Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][OH:11]>CO>[NH2:9]/[C:8](=[N:10]\[OH:11])/[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C#N
Reactant: NO
Solvent: CO
Product: CCOC(=O)C(C)/C(N)=N/O
Temperature: 50 °C

Procedure:
Ethyl 2-methylcyanoacetate (5 g, 39 mmol) and hydroxylamine (2.6 g, 39 mmol) were dissolved in 50 mL of MeOH. The solution was heated at the 50° C. overnight. The solution was then concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (DMSO-d6): 9.05 (1H, s), 5.40 (2H, s), 4.06 (2H, dd, J=12.8, 7.0 Hz), 3.15 (1H, m), 1.24 (3H, d, J=7.2 Hz), 1.18 (3H, t, J=7.1 Hz). m/z=161.1 (M+H)
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:6]([F:18])[CH:5]=1)[CH3:3].Cl[C:20]1[N:25]=[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]2=[O:34])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:18][C:6]1[CH:5]=[C:4]([C@@H:2]([NH:1][C:20]2[N:25]=[C:24]([N:26]3[C@@H:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][O:28][C:27]3=[O:34])[CH:23]=[CH:22][N:21]=2)[CH3:3])[CH:9]=[CH:8][C:7]=1[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccc(C(=O)N2CCCCC2)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C(=O)N3CCCCC3)c(F)c2)n1
Temperature: 107.5 °C
Yield: 11.6 %

Procedure:
To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019 g, 0.076 mmol) was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.028 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110° C. for 16 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP was added, filtered, purified by prep LC and lyophilized to give 4.0 mg of (S)-3-(2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as TFA Salt. LCMS m/z 456.1 (M+H)+, rt 0.74 min.
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: CCCCCC
Solvent: C1CCOC1
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: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][O:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:8]4[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cn1c2ccc(Cl)cc2c2c3ccccc3c(OCC3CC3)nc21

Procedure:
5-Cyclopropylmethyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 141°-142° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and cyclopropylmethyl bromide by the method described in Example 8.
Reaction SMILES: C(OCCOCCl)(=O)C.[CH:10]([O:13][P:14]([O:19]C(C)C)[O:15][CH:16]([CH3:18])[CH3:17])([CH3:12])[CH3:11]>>[PH:14](=[O:19])([O:15][CH:16]([CH3:18])[CH3:17])[O:13][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: CC(=O)OCCOCCl
Product: CC(C)O[PH](=O)OC(C)C
Temperature: 125 °C
Yield: 47 %

Procedure:
A 500 mL three-neck flask was charged with the crude chloromethylether 1 (317 g, 2.00 mol). Triisopropylphosphite (494 mL) was added dropwise through an additional funnel while heating in a 125° C. oil bath and stirring vigorously. Collect 2-chloropropane distillate via short-path head in a dry ice cooled receiver, argon blanket, collected 140 g distillate (theoretical 157 g). Phosphite blanched reaction to yellow, continue heating another 2 h at 125° C. oil bath, then arrange for vacuum distillation using a vacuum pump. Distilled a yellow front cut (140 g, head to 135° C., bottom to 190° C.), then changed to clean receiver. Main fraction was collected at head temperature of 178-187° C. (mostly 185-187° C.) with vacuum unknown at bath temperature of 222-228° C. 258 g of the product 2 was given (47% yield from 1,3-dioxolane).
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[N:7]=1.[CH2:19]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:18][C:3]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([NH:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])=[C:30]([F:38])[CH:31]=2)=[N:7][C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Reactant: Nc1ncc(C2CCC3(CC2)OCCO3)nc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCC3(CC2)OCCO3)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Yield: 46.6 %

Procedure:
To 3-bromo-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-amine (630 mg, 2.005 mmol) was added (4-(benzylcarbamoyl)-3-fluorophenyl)boronic acid (767 mg, 2.81 mmol), PdCl2(dppf)CH2Cl2 adduct (164 mg, 0.201 mmol), DME (9 mL) and then last sodium carbonate 2M (3.01 mL, 6.02 mmol). The reaction was microwaved at 115° C. for 12 min. To the reaction was added 400 mL of ethyl acetate washed with water (2×), dried with sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 40 gram column eluting with 20-100% ethyl acetate and heptane. The desired fractions were concentrated to constant mass to give 432 mg of the desired product as free base used as is, (47% yield). LCMS (m/z): 463.2 (MH+), 0.82 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94-8.81 (m, 1H), 7.89 (s, 1H), 7.80-7.69 (m, 1H), 7.67-7.52 (m, 2H), 7.33 (d, J=4.3 Hz, 4H), 7.27-7.18 (m, 1H), 6.09 (s, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.85 (s, 4H), 2.70-2.61 (m, 1H), 1.84-1.67 (m, 6H), 1.65-1.48 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH:6]=[CH:5][C:4]2=[O:21].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O1CCOCC1.C(OC)(OC)OC>[CH3:22][O:20][C:13]1[CH2:14][CH2:15][C@H:16]2[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:17]2[CH2:18][CH2:19][C@@:3]2([CH2:2][CH3:1])[C@H:7]3[CH:6]=[CH:5][C:4]2=[O:21])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Solvent: COC(OC)OC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Reaction time: 2.5 h
Yield: 1009.8 %

Procedure:
Under argon, 20.0 g of 18-methyl-4,15-estradiene-3,17-dione in 100 ml of 1,4-dioxane and 100 ml of trimethyl orthoformate is agitated with 800 mg of p-toluenesulfonic acid at 50° C. After 2.5 hours, 10 ml of pyridine is added and the solution extensively distilled under vacuum. The residue is dissolved in ethyl acetate, washed with water, and dried. Chromatography of the crude product with 0-20% ethyl acetate-hexane yields 14.0 g of 3-methoxy-18-methyl-3,5,15-estratrien-17-one, melting point 162.1° C. (from methanol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:36][O:37][CH2:38][C:39]1[S:40][CH:41]=[C:42]([CH2:44][N:45]2[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]2=[O:58])[N:43]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:42]2[N:43]=[C:39]([CH2:38][O:37][CH3:36])[S:40][CH:41]=2)[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCc1nc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution of the product from Example 6A (0.034 g, 0.089 mmol) in THF (0.9 mL) was treated with the product from Example 6H (0.035 g, 0.103 mmol), DEPBT (0.040 g, 0.134 mmol), and N,N-diisopropylethylamine (0.075 mL, 0.431 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography using C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.047 g, 75% yield).
Reaction SMILES: N12CCCN=C1CCCC=C2.[Cl:12][C:13]1[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[N:15][NH:16][CH:17]=1.[CH2:28]=[O:29]>C1COCC1>[OH:29][CH2:28][N:16]1[CH:17]=[C:13]([Cl:12])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[N:15]1
Reactant: C=O
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Agent: C1=CN2CCCN=C2CCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Cl)cccc1-c1nn(CO)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
0.40 ml of 1,8-diazabicyclo[5.4.0]undecen-7-ene is added, at room temperature, to a solution of 7.0 g (0.027 mol) of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole and 2.40 g of paraformaldehyde in 100 ml of THF. The reaction mixture is stirred for 4 hours at room temperature, concentrated under reduced pressure and taken up in a mixture of 150 ml of water and 150 ml of methylene chloride. The organic phase is dried over magnesium sulphate and concentrated under vacuum. 7.40 g of 1-hydroxymethyl-4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole melting at 146° C. are obtained (yield: 95.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([NH:27][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[C:8]3[S:13][CH:12]=[CH:11][C:9]=3[N:10]=2)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccs1)c1nc(NCCNC(=S)Nc2ccccc2)nc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with phenyl isothiocyanate (33 mg, 0.25 mmol), shaken at room temperature for 2 h, poured into water (20 mL) and the resulting yellow precipitate was filtered and dried in vacuo to give the title compound (44 mg, 61%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:14]([NH2:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>C1COCC1>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][NH:20][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCc1ccco1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1F
Reaction time: 18 h
Yield: 98.1 %

Procedure:
To a 0.2M solution of 2-fluoro-5-nitrobenzoic acid (1.0 g, 5.4 mmol, Aldrich) in anhydrous THF at ambient temperature was added furfurylamine (1.1 g, 5.9 mmol), HBTU (2.24 g g, 5.9 mmol, Chem-Impex), HOBT (0.8 g, 5.9 mmol, Novabiochem) and NMM (0.59 mL, 5.4 mmol, Aldrich). The resulting solution was stirred for 18 hr. To the reaction mixture was added a 1M solution of aqueous hydrochloric acid (30 mL). The crude mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined, washed one time with a saturated aqueous solution of NaHCO3 (100 mL), one time with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to yield 1.4 g (100%) of product as an off white solid which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:25])[N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Temperature: 90 °C
Yield: 93.1 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (250 mg, 0.72 mmol) in dioxane (3 mL) was added aqueous sodium hydroxide (2 M, 2.0 mL, 2.0 mmol). After heating at 90° C. for 1 h the solution was cooled to room temperature and neutralized with aqueous hydrogen chloride (2 N). The resulting mixture was then extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated to afford the title compound (222 mg, 92%) which was obtained as a white solid. MS: m/e=330.1 [M−H]−.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: Ic1cccnc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)Oc1ccc(C#Cc2cccnc2)cc1

Procedure:
A solution of 3-iodopyridine (205 mg, 1.0 mg) in triethylamine was treated with tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol), copper iodide (18 mg, 0.097 mmol) and a solution of 1-(difluoromethoxy)-4-ethynylbenzene (168 mg, 1.0 mmol) in acetonitrile at room temperature, heated at 60° C. for 1 h, cooled and concentrated to dryness to afford 3-{[4-(difluoromethoxy)phenyl]ethynyl}pyridine as a residue. The residue (240 mg) was dissolved in acetone, treated sequentially with a solution of NaHCO3 (50 mg) and MgSO4 (180 mg) in H2O and KMnO4 (327 mg), stirred for 10 minutes at room temperature and extracted with 1/1 Et2O/hexane. The combined extracts were concentrated to dryness to give 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione. A mixture of 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione (230 mg), N-methylguanidine hydrochloride (155 mg) and Na2CO3 (240 mg) in ethanol was heated at reflux temperature for 1.5 h. and concentrated in vacuo. The resultant residue was purified by chromatography (silica gel, EtOAc/2.0 M NH3 in EtOH: 97/3) to give the title compound (130 mg) as a solid, mp: 173-175° C., identified by NMR and mass spectral analyses. MS (+) APPI: 333 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24](O)=[O:25])=[C:4]([C:18]([Cl:23])=[C:19]([Cl:22])[C:20]=1[Cl:21])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:8]=1)=[O:6].[CH2:27]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]3=2)[CH:31]=[C:30]1[CH3:42])[CH3:28].N>C(OC(=O)C)(=O)C>[CH2:14]([N:13]([CH2:16][CH3:17])[C:10]1[CH:9]=[CH:8][C:7]([C:5]2([C:31]3[C:32]4[C:37](=[C:36]5[CH:38]=[CH:39][CH:40]=[CH:41][C:35]5=[CH:34][CH:33]=4)[N:29]([CH2:27][CH3:28])[C:30]=3[CH3:42])[C:4]3[C:3](=[C:2]([Cl:1])[C:20]([Cl:21])=[C:19]([Cl:22])[C:18]=3[Cl:23])[C:24](=[O:25])[O:6]2)=[CH:12][CH:11]=1)[CH3:15]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Agent: N
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4c3ccc3ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Yield: 100.2 %

Procedure:
A solution of about 6.5 grams of 3,4,5,6-tetrachloro-2-carboxy-4'-diethylaminobenzophenone and about 3.1 grams of 1-ethyl-2-methyl-1H-benz[g]indole in 50 milliliters of acetic anhydride is refluxed for about one hour and then cooled. That reaction mixture is poured over ice and ammonia, extracted twice with a 1:1 toluene-chloroform mixture and dried using sodium sulfate. The solution is concentrated by evaporation of the solvent and the title compound is crystallized by washing with petroleum ether. 9.3 grams of the title compound is obtained having a melting point of 232°-235° C. A solution of product imparts a blue color to paper coated with a phenolic resin or silton clay or a combination of the two. The calculated analysis for C33H28N2O2Cl4, the title compound, is C, 63.28%; H, 4.51%; N, 4.57%; and Cl, 22.64%. Found, on analysis: C, 63.37%; H, 4.42%; N, 4.54%; an Cl, 22.49%.
Reaction SMILES: [N:1]1([S:10]([N:13]2[CH2:17][CH2:16][O:15]C2=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>[OH-].[Na+].C(O)C>[OH:15][CH2:16][CH2:17][NH:13][S:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:12])=[O:11]
Reactant: O=C1OCCN1S(=O)(=O)N1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(NCCO)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Step 1 is dissolved in a solution of 3.2 g of sodium hydroxide in 80 ml of ethanol. After stirring for 48 hours at ambient temperature, the mixture is filtered. The filtrate is concentrated under reduced pressure, taken up in dichloromethane and washed with water. After drying and filtration, the organic phase is concentrated under reduced pressure, allowing the expected product to be obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[C:31]([O:33][CH3:34])=[O:32]>N1C=CC=CC=1>[CH3:34][O:33][C:31]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:18]([C:14]([CH:12]([C:11]4[C:2]([F:1])=[C:3]5[C:8](=[CH:9][C:10]=4[F:29])[N:7]=[CH:6][CH:5]=[CH:4]5)[CH3:13])=[CH:15][N:16]=3)[N:19]=2)[CH2:24][CH2:25]1)=[O:32]
Reactant: COC(=O)Cl
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Solvent: c1ccncc1
Product: COC(=O)N1CCN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 35 mg, 0.089 mmol) was dissolved in pyridine (0.89 mL) and methyl chloroformate (0.010 mL, 0.133 mmol) was added. The RM was stirred at RT for 1.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a beige foam (tR 3.70 min (conditions 1), MH+=453).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10](Br)=[O:11].C(N(CC)CC)C>ClCCl>[Br:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C

Procedure:
A solution of aniline (0.016 mol) in 40 mL of dichloromethane is cooled on ice, and 1.0 equivalent of bromoacetyl bromide in 3 mL of dichloromethane is added dropwise, followed by 0.019 mol of triethylamine (TEA). The solution turns dark and a precipate forms, as the reaction mixture is warmed to RT over 3 h. The mixture is concentrated and taken up in ethyl acetate (EtOAc) and washed three times with water. The organic phase is dried over anhydrous sodium sulphate (Na2SO4), filtered and concentrated. The residue is purified by crystallization from EtOAc to afford 2-bromo-N-phenylacetamide: m.p. 131-135° C.; 1H-NMR (CDCl3) δ 4.01 (s, 2H), 7.18 (m, 1H), 7.36 (m, 2H), 7.54 (2H), 8.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([CH3:36])=[C:34]=[O:35]>ClCCl>[CH3:36][NH:33][C:34]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)=[O:35]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.2 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (32.4 mg, 0.3 mmol) (Aldrich), followed by the addition of isocyanatomethane (14.6 mg, 0.24 mmol) (Chem Service). The mixture was stirred at room temperature for 30 minutes. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was triturated with dichloromethane-hexanes to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid methylamide as a white solid. (Yield 35 mg, 50%).