 h at 65° C. The mixture was diluted with DCM (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 43.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to give the desired 2-[(3R)-12-([4-[(2-methoxyethyl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide (50 mg) as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 5.32-5.23 (m, 2H), 3.91-3.83 (m, 1H), 3.52 (t, 2H, J=5.1 Hz), 3.38 (s, 3H), 3.19-2.98 (m, 3H), 2.91-2.71 (m, 3H), 2.69-2.55 (m, 1H), 2.39-2.21 (m, 4H), 2.11-2.01 (m, 2H), 1.72-1.23 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[C:17](O)=[O:18])[CH3:12].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][CH:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:18])[CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[CH3:10]
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
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: CN(C)C=O
Product: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
DIPEA (0.26 mL, 1.5 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (185 mg, 0.5 mmol), 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) and HATU (247 mg, 0.65 mmol) in DMF (2 mL) and the mixture stirred at RT for 16 hours. The mixture was poured onto water (30 mL), extracted with ethyl acetate (3×15 mL), the combined organic extracts washed with 1N citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired compound (32 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 1.55 (s, 9H), 3.15 (s, 3H), 3.5 (t, 2H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (s, 1H), 6.7 (m, 2H), 7.1 (d, 1H), 7.8 (d, 1H), 7.95 (d, 1H), 8.7 (s, 1H); m/z 535 (M−H)−
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.C[N:17](C=O)C>>[F:15][C:4]([F:3])([F:14])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[NH2:17])=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: Nn1ccc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A suspension of NaH (6.5 g, 162 mmol, 60% in mineral oil) in DMF (54 mL) at 0° C. is treated with 6-trifluoromethylindole (2.0 g, 10.8 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (6.1 g, 54 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice and filtered through a pad of Celite. The filtrate is extracted with Et2O (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-30% EtOAc in heptane to afford 6-trifluoromethyl-indol-1-ylamine (1.79 g, 83%). MS: 201 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H), 7.67 (d, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 6.45 (d, 1H), 4.83 (s, NH2, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[C:22](Cl)(Cl)=[O:23]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22](=[O:23])[NH:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2

Procedure:
0.15 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine is dissolved in 10 ml of pyridine and treated with 1.44 ml of a 14.3% solution of phosgene in toluene. The mixture is heated to 60° for 5 minutes and then evaporated in vacuo. The residue is partitioned between benzene and water. The benzene phase is washed successively with water, with sodium hydrogen carbonate solution and with water. The solvent is evaporated in vacuo. The residue is chromatographed on 15 g of silica gel while eluting with benzene/ethyl acetate (19:1 and 9:1). After recrystallization from ether/hexane, there is obtained pure 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 223°-225°.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([C:7]2[N:8]([S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cccs2)c(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 603 mg) at room temperature, and the mixture was stirred for 15 min. Thiophene-2-sulfonyl chloride (2.39 g) was added to the reaction mixture, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2→2:3) to give the title compound as a colorless oil (yield 750 mg, 23%).