Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CN(C=O)C.[CH3:24][S-:25].[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:25][CH3:24])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-β-carboline (Intermediate 5, 3.959 g, 14.9 mmol) and 100 ml anhydrous DMF. The resulting orange mixture was cooled to 0° C. (ice and water bath) and sodium thiomethoxide (1.809 g, 25.8 mmol) in powder form was added slowly thereto. The reaction mixture was stirred for 1 hr at 0° C., warmed to RT, and added slowly to a stirring mixture of 4:1H2O/saturated aqueous sodium bicarbonate (500 ml). The precipitated solid was collected via suction filtration and air-dried to afford 4.017 g of 6-chloro-7-methylsulfanyl-8-nitro-9H-β-carboline as an orange powder. The crude material was used directly in subsequent steps. 1H-NMR (300 MHz, Methanol-d4): δ 8.91 (1H, d) 8.63 (1H, s) 8.42 (1H, d) 8.17 (1H, dd) 2.54 (3H, s). LCMS (formic acid standard method) retention time=1.43 min. MS (M+H+): 294.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[C:10]([N+:18]([O-:19])=[O:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cccc(Br)n2n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 57.1 %

Procedure:
To a solution of 7-bromo-2-methylpyrazolo[1,5-a]pyridine (1.3 g) dissolved in acetonitrile (25 mL) was added nitronium tetrafluoroborate (900 mg) while stirring on ice, and the reaction mixture was stirred for 10 minutes. The obtained reaction mixture was added to ice water, and the precipitated crystals were collected by filtration, washed with water and then dried under reduced pressure to afford crude crystals. These were purified by silica gel column chromatography and the title compound (900 mg) was obtained as yellow crystals from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]O)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccccc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 151.5 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-(2-propoxyethoxy)benzyl alcohol (0.63 g) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene, 1.36 ml), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.04 g).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][O:21]3)=[CH:16][C:15]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(#N)C>O>[C:1]([C:5]([N:7]1[C:8]([NH2:9])=[CH:13][CH:12]=[CH:11][CH:10]1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:21])[CH2:22][N:38]2[CH2:39][CH2:40][N:35]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:16][C:15]=1[O:23][CH:24]([CH3:25])[CH3:26])=[O:6])([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(C(O)CN2CCN(CCc3ccccc3)CC2)ccc1C1C=CC=C(N)N1C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a 25 mL round-bottomed flask equipped with condenser and N2 inlet were added 300 mg (0.847 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-oxiranylphenyl)-pyridin-2-ylamine, 193 mg (1.017 mmol) N-phenethylpiperazine, 9 mL acetonitrile, and 0.85 mL water. The reaction was heated to 80° C. for 20 hours, cooled, and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride/ammonium hydroxide as eluant to afford 283 mg (62%) of an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperidine-1-carboxylate (0.0518 g, 0.143 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0220 g, 0.151 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0525 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (97 mg, 80%).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:27])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:6]([OH:8])=[O:7].[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>CN(C=O)C>[CH3:1][N:2]=[C:3]([OH:27])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[C:11]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: O=S([O-])c1ccccc1
Reactant: CCCCCCCCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1cc(S(=O)(=O)c2ccccc2)cc(C(O)=NC)c1C(=O)O

Procedure:
2.0 g (5.28 mmols) of 3-n-decylthio-5-nitrophthalic acid N-methylimide, 1.73 g (10.57 mmols) of sodium phenylsulfinate and 20 ml of DMF are stirred for 17 hours at 120° C. The mixture is concentrated and the residue is taken up in methylene chloride/dilute hydrochloric acid. The organic phases are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from cyclohexane, 1.83 g (73% of theory) of the title imide, with a melting point of 86°-88° C., are obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.Cl[C:12]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[S:5][C:6]([CH2:9][O:10][C:12]2[C:17]([CH3:18])([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=2)=[CH:7][N:8]=1
Reactant: OCc1cnc(Br)s1
Reactant: CC1(C)C(=O)C=C(Cl)C(C)(C)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)C=C(OCc2cnc(Br)s2)C(C)(C)C1=O
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in mineral oil solution (1.6 g, 40 mmol) in tetrahydrofuran (50 ml) is added a solution of (2-bromothiazol-5-yl)methanol (6.75 g, 35 mmol) in tetrahydrofuran (50 ml) at 0° C. A solution of 5-chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (7.0 g, 35 mmol) in tetrahydrofuran (50 ml) is then added and the reaction mixture is heated to reflux for 18 hours. The reaction mixture is poured into water, acidified to pH4 with dilute aqueous hydrochloric acid and extracted with ethyl acetate (4×50 ml). The combined organic layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to a brown oil. The crude product is purified by flash chromatography on silica gel to give 5-(2-bromothiazol-5-ylmethoxy)-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.75 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1.[C:13](O)(=[O:15])[CH3:14].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:9]1([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:10][CH2:11]1)(=[O:15])[CH3:14]
Reactant: OC1(COC2CCCCO2)CC1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(COC2CCCCO2)CC1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (172 mg, 1 mmol) and acetic acid (120 mg, 2 mmol, Shantou Xilong chemical factory) in 2 mL of DCM was added DMAP (12 mg, 0.1 mmol, aladdin) at rt. After stirring for 30 min, DCC (840 mg, 4 mmol, Aldrich) was added at 0° C. The reaction was quenched with water after all of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol disappeared (monitored by TLC) (about 4 hours). The solid formed during the reaction was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give the desired compound as yellow oil (130 mg, 60.7%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=S.CCN(C(C)C)C(C)C>C(#N)C>[OH:7][CH2:6][C@H:2]([NH:1][C:9]1[S:8][CH2:14][C:12](=[O:13])[N:11]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@H](CO)NC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 48 h
Yield: 41.8 %

Procedure:
To a suspension of (R)-valinol (1 g, 9.69 mmol) and Rhodanine (1.3 g, 9.69 mmol) in acetonitrile (40 mL) was added DIPEA (5.06 mL, 29 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (2.72 g, 10 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The filtrate was removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.82 g (42% yield) of 2-(1-(R)-hydroxymethyl-2-methylpropylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C8H14N2O2S (M+) 202.0776. found 202.0778.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([S:7][CH:4]2[CH2:3][CH2:2][N:1]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(SC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
4-(Piperidin-4-ylthio)aniline (6.69 mmol, 1.3946 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (6.69 mmol, 2.256 g), and potassium carbonate (13.39 mmol, 1.850 g) were combined in acetonitrile (20 mL) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and partitioned between dichloromethane and water. The organic layer was separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with 2.5-5% methanol/dichloromethane gradient) to afford the title compound (1.93 g). MS m/z 465.0 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>>[C:16]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=[C:14]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=2)[CH:15]=1
Reactant: C#Cc1cccc(CCCO)c1
Reactant: Brc1cccc(-c2ccccc2)c1
Product: OCCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1

Procedure:
Coupling of alcohol 50 with 3-bromobiphenyl was conducted following the method described in Example 21 to give 3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol. Purification by flash chromatography (5% EtOAc-hexanes) gave a brown oil. Yield (0.560 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.78 (br s, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.37-7.48 (m, 6H), 7.29 (d, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 3.70 (dt, J=6.2, 5.2 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 1.92 (quint, J=6.8 Hz, 2H), 1.27 (t, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14](=[O:16])[NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:14](=[O:16])[NH2:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-3-carbamoylpiperazine (ref Bruce et al. Syn. Comm. 1995, 2673-84) (25 g, 0.109 mol) and benzaldehyde (11.1 ml, 0.109 mol) in 1,2-dichloroethane (550 ml) was stirred at room temperature for 1.5 h. Sodium triacetoxyborohydride (34.7 g, 0.163 mol) was added in one portion and the resultant stirred for a further 18 h. Dichloromethane (400 ml) was added and the mixture washed with saturated sodium hydrogen carbonate (600 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-70% ethyl acetate in hexane to afford the title compound as a colourless solid (32.4 g, 93%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[NH:39][N:38]=[C:37]([CH:40]3[CH2:42][CH2:41]3)[CH:36]=2)[CH:31]=[CH:30][N:29]=1>CC(O)C>[CH:40]1([C:37]2[NH:38][N:39]=[C:35]([NH:34][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:33]=3)[CH:36]=2)[CH2:42][CH2:41]1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2ncn(C3CCCCO3)c2c1
Yield: 29.4 %

Procedure:
A mixture of 58 (200 mg, 0.87 mmol), DIPEA (335 mg, 2.61 mmol) and 53 (203 mg, 0.87 mmol) in IPA (3 mL) was irradiated in a microwave reactor at 120° C. for 2 h. The solvent was removed under reduced pressure to afford 110 mg (30%) of crude N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (60) as brown solid, which was used in the step without further purification: MS (ESI) m/z=431.7 [M+1]+.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[CH2:9][CH:10](O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([CH:10]1[O:21][C:6](=[O:5])[CH2:7][C:8](=[O:20])[CH2:9]1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(=O)OC(CCc2ccccc2)C1

Procedure:
A solution of 5-hydroxy-3-oxo-7-phenyl-heptanoic acid tert-butyl ester (0.96 g, 3.3 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (60 mL) was stirred at rt for 18 h. Removal of the volatile components under reduced pressure afforded the product 6-Phenethyl-dihydro-pyran-2,4-dione as an off white solid (0.56 g, 78%). 1H NMR (300 MHz, CDCl3) δ1.9-2.2 (m, 2H), 2.4-2.7 (m, 2H), 2.75-2.95 (m, 2 H), 3.5 (q, 2H), 4.55-4.65(m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C13H14O3): 218.1; found: 219.1 (M+H)+.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([OH:24])=O)=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.[F:30][C:31]([F:50])([F:49])[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=3[CH:41]=[N:40]2)=[N:36][CH:37]=1>CC(N(C)C)=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([NH:48][C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[N:40][N:39]5[CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:50])([F:49])[F:30])=[CH:37][N:36]=4)=[O:24])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Reactant: Nc1cccc2c1cnn2Cc1ccc(C(F)(F)F)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4ccc(C(F)(F)F)cn4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium chloride (0.0653 g, 0.188 mmol) in dry DMA (2.0 mL) at 0° C. was added POCl3 (0.0345 mL, 0.376 mmol) and the mixture was stirred at 0° C. for 30 minutes. 1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g, 0.188 mmol) was added as a DMA solution (1.0 mL) and the mixture was gradually warmed to ambient temperature and stirred overnight. The mixture was concentrated under vacuum and 2M LiOH (2.5 mL) was added. The mixture was stirred for 10 minutes. The mixture was diluted with CHCl3 (20 mL) and with saturated aqueous NaHCO3 and the layers were mixed and separated. The aqueous phase was further extracted with CHCl3 and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by preparative TLC (15% MeOH/CH2C12 adding 1% 7N NH3/MeOH) to provide 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid (0.028 g). The solid was dissolved in MeOH (2.0 mL) and HCl (1.88 mL, 3.76 mmol, 2.0M in Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and finally with hexanes and dried under vacuum to provide the title compound (0.032 g, 24%). MS (ES+APCI) m/z=579 (M+H-3HCl).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)NC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-3-fluoro-4-nitrobenzamide (300 mg, 1.64 mmol) and diisopropylethylamine (0.43 mL, 2.46 mmol) in DMF (7 mL) was added butylamine (0.203 mL, 2.05 mmol) and the solution was stirred at room temperature overnight. The solution was concentrated, the residue dissolved in ethyl acetate and washed with 1 N HCl. The organic phase was dried over MgSO4 and concentrated to give N-methyl-3-butylamino-4-nitrobenzamide as a yellow oil that was used without further purification (380 mg, 92%).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]([OH:23])CO)[N:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=O.[Na+].O>CO>[C:8]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[O:23])[N:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(O)c1csc(NC(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=Cc1csc(NC(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 50, the desired compound was prepared from 2.11 g of 1-(2-diphenylmethylaminothiazol-4-yl)ethane-1,2-diol, 3.15 g of sodium metaperiodate, 40 ml of water and 20 ml of methanol. The resulting product was a pale brown foam having the following physical properties.