Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A mixture of 71 mg N-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenyl)-methane sulfonamide obtained in Example 20, 0.36 mL trifluoroacetic acid and 5 mL dichloromethane was stirred overnight at room temperature. The reaction solution was cooled and made weakly alkaline with 5 N aqueous sodium hydroxide, followed by adding ethyl acetate and water to separate an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, the residue was triturated with diethyl ether, and the crystals were separated by filtration. This product was dried under vacuum to give 33 mg of the title compound as a white solid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:19]([O:20]COC)=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.CCOCC>CO>[OH:20][C:19]1[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: COCOc1cc(C#N)cnc1Oc1ccc2c(c1)COB2O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: N#Cc1cnc(Oc2ccc3c(c2)COB3O)c(O)c1
Temperature: 65 °C
Yield: 41.9 %

Procedure:
To a suspension of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-5-methoxymethoxy-nicotinonitrile (0.28 g, 0.89 mmol) in methanol (4 mL) was added 1 M HCl in ether (1.79 mL, 1.79 mmol) at 0° C. The reaction was heated at 65° C. for 2 hours. Methanol was removed under reduced pressure and the product was purified by reverse phase prep HPLC using CH3CN/H2O (0.1% AcOH) as the eluent to yield the title compound (0.10 g, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 7.15-7.09 (m, 1H), 4.98 (s, 2H); MS (ES) m/z: 267 (M−1)−; HPLC purity 92.91% (Maxplot), 92.41% (220 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[C:38](O)=[O:39]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:28]4[N:29]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[O:31][C:27]=4[CH3:26])=[O:39])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cc3)cc2C1=O
Yield: 43 %

Procedure:
The compound of example 642 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available 5-methyl-2-phenyloxazole-4-carboxylic acid (Maybridge Chemical Company, Ltd., UK).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Br:17])[CH2:6][C:5]=2[N:19]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2ccccc2Br)CC1=O
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1Br)C2

Procedure:
The title compound was prepared from 2-acetyl-5-(2-bromo-phenyl)-cyclohexane-1,3-dione, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=CC(N)=CC=2)[CH:34]=[N:33][N:32]=[N:31]1>>[N:30]1([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)=[CH:17][CH:18]=2)[CH:34]=[N:33][N:32]=[N:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1ccc(-n2cnnn2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2cnnn2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(1H-tetrazol-1-yl)aniline in step 1. MS: 395.28 (M+H).
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][CH:6]([F:22])[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:20]=[O:21])=[C:12]2[C:16]=1[O:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13]2.S(N)(=O)(=O)[OH:24]>O.C(O)(=O)C>[F:22][CH:6]([F:5])[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:20]([OH:24])=[O:21])=[C:12]2[C:16]=1[O:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13]2
Reactant: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc2c(C(=O)O)ccc(OC(F)F)c2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.88 g of sodium chlorite in 5 ml of water is added dropwise to 1.6 g of 7-difluoromethoxy-2-(1-methylethyl)benzofuran-4-carbaldehyde and 0.83 g of amidosulfuric acid, dissolved in 15 ml of glacial acetic acid, such that the internal temperature is kept between 15 and 20° C. The mixture is stirred for a further 1 h and then poured into 150 ml of ice water, and the precipitate formed is filtered off with suction and washed with water until acid-free. For purification, the crude product is dissolved in halfconcentrated, aqueous ammonia, and the aqueous solution is extracted with toluene and acidified with 2 N hydrochloric acid to pH 1-2. The precipitate formed is filtered off with suction, washed with water until acid-free and dried in vacuo: m.p. 169° C.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:34][C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])[CH:32]=[CH:33][C:2]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1
Temperature: 100 °C
Yield: 117.8 %

Procedure:
A mixture of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74 (0.300 g, 0.53 mmol), phenylboronic acid (0.098 g, 0.80 mmol) and potassium carbonate (0.221 g, 1.60 mmol) in dimethoxyethane:water (8 mL:2 mL) was purged with nitrogen for 10 minutes. [1,1′-bis(Diphenylphosphino)ferrocene]dichloropalladium[II] (0.022 g, 0.0266 mmol) was then added and the reaction mixture heated to 100° C. for 4 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 1 M sodium hydroxide (100 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an olive syrup (0.32 g). Purification by flash chromatography using ethyl acetate as solvent afforded the title compound (0.260 g, 95%) as a white foam, m.p. 108-112° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:19]>>[NH2:19][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCC(O)OCn1cc(Cl)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Temperature: 135 °C

Procedure:
Compound 22a was prepared by heating the 4,5-dichloro-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine with saturated methanolic ammonia (15 mL) in a steel reaction vessel. The vessel was then heated to 135° C. for eight hours after which time the vessel was cooled and the solvent was removed in vacuo at 40° C. The resulting solid was then recrystallized from methanol to yield 0.28 g (61%). mp=175°-176.5° C. 1H NMR (DMSO-d6): δ3.22-3.50 (m, 5), 4.58 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'); 6.88 (bs, 2, exchanges with D2O, NH2) 7.47 (s, 1, C6), 8.11 (s, 1, C-2). Anal. for C10H13N4O3Cl. (C,H,N).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)cnnc2C1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)cnnc2C1
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 92.8 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) and aminoguanidine hydrochloride (0.12 g) in ethanol (3 ml) was added concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 110° C. (bath temperature) for 3.5 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 174) (0.33 g) as blue gray crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.OS(O)(=O)=O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[NH:3]1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (2.0 g, 10.4 mmol) in 100 mL methanol was added 2 mL conc. H2SO4 over 5 min. The mixture was stirred at room temperature for 16 h. Solvent was evaporated, the crude oil was dissolved in 200 mL EtOAc, then washed with 50 mL sat'd NaHCO3 and 2×50 mL water. The organic phase was dried (Na2SO4), filtered, and solvent was evaporated. The title compound was isolated as a yellow oil (2.1 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[CH:27][C:28]=1[Br:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (intermediate i-13b, 108 mg, 0.282 mmol) in DMF (1.5 mL) cooled to 0° C. via ice/water bath was added NBS (55.3 mg, 0.311 mmol) and the resulting solution stirred for 3 h allowing to warm to rt. The mixture was evaporated under vacuum and the residue purified via Biotage Horizon MPLC using a gradient of 0-40% ethyl acetate in hexane to afford the product (83.9 mg, 64%) as a white foam. LC-MS: m/z (ES) 483 (MNa)+ and 485 (MNa+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:16].CC1C=CC(N=CC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(N)cc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: COc1cc(C=Nc2ccc(C)cc2)cc(OC)c1OC
Product: CCOc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
From 3,4,5, trimethoxybenzaldehyde 106 (6.0 g, 30 mmol) and 4-ethoxyaniline 107d (4.1 g, 30 mmol), a similar procedure as described for 108a (5.9 g, 97.4%) as yellow crystals: mp 75°-7° C. after recrystallization from ethanol. 1H NMR (200 MHz, CDCl3) δ8.37 (s, 1H), 7.21 (d, J=8 Hz, 2H), 7.14 (s, 2H), 6.91 (d, J=8 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 3.94 (s, 6H), 3.91 (s, 3H), 1.43 (t, J=6 Hz, 3H). EIMS m/e 315 (M+, 93).
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC)=O)[C:4](=O)[CH:5]=[C:6]2[CH2:10][N:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:15]=3)[C:8](=[O:21])[C:7]=12.Cl.P(Cl)(Cl)([Cl:31])=O>C1COCC1>[Cl:31][C:4]1[N:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:21])[N:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:15]=3)[CH2:10][C:6]=2[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)n1c(C)c2c(cc1=O)CN(c1cnn(CC(F)(F)F)c1)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 95 °C
Yield: 68.1 %

Procedure:
As shown in step 21-iv of Scheme 21, to a solution of Compound 2066 (614 mg, 1.58 mmol) in THF (10 mL) was added HCl (6 M, 10 mL) at rt. The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. To the residue was added phosphorus oxychloride (15 mL, 161 mmol) and the reaction mixture was heated at 95° C. for 3 hours under an atmosphere of nitrogen. After cooling and concentrating the mixture under reduced pressure, ice was added followed by the addition of EtOAc 30 minutes later. The aqueous layer was extracted with EtOAc and the combined organics washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether:EtOAc, 1:1) gave 6-chloro-4-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (Compound 2067, 356 mg, 68%) as a white solid: ESMS (M+H) 330.90.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1>CC(C)=O>[C:35]([N:29]1[CH2:28][CH2:27][N:26]([C:16]2[N:17]=[C:18]([N:19]3[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[N:15]=2)[CH2:31][CH2:30]1)(=[O:36])[CH2:34][C:33]([CH3:32])=[O:37]
Reactant: C=C1CC(=O)O1
Reactant: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccccc4)ncnc23)CC1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)N1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(NCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 5 from 8-benzylamino-4-(1-oxido-thiomorpholino)-2-piperazino-pyrimido-[5,4-d]-pyrimidine and diketene in acetone under reflux.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:12][CH2:11][C:10]2=[O:13])=[CH:5][CH:4]=1.FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C.[BH4-].[Na+]>ClCCCl.C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH2:12][CH2:11][CH:10]2[OH:13]
Reactant: O=C1CCN1c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: OC1CCNc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
1-[4-(Trifluoromethyl)phenyl]azetidin-2-one (2.3 g, 10.7 mmol) was dissolved in 1,2-dichloroethane (20 mL), trifluoromethanesulfonic acid (1 mL) was added at 0° C., and the mixture was stirred at room temperature for 30 min. Triethylamine (2.2 mL) was added to the reaction mixture, and the mixture was worked-up according to a conventional method to give a crude product. The obtained crude product was dissolved in ethanol (10 mL), sodium borohydride (0.81 g, 21.4 mmol) was added, and the mixture was stirred for 4 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (0.35 g, 1.6 mmol, 15%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(C)=O
Yield: 99.2 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 17.0 g.), 2,4-dichlorobenzyl chloride (25 g.), potassium carbonate (22.0 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) were treated in a similar manner to that of Example A-(1) to give ethyl 2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 33.7 g.)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:15]1([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
Pd2(dba)3 (1.095 g, 1.196 mmol) and tri-tert-butylphosphine (4.78 ml, 4.78 mmol, 1.0 M in toluene) were mixed in 400 mL of xylene. The mixture was stirred under N2 for 20 min. 9H-carbazole (20 g, 120 mmol), bromobenzene (28.2 g, 179 mmol), 18-Crown-6 (3.16 g, 11.96 mmol), and potassium carbonate (24.80 g, 179 mmol) were then added in sequence, and the mixture was heated to reflux under N2 for 18 h. The xylene solution was decanted. The solvent was evaporated and residue was purified by vacuum distillation. 22.3 g (97% yield) of product was obtained after purification.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=[C:3]([CH2:15]O)[N:2]=1.ClCCCl.S(Br)([Br:23])=O>C(Cl)(Cl)Cl>[Br:23][CH2:15][C:3]1[N:2]=[N:1][C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=1
Reactant: O=S(Br)Br
Reactant: OCc1cc2c(nn1)Oc1ccccc1O2
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: BrCc1cc2c(nn1)Oc1ccccc1O2
Yield: 76.5 %

Procedure:
To [1,4]benzodioxino[2,3-c]pyridazin-3-ylmethanol (8.1 g) was added 1,2-dichloroethane (80 ml) and the mixture was stirred. Thionyl bromide (38.9 g) was added, and the mixture was stirred with heating under reflux for 2 hr. The mixture was diluted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with diethyl ether to give 3-(bromomethyl)[1,4]benzodioxino[2,3-c]pyridazine (8.0 g).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:6][C:7]1[S:8][C:9]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][N:11]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Butyllithium (1.6M in THF, 3.5 ml, 5.5 mmol) was added to a stirred solution of 2-methylthiazole (0.45 ml, 5.0 mmol) in THF (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 40 min. Chlorotrimethylstannane (1M in THF, 5.0 ml, 5.0 mmol) was added. Stirring was continued at −78° C. for 45 min. The reaction mixture was quenched with a satured aqueous solution of NaHCO3. The aqueous layer was extracted with Et2O. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Used in the next step without purification (obtained 1.29 g). MS m/z=264.1. Calc'd for C7H13NSSn: 261.94.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[C:18]([CH3:22])([CH3:21])[C:19]#[N:20].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@@H:17]([C:18]([C:19]#[N:20])([CH3:22])[CH3:21])[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C(C)(C)C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C#N
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 0.911 mmol) and (R)-3-amino-2,2-dimethylbutanenitrile hydrochloride (165 mg, 0.408 mmol) in DMF (10 mL) taken in a pressure tube (25 mL) was added DIPEA (0.477 mL, 2.73 mmol) at rt. The resulting reaction mixture was heated 100° C. and stirred for overnight. Reaction was monitored by LCMS. Reaction mass was quenched with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried and concentrated under reduced pressure to get crude as brown colored oil. The crude was purified by combiflash using 24 g silicycle column eluted with 50% EA in hexane. The fractions were concentrated under reduced pressure to get (R)-6-bromo-4-((3-cyano-3-methylbutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (165 mg, 0.408 mmol, 44.7% yield) as pale brown solid. 1HNMR (400 MHz, DMSO-d6) δ ppm: 11.16-11.13 (d, J=9.6 Hz, 1H), 8.32 (s, 1H), 7.96-7.93 (d, J=13.2 Hz, 2H), 7.92 (bs, 2H), 7.22-7.21 (d, J=1.6 Hz, 2H), 4.43-4.39 (q, J=6.4, 3.6 and 6.4 Hz, 1H), 1.43-1.35 (m, 9H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5μ, Buffer: 0.05% TFA in H2O pH 2.5, Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 9.68: Purity: 91.94%. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90).Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.688 min. Purity: 91.5% (m/z=348.2 M-2).