Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(O[C@H:14]1[O:36][C@@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:17]([O:16][C@H:15]1[C@@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:36][C@@H:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@@H]1O[C@H](n2cc(F)c(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 61.8 %

Procedure:
To a mixture of 5-fluorouracil (0.85 g, 6.54 mmol) and compound 2 (3.0 g, 5.94 mmol) in anhydrous MeCN (100 ml) were successively added HMDS (1.25 ml, 5.95 mmol), ClSiMe3 (0.6 ml, 4.76 mmol) and SnCl4 (0.83 ml, 7.13 mmol). The resulting clear solution was refluxed for 1 hour when TLC indicated completion of the reaction. The solvent was evaporated and the residue dissolved in EtOAc (250 ml), washed with NaHCO3 and H2O. The EtOAc layer was dried, filtered and evaporated to give a white solid and it was crystallized from CHCl3 /MeOH (1-2%) to give compound 5 (2.11 g, 61.9%) as white crystals: m.p. 208°-209° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>CO.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Reaction time: 3 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.109 mmol, 64.1 mg) in MeOH (0.5 mL) was added 4 N HCl in dioxane (0.5 mL), and the reaction mixture was stirred for 3 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The green-yellow solid was dried overnight under high vacuum to provide 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (61.3 mg).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.CO.[NH4+].[OH-].[Cu]I>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][N:33]([C:2]2[CH:21]=[CH:20][C:5]3[N:6]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]4=[N:8][C:4]=3[CH:3]=2)[C:32](=[O:36])[CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc32)C1
Temperature: 110 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
tert-Butyl 8-bromo-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (188 mg, 0.534 mmol), 4-(benzyloxy)pyridin-2(1H)-one (118 mg, 0.589 mmol), CuI (203 mg, 1.07 mmol), trans-N,N′dimethylcyclohexane-1,2-diamine (76 mg, 0.54 mmol) and Cs2CO3 (192 mg, 0.591 mmol) in 1,4-dioxane (15 mL) were sparged with a nitrogen stream for 45 min and then stirred at 110° C. for 16 h. The mixture was diluted with 90:9:1 CH2Cl2/MeOH/NH4OH (50 mL) and washed with brine (3×50 mL). The resulting solution was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (131 mg, 28%) as a brown solid: ESI MS m/z 473 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.C#N.[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29]Br)=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]>O.C(#N)C>[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29][C:1]#[N:2])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]
Reactant: [C-]#N
Reactant: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Agent: C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 60 °C

Procedure:
To a mixture of sodium cyanide (562 mg, 11.5 mmol) in water (3 mL) was carefully added mixture of sulfuric acid (2.9 mL, 5.5 mmol) at 0° C. (the reaction generates hydrogen cyanide and must be run in a fume hood with good ventilation), followed by a solution of 6-acetyl-3-(bromomethyl)-4-chloro-3′-fluorobiphenyl-2-carbonitrile (414 mg, 1.13 mmol) in acetonitrile (10 mL). The reaction was heated at 60° C. for 1 hour with pH adjusting to 9 by the addition of solid sodium cyanide. The reaction was cooled and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane (146 mg, 41%). LCMS calculated for C17H11ClFN2O (M+H)+: m/z=313.1; Found: 313.1.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:36]=[S:37]1(=[O:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:40]3[CH2:41][CH2:42][S:37](=[O:43])(=[O:36])[CH2:38][CH2:39]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCS(=O)(=O)CC3)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (1.0 g, 2 mmol) obtained in Step 2 was dissolved in DCM (10 mL), and thereto Et3N (560 uL, 4 mmol) and 1,1-dioxo-thio-morpholine (300 mg, 3 mmol) were added. The mixture was stirred for 12 hours at room temperature. At the end of the reaction, added saturated aqueous NH4Cl solution, extracted with DCM. After drying the extract, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give 1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole (825 mg, 78%).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17][OH:18])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=3)[CH2:17][O:18][CH2:36][CH:33]3[CH2:35][CH2:34]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: Cl
Product: FC(F)(F)c1cc(C(COCC2CC2)OCC2(c3ccccc3)CCNCC2)cc(C(F)(F)F)c1

Procedure:
This was prepared in a similar manner to Example 2 using the compound of Example 1 (d) and cyclopropyl methyl bromide. 1H NMR (360MHz, d6 -DMSO) δ 7.91 (1H, s), 7.66 (2H, s), 7.35-7.19 (5H, m), 4.58 (1H, t, J=4.7 Hz), 3.50-3.06 (6H, m), 2.76-2.61 (2H, m), 2.33-2.17 (2H, m), 2.08-1.94 (2H, m), 0.84-0.77 (1H, m), 0.36-0.30 (2H, m), 0.01-0.06 (2H, m). MS (Cl+) 502 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: COc1cccc(C(=CCCBr)c2cccnc2)c1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution the product of step 2 (500 mg) in DMF (20 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), potassium carbonate (430 mg), potassium iodide (130 mg) and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (225 mg) and minor one (140 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (3.0 g, 8.5 mmol) 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.5 g, 9.3 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (1.86 g, 0.52 mmol). The title compound was obtained as a solid (3.1 g, 70% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.91 (1H, m), 8.52 (1H, s), 4.29 (1H, m), 3.49 (1H, m), 3.30 (1H, m), 3.15 (1H, m), 2.06 (1H, m), 2.03 (1H, m), 1.83 (1H, m), 1.40 (9H, s).
Reaction SMILES: [C:1](C1C=CC(C(C2C(=O)CCCC=2OC)NC(NC2C=C(C(F)(F)F)C=CN=2)=O)=CC=1)#N.[C:33]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]([C:56]2[C:61](=[O:62])[CH2:60][CH2:59][CH2:58][C:57]=2[OH:63])[NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=2)=[O:44])=[N:39][CH:40]=1)#[N:34]>>[C:33]([C:35]1[CH:36]=[CH:37][C:38]([CH:41]([C:56]2[C:57](=[O:63])[CH2:58][CH2:59][CH2:60][C:61]=2[O:62][CH3:1])[NH:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:55])[F:53])[CH:47]=2)=[O:44])=[N:39][CH:40]=1)#[N:34]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)nc1
Reactant: COC1=C(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)c2ccc(C#N)cc2)C(=O)CCC1
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cn2)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-methoxy-6-oxocyclohex-1-enyl)methyl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (intermediate 25) using 1-((5-cyanopyridin-2-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl) urea (intermediate 28, 330 mg, 0.767 mmol) as starting material. Yield: 203 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.05 min (V011_S01).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22]>CCOCC>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:20](=[O:24])[C:21](=[O:22])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCc1ccc2oc(=O)c(=O)oc2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 4.16 g (25 mM) of 4-n-butylcatechol, 5.06 g (50 mM) of triethylamine and 50 ml of dry ether was cooled in an ice water bath so as to maintain the temperature at 5° C. or below. The mixture was added dropwise over 2 hours under stirring with a solution of 3.50 g (28 mM) of oxalyl chloride in 10 ml of dry ether. After completing the dropwise addition, the temperature of the reaction mixture was gradually raised to the room temperature and then aging was conducted for an hour. The resultant mixture was heated under reflux for 3 hours in order to complete the aging. The separated crystals of triethyl ammonium chloride was filtered. After thoroughly washing the crystals with ether, the ether solution was collected and dried with anhydrous sodium sulfate. After distilling off ether, the reaction product was recrystallized from a solvent mixture of carbontetrachloride and petroleum benzine to obtain 5.26 g (23 mM) of 6-n-butyl-1,4-benzodioxine-2,3-dione 2/5 hydrate as colorless crystals having a melting point of 88°-93° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br:17]Br>CC(O)=O>[Br:17][CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][C:13]1=[O:15]
Reactant: CSc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(C2CC(=O)C(Br)C(=O)C2)cc1
Yield: 71.5 %

Procedure:
To a stirred solution of 5-[4-(methylthio)phenyl]cyclohexane-1,3-dione (1.08 g, 4.6 mmol) in AcOH (10 mL) at r.t. was added bromine (0.74 g, 0.23 mL, 4.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (1.03 g, 70%) as a white solid. LCMS (ES+) 314.9 (M+H)+.
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:10][CH:11]3[CH2:13][C:12]3([F:15])[F:14])[C:7](=[O:9])[S:8][C:4]=2[C:3]=1[Br:18].[I-:19].[K+].O.CC1C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+]>O.CCOC(C)=O.O1CCOCC1>[Br:18][C:3]1[C:4]2[S:8][C:7](=[O:9])[N:6]([CH2:10][CH:11]3[CH2:13][C:12]3([F:15])[F:14])[C:5]=2[CH:16]=[CH:17][C:2]=1[I:19]
Reactant: Nc1ccc2c(sc(=O)n2CC2CC2(F)F)c1Br
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1sc2c(Br)c(I)ccc2n1CC1CC1(F)F
Temperature: 25 °C

Procedure:
To a round bottom flask was added 6-amino-7-bromo-3-[(2,2-difluorocyclopropyl)methyl]-1,3-benzothiazol-2(3H)-one (13-3) (0.205 g, 0.612 mmol), Dioxane (2.5 mL), water (2.0 mL), potassium iodide (1.015 g, 6.12 mmol), and 4-methylbenzenesulfonic acid hydrate (0.349 g, 1.835 mmol), then dropwise addition of a solution of sodium nitrite (0.084 g, 1.223 mmol) in water (0.5 mL). Reaction mixture was then stirred at room temperature for a few hours, then heated to 75 C in a hot oil bath with stirring overnight (˜15 hours). The reaction mixture was then cooled to room temperature then suspended in EtOAc, washed with sat'd Na2S2O3, then with sat'd NaHCO3, then water, then brine. Organics were then dried over Na2SO4 filtered & concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 40% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 7-bromo-3-[(2,2-difluorocyclopropyl)methyl]-6-iodo-1,3-benzothiazol-2(3H)-one (13-4) as a pink solid. HRMS (M+H)+: observed=445.852, calculated=445.8517.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[C:10]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(O[Si](C)(C)C(C)(C)C)ccc34)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(O)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of 6-(tert-butyl-dimethyl-silanyloxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylic acid tert-butyl ester 1.88 g (3.33 mmol) in dry THF (20 ml) was treated with 1M TBAF in THF (4 ml, 4 mmol) and stirred at r.t. for 30 min. Water (20 ml) was then added and the mixture extracted with EtOAc (100 ml). The separated organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography over silica gel eluting with DCM/MeOH/30% NH3 92:8:0.8 affording, after trituration with Et2O, 1.5 g (yield: 100%) of the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].CC(OC(C)(C)C)(C1N(C)N=C(C2SC=CC=2)C=1C1C=CC2OCCCC=2C=1)C(O)=O>>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2cccs2)nn1C
Agent: Cn1nc(-c2cccs2)c(-c2ccc3c(c2)CCCO3)c1C(C)(OC(C)(C)C)C(=O)O
Product: Cn1nc(-c2cccs2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
Using the procedure described in example 1, step 7, methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]acetate (3f) (110 mg, 0.25 mmol) is converted into methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]acetic acid (example 3) (97 mg, 0.23 mmol, 91%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH:17]=[N:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]2[CH2:7]1>FC(F)(F)C(O)=O>[O:13]=[C:12]1[C:11]2[S:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH:17]=[N:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]2[CH2:7][NH:6]1
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1sccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNC(=O)c1sccc1-2
Yield: 68.5 %

Procedure:
3. 3.6 g of ethyl 5-(2,4-dimethoxybenzyl)-5,6-dihydro-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate are heated to reflux in 12.5 ml of trifluoroacetic acid for 2 h. The reaction mixture is then evaporated in a vacuum and the residue is partitioned between dichloromethane and water. The mixture is neutralized by the addition of sodium hydrogen carbonate. The emulsion obtained is filtered through Dicalite and the Dicalite is rinsed with dichloromethane. The phases of the filtrate are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried and evaporated in a vacuum. The residue is boiled in ethyl acetate; the crystals obtained are filtered off. There are obtained 1.6 g of ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate of m.p. 263°-264° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13]C)=[O:12].CO.[OH-].[Na+]>O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 1B (2.38 g) and methanol (20 ml) was added to a stirred solution of sodium hydroxide (1.68 g) in water (20 ml). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was cooled to 5° C. and acidified with concentrated HCl (3.5 ml). The resulting suspension was stirred at 5° C. for 30 minutes. The solid was collected by filtration, washed with water, then dried in vacuo at 35°-40° C. to give the free acid (1.45 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=O)=[C:6]([NH2:10])[N:5]=[CH:4][N:3]=1.[CH:11]([O-])=O.[Na+].C(O)=O.O>C(N)=O.[Pd]>[N:5]1[C:6]([NH2:10])=[C:7]2[C:2]([N:1]=[CH:11][NH:8]2)=[N:3][CH:4]=1
Reactant: O=C[O-]
Reactant: Nc1ncnc(N)c1N=O
Agent: [Pd]
Agent: [Na+]
Solvent: NC=O
Solvent: O=CO
Solvent: O
Product: Nc1ncnc2nc[nH]c12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
13.9 g (0.1 mol) 4,6-diamino-5-nitrosopyrimidine was suspended in 50 ml formamide, 6.8 g (0.1 mol) sodium formate, 27.0 g (0.5 mol) 85% formic acid and 0.5 g palladium catalyst were added according to example 1 and the mixture was heated for 4 hours to 110° C. The decolorized suspension was subsequently heated for 3 hours to 180° C. and then cooled. In order to improve the processing, 50 ml water was added and the solid was filtered. The filter cake was dissolved in 160 ml 5% sodium hydroxide solution and the insoluble Pd catalyst was separated. The clear filtrate was adjusted with sulphuric acid to a pH value of 8.5 after a 30 minute treatment at 50° C. with 3 g active carbon. In this process a colorless precipitate separated out from adenine which was suction filtered, washed twice with 30 ml water and dried in a vacuum at 80° C. 12.2 g adenine (0.090 mol, 90% of theory) was obtained in this way as a white powder.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5ccc(NC(=O)c6cccs6)cc5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (53.9 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 59% (86 mg, 0.153 mmol) of the title compound.