Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O1CCOCC1>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(OC2=Cc3[nH]nc(C=Cc4ccccc4)c3CC2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Oc2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-(3-styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine (50 mg, 0.15 mmol) and N,N-diisopropylethylamine (54 μl, 0.31 mmol) in 5 mL of CH2Cl2, was added benzoyl chloride (36 μl, 0.31 mmol). After 15 min, the reaction mixture was diluted with CH2Cl2 and washed sequentially with 0.5N HCl, saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated under reduced pressure. To a stirred solution of the residue in 1,4-dioxane was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (35 mg, 0.15 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, N-[3-(2-benzoyl-3-styrl-1H-indazol-6-yloxy)-phenyl]-benzamide was prepared as a rust colored solid (90 mg, ˜quantitative): 1H NMR (CDCl3) δ 8.13 (s, 1H), 8.02 (d, 2H, J=7.0 Hz), 7.94 (d, 1H, J=8.7 Hz), 7.74 (d, 2H, J=6.8 Hz), 7.57-7.19 (m, 17H), 6.84 (d, 1H, J=8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][C:6]#[CH:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>C1COCC1.C(NC(C)C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][C:6]#[C:7][C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(Oc2ncccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC#Cc1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Under an argon atmosphere, copper iodide (2.8 mg) and dichlorobis(triphenylphosphine)palladium (5.2 mg) were added to a solution of 2-(2,6-dichlorobenzamido)pent-4-ynoic acid methyl ester (74 mg) and 2-(4-iodophenoxy)pyrimidine (81 mg) in THF/diisopropylamine (3/1) mixture (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and ethyl acetate was added to the residue. The insoluble matter was removed by filtration, and the filtrate was washed once with water and once with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/3) to obtain 2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-ynoic acid methyl ester (100 mg).
Reaction SMILES: [C:1]1([C:7]2([C:14]#N)[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:30])C>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH:14]=[O:30])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccccc2)CCC=CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2)CCC=CCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (Z)-1-phenylcyclohept-4-enecarbonitrile from step B in toluene (15 mL) at −78° C. was added diisobutylaluminum hydride (1.0 M solution in toluene, 4.88 mL), and the resulting solution was stirred at −78° C. for 2 h. Saturated ammonium chloride was added drop wise followed by ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give the title compound. 1H NMR (400 MHz, CDCl3) δ 2.21 (6H, m), 2.37 (2H, m), 5.69 (2H, s), 7.30 (5H, m), and 9.38 (1H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([CH:29]4[CH2:31][CH2:30]4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[ClH:32].[CH:29]1([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CNC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(7-cyclopropylimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (100 mg; 0.238 mmol) in 1,4-dioxane (1 mL) was added hydrogen chloride in 1,4-dioxane (2.4 mL; 4M solution). The mixture was stirred in a sealed vial for 3 hours. The solvent was removed under reduced pressure to give the product (100 mg) as an off white solid. MS (apci) m/z=320.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[NH:49][CH:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:48][CH2:47]1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2[nH]c1=O
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(Nc2c(C(=O)OC)c(=O)[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a suspension of 6-Chloro-4-hydroxy-2-oxo-1,2dihydro-quinoline-3-carboxylic acid methyl ester (445 mg, 1.8 mmol) and diisopropylethlyamine (607 uL, 3.5 mmol) in acetonitrile (30 mL) was added p-toluenesulfonyl chloride (400 mg, 2.1 mmol). The reaction was stirred at room temperature and monitored by TLC to completion (2 h). 4-amino-piperidine-1-carboxylic acid ethyl ester was then added to the reaction mixture which was stirred at 50° C. for 8 h. The reaction mixture was then diluted up with CH2Cl2 and washed with water. The organic portion was dried with MgSO4 and evaporated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide a white solid (235 mg, 32%) which was carried onto the next step without characterization.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC(Cl)=O)(=O)C.N1C=CC=CC=1.[O:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:45][CH2:44][CH2:43][C:42]5=[O:41])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), acetoxyacetyl chloride (64 mg), pyridine (3 ml) and tetrahydrofuran (5 ml) was stirred under ice cooling for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added methanol (10 ml) and potassium carbonate (100 mg) followed by stirring for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (140 mg) as white scales (yield: 80%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])C1C=CC=CC=1.CS(O[C@@H](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.CN1C2C(=CC=CC=2)CC1=O>>[CH2:28]([N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([C@H:17]3[C@@:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:8]([CH3:1])[C:9]4=[O:35])[CH2:18]3)[CH:27]=2)[CH:23]=[N:24]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: CN1C(=O)Cc2ccccc21
Agent: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3cnn(Cc4ccccc4)c3c2)c2ccccc21
Yield: 84 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (6.70 g, 15.8 mmol) and 1-methylindolin-2-one (2.33 g, 15.8 mmol). Purification via column chromatography (silica gel, 25-50% EtOAc in hexane) yielded the title compound as a pale-orange crystalline solid (5.01 g, 84%); 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.30-7.25 (m, 3H), 7.18 (s, 1H), 7.13-7.10 (m, 3H), 6.92 (d, J=8.6 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.55 (t, J=7.0 Hz, 1H), 5.76 (d, J=7.2 Hz, 1H), 5.63-5.49 (m, 2H), 3.41 (t, J=8.8 Hz, 1H), 3.33 (s, 3H), 2.22-2.18 (m, 1H), 2.00-1.96 (m, 1H); MS ESI 380.2 [M+H]+, calcd for [C25H21N3O +H]+ 380.18.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[CH:20]1([CH2:19][O:13][CH2:12][CH:9]2[O:8][C:7]3[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[O:11][CH2:10]2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(CO)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OCC(COCC1CC1)O2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
(2,3-dihydro-6-nitrobenzo[b][1,4]dioxin-2-yl)methanol (500 mg, 0.002 mol) and sodium hydride (0.28 g, 0.0070 mol) were placed in a flask under nitrogen. The flask was placed in an ice bath and 25 mL DMF was added. The reaction was stirred at 0° C. for 10 minutes and then (chloromethyl)cyclopropane (440 μL, 0.0048 mol) was added. The mixture was warmed to room temp over 20 min then tetra-N-butylammonium bromide (1.53 g, 0.00475 mol) was added to the mixture and the reaction was stirred at room temperature overnight. The reaction was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated under vacuum to an oil. The oil was purified by column chromatography on silica gel using EtOAc/hexanes (10%) as eluent to give a yellow solid (0.33 g, 50%). m/z=266 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=3[CH3:31])=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.O=C1CCC(=O)N1[O:43][C:44](=O)[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][NH:59][C:60](=[O:70])[CH2:61][CH2:62][N:63]1[C:67](=[O:68])[CH:66]=[CH:65][C:64]1=[O:69].CCN(C(C)C)C(C)C>>[O:69]=[C:64]1[CH:65]=[CH:66][C:67](=[O:68])[N:63]1[CH2:62][CH2:61][C:60]([NH:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][C:44]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=3[CH3:31])=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:43])=[O:70]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCN)CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(4-aminobutyl)cyclopentanecarbonyl]amino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid (300 mg, 0.62 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (318 mg, 0.62 mmol), and DIPEA (160 mg, 215 uL, 1.24 mmol), and after HPLC purification, resulted in a light yellow solid (274 mg, 50%). ES(+)-HRMS m/e calcd. for C44H62N6O13 (M+H)+ 883.4448, obsd. 883.4449.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[C:10]([CH2:23][CH:24]=[CH2:25])[CH:9]=1)\[CH3:7])[CH3:2].[B]1OC2C(=CC=CC=2)[O:30]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1COCC1>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4](=[O:26])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[C:10]([CH2:23][CH2:24][CH2:25][OH:30])[CH:9]=1)\[CH3:7])[CH3:28]
Reactant: C=CCc1cc(/C(C)=C/C(=O)N(CC)CC)ccc1OC(C)c1ccccc1
Reactant: [B]1Oc2ccccc2O1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(CCCO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N,N-diethyl (E)-3-[3-allyl-4-(1-phenylethoxy)-phenyl]-but-2-enamide (2.61 g, 6.92 mmol) and Wilkinson's catalyst (tris(triphenylphosphine)rhodium (I) chloride, 64 mg, 0.069 mmol) in THF(40 mL) at 0° is added a 1.0 M solution of catecholborane in THF (7.62 mL, 7.62 mmol), via syringe. After stirring for 3 hours at 0°, the solution is quenched with methanol (15 mL), followed by addition of a solution 30% hydrogen peroxide (1.94 mL) in 3 M NaOH (18 mL). The solution is then warmed to room temperature over 3 hours. The solution is concentrated to 25 mL in vacuo, and the residue is taken up in H2O (100 ML) and extracted with ether (3×50 mL). The combined organic phase is washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 4:1 EtOAc/hexane) yields N,N-diethyl (E)-3-[3-(3-hydroxypropyl)4-(1-phenylethoxy)-phenyl]-but-2-enamide.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[C:7](O)=[O:8])[CH2:5][CH2:4]1.II.[H][H]>C1COCC1>[CH:3]1([CH:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:7][OH:8])[CH2:5][CH2:4]1
Reactant: O=C(O)C(NC1CC1)C1CC1
Reactant: [H][H]
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(NC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (200 mg) was added to THF (10 mL), followed by cyclopropyl-cyclopropylamino-acetic acid (1 g of the material obtained in step B]). The mixture was cooled to 0° C. and a solution of iodine (558 mg) in THF (5 mL) was added carefully drop by drop over a period of 30 minutes. Vigorous hydrogen evolution was observed. The mixture was stirred at 0° C. for 30 minutes and then heated to reflux for 2 hours. The mixture was cooled and quenched with methanol until a clear solution was obtained. The solution was stirred for 30 minutes and then evaporated in vacuo. The residue was treated with 20% KOH (10 mL) and extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography using methanol/ethyl acetate 2:3 as an eluent to give 2-cyclopropyl-2-cyclopropylamino-ethanol (73 mg) as a colorless oil. MS (ESI): 142.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(N)nc(-c2ccccc2)n1

Procedure:
Using the method of Example 33, 4-amino-6-chloro-2-phenylpyrimidine was reacted with sodium methoxide to provide solid 4-amino-6-methoxy-2-phenylpyrimidine. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH:18]=O)[CH2:10]2.[CH3:29][NH2:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:18][NH:30][CH3:29])[CH2:10]2
Reactant: Cn1ncc(Cl)c1-c1ccc2c(c1)CN([C@H](C=O)Cc1cccc(F)c1)C2=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC[C@H](Cc1cccc(F)c1)N1Cc2cc(-c3c(Cl)cnn3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S)-2-[5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-(3-fluorophenyl)propanal (40.0 mg, 0.100 mmol), methylamine (20.3 μL, 0.151 mmol) and sodium triacetoxyborohydride (42.6 mg, 0.201 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature overnight. Direct purification on prep.—HPLC (pH=10) gave the desired product as white solid. LC-MS found: 413.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11]>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: COc1cc(C=O)ccc1Cl
Yield: 89.7 %

Procedure:
To a solution of (4-chloro-3-methoxyphenyl)methan-1-ol (5.08 g, 29.4 mmol) in benzene (120 mL) was added MnO2 (5.65 g, 65 mmol). The reaction mixture was refluxed for 17 hr, chilled, and filtered through Celite, washing the cake with CH2Cl2 (300 mL). The filtrate was concentrated in vacuo to give 4-chloro-3-methoxybenzaldehyde (4.5 g, 89%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19](=O)[C:20]([N:22]([CH3:24])[CH3:23])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:26])[O:5][N:4]=1)[CH3:2]>C1COCC1>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20][N:22]([CH3:23])[CH3:24])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:26])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCC(=O)C(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CCCCN(C)C

Procedure:
A solution of 5.3 grams (0.015 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-N,N-dimethyl- -oxo-indole-3-butanamide in 75 ml dry THF is added dropwise to a refluxing suspension of 1.71 grams (0.045 mole) of LiAlHy and 50 ml THF. The mixture is refluxed 2 hours after addition and then cooled and quenched by the addition of ethyl acetate, 2N sodium hydroxide and water. The mixture is filtered and the THF evaporated. The residue is dissolved in CH2Cl2, washed with water, dried over MgSO4, filtered and evaporated. The residue is dissolved in ether and converted to the hydrochloride salt with gaseous HCl giving the title compound as the hydrochloride, m.p. 155.5°-157.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13]CCC1.C1(C2C=C(C)NC(=O)C=2C#N)CC1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13]1
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: Cc1cc(C2CC2)c(C#N)c(=O)[nH]1
Product: Cc1cc(C2CC2)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3) using 4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g, 28.7 mmol). Obtained: 0.50 g (10%). LCMS E-S(M+H)=179.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76-11.78 (br s, 1H), 7.82-7.92 (br s, 3H), 5.61 (s, 1H), 3.94-3.99 (m, 2H), 2.11 (s, 3H), 1.98-2.05 (m, 1H), 0.95-1.01 (m, 2H), 0.74-0.79 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=4[CH3:30])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.[Cu]Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH3:30][C:24]1[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:41]4[CH:40]=[N:39][C:38]([CH3:37])=[CH:43][CH:42]=4)=[N:7][CH:6]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]2=[N:19]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1cccc(-n2nc3c4cccnc4n(Cc4ccc(Cl)nc4)nc-3c2=O)c1C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl[Cu]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n(-c5cccc(C)c5C)nc-4c4cccnc43)cn2)cn1
Reaction time: 0.75 h

Procedure:
5-[(6-Chloropyridin-3-yl)methyl]-2-(2,3-dimethylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one [(Example 4), 47 mg, 0.11 mmol], cesium carbonate (92 mg, 0.28 mmol, 2.5 equiv), copper(I) chloride (11 mg, 0.11 mmol, 1 equiv), 2-methyl-5-pyridinylboronic acid (39 mg, 0.28 mmol, 2.5 equiv) and bis(tri-tert-butylphosphine)palladium(0) (11 mg, 0.023 mmol, 0.2 equiv) were combined in tetrahydrofuran (4 mL) and placed into a preheated oil bath at 70° C. After 45 minutes, water (1 mL) was added and after 45 minutes, the mixture was poured into sodium bicarbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.04 (1H, d, J=1.4 Hz), 8.89 (1H, d, J=2.3 Hz), 8.79 (1H, dd, J=4,6, 1.7 Hz), 8.55 (1H, dd, J=8.0, 1.8 Hz), 8.18 (1H, dd, J=8.1, 2.3 Hz), 8.03 (1H, dd, J=8.2, 2.2 Hz), 7.70 (1H, d, J=8.2 Hz), 7.52 (1H, dd, J=8.0, 4.6 Hz), 7.27-7.25 (1H, m), 7.24-7.22 (3H, m), 6.02 (2H, s), 2.61 (3H, s), 2.36 (3H, s), 2.16 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 474.2043 [(M+H)+; calculated for C28H24N7O: 474.2037].