Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([OH:37])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C>[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-[N-methyl-N-[(4,5-diphenyloxazol-2.-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (109 mg) in dichloromethane (2 ml) was added 1M boron tribromide dichloromethane solution (1 ml) at 0° C. After being stirred for 4 hours at 0° C., the solvent was evaporated in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo to afford crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg). To a solution of crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg) and ethyl bromoacetate (80 mg) in DMF (3 ml) was added K2CO3 (80 mg). After being stirred for 24 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-ethoxycarbonylmethoxy-1H-indene (80 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[NH2:11])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>C1C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=[N:11][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Reactant: CN1CCC(=O)CC1
Solvent: c1ccccc1
Product: Cc1ccc(N(CCc2ccc(C)nc2)N=C2CCN(C)CC2)cc1

Procedure:
The crude N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine was dissolved in benzene (20 cm3) and 4 Å molecular sieves added (˜5 g), followed by 1-methylpiperidin-4-one (346 μL, 3.0 mmol). The reaction was heated to reflux for 2 hours, cooled, and filtered. Solvent was removed in vacuo to yield a crude orange oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:12]1[C:16]([NH2:17])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2>N1C=CC=CC=1>[S:12]1[C:16]([NH:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: Nc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (0.661 mL, 5.15 mmol) was added to a solution of compound 1-C (0.87 g, 4.69 mmol) in pyridine (10 mL) at 0° C. The ice bath was removed and the solution was stirred at ambient temperature for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between 2N HCl and dichloromethane. The organic layer was dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was pre-absorbed on silica gel and purified by flash column chromatography, eluting with a gradient of ethyl acetate (10-50%) in heptane, to afford compound 1-D as a colorless solid (1.19 g, 88%). 1H-NMR (CDCl3): δ 6.96 (s, 1H), 7.25-7.34 (m, 2H), 7.44-7.49 (m, 2H), 7.55-7.66 (m, 3H), 7.84-7.88 (m, 2H); MS: m/z 290.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][O:24][C:30]3[CH:29]=[CH:28][C:27]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:26]([F:25])[CH:31]=3)=[CH:21][CH:22]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3-c3ccccc3)cc2)cc1F
Temperature: 25 °C

Procedure:
To a mixture of {4-[(3-tert-butyl-5-phenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (320 mg, 1.0 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (212 mg, 1.0 mmol), triphenylphosphine (262 mg, 1.0 mmol) and dichloromethane (5 mL) added dropwise diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 1.37 (9H, s), 2.58 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=7.6 Hz), 4.12 (2H, q, J=7.2 Hz), 4.97 (2H, s), 5.32 (2H, s), 6.20 (1H, s), 6.60-6.70 (2H, m), 7.02 (2H, d, J=8.1 Hz), 7.09 (1H, t, J=8.8 Hz), 7.25-7.40 (7H, m).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(#N)C.[CH:18]1(C#C)[CH2:23][CH2:22]C[CH2:20][CH2:19]1>ClCCl.[Zn]>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:3]([CH:4]=1)=[CH:9][N:10]=[C:11]([CH:13]1[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20]1)[CH:14]=2
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Reactant: C#CC1CCCCC1
Agent: [Zn]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cc2cnc(C3CCCCC3)cc2cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A round-bottom flask containing N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (164.5 mg, 0.5969 mmol), DPPPNiCl2 (16.0 mg, 0.0295 mmol) and zinc (84.0 mg, 1.28 mmol) was evacuated and purged with nitrogen 5 times. Acetonitrile (6 mL, 100 mmol) and cyclohexylacetylene (86.0 uL, 0.658 mmol) were added to the flask and the reaction mixture was stirred at 80° C. under a nitrogen balloon for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through celite, rinsing with dichloromethane. The filtrate was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-40% ethyl acetate in dichloromethane) to yield 80.4 mg (55%) of 3-chloro-7-cyclohexyl-2,6-naphthyridine. LCMS (ESI): M+H=247.2; 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 2.91-2.81 (m, 1H), 1.97 (d, J=11.3 Hz, 2H), 1.84 (d, J=13.0 Hz, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.58 (ddd, J=24.8, 12.5, 2.9 Hz, 2H), 1.49-1.37 (m, 2H), 1.27 (ddd, J=16.3, 12.6, 9.2 Hz, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+].CN([CH:32]=[O:33])C>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[CH:17]=[C:16]([CH:32]=[O:33])[NH:15][C:14]=2[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2cc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(C=O)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To 25 ml DMF at 0° was added dropwise with stirring 30 g of phosphorus oxychloride. The mixture was stirred for 15 minutes at room temperature, then a solution of 5.6 g (0.02 mole) of 2,3-bis(4-methoxyphenyl)pyrrole in 40 ml DMF was added dropwise with cooling in an ice bath. The mixture was then heated at 70°-80° for one hour, then cooled. Aqueous sodium hydroxide (50%) was added until the mixture was basic. The reaction mixture was then heated again at 70° for 15 minutes. The cooled reaction mixture was poured into ice water. The precipitated material was collected and purified by chromatography on 600 g Silic AR CC-7 (eluting with toluene containing 1-2% ethyl acetate) to give 3.4 g (55%) of product, m.p. 165°-6° (methylcyclohexane/toluene).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:21][C@@H:22]([CH3:26])[C:23]([OH:25])=[O:24])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([F:20])[CH:9]=2)[CH:7]=1.B(C1C=C([C:42]([F:45])([F:44])[F:43])C=CC=1O[C@@H](C)C(O)=O)(O)O>>[F:20][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([C:42]([F:45])([F:44])[F:43])[CH:3]=[CH:4][C:5]=2[O:21][C@@H:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH:13]=[CH:12][C:11]=1[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: CC(C)NC(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F
Product: CC(C)NC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2O[C@@H](C)C(=O)O)cc1F

Procedure:
The title compound was prepared using the product of example 34 step a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:33]=[C:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)[N:29]=[C:28]([C:50]2[CH:51]=[C:52]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:55]=2)[N:27]=1>CN(C)C=O>[C:62]1([C:52]2[CH:51]=[C:50]([C:28]3[N:29]=[C:30]([C:32]4[CH:37]=[C:36]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[C:34]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:33]=4)[N:31]=[C:26]([N:13]4[C:12]5[CH:11]=[C:10]6[C:2]([CH3:22])([CH3:1])[C:3]7[C:8]([C:9]6=[CH:21][C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)=[CH:7][CH:6]=[CH:5][CH:4]=7)[N:27]=3)[CH:55]=[C:54]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:53]=2)[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: Clc1nc(-c2cc(-c3ccccc3)cc(-c3ccccc3)c2)nc(-c2cc(-c3ccccc3)cc(-c3ccccc3)c2)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5cc(-c6ccccc6)cc(-c6ccccc6)c5)nc(-c5cc(-c6ccccc6)cc(-c6ccccc6)c5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.3 g (40 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 285 ml of dimethylformamide under a protective-gas atmosphere, and 1.9 g of 60% NaH in mineral oil (19 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-bis-[1,1′;3′,1″]terphenyl-5′-yl-1,3,5-triazine (25.1 g, 44 mmol) in 315 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 23 g (28 mmol, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C=O.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(O)cc1Cl
Reaction time: 3.5 h

Procedure:
3-Chloro-4-methoxybenzaldehyde (2.50 g, 15.0 mmol) was dissolved in 30 mL of CH2Cl2, treated with 3-chloro-perbenzoic acid (4.84 g, 70%, 1.4 eq.), and then kept for 3.5 h at ambient temperature. Pouring onto crashed ice/pyrosulfite-solution, twofold extraction with AcOEt, washing with Na2CO3-solution, drying over sodium sulfate, and evaporation of the solvents left 2.89 g of the intermediate formiate which was hydrolysed by stirring for 20 Min. in 25 mL of MeOH containing 2.113 g of K2CO3. Standard extractive work-up delivered then 2.60 g of the title compound sufficiently pure for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].O>O1CCCC1.[Cu]Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([CH3:15])([CH3:10])[CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)=CC=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cu]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 21.6 grams (0.10 mole) of 4-chlorophenylmagnesium bromide (1M in diethyl ether) in 100 mL of tetrahydrofuran is cooled to -15° C., and 0.7 grams (catalyst) of copper(I) bromide is added in one portion. Upon completion of addition, 9.7 mL (0.10 mole) of 3-methyl-2-butenal is added dropwise during a 1.5 hour period, while maintaining the reaction mixture temperature below -10° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature, where it is stirred for about 18 hours. The reaction mixture is then poured into 300 mL of water and extracted with two 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue, is subjected to column chromatography on silica gel, using 50% petroleum ether in methylene chloride as the eluant. The appropriate product-containing containing fractions are combined and concentrated under reduced pressure, yielding 7.6 grams of 3-(4-chlorophenyl)-3-methylbutyraldehyde. The NMR spectrum is consistent with the proposed structure. The reaction is repeated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Cl.Cl[CH2:25][C:26]1[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ncc(C)c(OC)c3C)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[CH3:12][N:13]1C(=O)CCC1>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.[C-]#N.[C-]#N.[Zn+2]>[F:11][C:3]1[C:2]([C:12]#[N:13])=[CH:10][C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: Fc1cc2nc[nH]c2cc1Br
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc2[nH]cnc2cc1F
Temperature: 110 °C
Yield: 93.5 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-benzo[d]imidazole (10.0 g, 46.5 mmol), Pd(PPh3)4 (7.97 g, 6.9 mmol), and Zn(CN)2 (8.46 g, 93 mmol) in NMP (150 mL) under nitrogen was heated at 110° C. for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (100 mL×5). The combined extracts were washed with brine (300 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 6-fluoro-3H-benzo[d]imidazole-5-carbonitrile as white solid (7.0 g, 93.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:23])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[F:23][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Procedure UU: To a stirring solution of 3-Fluoro-4′-(methanesulfonyl-methyl-amino)-biphenyl-4-carboxylic acid methyl ester (see Intermediate Preparation 33) (11.0 mmol) in 1:1 methanol/tetrahydrofuran, add 2N sodium hydroxide (3.0 mmol) and stir at room temperature for 4 hours. After this time wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Dry the organics with sodium sulfate, decant, and concentrate in vacuo. MS (m/e): 322.1 (M−1)
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: C#Cc1cccnc1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccnc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 4.0 g (15 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 2.0 g (19 mmol) 3-ethynyl-pyridine using 282 mg (1.5 mmol) CuI, 1.0 g (1.5 mmol) PdCl2(PPh3)2 and 21 mL (148 mmol) triethylamine in 200 mL dry DMF. For the work-up the reaction mixture is concentrated in vacuo before water is added. The precipitate is collected, dried at 40° C. and crystallized from MeOH/H2O. Yield: 3.0 g (83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl.CCOC(C)=O.C(=O)(O)[O-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH3:15])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCCN(C)c1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Example 619, Step 1) (0.54 g, 1.7 mmol) in 20 ml EtOH was added SnCl2 (0.51 g, 2.67 mmol). The mixture was sealed and was heated to 80° C. for 12 h. An additional amount of SnCl2 (0.51 g, 2.67 mmol) was added and heating continued for 12 h. The reaction was cooled to ambient temperature, and was poured into a mixture of EtOAc and saturated aqueous sodium bicarbonate. The mixture was filtered through celite, and the organic layer was removed. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried with Na2SO4, filtered, and concentrated to give a cloudy oil. This material was filtered through silica gel with 90/10/1 dichloromethane/MeOH/conc. NH4OH and concentrated in vacuo to give the title compound as a red oil. MS (ES+): 285.9 (M+H)+. Calc'd for C12H20BrN3: 286.21.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[C-:17]#[N:18].[Na+].O>CN(C)C=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:17]#[N:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCCCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCCc1ccccc1
Yield: 949.6 %

Procedure:
A stirred solution of 15.0 grams (0.0062 mole) of 1- methylsulfonyloxy-5-phenylpentane and 9.1 grams (0.190 mole) of sodium cyanide in 150 mL of N,N-dimethylformamide was heated at 50° C. to 55° C. for about 60 hours. After this time the reaction mixture was poured into 400 mL of water. The mixture was extracted with three 250 mL portions of diethyl ether. The combined extracts were then washed with three 200 mL portions of water and 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of 6-phenylhexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1>C(OCC)(=O)C>[CH:14]1[C:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][C:13]=1[NH:12][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 140 °C
Reaction time: 9 h

Procedure:
2.17 g of 3-fluoro-4-nitrophenol and 5 g of 2-aminofluorene were mixed and stirred for 9 hours at 140° C. The raw mixture was taken up in ethyl acetate and water and washed with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed three times with 2N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[F:19][C:20]([F:30])([F:29])[C:21]([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)=[O:22]>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][C:21]([OH:22])([C:23]1[S:27][C:26]([SH:28])=[N:25][CH:24]=1)[C:20]([F:29])([F:19])[F:30])[CH3:13]
Reactant: CCOC(C)=O
Reactant: O=C(c1cnc(S)s1)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
iPr2NH (205 mg, 2.0 mmol) was dissolved in THF (3.5 mL) and cooled to −10° C. n-Butyllithium (2.5M, 0.81 mL, 2.0 mmol) was added dropwise, and the reaction was cooled to −78° C. EtOAc (179 mg, 2.0 μmmol) in THF (0.5 mL) was added, followed by 10a (188 mg, 0.9 mmol) in THF (10.5 mL), and the reaction was stirred at −78° C. for 1 hour. The reaction was warmed to −10° C. and quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 1N HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% Et2O in hexanes) to give the desired product, 10b.