Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:23][OH:22])[CH:29]=3)[CH:21]=[CH:20][C:5]=2[C:6]=1[CH3:19])=[O:10]
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CO)c3)ccc12

Procedure:
(2,4-Dichloro-phenyl)-[6-(3-hydroxymethyl-phenyl)-3-methyl-benzofuran-2-yl]-methanone was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone and 3-(Hydroxymethyl)phenylboronic acid as described in method 1 step 5. 1H-NMR (CDCl3) δ 7.62 (d, J=8 Hz 1H), 7.57-7.53 (m, 1H), 7.48 (dd, J=9 Hz, J=2 Hz, 1H), 7.46-7.44 (m, 2H), 7.40 (d, J=2 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.26 (m, 2H), 4.68 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(isopropyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C23) (4.07 g, 11.8 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (3.08 g, 83%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.4 mmol), N-methyl-piperazine (123 mg, 1.2 mmol) and acetic acid (120 mg, 1.2 mmol) in methanol (50 mL) was stirred at room temperature for 60 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (130 mg, 0.6 mmol) was added. After the addition, the mixture was stirred at room temperature for overnight. Methanol was removed under reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (36 mg, yield 19%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.29 (s, 3H), 2.12-2.73 (br s, 8H), 3.47 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.18-7.21 (m, 6H), 7.23-7.25 (m, 2H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][C@@H:25]([CH3:28])[CH2:26][NH2:27])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:27][CH2:26][C@@H:25]([NH:24][C:23](=[O:29])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:28])[N:8]=1
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)[nH]1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 127.4 %

Procedure:
A mixture of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine (2.0 g, 4.5 mmol; Example 6, Step 4), (S)-tert-butyl-1-aminopropan-2-ylcarbamate (1.0 g, 5.8 mmol; Example 23, Step 2), and diisopropylethyl amine (2.4 mL, 13.5 mmol) in dry acetonitrile was heated at 85° C. for 16 h. An additional charge of (S)-tert-butyl-1-aminopropan-2-ylcarbamate (145 mg, 0.8 mmol) was added and the reaction was maintained at 85° C. for 5 h. After allowing to cool to rt, the reaction was diluted with EtOAc (40 mL), washed with water (2×15 mL), dried (Na2SO4), and concentrated to provide 2.6 g of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate which was carried forward without further purification: LCMS (m/z): 585.0 (MH+), tR=1.07 min.
Reaction SMILES: C1COCC1.FC(F)(F)S(O[C@H:12]1[CH2:19][C@@:18]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:20](=[O:21])[C@H:14]([C:15](=[O:29])[CH:16]=[C:17]2[O:27][CH3:28])[C@:13]1([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])(=O)=O.Cl[Si:40]([CH3:43])([CH3:42])[CH3:41].C([N-]C(C)C)(C)C.[Li+]>CCOC(C)=O.CCCCCC>[CH3:28][O:27][C:17]1[C:18]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:20](=[O:21])[C:14]3([C:15](=[O:29])[C:16]=1[Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:12]([C:13]3([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:19]2
Reactant: C[Si](C)(C)Cl
Reactant: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](OS(=O)(=O)C(F)(F)F)[C@@]2(C)CCC=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1=C([Si](C)(C)C)C(=O)C23C(=O)C1(CC=C(C)C)CC2C3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A THF (6 mL) solution of 21 (148 mg, 0.300 mmol, 1 equiv.) and chlorotrimethylsilane (1.9 mL, 15 mmol, 50 equiv.) was cooled to −78° C. in a 25-mL recovery flask, and a freshly prepared THF solution of lithium diisopropylamide (0.50 M, 3.0 mL, 1.5 mmol, 5 equiv.) was added slowly. The resulting yellow-orange solution was stirred at −78° C. for 30 min and subsequently quenched at −78° C. with saturated aqueous NaHCO3. After warming to room temperature, the mixture was extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. Flash column chromatography (100 mL SiO2, 95:5 hexane:EtOAc) afforded 69.7 mg (0.168 mmol, 56% yield) of 22 as a faint yellow oil. TLC Rf 0.52 (8:2 hexane:EtOAc). 1H NMR (600 MHz; C6D6): δ 5.41 (t, J=7.4 Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.22 (s, 3H), 2.59 (dd, J=15.1, 6.4 Hz, 1H), 2.53-2.49 (m, 1H), 2.48 (dd, J=15.1, 8.4 Hz, 1H), 2.18 (m, 1H), 1.86 (ddd, J=13.5, 11.2, 5.2 Hz, 1H), 1.79 (ddd, J=13.5, 11.2, 5.4 Hz, 1H), 1.74 (dd, J=14.0, 5.4 Hz, 1H), 1.68-1.66 (m, 1H), 1.66 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H), 1.07 (s, 3H), 0.98 (dd, J=7.9, 5.4 Hz, 1H), 0.35 (s, 9H). 13C NMR (126 MHz; C6D6): δ 200.2, 194.7, 184.3, 134.4, 131.56, 131.55, 124.6, 119.5, 74.1, 61.8, 56.8, 48.0, 38.7, 37.7, 27.7, 26.21, 26.10, 25.8, 17.92, 17.77, 16.3, 0.7. FTIR (thin film) νmax: 2968, 2918, 2860, 1762, 1664, 1523, 1451, 1438, 1386, 1233, 1201, 1157, 1042, 962, 845, 761, 691 cm−1. HRMS-ESI (m/z): [M+H]+ calculated for C25H38O3Si, 415.2663. found, 415.2650.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[C:32]([CH:39]=O)=[CH:31]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:39][C:32]4[C:33]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:30][CH:31]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3N)ccc2C(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 7-[(2-amino-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol), 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (730 mg, 5.0 mmol), and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol) in 50 mL of anhydrous toluene was stirred at reflux for 1 h. After being cooled to RT, the mixture was diluted with 2 mL of MeOH and NaBH4 (475 mg, 12.5 mmol) was added, and the mixture was stirred at RT for 30 min. The reaction was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was taken up in water, AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and condensed. The residue was purified by flash column chromatography to give 4,4-dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. MS (ES+): 527.2 (M+H)+. Calc'd for C30H34N6O3 526.27.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:10])[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CC(CC)CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[C:5]#[N:6]
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1cc(N)cc(N)c1
Agent: Cl
Solvent: CCC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N)cc(NCCN2CCCCC2)c1
Yield: 80 %

Procedure:
3,5-Diaminobenzonitrile prepared from step A of example 19 (511 mg, 3.84 mmol), 1-(2-chloroethyl)piperidine hydrochloride (707 mg, 1 eq) and DIEA (1.97 mL, 3 eq) were refluxed in 50 mL of 2-methylbutan-1-ol for 24 h. The reaction mixture was then evaporated to give 751 mg of expected compound which was used in the next step without further purification. m/z (ESI) 245.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(O)(=O)C.ClC(Cl)C>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C1CCN(c2ccc(F)cc2)CC1
Reactant: c1ccc2c(c1)CCN2
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 2 h
Yield: 63 %

Procedure:
Triacetoxylated sodium borohydride (760 mg) was added to a mixture of indoline (300 mg), 1-(4-fluorophenyl)-4-piperidone (580 mg), acetic acid (650 mg) and dichloroethane (30 ml), and the mixture was stirred for 2 hr. The obtained reaction solution was mixed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (470 mg) as white prismatic crystals (yield: 63%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1
Reactant: CN1CCC(O)CC1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCC(Oc2ncccc2OCCO)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 4-hydroxy-N-methylpiperidine (67 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 62 mg (0.25 mmol, 63%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (454 mg, 2.36 mmol) and 2-bromo-3-chloropyridine (418 mg, 1.97 mmol) were combined in dry N,N-dimethylformamide (10 mL) and treated with potassium carbonate (408 mg, 2.95 mmol). After stirring at 120° C. for 48 hours, the mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (4:1, hexanes:ethyl acetate) to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: Cc1cc(SC[C@@H]2[C@@H](N)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1CSc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.15 g, 264.67 μmol) is dissolved in dichloromethane (10 mL). To this mixture is added triethylamine (55.34 μL, 397.01 μmol) and acetyl chloride (28.25 μL, 397.01 μmol). The mixture is stirred at ambient temperature for 10 minutes. The solvent is removed under reduced pressure to give a residue. The residue is purified by flash chromatography (10% to 100% ethyl acetate/hexanes) to give the title compound (100 mg, 164.27 μmol, 62.06% yield); 1H NMR (CD3Cl) δ 1.44 (t, 27H), 1.95 (s, 3H), 2.16 (m, 1H), 2.22 (s, 3H), 2.60 (dd, 1H), 2.78 (bs, 1H), 3.10 (dd, 1H), 4.59 (m, 1H), 5.50 (d, 1H), 6.92 (t, 1H), 7.06 (m, 1H), 7.11 (d, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:32][CH2:31][C:15]2([CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].C1CCCCC=1>C(O)C.[Pd]>[CH2:16]1[C:15]2([CH2:31][CH2:32][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14]2)[CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 106.4 %

Procedure:
Suspend benzyl 9-[2-(isobutylcarbamoylamino)acetyl]-2,9-diazaspiro[5.5]undecane-2-carboxylate (239.78 mmoles; 106.60 g) in ethanol (852.80 mL) and cyclohexene (1.20 moles; 121.90 mL), and add 5% palladium on charcoal (24 g; 55.4% moisture content). Heat the mixture to reflux and stir for 45 mins. Cool the mixture to room temperature, filter through a pad of diatomaceous earth washing the solid with ethanol, and concentrate under reduced pressure to give the final title compound, 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (79.2 g; 94% purity; 100% yield) mass spectrum (m/z):311.2 (M+1).
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:25]3[C:21](=[CH:22][CH:23]=[N:24]3)[N:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][N:18]3[OH:26])=[CH:9][CH:8]=1)[CH3:5].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:26][N:18]1[CH2:17][CH2:16][C:15]2[C:19]1=[N:20][C:21]1[N:25]([C:14]=2[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:4][CH3:5])=[CH:12][CH:11]=2)[N:24]=[CH:23][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CCOc1ccc(Nc2c3c(nc4ccnn24)N(O)CC3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c3c(nc4ccnn24)N(OC(C)=O)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a methylene chloride (0.5 mL) solution containing 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol (2.8 mg), triethylamine (50 μL) and acetic anhydride (50 μL) were added. After this solution was stirred at room temperature for 30 min, the solvent was concentrated, and the residue was purified with PTLC (70% ethyl acetate-hexane) to obtain the title compound (2.3 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:26])[CH2:24][Cl:25].O>CN(C)C=O>[CH3:1][N:2]([CH:24]([Cl:25])[CH:23]([CH3:26])[CH3:22])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: CC(CCl)CBr
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Yield: 40 %

Procedure:
8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g of anhydrous potassium carbonate and 14.4 ml of 1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at a room temperature for 12 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to obtain 4.67 g of the title compound as a pale yellow oil (yield : 40%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C@H:11](CO)[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CN=C1.CN(C)C=[O:44]>>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C@@H:11]([O:44][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Reactant: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)-2-methylpropyl]carbamic acid benzyl ester (4.56 g, 19.2 mmol) in dimethylformamide (140 ml) were added t-butyldiphenylsilyl chloride (6.00 ml, 23.1 mmol) and imidazole (1.57 g, 23.1 mmol) in an ice bath, and the resulting mixture was stirred at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→6:1) as the eluant to afford [(1S)-1-(t-butyldiphenylsilyloxy)-2-methyl-propyl]-carbamic acid benzyl ester (10.1 g, yield 100%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C=CC(Br)=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24]C(N2CCNCC2)=[N:26][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Yield: 93 %

Procedure:
Prepared according to the method for the preparation of 4-(4-bromophenyl)-piperazine-1-carboxylic acid tert-butyl ester, from 5-bromo-2-piperazin-1-ylpyrimidine (5.00 g), to yield the title compound as a white solid (6.55 g, 93%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>C(O)(=O)C.O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:22])(=[O:21])([OH:24])[OH:23]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (400 g, 6.66 mols) in acetic acid (500 ml), sulphuric acid (15 ml) was added, followed by iminostilbene (100 g, 0.518 mols), under stirring at 25-30° C. The resulting reaction mixture was heated to 80-85° C. and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189° C.) separated by filtration, washed with water until neutral and dried at 90-100° C. until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254 nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax=3466, 1677, 1605, 1595 cm−1.