Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][OH:12])[NH:2]1.[CH3:13][C:14](OC(C)=O)=[O:15].C([O-])([O-])=O.[K+].[K+].CC(O)=O>CCOC(C)=O.CO>[OH:12][CH2:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:14](=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (Aldrich, 350 mg, 2.14 mmol) in EtOAc (4.3 mL) and MeOH (1.1 mL) was added Ac2O (243 μL, 2.57 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. K2CO3 was then added to neutralize the AcOH, and the reaction mixture was filtered through a pad of CELITE®, washing with EtOAc. The filtrate was concentrated in vacuo to give the title compound (316 mg, 72%) as a white solid. 1H NMR (CDCl3, 1.5:1 mixture of amide rotamers) δ 7.26-7.10 (m, 4H), 5.17 (d, J=18.0 Hz, 0.5H), 4.90 (dt, J=5.1, 9.4 Hz, 0.5H), 4.66-4.44 (m, 1H), 4.39-4.23 (m, 1H), 3.66-3.55 (m, 1H), 3.55-3.45 (m, 1H), 3.14 (dd, J=5.9, 16.3 Hz, 0.5H), 3.02 (dd, J=6.2, 15.8 Hz, 0.5H), 2.92-2.76 (m, 1H), 2.27 (s, 1H), 2.24 (s, 2H); MS(ESI+) m/z 206.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Br:24]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Br:24]
Reactant: CCC1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC1N=C(c2ccccc2F)c2c(ccc(N)c2Br)N(C)C1=O
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
9.3 g (0.03 M) of rac-7-amino-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 80 ml of glacial acetic acid. The solution is cooled to 10° C., treated dropwise with 5 g (1.62 ml) of bromine, stirred at 10° C. for a further 10 minutes after the addition of bromine and then concentrated. The residue is treated with a mixture of ice and 10% sodium bicarbonate solution, extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. The residual oil is purified on a 200 g silica gel column with methylene chloride/ethyl acetate (10:1) and crystallised from ether. There is obtained rac-7-amino-3-ethyl-6-bromo-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 248° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][CH:14]=[C:13]([O:25]CC2C=CC=CC=2)[C:12]=1[O:33][CH3:34])[CH3:2].Cl.[H][H]>CCOCC.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([OH:25])[C:12]=1[O:33][CH3:34])[CH3:2]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OCc2ccccc2)ccc(OCc2ccccc2)c1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Yield: 113.2 %

Procedure:
A mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dibenzyloxy-2-methoxybenzamide (130 mg, 0.27 mmol), 5% Pd/C (50 mg), 0.5 ml 4 M HCl in ether and 5 ml ethanol was shaken in a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg pure title compound as an oily hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:40]=[C:35]5[CH2:36][O:37][CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:41])[N:27]([CH3:42])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:40]=[C:35]5[CH2:36][O:37][CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:41])[N:27]([CH3:42])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCOC3)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 131e (220 mg, 1.0 eq., 0.39 mmol), NaBH4 (73 mg, 5.0 eq., 1.90 mmol), and methanol (10 mL). The mixture was stirred at room temperature for 1 h and quenched with water (5 mL). It was then concentrated under reduced pressure and resulting residue was extracted with dichloromethane (3×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 131 (105 mg, 47%). MS-ESI: [M+H]+ 571.8. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.59-7.53 (m, 4H), 7.48 (s, 1H), 5.73 (s, 1H), 4.81 (s, 2H), 4.51 (bs, 2H), 4.12-4.05 (m, overlap, 5H), 3.73 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH2:15])=[S:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH:18]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[S:14][C:18]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: NC(=S)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(CNC(=O)OCc3ccccc3)sc2-c2cccnc2)cc1
Reaction time: 2 h
Yield: 60.3 %

Procedure:
In 40 ml of acetonitrile was dissolved 1.12 g of benzyloxycarbonylaminothioacetamide. In the solution was suspended 2.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added while stirring 0.8 ml of triethylamine. The mixture was stirred for 2 hours under reflux. The resultant was left standing for cooling, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. The residue was recrystallized from ethyl acetate-isopropylether to give 1.3 g (yield 56%) of 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 93°-94° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16])(=O)C.[OH-].[Na+]>CCO>[Br:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:15])([CH3:14])[C:5](=[O:16])[NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-acetyl-6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (5.2 g) were added 1N aqueous NaOH solution (11 ml) and EtOH (44 ml), and the mixture was stirred at room temperature for one hour. After the reaction was complete, the solvent was concentrated, and thereto was added dropwise a 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate, and this ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue (4.1 g) was used in the subsequent reaction without further treatment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH3:24])=[CH:22][CH:21]=3)[N:12]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: Cc1ccc(CBr)cc1
Reactant: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2cnn(Cc3ccc(C)cc3)n2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-1,2,3-triazol-5-yl)phenyl]methyl]carbamate (i.e. the product of Step E, Example 9) (0.24, 0.9 mmol), 4-methylbenzyl bromide (0.17 g, 1.1 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (4.5 mL) was heated at 100° C. for 24 h. The reaction mixture was allowed to cool and then partitioned between diethyl ether (50 mL) and water (30 mL). The organic layer was separated, washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and ethanol (2:1 mixture) and concentrated onto silica gel, and then purified by flash column chromatography using 5 g of silica gel (0 to 50% gradient of ethyl acetate in hexanes as eluant) to provide methyl N-[[2-chloro-5-[2-[(4-methylphenyl)methyl]-2H-1,2,3-triazol-4-yl]phenyl]methyl]carbamate, a compound of the present invention, as a colorless oil (0.11 g)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=[N:12]O)=[CH:9][CH:10]=1)=[O:5])[CH3:2]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]#[N:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C=NO)[nH]1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc(C#N)[nH]1
Temperature: 140 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 5-(hydroxyimino-methyl)-1H-pyrrole-2-carboxylic acid ethyl ester (as prepared in the previous step) (500 mg, 2.75 mmol) in acetic anhydride (5 mL) was stirred at 140° C. for 2 h. The cooled mixture was quenched with ice and then dichloromethane was added and the mixture was made basic with solid sodium bicarbonate. The layers were separated, the organic layer was washed with saturated sodium bicarbonate (2×10 mL), water (2×10 mL), then dried over Na2SO4. The solvent was removed in vacuo to yield 260 mg (58%) of the title compound as a light brown crystalline solid. 1H-NMR (400 MHz, CDCl3): δ 10.45 (br s, 1H), 6.89 (m, 1H), 6.83 (m, 1H), 4.42 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[O:21][CH3:22]>CN(C=O)C.CCO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 10% Pd/C (0.068 g) in DMF (2 mL) under nitrogen was added a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I33) (2.0 g, 6.5 mmol) in EtOH (50 mL) and the resulting suspension was stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was filtered through celite, washing with ethyl acetate (100 mL). The filtrate was evaporated to dryness to give the title compound (I26) (1.42 g, 72%) as a light brown solid; 1H NMR (400 MHz, CDCl3) δ 6.66-6.58 (m, 3H), 4.21 (s, 2H), 3.76-3.88 (m, 4H), 2.53 (tt, J=12.1, 3.5 Hz, 1H), 1.84-1.75 (m, 2H), 1.55 (tdd, J=11.5, 6.4, 3.1 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>CS(C)=O.[Cu]I>[N:37]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]2[N:17]4[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc2nnc(Cc3ccc4ncc(-n5ccnc5)cc4c3)n2n1
Temperature: 120 °C
Yield: 22 %

Procedure:
To a reaction vial was added 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (71 mg, 0.2 mmol, 1.0 equiv), CuI (7 mg, 0.04 mmol, 0.008 equiv), L-proline (9 mg, 0.08 mmol, 0.4 equiv) and K2CO3 (83 mg, 0.60 mmol, 3.0 equiv). The system was evacuated and filled with nitrogen (3×). A solution of degassed imidazole (27 mg, 0.4 mmol, 2.0 equiv) in DMSO (1 mL) was then added. The reaction was heated at 120° C. for 18 hours. The solvent was removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10 to return the title compound (15 mg, 22% yield). Analytical data presented in Table 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[F:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:25][CH2:24][CH2:23][F:22])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OCCF
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCCF)nc3ccc(Br)cc32)n1
Yield: 78.5 %

Procedure:
A solution of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), 2-fluoroethan-1-ol (236 mg, 3.68 mmol) and cesium carbonate (1.2 g, 3.68 mmol) in N,N-dimethylformamide (3 mL) was stirred in a 20-mL sealed tube under nitrogen overnight at room temperature. The reaction mixture was diluted with 30 mL of water and the precipitate was collected by filtration to give 340 mg (79%) of 4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid; LC-MS: m/z=+352 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[NH:27][C:22]=2[CH:21]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccc(Cl)cc3[nH]2)[nH]1
Yield: 49.1 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 400 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 436 mg of 4-chlorobenzene-1,2-diamine and 440 mg N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 3.5 ml of pyridine and 3.5 ml of dimethylformamide and then in 7 ml of acetic acid. After refluxing for thirty minutes and purification by silica column chromatography, eluent: CH2Cl2/MeOH: gradient from 100/0 to 90/10, 260 mg of 2-[(6-chloro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[Cl:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:14])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)[CH2:18][CH2:17][CH2:16][Cl:15]
Reactant: ClCCCBr
Reactant: COC(=O)Cc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCl)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a suspension of NaH (60%, 1.8 g, 44.9 mmol) dispersion in a mixture of DMF (60 mL), (5-Bromo-pyridin-2-yl)-acetic acid methyl ester (8.6 g, 37.4 mmol) was added under N2. After stirring and cooling on ice for 1 h, 3-chloro-1-propyl bromide (7.07 g, 44.9 mmol) was added dropwise and stirring was continued for 30 min under 10 degrees Celsius, then water was added and the mixture and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated in vacuo. The oily residue was purified by chromatography (Petroleum ether:EtOAc=15:1) to give an oil (6.87 g, 60%). MS: calc'd 305 (MH+), exp 305 (MH+). 1H NMR (400 MHz, CDCl3-d) 8.64 (d, 1H, J=2.4 Hz), 7.84 (dd, 1H, J=2.4, 8.4 Hz), 7.28 (s, 1H), 3.90-3.84 (m, 1H), 3.71 (s, 3H), 3.55 (t, 2H, J=6.4 Hz), 2.32-2.20 (m, 1H), 2.14-2.05 (m, 1H), 1.88-1.67 (m, 2H).
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]1=O.Cl>CS(C)=O.CO.C(OCC)(=O)C>[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][CH:22]1[C:11]#[N:12]
Reactant: CC1(C)CCCC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)CCCC1C#N
Temperature: 0 °C
Reaction time: 30 h
Yield: 31 %

Procedure:
Tosylmethyl isocyanide (3.76 g, 19.3 mmol) was dissolved in dimethylsulfoxide (15 mL) and cooled to 0° C. Solid potassium t-butoxide (6.3 g, 59.2 mmol) was added and a thick brown precipitate formed. The reaction mixture was warmed to room temperature and 2,2-dimethylcyclopentanone (2.0 mL, 16.0 mmol) was added in anhydrous methanol (680 μL) and the reaction mixture was stirred for 30 hours. It was diluted with ethyl acetate, acidified with hydrochloric acid and extracted with hexanes. The extracts were dried over magnesium sulfate, filtered and the solvent was removed to provide a brown oil which was purified by chromatography on silica gel eluted with 0-50% dichloromethane in hexanes to yield a yellow oil (612 mg, 31%).
Reaction SMILES: C([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21]([OH:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>>[CH2:19]1[C:20]2[NH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]([C:21]([OH:23])=[O:22])[CH2:17][CH2:18]1
Reactant: O=C(O)C1CCCc2c1c1ccccc1n2Cc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(O)C1CCCc2[nH]c3ccccc3c21

Procedure:
To 40 g. 9-benzyl-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid in one liter of liquid ammonia was added, with stirring and portionwise, 8.6 g. of sodium. Ammonium chloride was added portionwise until the blue color of the mixture was dissipated. The ammonia was evaporated, water was added and the mixture was extracted with ether. The aqueous solution was chilled and acidified with dilute hydrochloric acid and the resulting solid was collected by filtration and washed with water to give 23 g. of the title compound; m.p. 163°-165°C. (benzene-methyl alcohol).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:15])([CH3:3])[CH3:2].[CH2:16]([O:19][C:20]1[C:29]([CH3:30])=[CH:28][C:23]([C:24]([NH:26]O)=[NH:25])=[CH:22][C:21]=1[CH3:31])[CH:17]=[CH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:16]([O:19][C:20]1[C:29]([CH3:30])=[CH:28][C:23]([C:24]2[N:26]=[C:9]([C:8]3[CH:7]=[C:6]([CH3:15])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:13]([CH3:14])[CH:12]=3)[O:11][N:25]=2)=[CH:22][C:21]=1[CH3:31])[CH:17]=[CH2:18]
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1C
Reactant: Cc1cc(C(=O)O)cc(C)c1OC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1c(C)cc(-c2noc(-c3cc(C)c(OC(C)C)c(C)c3)n2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
To a mixture of 4-isopropoxy-3,5-dimethyl-benzoic acid (175 mg, 794 μmol), 4-allyloxy-N-hydroxy-3,5-dimethyl-benzamidine (165 mg, 792 μmol) and DIPEA (128 mg, 993 μmol) in DCM (10 mL), TBTU (321 mg, 1.00 mmol) is added at 0° C. The mixture is stirred at 0° C. for 1 h, then at rt for 5 h, before it is diluted with EA (100 mL) and washed with sat. aq. NaHCO3 solution (2×30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The residue is dissolved in dioxane (10 mL) and stirred at 90° C. for 2 days. The solvent is evaporated and the residue is dried to give crude 3-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isopropoxy-3,5-dimethyl-phenyl)-[1,2,4]oxadiazole (346 mg); LC-MS: tR=1.25 min, [M+1]+=393.47.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH3:24].C(OCC)(=O)C>COCCOC.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.CCCCCCC>[F:23][C:21]1[CH:22]=[C:17]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:18]([CH3:24])=[CH:19][CH:20]=1
Reactant: Cc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(F)cc1-c1ccccc1
Yield: 85.5 %

Procedure:
Potassium carbonate (659 mg, 4.27 mmol), phenylboronic acid (388 mg, 3.18 mmol), 2-bromo-4-fluorotoluene (0.20 mL, 1.59 mmol), and tetrakis(triphenylphosphine)palladium(0) (92 mg, 5mol %), in DME (3 mL) were sealed in a microwave vessel and heated at 80° C. for 1200s, then 120° C. for 1200s. Ethyl acetate (5 mL) was added and the reaction was filtered and concentrated in vacuo. The crude material was then purified by flash column chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 3-fluoro-6-methylbiphenyl (253 mg, 1.36 mmol, 86%).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C@@H:8]([N:23](C)[C:24]([NH:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:25])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.[CH3:50]OC1C=C(NC(N[C@H](CO)CCN2CC(C(=O)C3C=CC(F)=CC=3)C2)=O)C=C(OC)C=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:13]2[CH2:12][N:11]([CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:25])[N:26]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH3:50])[CH2:7][OH:6])[CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1cc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(F)cc3)C2)cc(OC)c1
Reactant: COc1cc(NC(=O)N(C)[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc(OC)c1
Product: COc1cc(OC)cc(N(C)C(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)c1

Procedure:
1-{(S)-1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-1-methyl-urea is deprotected in the same manner as 1-(3,5-Dimethoxy-phenyl)-3-{(S)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-urea in Example 34 to afford 3-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-1-(3,5-dimethoxy-phenyl)-1-methyl-urea. [M+H] 463.5