Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Br)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:13][N:12]([CH2:6][CH3:5])[CH2:11][CH3:10])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:23]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(C)n1-2
Agent: CC(=O)Br
Agent: CCN(CC)CN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCc1nnc2n1-c1ccc(SC)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-methylthio-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetyl bromide (in 0.5 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-methylthio-1-[2-(diethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[N:7]2N=N[N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:29][CH2:30][CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][O:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[C:4]=2[C:3]=1[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[NH2:18][O:17][CH2:16][CH2:15][CH2:14][N:13]1[C:4]2[C:3]([CH3:32])=[C:2]([CH3:1])[N:7]=[C:6]([NH2:10])[C:5]=2[N:11]=[C:12]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCON1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCON
Temperature: 50 °C
Reaction time: 72 h
Yield: 18.4 %

Procedure:
A solution of 2-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-α]pyridin-7-yl)propoxy]-1H-isoindole-1,3(2H)-dione (8.50 g, 19.6 mmol) and triphenylphosphine (10.3 g, 39.2 mmol) in 1,2-dichlorobenzene (200 mL) was heated at 125° C. for 2 days, then was allowed to stand at room temperature for 3 days. The solvent was removed under reduced pressure. To the resulting residue was added methanol (40 mL) and 1 M HCl (20 mL). The solution was heated at 50° C. for 5 h, then was allowed to cool to room temperature and was concentrated under reduced pressure. Water (20 mL) was added and the mixture was extracted with chloroform (3×10 mL). NaOH (1 M) was added to the aqueous layer to adjust the pH to 11. The aqueous layer was extracted with chloroform (4×30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with CMA in chloroform) to yield 1.00 g of 1-[3-(aminooxy)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][OH:11]
Reactant: COc1cccc(OC)c1
Reactant: CCCCC1CO1
Agent: Cl
Solvent: ClCCl
Product: CCCCC(CO)c1ccc(OC)cc1OC
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 5° C mixture of m-dimethoxybenzene 27.6g (0.20 mole), anhydrous stannic chloride 52.1g (0.20 mole) and 200 ml of methylene chloride which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 20.0g (0.20 mole) in 50 ml of methylene chloride. The exothermic reaction temperatutre is maintained at 3° C by the rate of addition. After the addition is complete, the reaction is stirred at 5° C for 30 minutes, at which time it is poured into iced concentrated hydrochloric acid. The layers are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with water followed by 5% sodium bicarbonate solution and finally water. The last water wash is neutral to pH paper. The methylene chloride solvent is removed on a rotary evaporator at 40° C bath temperature. This residue is then fractionally distilled in vacuo. The third fraction, 140°-142° C/.2 mm, is shown by nmr and ir to be the desired product. The yield is 25.32g (55%, theory).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:16]([OH:17])=[O:15])=[CH:19][CH:20]=1)[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1

Procedure:
Followed Scheme 2, A conditions: Starting materials: 2-chloro-6-methoxyquinoline (Intermediate 1) (100 mg, 0.52 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid. 1H NMR (DMSO-d6, 400 MHz): δ 13.06-12.90 (bs, 1H), 10.14 (s, 1H), 8.36-8.33 (d, 2H), 8.30-8.27 (d, 1H), 8.11-8.06 (m, 3H), 7.97-7.94 (d, 1H), 7.38-7.34 (dd, 1H), 7.20 (s, 1H). MS (ESI): m/z 266.08 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:28][Mg+].[Br-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][C:17]([OH:19])([CH3:28])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (18.5 mg, 0.043 mmol) in dry toluene (3 mL) was cooled to 0° C. A solution of MeMgBr (3.0M in THF, 45 μL, 3 equiv) was added. After 15 min, the mixture was warmed to rt slowly and stirred 2 h. LC-MS found reaction completed. The reaction was quenched by satd aq NH4Cl solution (2 mL), diluted with EtOAc (10 mL), washed with 1% aq HCl (3 mL), brine (3 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to afford (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one (8.0 mg, 42%). LC-MS (3 min) tR=1.75 min, m/z=472, 474 (M+Na); 1H NMR (CDCl3) 7.32-7.21 (m, 3H), 7.12-6.98 (m, 4H), 6.89 (m, 1H), 5.65 (q, 1H), 2.89 (m, 1H), 1.50 (d, 3H), 1.15 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[NH:19][C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[N:19]([CH2:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])[C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cscc2c(=O)n1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCn1c(=O)n(CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 62 %

Procedure:
The title compound was prepared by starting with 3-[2-[4-(bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (7.48 g, 16 mmol) was reacted with methyl acrylate as described in Example 1 to produce 5.48 g (62%) of methyl 3-[3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as a cream-colored solid after recrystallization from CH2Cl2 /ether/hexane, mp 111°-114° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH:10]2[C:15]3([CH2:21][C:20](=[O:22])[NH:19][CH2:18][CH2:17][S:16]3(=[O:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CS(C)=O.C(OCC)(=O)C>[C:3]1([CH2:9][CH:10]2[C:15]3([CH2:21][C:20](=[O:22])[N:19]([CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH2:18][CH2:17][S:16]3(=[O:23])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1CCCCBr
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (30 mg) in dimethylsulfoxide (5 ml) was heated at 60° C. under nitrogen atmosphere. After one hour, 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (0.32 g) and 1,4-dibromobutane (5 ml) were added to the mixture at room temperature. After two hours, the mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml) and brine (30 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column (10 g) (ethyl acetate:hexane=1:1) to give 1-phenylmethyl-10-(4-bromobutyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.CCCCCC.C([Li])CCC.[C:30]1(=[O:35])[O:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[OH:35][CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:34]
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCO)Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 11.9 %

Procedure:
A solution of 1.0 g of 2-(trans-3-aminostyryl)benzothiazole dissolved in 15 ml of anhydrous tetrahydrofuran was cooled to -78° C. and 2.8 ml of a n-hexane solution (1.55M) of n-butyl lithium was added dropwise in a nitrogen gas atmosphere. After a mixture was stirred at the same temperature for 25 minutes, 375 mg of γ-butyrolactone was injected, followed by stirring for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude crystals obtained were washed with ethyl ether and dried to obtain 160 mg (yield 12%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:34][N:35]([CH:37]=O)[CH3:36].S(Cl)(Cl)=O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:25][C:18]4[CH:19]=[CH:33][C:15]([CH2:37][N:35]([CH3:34])[CH:36]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (200 mg) in tetrahydrofuran (10 ml) was added a drop of DMF. Then, after adding thionyl chloride (0.042 ml), the mixture was stirred under nitrogen atmosphere for 1 hour. After the solvent and excessive thionyl chloride were distilled off under reduced pressure, the mixture was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]anilin (127 mg) and triethylamine (1.6 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. After stirring the mixture at room temperature under nitrogen atmosphere overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (methanol:ethyl acetate=1:8) to give 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (257 mg) as a yellow amorphous material (Compound 42).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>C1CCCCC1.CCOC(C)=O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(OC)cc1[N+](=O)[O-])OCC
Temperature: 120 °C
Yield: 97.4 %

Procedure:
A mixture of 1-(bromomethyl)-4-methoxy-2-nitrobenzene (14.2 g; 57.71 mmol; 1 eq) and triethyl phosphite (9.49 mL; 54.82 mmol; 0.95 eq) is heated at 120° C. for 1 h. TLC analysis using cyclohexane/EtOAc [1/1] as eluent showed that the reaction is complete. The reaction mixture is cooled down to room temperature. The crude is purified by flash chromatography to afford 16.2 g (93%) of an orange oil. Storage at −25° C. allows the product to crystallize. It is then washed with petroleum ether and filtered to afford 14.4 g (82%) of the title compound. 1H NMR (DMSO-d6) δ 7.50 (d, J=3.0 Hz, 1H), 7.45 (dd, J=9.0, 2.0 Hz, 1H), 7.28 (dd, J=9.0, 2.0 Hz, 1H), 3.98-3.89 (m, 4H), 3.84 (s, 3H), 3.64 (s, 1H), 3.57 (s, 1H), 1.14 (t, J=7.0 Hz, 6H). HPLC (max plot) 99%; Rt 3.29 min. LC/MS: (ES+): 304.3, (ES−): 302.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH3:15])[N:3]=1.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.[OH-].[Na+]>CC#N.O.O>[CH3:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[C:2]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[N:3]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNc1nc(Cl)nc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
To a mixture of 4-chloro-N-methyl-6-phenyl-1,3,5-triazin-2-amine (1.0 g, 4.5 mmol) in CH3CN:H2O (1:1, 5 mL) was added trans-4-aminocyclohexanecarboxylic acid (973 mgs, 6.80 mmol). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred at 80° C. for 36 h. The resulting mixture was diluted with water and filtered to provide the crude product, which was purified by HPLC to afford 300 mg (20% yield) of the desired product. MS (ES+): m/e 328.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([CH3:30])[CH2:28]OS1(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:29]([CH3:28])[CH2:30][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Product: COc1ccc(-c2ccc3ccn(C[C@H](C)NC(=O)OC(C)(C)C)c3c2)cc1

Procedure:
This compound was synthesized from 6-(4-methoxy-phenyl)-indole (synthesized from 6-bromo-indole according to Carrera, G. M. et al. Synlett 1994, 1, 93-94) and (S)-4-methyl-2,2-dioxo-[1,2,3] oxathiazolidine-3-carboxylic acid tert-butyl ester as described in example 4, step A].
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].O1CCCC1.[CH3:18][C:19]([CH3:29])([CH2:27][CH3:28])[CH:20]([CH2:23][C:24](=O)[CH3:25])[CH:21]=O>Cl.C(OCC)(=O)C>[CH3:18][C:19]([C:20]1[CH:23]=[C:24]([CH3:25])[N:1]([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH:21]=1)([CH3:29])[CH2:27][CH3:28]
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: CCC(C)(C)C(C=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1cc(C)n(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
N-aminophthalimide (476 mg) and 5N hydrochloric acid (5 drops) were added to the tetrahydrofuran solution (20 mL) of the compound prepared in Example 54 (1 g). The reaction mixture was stirred for 20 minutes under argon gas atmosphere. Ethyl acetate (100 mL) was added to the reaction mixture. The reaction mixture was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (Yamazen corporation, high flash 2 L, n-hexane→ethyl acetate/n-hexane=1/4) to obtain the title compound (675 mg) having the following physical data.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H:5]([NH2:20])[CH2:4][C@@H:3]1[NH:21][C:22]([C:24]([OH:26])=[O:25])=[NH:23].[ClH:27]>>[CH3:1][C@H:2]1[O:7][C@H:6]([O:8][CH:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[CH:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H:5]([NH2:20])[CH2:4][C@@H:3]1[N:21]=[C:22]([NH2:23])[C:24]([OH:26])=[O:25].[ClH:27]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](N)C[C@@H]1NC(=N)C(=O)O
Agent: Cl
Product: C[C@H]1O[C@H](OC2[C@@H](O)[C@@H](O)C(O)[C@H](O)[C@H]2O)[C@@H](N)C[C@@H]1N=C(N)C(=O)O

Procedure:
The first two process steps are directed to the hydrolysis of kasugamycin with hydrochloric acid. First, a 30% weight per volume (w/v) solution of kasugamycin hydrochloride in 5 N HCl is produced, e.g., 225 grams of kasugamycin+700 ml of 5 N HCl, and the solution is heated and stirred to yield a clear solution. Second, the solution is heated for eight hours at 90° C. using a forced air oven or the like. The solution does not need to be agitated while it is heated for the eight hours. After the eight hours has expired, the solution will be brown in color.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]3[CH2:20][CH:15]2[C:16](=[O:21])[O:17]3)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:22][CH2:23][N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].[OH2:31]>>[CH:25]([N:24]([CH:28]([CH3:30])[CH3:29])[CH2:23][CH3:22])([CH3:27])[CH3:26].[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:19][CH:18]([OH:17])[CH2:20][CH:15]2[C:16]([OH:21])=[O:31])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Reactant: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Temperature: 40 °C

Procedure:
To a solution of 3 (800 mg, 2.73 mmol) in water (15 ml) in a 20 ml microwave reaction vessel was added DIPEA (1.2 ml, 6.8 mmol) and a stir bar. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. After 1 min of pre-stirring, the reaction was irradiated for 40 min to a set temperature of 100° C. After cooling to 40° C., the transparent solution was concentrated in vacuo, and the residual brown oil co-evaporated 3 times with acetonitrile to remove any residual water. The crude product 4, in the form of a DIPEA salt, was immediately taken forward to the next step. LC/MS (Method A): tR=1.29 min, >95%, m/z (ESI+)=312 (MH+).
Reaction SMILES: ClC1C=C2C(C(N)=NN2C)=CC=1.[NH2:13][C:14]1[CH2:19][O:18][CH2:17][C@:16]([C:21]2[CH:22]=[C:23]([NH:28][C:29]3[C:37]4[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=4)[N:31]([CH3:39])[N:30]=3)[CH:24]=[CH:25][C:26]=2[F:27])([CH3:20])[N:15]=1>>[Cl:38][C:34]1[CH:33]=[C:32]2[C:37]([C:29]([NH:28][C:23]3[CH:24]=[CH:25][C:26]([F:27])=[C:21]([C@@:16]4([CH3:20])[CH2:17][O:18][CH2:19][C:14]([NH2:13])=[N:15]4)[CH:22]=3)=[N:30][N:31]2[CH3:39])=[CH:36][CH:35]=1
Reactant: Cn1nc(Nc2ccc(F)c([C@]3(C)COCC(N)=N3)c2)c2ccc(Cl)cc21
Agent: Cn1nc(N)c2ccc(Cl)cc21
Product: Cn1nc(Nc2ccc(F)c([C@@]3(C)COCC(N)=N3)c2)c2ccc(Cl)cc21

Procedure:
With 6-chloro-1-methyl-1H-indazol-3-ylamine (CAS1031927-22-6) the [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(6-chloro-1-methyl-1H-indazol-3-yl)-amine as a light grey solid; (calculated) C19H19ClFN5O [387.84]; (found) [M+H]+=388.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:15]C(C)(C)C)(=[O:14])=[O:13])[C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1cn2cc(Br)cc(S(=O)(=O)NC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn2cc(Br)cc(S(N)(=O)=O)c2n1
Yield: 55.4 %

Procedure:
6-bromo-N-tert-butyl-2-methylimidazo[1,2-a]pyridine-8-sulfonamide (1.0 g, 2.8 mmol) was stirred in TFA (6 mL) for 16 h. The TFA was removed in vacuo and a saturated solution of NaHCO3 was added. The aqueous layer was extracted with DCM, the combined organic portions dried, filtered and concentrated to yield 6-bromo-2-methylimidazo[1,2-a]pyridine-8-sulfonamide (0.45 g, 54%), which was used without further purification. LCMS Method Y: retention time 1.44 min; [M+1]=292.16.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[C:5]([F:15])[CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:24][C:23]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:38][CH:39]=4)=[O:32])=[CH:24][C:23]=3[CH:49]=2)=[CH:4][C:5]=1[F:15]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-[(2-ethoxy)ethoxy]-3-fluorophenyl borate (355 mg) and 7-bromo-1-formyl-N-(4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (517 mg). To the solution was added potassium carbonate (344 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (48 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10 :1) and recrystallized from ethanol to give 7-[4-(2-ethoxy)ethoxy-3-fluorophenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 20) (476 mg, 76%) as white crystals.