Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([NH2:10])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.CCOC(C)=O>[C:21]1([O:20][C:18](=[O:19])[NH:10][C:3]2[N:4]3[N:5]=[CH:6][CH:7]=[CH:8][C:9]3=[N:1][CH:2]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cnc2cccnn12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2cccnn12)Oc1ccccc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of imidazo[1,2-b]pyridazin-3-ylamine (209 mg, 1.56 mmol) in dry DMF (5.0 mL) was added pyridine (382 μL, 4.68 mmol) and phenyl chloroformate (244 mg, 1.56 mmol). After 3 h at rt, the mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (285 mg, 72%). MS (ESI+): calcd for C13H10N4O2 m/z 254.08. found 255.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 99.9 %

Procedure:
Methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (960 mg, 3.01 mmol) and palladium, 10% on carbon (96 mg, 0.09 mmol) in ethanol (10 ml) and ethyl acetate (40.0 ml) were stirred under an atmosphere of hydrogen at atmospheric pressure and ambient temperature for 18 h. The reaction mixture was filtered through celite, washing with methanol, ethyl acetate and dichloromethane and concentrated under reduced pressure to give methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-5-carboxylate (966 mg, 100%) as a yellow oil, which crystallised on standing. This was used directly with no further purification.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=[O:4].[Cl:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[CH2:56]1[CH2:60][O:59]C[CH2:57]1>O>[Cl:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][C@@H:56]([CH3:57])[C:60]([OH:59])=[O:4]
Reactant: C1CCOC1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CS(=O)(=O)c1ccc(Nc2cc(F)ccc2O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C[C@H](Oc1ccc(F)cc1Nc1ccc(S(C)(=O)=O)cc1Cl)C(=O)O
Reaction time: 20 h

Procedure:
Diisopropyl azodicarboxylate (0.14 ml) was added to a stirred solution of the product from example 56 step (ii) (0.2 g), triphenylphosphine (0.18 g), R-methyl lactate (0.1 g) in THF (10 ml). After 20 h, aqueous 1M sodium hydroxide solution (2 ml) was added and stirred for 4 h. The mixture was diluted with water (30 ml) then partitioned between ethyl acetate/2M hydrochloric acid. The organics were separated, washed with brine, dried and evaporated under reduced pressure. The residue was purified by RPHPLC, yield 0.094 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1I.C([Li])CCC.C1(C)C=CC(S([C:27]#[N:28])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]2[C:11]=1[C:27]#[N:28]
Reactant: Fc1ccc2nc(Cl)c(I)n2c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 3 Step A (0.30 g, 1.01 mmol) in tetrahydrofuran (5.06 ml) was added a solution of n-butyllithium in hexanes (1.6 M, 0.696 ml, 1.11 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.238 g, 1.32 mmol) was added, and the resulting mixture was allowed to slowly warm to room temperature overnight. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (10-50% ethyl acetate in hexanes) to afford the title compound: LCMS m/z 195.88 [M+H]+, 197.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.69 (dd, J=9.6, 4.8 Hz, 1H), 7.46-7.42 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[Br:24][CH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[C:6]([Cl:20])[CH:5]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of the title compound of Step A (75 mg, 0.22 mmol) in dry methylene chloride (2 ml) at room temperature under nitrogen was added boron tribromide (1M in methylene chloride, 0.44 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for about one hour, quenched with water (5 ml) and extracted with methylene chloride (3×5 ml). The combined organic exrtracts were dried, filtered, and concentrated. The crude product was purified by preparative TLC (methylene chloride) to afford the title compound (59 mg) as an oil. MS (APCl−) Calc: 388.0, found: 386.9 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:4][C:3]1=[S:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(O)(=O)C>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][S:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1-c1cccnc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-(3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.85 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.31 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.360 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (7.5 g) and sodium hydroxide (3 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (4.3 g). M.p. 213°-215° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CN([CH:38]=[O:39])C>>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:39][CH3:38])([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Product: COC1(Oc2ccc3[nH]cc(C)c3c2)NC=Nc2cc(OC[C@H](O)CN3CCOCC3)ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and morpholine (0.24 ml, 2.78 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-methoxy-4-(3-methylindol-5-yloxy)quinazoline (398 mg, 93%).
Reaction SMILES: [CH:1](=[N:8][CH:9]=[C:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](C(=CCCC)C=O)[CH3:26]>>[CH2:11]([C:10]1([CH2:25][CH3:26])[CH2:15][CH:16]=[CH:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:18][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC=C(C=O)CC
Reactant: CCCCC(=CN=Cc1ccccc1)CC
Reactant: NCc1ccccc1
Product: CCCCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1

Procedure:
The procedure described in Example 1(a) is repeated, except that 215.3 g (1 mol) of N-benzylidene-(2-ethyl-1-hexenylamine) [1-phenyl-4-ethyl-4-n-butyl-2-aza-1,3-butadiene; prepared by reacting benzylamine with 2-ethyl-hexenal and then isomerising the reaction product with potassium tert.-butylate; boiling point 90° C./7 Pa; nD20 =1.5630] are used. Distillation yields 288 g (0.891 mol) of 3-n-butyl-3-ethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene; boiling point 130° C./2 Pa; nD20 =1.5296.
Reaction SMILES: [Cl:1][N:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[CH:9]2)=[CH:4][NH:3]1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][O:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C(O)C>[ClH:1].[Cl:12][C:6]1[C:5]2[C:10](=[CH:11][N:2]([N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=4)[CH2:17][CH2:18]3)[NH:3][CH:4]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc2c1=CNN(Cl)C=2
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCC2CCN(N3C=c4cccc(Cl)c4=CN3)CC2)cc1
Product: Cl
Yield: 46.2 %

Procedure:
A mixture of 4 parts of 3,8-dichlorophthalazine, 4.2 parts of ethyl 4-[2-(4-piperidinyl) ethoxy]benzoate, 4 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred and refluxed overnight. After evaporation, the residue was taken up in water and dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 50° C., yielding 3.3 parts (46.2%) of ethyl 4-[2-[1-(8-chloro-3-phthalazinyl)-4-piperidinyl]ethoxy]benzoate monohydrochloride; mp. 172.4° C. (comp. 86).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([N:29]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1.O.O.NN>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:29])[CH2:12][O:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)=[N:17][N:18]=2)=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12
Temperature: 100 °C

Procedure:
(S)-2-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)isoindoline-1,3-dione (150 mg, 0.47 mmol) and 60% sodium hydride in mineral oil (37.6 mg, 0.94 mmol) was mixed in 2 ml N-methylpyrrolidinone. After stirring for ten minutes, compound 1b suspended in 2 ml N-methylpyrrolidinone was added and the reaction mixture was stirred at 20° C. for an hour. The reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride. The ethylacetate phase was washed with more saturated aqueous ammonium chloride and dried over anhydrous sodium sulfate. After removing the ethylacetate, the remaining residue was subjected to a silica gel column chromatography separation to yield the intermediate 2-((S)-3-(1H-indol-3-yl)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-yl)isoindoline-1,3-dione (3a). Compound 3a was dissolved in 4 ml ethyl alcohol, 0.5 ml water and 0.5 ml hydrazine monohydrate in a microwave heating tube. The tube was heated at 100° C. under microwave for five minutes. After removing all the solvent, the residue was subjected to a C18 reverse phase HPLC separation to yield (2S)-1-(1H-indol-3-yl)-3-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-amine (3) (2.4 mg) as a TFA salt. 1H NMR (400 MHz, Methanol-d4): δ 3.08 (m, 1H), 3.12 (m, 1H), 3.58 (m, 2H), 3.74 (m, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.32 (m, 2H), 8.46 (d, J=8.8 Hz, 1H), 8.53 (m, 2H), 8.72 (s, 1H), 9.60 (s, 1H); MS (API-ES) m/z (%): 402 (95%, M++1), 424 (100%, M+Na+); HRMS (ESI): calculated for C22H19N5OS [M+1]: 402.1388; found: 402.1394.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:18]([C:17](=[O:38])[N:14]2[CH2:15][CH2:16][N:11]([C:3]3[C:2]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:12][CH2:13]2)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:32][CH:33]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
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+]
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 2 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.150 g, 0.248 mmol, see Example 4), phenylboronic acid (0.0363 g, 0.298 mmol), Pd(PPh3)4 (0.0143 g, 0.0124 mmol) and 10% K2CO3 (aq., 0.517 mL, 0.372 mmol) were placed in Ar degassed 2:1 toluene:EtOH and heated to 80° C. overnight. The reaction was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic fractions were dried, filtered, concentrated, and purified (500:7 DCM:MeOH) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (0.003 g, 2.0% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@H:30]2[O:32][CH2:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:29][C@@H:30]3[CH2:31][O:32]3)[C:7]=2[N:13]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(C[C@@H]3CO3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
In dimethylformamide (140 ml) was dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (5.0 g, 28.22 mmol), and sodium hydride (1.35 g, 31.04 mmol) was then added to the solution under cooling on ice. The obtained mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled on ice again, and (S)-glycidyl 3-nitrobenzenesulfonate (8.78 g, 33.86 mmol) was then added thereto. While slowly raising the temperature to room temperature, the mixture was stirred for 15 hours. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate. The resultant was washed with saturated sodium chloride solution, and it was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate) to yield 4.98 g (76%) of the above-captioned compound in the form of a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O-][CH2:18]C.[Na+].CI>C1COCC1.CO>[C:6]([O:5][C:3]([NH:10][C@@H:11]([CH2:12][O:13][CH3:18])[C:14]([OH:16])=[O:15])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Under nitrogen a mixture of 74 ml abs. THF and 6 ml abs. methanol is cooled to −70° C. and 2 g sodium hydride (55-65% dispersion) are added. The suspension is stirred for 0.4 hour at ambient temperature. Under nitrogen, 2.05 g N-Boc-L-serine are suspended in 100 ml abs. THF and 40 ml of the prepared sodium ethoxide solution are added. The suspension is stirred for 1 hour at ambient temperature and 1 ml methyliodide are added. After 1 hour the remainder of the sodium ethoxide solution and another 2 ml of methyliodide are added. After 18 hours the reaction mixture is evaporated to dryness. The residue is washed with water and ether and extracted. The water phase is acidified and extracted with ethyl acetate and dichloromethane. 0.52 g of the product are obtained.
Reaction SMILES: C[Si](C[Li])(C)C.[Cl:7][C:8]1[C:9]([O:26][CH2:27][O:28][CH3:29])=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][O:21][CH3:22])=O.[CH3:30]C(C)([O-])C.[K+]>CCCCC.O1CCCC1.CCOCC>[Cl:7][C:8]1[C:9]([O:26][CH2:27][O:28][CH3:29])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][O:21][CH3:22])=[CH2:30])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[O-]
Reactant: COCOc1ccccc1C(=O)c1cccc(Cl)c1OCOC
Agent: [K+]
Agent: [Li]C[Si](C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C(c1ccccc1OCOC)c1cccc(Cl)c1OCOC
Reaction time: 0.67 h
Yield: 230.5 %

Procedure:
A 1.0M solution of trimethylsilylmethyl lithium in pentane (160 ml) was added with stirring to a solution of 50.5 g of 3-chloro-2-methoxymethoxy-2'-methoxymethoxybenzophenone in 500 ml of tetrahydrofuran over a 45 min period. There was a mild exotherm. Analysis by gas-liquid chromatography indicated the reaction was incomplete so another 10 ml of the trimethylsilylmethyl lithium solution was added. After a 20 min reaction period 7.3 g of potassium t-butoxide were added and the reaction was heated to reflux with a heating mantle and held there for 40 min. The mixture was then allowed to cool and was diluted with 1 l of ether. The ethereal solution was extracted with 6-300 ml portions of water and 200 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 50.2 g of the title compound as a pale orange oil. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.[CH:34](=O)[CH3:35].C(O)(=O)C.[BH4-].[Na+]>O1CCCC1.O>[CH2:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)[CH3:35]
Reactant: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 626, 40 mg, 0.092 mmol), acetaldehyde (4.1 mg, 0.092 mmol, 1 equiv) and acetic acid (32 μL, 0.55 mmol, 6 equiv) were combined in tetrahydrofuran (1 mL) and stirred at ambient temperature for 10 minutes. The mixture was treated with sodium borohydride (1.2 mg, 0.046 mmol, 0.5 equiv) and after 2 hours at ambient temperature, the mixture was poured into water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.18 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.23 (1H, dd, J=7.7, 1.2 Hz), 7.83 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=8.8 Hz), 7.72 (1H, d, J=1.2 Hz), 7.65-7.61 (1H, m), 7.55 (1H, t, J=7.8 Hz), 7.47 (2H, d, J=8.6 Hz), 7.37 (1H, dd, J=7.9, 1.2 Hz), 7.25-7.20 (1H, m), 6.82 (1H, d, J=8.1 Hz), 6.75 (1H, t, J=7.5 Hz), 6.53 (1H, br m), 5.79 (2H, s) 3.14 (2H, q, J=7.2 Hz), 1.18 (3H, t, J=7.0 Hz) ppm; low resolution mass spectrometry (ES+) m/z 461.0 [(M+H)+; calculated for C28H25N6O: 461.2].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1OC)=O.[OH:16][C:17]1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:35][C:36]([NH2:38])=[S:37]>C(#N)C>[NH2:35][C:36]1[S:37][C:4]([C:3]([O:2][CH3:1])=[O:15])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[N:38]=1
Reactant: COC(=O)CC(=O)c1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: NC(N)=S
Solvent: CC#N
Product: COC(=O)c1sc(N)nc1-c1ccc(OC)cc1

Procedure:
Methyl-3-(methoxyphenyl)-3-oxopropionate (33.34 g, 95.75 mmol) and hydroxy(tosyloxy)Iodobenzene (37.55 g, 95.75 mmol) were combined in 350 mL of acetonitrile and refluxed for 45 min. followed by the addition of thiourea (7.29 g, 95.75 mmol) and refluxed for 2 h. The volatiles were removed in vacuum and the residue dissolved in 50/50 EtOAc/Hexane and passed through a plug of silica gel. Once the impurities eluted, the product was recovered by eluting with 100% EtOAC and removing the volatiles in vacuum. The title compound was obtained as a tan solid (38.52 g, 75%) MS (NH3-DCI) 254.2 (M+H)+.