Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.Br[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>C(Cl)Cl.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol), and THF (5 mL) is added 1.34 M n-Bu-Li (1.0 mL, 1.34 mmol). The solution is stirred for at −78° C. for 30 minutes and 0.5 M ZnCl2 in THF (2.7 mL, 1.34 mmol) is added and the solution warmed to ambient temperature. After 30 minutes 3-bromopyridine (0.15 mL, 1.53 mmol) and PdCl2(dppf) (0.047 g, 0.064 mmol) is added and the solution heated at 65° C. overnight. The solution is diluted with CH2Cl2 (40 mL), washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-40% EtOAc/hexane gradient) concentrated and re-dissolved in Et2O. The solution is treated with Darco®-60 for 15 minutes, dried over Na2SO4, and filtered thru Celite® furnish the title compound (0.26 g, 0.67 mmol, 52%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.26-7.32 (m, 2H), 7.86 (dt, J=7.9, 1.8 Hz, 1H), 850 (d, J=3.2 Hz, 1H), 8.89 (s, 1H). LC/MS (m/z): calcd. for C23H26N4S (M+H)+: 391.6; found: 391.2.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:1](=[O:3])[C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reaction time: 18 h

Procedure:
A suspension of 4-carboxybenzaldehyde (3.10 g) in CH2Cl2 was treated sequentially with piperazine-1-carboxylic acid tert-butyl ester (3.6 g), EDCl (3.86 g), HOBt (2.68 g), and 4-dimethylaminopyridine (˜0.020 g). After 18 h, the mixture was extracted with 1 N NaOH and then with 1 N HCl. The organic layer was dried (Na2SO4) and concentrated to yield the title compound.
Reaction SMILES: CN[C@H](C(N[C@H:13]([C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=O)CC1N=CNC=1.C([N:30](CC)CC)C.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[NH2:30][CH:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:13][C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCC(C)C
Reactant: CCN(CC)CC
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)CC[C@H](O)CC(N)C1CCCCC1
Reaction time: 1 h
Yield: 270.1 %

Procedure:
To a solution of 2(S)-(Nα -methyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (900 mg) and triethylamine (494 mg) in methylene chloride (20 ml) was added trityl chloride (696 mg) at 0° C. The mixture was stirred at the same temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave 2(S)-(Nα -methyl-Nim -trityl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.46 g) as an amorphous powder.
Reaction SMILES: C12(C[O:12]C3C=CC(C#N)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[CH:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH:30]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=1[CH:49]1[CH2:51][CH2:50]1)[CH2:36]2>>[CH:31]12[CH2:37][CH:35]3[CH2:34][CH:33]([CH2:38][CH:29]([CH2:36]3)[CH:30]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]([NH2:46])=[O:12])=[CH:43][C:42]=1[CH:49]1[CH2:51][CH2:50]1)[CH2:32]2
Reactant: N#Cc1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Product: NC(=O)c1ccc(OCC2C3CC4CC(C3)CC2C4)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 38 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with 4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzonitrile, the title compound was obtained as a colorless solid (0.62 g, 95%): MS (ES+) m/z 326.3 (M+1);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CN=C1.Cl[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:12])=[CH:6][CH:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of 4-hydroxyphenylacetic acid methyl ester (2000 mg, 12036 μmol), 1H-imidazole (2048 μl, 18053 μmol), and chloro-tert-butyldimethylsilane (1814 mg, 12036 μmol) in DMF (10 mL) was stirred at 23° C. for 18 h. The mixture was partitioned between EtOAc (50 mL) and 5% NaHCO3 (25 mL). The organic layer was dried over MgSO4 and concentrated to a colorless oil from toluene under reduced pressure. MS (ESI pos. ion) m/z (MH+): 281. Calc'd exact mass for C15H24O3Si: 280.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][C:10]=1[CH:18]=[CH:19][C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][CH:33]=2)=[CH:28][CH:27]=1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][C:10]=1[CH2:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: N=C(N)c1ccc(O)c(C=C[C@H]2CCCN2C(=O)c2ccc(-c3ccc(=O)[nH]c3)cc2)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N=C(N)c1ccc(O)c(CC[C@@H]2CCCN2C(=O)c2ccc(-c3ccc(=O)[nH]c3)cc2)c1
Yield: 50.6 %

Procedure:
4-Hydroxy-3-(2-{1-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoyl]pyrrolidin-2-(R)-yl}-vinyl)benzamidine trifluoroacetate (0.0065 g, 0.01198 mmol) in MeOH (10 mL) and 5% Pd/C (catalytic amt.) is hydrogenated using a balloon filled with H2 gas for 4 h. The reaction is filtered, evaporated and the residue is diluted with H2O (10 mL). The aqueous solution is lyopholized to give the title compound as a white solid (0.0033 g, 0.00606 mmol). 1H NMR (DMSO-d6, 300 MHz) 8.97(s, 2H), 8.60(s, 2H), 7.93-7.26(m, 8H), 6.93(d, 1H), 6.42(d, 1H), 4.15(m, 1H), 3.61-3.35(m, 1H), 2.70-2.51(m, 2H), 2.45-1.98(m, 4H), 1.93-1.55(m, 3H). MS m/z: [M+H]+=431.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C1(C)C=CC=CC=1.CCOC(C)=O.O.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>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[O:31])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COc1ccc(C(=O)Cl)cc1OC
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cnc3[nH]ccc3c2)cc1OC
Temperature: 100 °C
Reaction time: 22 h
Yield: 3.5 %

Procedure:
To the crude pinacol ester 44 (310 mg, 1.27 mmol) in dry toluene (25 mL) was sequentially added cesium carbonate (2.07 g, 6.35 mmol), tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.06 mmol) and 3,4-dimethoxybenzoyl chloride (510 mg, 2.54 mmol). The mixture was heated at 100° C. in the dark. After 28 h a further portion of tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) was added. Following another 22 h the mixture was allowed to cool to ambient temperature and diluted with EtOAc and water and partitioned. The organic layer was washed with saturated sodium hydrogen carbonate, saturated brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford ketone 45 [12.6 mg, 3.6% (2 steps)] as a white solid. 1H NMR (400 MHz; CDCl3) δ 3.99 (s, 3H), 4.00 (s, 3H), 6.54 (dd, J=2.0 and 3.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 7.38 (dd, J=2.5 and 3.5 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.81 (dd, J=0.7 and 2.5 Hz, 1H), 7.93 (dd, J=2.0 and 8.5 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H) and 8.90 (brs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>C(O)C.[Pt]>[NH2:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9]
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1N
Yield: 69.3 %

Procedure:
To a solution of 2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.2 g, 5.05 mmol) in ethanol (50 mL) in a par bottle was added 5% platinum on carbon (2.2 g). The reaction mixture was subjected to hydrogen gas (35 psi) for 30 minutes. The reaction mixture was filtered through celite and the filter cake was washed with ethanol. The filtrate was concentrated in vacuo. Chromatography on silica gel gave the title compound (1.42 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br>C(OCC)(=O)C>[Br:24][CH2:25][CH2:26][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: BrCCBr
Reactant: Oc1ccc(-c2noc3cc(F)ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Yield: 41 %

Procedure:
Combine 4-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (2.00 g, 8.726 mmol) and potassium carbonate (1.81 g, 13.088 mmol) in 1,2-dibromoethane (9.70 mL) and heat at reflux for 6 hours. Cool reaction mixture to room temperature and dilute with ethyl acetate (150 mL) and wash with water (50 mL), 10% HCl (50 mL), water (50 mL), saturated sodium chloride (50 mL), dry (MgSO4), filter and evaporate. Purify the residue by column chromatography (5% ethyl acetate in heptane) to obtain the title compound as a white solid (1.21 g, 41% Yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([CH3:31])[NH:27]1.N12CCCN=C1CCCCC2.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:27]4[C@@H:28]([CH3:31])[CH2:29][CH2:30][C@@H:26]4[CH3:25])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C[C@H]1CC[C@H](C)N1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3[C@@H](C)CC[C@@H]3C)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456, 100 mg, 0.289 mmol), (2S,5S)-2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60 mmol). The mixture was heated to 160° C. for 3 hours and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% acetone/dichloromethane as the eluent to produce 10 mg of P-577 as a pale viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 425.1 (M+1) LC-MS: 92%
Reaction SMILES: [C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[C:10]1[Se:11][CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Product: CC(=O)OC[C@H]1O[C@@H](c2nc(C(N)=O)c[se]2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-β-D-ribofuranosylselenazole-4-carboxamide (1.0 g, 3.25 mmol), N,N-dimethylaminopyridine (catalyst, 80 mg) and acetic anhydride (15 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and coevaporated with water (10 ml×2) to provide COMPOUND 3 as a white crystalline product which was triturated with water and collected by filtration. The product was recrystallized from water containing a few drops of ethanol to provide white needles: yield 1.2 g (85 percent), mp 117-119 degrees C.
Reaction SMILES: [C:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][N:4]1S(C1C=CC(C)=CC=1)(=O)=O)#[N:2].[H-].[Na+]>CN(C)C=O>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2C=Cc3cccc(-n4cccc4)c3C2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nccc2cccc(-n3cccc3)c12
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A mixture of 1-cyano-8-(pyrrol-1-yl)-2-toluene- p-sulphonyl-1,2-dihydroisoquinoline (446.2 g.) and sodium hydride (50% dispersion in mineral oil) (68.7 g.) in dimethylformamide (2,232 cc.) is kept at a temperature of about 20° C. for 16 hours. Crude 1-cyano-8-(pyrrol-1-yl)isoquinoline (261 g.), melting at 178° C., is thus obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH3:34])=[N:26][C:27]([N+:31]([O-:33])=[O:32])=[CH:28][C:29]=2[CH3:30])[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:34][C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[C:29]([CH3:30])[CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[N:26]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
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: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (237 mg, 1.139 mmol), 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (245 mg, 0.876 mmol), K2CO3 (363 mg, 2.63 mmol) and Pd(PPh3)4 (51 mg, 0.044 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT. The mixture was diluted with EtOAc. Washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 2,4-dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) which was used without further purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+:20].[K+]>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]#[N:15])=[CH:2][C:1]([O-:5])=[O:4])=[CH:9][CH:8]=1.[K+:20]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
133 g (0.9 mol) of 50% strength aqueous glyoxylic acid was added dropwise with stirring to 91.2 g (0.6 mol) of (4-chlorophenyl)acetonitrile and 210 g (1.5 mol) of potassium carbonate in 1.2 l of methanol such that the reaction temperature increased to 35° C. The mixture was stirred at room temperature for 6 h and then filtered, and the residue was washed with methylene chloride and dried under reduced pressure. At room temperature, the crude product was stirred with 3 l of water for 1.5 h, and the residue was filtered off, washed with water and dried. Yield: 138 g of a solid of m.p. 241-242° C.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]2[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]2=[O:41])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:35]1[CH2:36][CH2:37][N:38]([CH3:39])[CH:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:22]3[N:21]=[CH:20][C:19]4=[CH:18][CH:17]=[C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)(=[O:8])=[O:9])[CH:11]=5)[N:24]4[N:23]=3)[CH:28]=2)[C:34]1=[O:41]
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CCOCC6)c5)n4n3)c2)C1=O

Procedure:
1,4-Dimethyl-3-(3-{7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperazin-2-one was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a yellow foam (84 mg, 49%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.63 (d, 1H, J=7.5 Hz), 8.28 (s, 1H), 7.88-7.81 (m, 1H), 7.75-7.64 (m, 2H), 7.43-7.35 (m, 1H), 7.33 (s, 1H), 7.09 (d, 1H, J=7.6 Hz), 7.05 (d, 1H, J=4.8 Hz), 6.90 (s, 1H), 6.86 (d, 1H, J=4.8 Hz), 3.78-3.65 (m, 6H), 3.26-3.18 (m, 1H), 3.10-3.03 (m, 4H), 3.03-2.96 (m, 4H), 2.74-2.62 (m, 1H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[O:12][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:13][C:10]=2[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(Cl)c(O)c(O)c1Cl
Product: COC(=O)c1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
Methyl 2,5-dichloro-3,4-dihydroxybenzoate (1.1 g) (about 4.6 mmol) and 2.0 g (8.4 mmol) of dichlorodiphenylmethane are heated together to 150° C. After stirring for 1.5 hours the melt is cooled and the product is crystallized from diethyl ether. There are obtained 1.3 g of methyl 4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-carboxylate as white crystals of m.p. 112° C.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:20][C:21]([OH:23])=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CN(CC(=O)O)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
tert-Butyl {methyl [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained crystals were recrystallized from ethanol to give the titled compound (0.15 g, 87%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH2:20])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[NH2:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Temperature: 50 °C

Procedure:
A mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 14.60 mmol), 2-amino-benzoic acid (2.0 g, 14.60 mmol), TBTU (5.2 g, 16.06 mmol) and DIEA (2.7 mL, 16.06 mmol) in DMF (5 mL) was heated (50° C.) for 12 h in a sealed tube. The mixture was diluted with EtOAc and water. The aqueous layer extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid. MS (ES+): 396.0 (M+H)+. Calc'd for C23H29N3O3-395.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: NCCCN1CCOCC1
Product: N#Cc1cnc2cnc(NCCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 65 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-morpholinopropan-1-amine. The crude product was purified by flash column chromatography (5% methanol in methylene chloride) to give a yellow solid (0.065 g, 65%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 2.4 (d, J=13.1 Hz, 6 H) 3.3 (dd, J=12.9, 6.8 Hz, 2 H) 3.6 (m, 4 H) 6.9 (m, 2 H) 7.3 (m, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (dd, J=6.8, 2.5 Hz, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.7 (s, 1 H).