Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][C@@H:25]([CH3:29])[NH:24]1>C(#N)C>[ClH:1].[C:12]([C:11]1[C:2]([N:27]2[CH2:26][CH:25]([CH3:29])[NH:24][CH:23]([CH3:22])[CH2:28]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C#N)CC(C)N1
Product: Cl
Yield: 22.9 %

Procedure:
A solution of 500.0 mg (1.63 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see: DE 19854357) and 446.8 mg (3.91 mmol) of cis-2,6-dimethylpiperazine in 50 ml of acetonitrile is stirred over night at 50° C. The solvent is removed completely on a rotary evaporator, the residue is taken up in 50 ml of water and the pH is adjusted to pH 11 with a 1N sodium hydroxide solution (the residue dissolves). The solution is then adjusted to pH 7 with 1N hydrochloric acid. The precipitate is filtered off, washed with water and diethylether and dried under high vacuum. 157 mg of the title compound are obtained. The filtrate is extracted with dichloromethane, the organic phase is concentrated and the residue is purified by RP-HPLC. An additional 351 mg of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([C:10]3([CH2:9][NH:8][C:4]4[CH:3]=[CH:2][N:7]=[CH:6][N:5]=4)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:21][CH:20]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1cc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ncn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ncn1
Yield: 18.9 %

Procedure:
A solution of 6-chloro-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyrimidin-4-amine (50 mg, 0.12 mmol) and triethylamine (48.6 μl, 0.35 mmol) in ethanol (2 mL) was hydrogenated for 16 hours at room temperature at 50 psi in the presence of 10% Pd/C (5 mg, 10% w/w). The reaction mixture was filtered through Arbocel® and rinsed with ethanol and water. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium carbonate (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 95:5:0.5 by volume) to provide the title compound (9 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.Cl[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1.CC(O)=O>CS(C)=O>[O:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH:14]=[C:13]1[C:11]1[O:10][N:9]=[C:8]([CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=3)[CH2:2][CH2:3]2)[N:12]=1
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(Cc3noc(-c4cc5cnccc5o4)n3)CC2)nc1
Temperature: 25 °C

Procedure:
2-(3-Piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 50 mg, 0.176 mmol), ethyl 6-chloronicotinate (49 mg, 0.264 mmol) and DBU (40 mg, 0.264 mmol) were shaken in DMSO (1 mL) at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, before being acidified with AcOH. Purification by RP-HPLC yielded the title compound: RT=5.74 min; m/z (ES+)=434.4 [M+H]+.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5]NN1.C(N)CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1CCN>CN(C)C=O>[ClH:1].[S:13]1[C:14]2[CH2:15][CH2:16][NH:2][CH2:7][C:6]=2[CH:5]=[CH:17]1
Reactant: NCCc1cccs1
Reactant: C1CNNNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCN
Product: c1cc2c(s1)CCNC2
Temperature: 45 °C
Yield: 65 %

Procedure:
To 73 ml dimethylformamide heated at 45° C. in which are dissolved 0.45 mole gaseous hydrochloric acid, is added, over 25 minutes, a mixture of 17 g (0.2 M) s.hexahydrotriazine of n. n.butylamine/and 26 g 2-(2-thienyl)ethylamine. The temperature of the medium is maintained at 45° C. throughout the addition by means of a cold water bath. The desired product precipitates out at the end of the addition. Filtration gives 22.16 g 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[C:10]([O:14][C:15](=[O:29])[C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][NH:19]C)([CH3:13])([CH3:12])[CH3:11].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[C:10]([O:14][C:15](=[O:29])[C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][NH:19][C:6]1[C:5]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: OB(O)c1cccs1
Reactant: CNCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCNc1nc(Cl)ncc1-c1cccs1)C(=O)OC(C)(C)C

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodo-pyrimidine, (S)-2-tert-butoxycarbonylamino-4-methylaminobutyric acid tert-butyl ester and 2-thiophenboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:35][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added phenethylamine (28 μL, 0.22 mmol) and N,N-diisopropylethylamine (105 μL, 0.60 mmol). The resulting yellow solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (5 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as an off-white solid (89 mg, 93% yield).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Yield: 60.2 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.85 mol) in trifluoroacetic acid (10 mL) was refluxed overnight. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (160 mg, 60.2%). LCMS calculated for C12H14F3N6O (M+H): 315.1. Found 315.0.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51])=[O:44].[O:52]1[CH2:57][CH2:56][N:55]([C:58]2[C:59]([NH2:77])=[N:60][C:61]3[C:66]([CH:67]=2)=[CH:65][C:64](B2OC(C)(C)C(C)(C)O2)=[CH:63][CH:62]=3)[CH2:54][CH2:53]1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:77][C:59]1[C:58]([N:55]2[CH2:56][CH2:57][O:52][CH2:53][CH2:54]2)=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([C:36]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=3[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:44])[CH:65]=2)[N:60]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1ccccc1C(=O)c1cccc(C)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C(=O)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.013 g, 0.028 mmol), (2-bromo-3-methylphenyl)(o-tolyl)methanone (0.16 g, 0.563 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.050 g, 0.141 mmol), Pd2(dba)3 (6.44 mg, 7.04 μmol) were treated with dioxane (0.94 mL) and water (0.47 mL) in a medium-sized Smith synthesizer vial. The mixture was heated to 140° C. for 12 min in a microwave reactor. The reaction mixture was filtered then partitioned between EtOAc and water. The organic layer was washed with water and brine and then concentrated in vacuo. The crude product was purified first by column chromatography (1-10% MeOH:DCM) and then by HPLC (10-90% CH3CN/H2O; TFA modifier). A single fraction was treated with NH4OH, concentrated, filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(o-tolyl)methanone. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:15][CH:16]([CH3:25])[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18].[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:17]([OH:18])([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]([CH3:25])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1cncnc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)(C#Cc1ccc(Cl)cc1)c1cncnc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
1(4'-Chlorophenyl)ethyne (1.43g:0.01 mole) was dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to -35° C. Butyllithium was added (6.5 ml of 1.6M solution:0.0104 mole) causing the colour to change. The mixture was stirred for 1/2 hour during which time it thickened and the colour changed to pink (from purple). Addition of a solution of chlorotanium triisopropoxide (10.6 ml or a 1 molar solution:0.0106 mole) caused the colour to change to yellow and the mixture was stirred for 20 minutes. The mixture was cooled to -60° C. and a solution of 2-methyl 1(pyrimidin-5-yl)propan-1-one in tetrahydrofuran (10 ml) was added and the reaction mixture allowed to warm up to room temperature within the cold bath. A solution of ammonium chloride in water (20%) was added and the mixture filtered. The aqueous was extracted with ethyl acetate (×3), washed (with water then brine), dried and the solvent removed in vacuo. The product was passed through silica (in ether) and then titurated with pentane and ether (0.467g: off white solid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of Ethyl 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoate (14 g, 37 mmol) in Ethanol (80 mL) was added KOH (6.2 g, 111 mmol) and water (80 mL). The mixture was stirred at room temperature for 4 hours, and then concentrated under reduce pressure. The pH value of the solution was adjusted to 4 by concentrated HCl. The resulting mixture was extracted by EtOAc (200 mL×3). The organic layers were combined and dried over Na2SO4, then concentrated to give the desired compound (12 g, yield 92.5%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[C:9]([CH3:18])=[N:10][C:11]2[N:12]([N:15]=[CH:16][CH:17]=2)[C:13]=1[F:14].[OH2:19]>>[Cl:7][C:8]1[C:9]([C:18]([OH:2])=[O:19])=[N:10][C:11]2[N:12]([N:15]=[CH:16][CH:17]=2)[C:13]=1[F:14]
Reactant: Cc1nc2ccnn2c(F)c1Cl
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1nc2ccnn2c(F)c1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Potassium permanganate (2.00 equivalents) is added to 6-chloro-7-fluoro-5-methylpyrazolo[1,5-a]pyrimidine (1.00 equivalent) in water, and the mixture is heated at 100° C. After 3 hours, the reaction mixture is cooled to room temperature, and the precipitated oxides of manganese are filtered and washed with hot water. The filtrate is concentrated under reduced pressure, diluted with EtOAc, washed with 10% aqueous HCl solution, dried (MgSO4), and concentrated. The product may be triturated with an appropriate solvent such as diethyl ether or dichloromethane if further purification is necessary.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cu](C#N)[C:12]#[N:13].O>CN(C=O)C>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.6 mmol, 1.0 eq.) in 50 mL of DMF was added copper cyanide (2.47 g, 38 mmol, 1.2 eq.) and the reaction heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into 100 mL of water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate portions were dried over soduim sulfate and concentrated. The crude material was chromatographed on silica with 3:7 ethyl acetate/hexanes to give 2-cyano-3-nitropyridine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-Amino-2-(2-methylimidazol-1-yl)fluorobenzene (34.25 g, 0.179 M) was dissolved in dry dichloromethane (600 ml) under nitrogen, and cooled to −5°. Pyridine (17.7 g, 0.224 M) was added, followed by benzyl chloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 250 ml) was added, the organic layer separated, the aqueous layer re-extracted with dichloromethane (2×300 ml), and combined extracts dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (400 ml) to give title product (54.5 g). NMR (DMSO-d6) δ: 2.13 (s, 3H); 5.18 (s, 2H); 6.89 (s, 1H); 7.17 (s, 1H); 7.41 (overlapping m, 7H); 7.73 (dd, 1H); 10.21 (br, 1H). MS (ESP): 326 (MH+) for C18H16FN3O2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](Cl)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:25]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cl)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride (200 mg) in methylene chloride (4 ml) were added N,O-dimethylhydroxylamin e hydrochloride (70 mg) and triethylamine (0.2 ml) and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and crystallized from diisopropyl ether to give the title compound (180 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:24]3[C:25]([F:40])=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O>C(Cl)Cl>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:16]3[CH:15]=[C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[C:25]([F:40])=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cc4nn(Cc5ccccc5)cc4cc3F)c3c(N)ncnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3cc4nn(Cc5ccccc5)cc4cc3F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 4-[4-amino-5-(2-benzyl-5-fluoro-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (370 mg, 0.68 mmol) in DCM (12 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at rt under N2 for 18 h and poured into EtOAc. The organic phase was washed with saturated, aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether-hexane to provide the title compound (166.4 mg, 55.1%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), 7.85 (s, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.37 to 7.54 (m, 5H), 6.63 (s, 1H), 5.66 (s, 2H), 3.52 to 3.46 (m, 1H), 3.36 to 3.30 (m, 2H), 3.28 to 3.25 (m, 1H), 3.00 (dt, 2H), 2.25 (d, 2H), 1.92 to 1.80 (m, 2H); ES-MS m/z 442.2 [M+H]+, RT (min) 2.08.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]#[N:38]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:37]#[N:38])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-methyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenol (0.173 g, 0.472 mmol) was reacted with K2CO3 (0.078 g, 0.566 mmol) and bromoacetonitrile (0.068 g, 0.566 mmol) in acetone (10 ml) to give the product (0.160 g, 0.392 mmol, 83%) as a white solid, mp 101-102° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.14-1.22 (m, 4H), 1.52-1.98 (m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.56 (s, 3H), 5.21 (s, 2H), 7.16 (d, J=8.9 Hz, 2H), 7.43-7.51 (m, 5H), 7.55 (t, J=7.2 Hz, 2H), 7.69 (d, J=8.9 Hz, 2H), 7.76 (d, J=1.1 Hz, 1H); [ESI(+)], m/z 409 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[CH:48]([C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)=[CH2:49]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](/[CH:49]=[CH:48]/[C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1cccnc1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(/C=C/c3cccnc3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
A 50 mL round bottom flask charged with tert-butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (500 mg, 0.85 mmol), triethylamine (355 μL, 2.54 mmol), Pd2dba3 (19.4 mg, 0.021 mmol), tri-o-tolylphosphine (19.4 mg, 0.064 mmol), and DMF (7 mL) was purged under N2 (3 cycles). 3-vinylpyridine (270.24 mg, 1.7 mmol) was added, and the mixture was stirred at 100° C. under a N2 atmosphere for 6 hours. The reaction mixture was cooled to room temperature, diluted with warm EtOAc (100 mL) and washed with water (2×30 mL). The phases were separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage Flash 40S+) eluting with 25% EtOAc/hexane followed by 50% EtOAc/hexane to provide (E)-tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-(2-(pyridin-3-yl)vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (390 mg, 81% yield) as a solid. LCMS (APCI+) m/z 567.3 (M+H)+.