Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.O1CCOCC1.[Cl-].[Na+].[NH2:42][NH2:43]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:5]3[C:4](=[CH:9][CH:8]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:6]=3)[N:3]=[C:2]([NH:42][NH2:43])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NN)nc(-c3cccc(Cl)c3)c2c1
Yield: 76 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.0040 mol), described in International Patent Specification WO 00/39082, in hydrazine (20 ml) and dioxane (40 ml) was stirred at 70° C. for 20 minutes. Saturated sodium chloride solution was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (2.15 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH; 95/5 to 90/10; 70–200 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.5 g (76%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-hydrazino-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol, mp.186° C. (intermediate 11).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:23]=1>>[CH2:24]([C:21]1[S:20][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:23][CH:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCCCc1ccc(Br)s1
Product: CCCCc1ccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)s1

Procedure:
rac-3,4-Dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2,3 g (10 mmol) was reacted with 2.4 g (11 mmol) of 2-bromo-5-butylthiophene under the conditions described in Example 15. Chromatography of the crude product over 100 g of silica gel and crystallization from petroleum ether yielded colorless crystals with m.p. 80°-82°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21]
Reactant: O=Cc1ccccc1
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 75 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with benzaldehyde (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=150 cm) was 6.93 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, (2-bromophenyl)phenylmethanol (GC retention time: 23.7 min) was obtained in 75% yield. 1H NMR (400 MHz, CDCl3) δ: 2.59-2.78 (m, 1H), 6.11 (s, 1H), 7.09 (dt, J=7.6, 2.0 Hz, 1H), 7.19-7.36 (m, 6H), 7.47-7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 74.7, 122.6, 126.9, 127.51, 127.53, 128.25, 128.29, 128.9, 132.6, 141.9, 142.3.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(C)(C)C)=O.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1N>CC(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
In a 1.5 l sulfonation flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetone (240 ml), were added isopropenyl acetate (66 ml, 0.60 mol), tert-butyl nitrite (40 ml, 0.30 mol) and cupric sulfate pentahydrate (2.5 g, 0.001 mol). The resulting light green-blue suspension is stirred for 15 min at ambient temperature. A solution of 2,4,6-trichloroaniline (40 g, 0.20 mol), dissolved in acetone (320 ml) was added dropwise over a period of 2 hours. During the addition, bubbling observed, temperature rose to 30° C. and the mixture turned green. 1 Hour after the addition, an amber solution was obtained. The mixture was stirred for 6 hours. Completion of the reaction was confirmed by GC-MS. The crude mixture was concentrated under reduce pressure to remove most of the acetone and the residue was dissolved in ethyl acetate (300 ml) and wash with 1M hydrochloric acid (2×300 ml), water (2×300 ml) potassium carbonate solution (300 ml) followed by water (300 ml). Combined basic aqueous were re-extracted with of ethyl acetate (150 ml). Combined organics were dried over sodium sulfate, and the organics were concentrated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one (53 g) as a dark brown oil. The crude was dissolved again in ethyl acetate (200 ml) and washed with 1M sodium hydroxide (300 ml) 1M hydrochloric acid (100 ml) and water (200 ml). The organic layers were dried and evaporated to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one 49 g dark brown oil which crystallized.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9]NC(=O)C2C=CC=CC=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Sm+2].[I-]>CO.O1CCCC1>[CH3:8][C@H:7]([NH2:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NNC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Sm+2]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](N)c1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To (S)-(-)-2-phenyl-2-(2-benzoylhydrazino)ethane (0.40 g, 1.66 mmol, 89% ee) in methanol (7 mL) was added rapidly dropwise a solution of samarium(II) iodide (70 mL of a 0.05M solution in tetrahydrofuran). After complete addition, the reaction was allowed to stir for 30 min. The reaction was then concentrated on a rotovap, and to the resulting residue was added 1M HCl (15 mL). The aqueous layer was extracted with diethyl ether (8×25 mL). The aqueous layer was made basic to litmus by the addition of 3M NaOH and then was extracted with diethyl ether (8×25 mL). The combined ether extractions were dried over a small amount of magnesium sulfate. Concentration of the ether solution on a rotovap provided the product (S)-(-)-α-methylbenzylamine as a colorless oil (0.144 g, 72%): [α]D20 =-37.1° (c 1.33, C6H6), 1H NMR (CDCl3): δ 1.40 (d, JHH =6.3 Hz, 3H, CH3), 1.70 (br, 2H, NH), 4.14 (q, JHH =6.3 Hz, 1H, CH), 7.25 (m, 1H, Ph), 7.45 (m, 4H, Ph). The enantiomeric purity of the amine product (S)-(-)-α-methylbenzylamine was determined to be 89% ee using chiral capillary GC methods (J & W Cyclodex B column, 80° C., isothermal, (R) t1 20.57 min; (S) t2 21.33 min).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:11]([C:17]#[N:18])=[CH:10][CH:9]=1.[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@H:21]([CH3:23])[OH:22]>CS(C)=O>[C:17]([C:11]1[C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:8]([NH:19][C@H:20]([C@@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1)#[N:18]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Temperature: 80 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
K2CO3 (1.97 g, 14.3 mmol) was added to a mixture of 4-fluorobenzo[b]thiophene-7-carbonitrile [(1.01 g, 5.70 mmol), which was prepared according to the procedures reported in WO 2004016576] and D-threonine (815 mg, 6.84 mmol) in DMSO (15 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for 15 h. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried with Na2SO4. Removal of the solvent gave the crude (2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (1.20 g, 76%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.81 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 4.33 (m, 1H), 1.34 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(Cl)ccc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
2-Amino-6-chloro-3-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 811 mg of the titled compound (yield, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.Cl.Cl.[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CC(C)=O.O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:23])=[CH:17][CH:18]=2)[C:4](=[O:10])[CH:3]=1
Reactant: COc1ccc(O)cc1N
Reactant: Nc1ccc(N)cc1
Agent: Cl
Agent: N
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: NC1=CC(=O)C(Nc2ccc(N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.75 mole (10.5 g) of 3-amino-4-methoxy phenol is dissolved in 50 cc of acetone to which have been added 50 cc of ammonia (22° Be) and 250 cc of H2O2 (20 volumes). To this solution there is immediately added 0.05 mole (9.0 g) of paraphenylene diamine dihydrochloride in solution in 100 cc of water. The resulting reaction mixture is agitated for two hours at ambient temperature at which time the reaction mixture is filtered to recover the precipitate which has formed. After recrystallizing the precipitate in ethylacetate and washing the recrystallized product initially with a little methyl cellosolve and then with a little ether, 2-amino-5-[4'-(amino)anilino]-1,4-benzoquinone is obtained which is chromatographically pure and which melts with decomposition above 260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A solution of p-fluorophenol (28.1 g., 0.25 mole) is DMF (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in DMF (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. DMF is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 85°/0.05 mm to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). Ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4) δ 1.17 (6H, t J=7.5Hz), 3.57 (2H, q, J=7.5 Hz), 3.61 (2H, q, J=7.5 Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>ClCCl>[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:21])[F:22])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:35]([F:34])([F:45])[F:46])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CCNCC2)nc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To an ice-cold solution of 2-piperazin-1-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid (3-methylbutyl)amide (0.323 g, 0.935 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (0.242 mL, 1.40 mmol). The mixture was stirred for 10 minutes before 2-trifluoromethylbenzoyl chloride (0.175 g, 0.842 mmol) in 5 mL dichloromethane was added. The stirring was continued for another 15 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate solution, followed by water. The mixture was extracted with dichloromethane, and the organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in yield 76% (0.225 g, 0.435 mmol). 1H NMR (CDCl3) δ 8.59, 7.73-7.71, 7.64-7.51, 7.35-7.33, 5.76, 4.09-3.74, 3.44-3.37, 3.26-3.22, 1.68-1.59, 1.48-1.41, 0.09. MS (ES+) m/z 518.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Fc1ccc(F)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 2,5-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 159. 1H NMR(CDCl3) δ: 7.05-6.98 (m, 1H), 6.97-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.26 (d, 1H, J=2.5 Hz), 6.14 (d, 1H, J=2.2 Hz), 4.23 (broad s, 2H), 3.59 (ABq, 2H), 3.50-3.40 (m, 1H), 3.30-3.17 (m, 2H), 3.05-2.65 (m, 6H), 2.51 (dd, 1H, J=12.7, 9.5 Hz), 1.92-1.78 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCOCC1)c1cccc3c1N2CC3
Temperature: 25 °C

Procedure:
A mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 21.8 g (0.250 mole) of morpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 8.6 g (90%) of product. Recrystallization from a hot solution of dichloromethane (80 ml) to which methanol (80 ml) was added provided the analytical sample, mp 216°-218° C.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[F:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(C[Mg]Cl)c1
Reactant: O=C1CCC2CCC(=O)N12
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 62.3 %

Procedure:
Following the procedure described for Preparation 8, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2.5 h. Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to 2:1 EtOAc:hexanes to EtOAc to 2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 5-[4-(3-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.1730 g). 1H NMR (CDCl3) δ7.32-7.27 (m, 1H), 7.00-6.90 (m, 3H), 6.12 (bs, 1H), 3.69 (s, 2H), 3.59 (m, 1H), 2.52 (t, 2H), 2.30 (m, 2H), 2.19 (m, 1H), 1.75 (m, 2H), 1.65 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:25]5[S:26][CH:27]=[C:23]([CH3:22])[N:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1csc(CO)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-methyl-1,3-thiazol-2-yl)methanol (45.9 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (11.3 mg) as a white solid.
Reaction SMILES: FC1C(C2(C)OC=CO2)=CC=C(OC)C=1C=O.C([O:20][C:21](=[O:39])[CH:22]=[CH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([C:32]2([CH3:37])[O:36][CH:35]=[CH:34][O:33]2)[C:25]=1[F:38])C.[OH-].[K+]>O1CCOCC1.O>[F:38][C:25]1[C:26]([C:32]2([CH3:37])[O:33][CH:34]=[CH:35][O:36]2)=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=1[CH:23]=[CH:22][C:21]([OH:39])=[O:20]
Reactant: CCOC(=O)C=Cc1c(OC)ccc(C2(C)OC=CO2)c1F
Agent: COc1ccc(C2(C)OC=CO2)c(F)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2(C)OC=CO2)c(F)c1C=CC(=O)O

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g)(Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenyl)-N′-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (q, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).
Reaction SMILES: CCN(CC)CC.C(O)=O.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]([OH:34])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:18]=1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:34][C@@H:23]([C:19]1[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1)[CH2:24][CH2:25][NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1ccccc1

Procedure:
Et3N (2.0 mL, 14.35 mmol) and HCOOH (0.4 mL, 10.60 mmol) were added to a solution of (R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl trifluoromethanesulfonate (1.05 g, 2.63 mmol) and Ar was bubbled through the mixture for one minute. 1,3-Bis(diphenylphosphino)propane (1,3-dppp) (0.080 g, 0.194 mmol) and Pd(OAc)2 (0.050 g, 0.223 mmol) were added to the reaction mixture and the later was degassed by applying vacuum/Ar cycle three times. The reaction mixture was heated at +60° C. for 5 h and concentrated under reduced pressure. Aqueous NH4Cl (25%) was added to the residue and the mixture was extracted with MTBE twice. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc-hexanes gradient) gave (R)-tert-butyl (3-hydroxy-3-phenylpropyl)carbamate as a colorless oil. Yield (0.64 g, 97%); 1H NMR (400 MHz, DMSO-d6) δ 7.22-7.30 (m, 4H), 7.14-7.21 (m, 1H), 6.72 (br. t, 1H), 5.14 (d, J=4.4 Hz, 1H), 4.51 (dd, J=6.5, 10.9 Hz, 1H), 2.87-2.98 (m, 2H), 1.60-1.70 (m, 2H), 1.33 (s, 9H).