Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2.CN.[CH2:20]([N:22](CC)CC)C.C(Cl)(Cl)Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH:22][CH3:20])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Agent: CN
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O

Procedure:
To a suspension of 5-bromo-6-chlorosulfonyl-N-acetylindoline, 71.83 g (0.212 mol) in tetrahydrofuran was added a 40% aqueous solution of 2 equivalents of methylamine and 2 equivalents of triethylamine. The mixture was heated to reflux for 1.5 hours, then allowed to cool. Thin layer chromatography with chloroform showed that the reaction was complete. The cooled mixture was evaporated under reduced pressure, and the resulting white solid was suppended in hot methanol, filtered and washed with methanol and allowed to dry overnight. 65.12 g of 5-bromo-6-methylsulfamoyl-N-acetylindoline was obtained (92% by weight yield).
Reaction SMILES: [CH:1]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:2]=1[NH:3][C:4]1[C:5]2=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23])[C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH2:28]1[C:33](=[O:34])[N:32](Cl)[C:30](=[O:31])[CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH:1]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:2]=1[NH:3][C:4]1[C:5]2=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][N:32]1[C:33](=[O:34])[CH2:28][CH2:29][C:30]1=[O:31])[C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccc1-n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(=O)N1Sc1ccccc1-n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
27.3 g (75 mmol) of 2-(12H-11,12-diazaindeno[2,1-a]fluoren-11-yl)benzenethiol are added to a solution of 10 g (75 mmol) of NCS in 150 ml of CH2Cl2 at 0° C., 10.5 ml (75.3 mmol) of Et3N are subsequently added, and the mixture is stirred at room temperature for 18 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 30 g (66 mmol), 85% of theory, purity according to HPLC 88.3%.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:5]2[C:6]3[N:7]([C:26]([C:29](=[O:38])NC4C=CN=CC=4F)=[CH:27][N:28]=3)[N:8]=[C:9]([NH:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]3)[CH:10]=2)[CH2:3][CH2:2]1.[OH-:48].[Na+].Cl>CO>[C:21]([O:20][C:19]([NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:11][C:9]2[CH:10]=[C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:6]3[N:7]([C:26]([C:29]([OH:48])=[O:38])=[CH:27][N:28]=3)[N:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:22])([CH3:24])[CH3:23]
Reactant: [OH-]
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)O)cnc23)C2CC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
83B (19 mg, 0.029 mmol) was dissolved in MeOH (1 mL). 0.5 mL of 1N NaOH was added, and the cloudy reaction mixture was stirred at 65° C. After 2 hrs, the reaction mixture was cooled to room temperature, the pH adjusted to pH 7 with 1N HCl, and the solid was collected via Buchner filtration to afford 6-((trans)-4-(tert-butoxycarbonylamino)cyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid as a white solid (10.6 mg, 0.019 mmol, 65.3% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=2.1 minutes. [M+H]=551.36.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Temperature: 70 °C
Yield: 93.5 %

Procedure:
7-cyano-1,2,3,4-tetrahydroisoquinoline (7 g; 44.3 mmol; 1 eq.) and potassium carbonate (10.4 g; 75.2 mmol; 1.7 eq.) were suspended in ACN (280 mL) to which was added t-butyl 3-bromopropionate (11.5 mL; 68.6 mmol; 1.05 eq.). The reaction mixture was heated to 70° C. for 24 h. Solvents were removed under vacuum and solid residue partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. Organic layers was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound (11.86 g; 94%) as a yellow oil. 1H NMR (DMSO-d6) δ 7.57-7.54 (m, 2H), 7.32-7.29 (m, 1H), 3.59 (s, 2H), 2.87-2.83 (t, J=5.94 Hz, 2H), 2.74-2.66 (m, 4H), 2.46-2.42 (t, J=7.01 Hz, 2H), 1.39 (s, 9H). LC/MS (Method B): 287.1 (M+H)+. HPLC (Method A) Rt 2.37 min (Purity: 96.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:10]=1[CH2:11][N:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:10]=1[CH2:11][N:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:30][N:29]=[N:28][N:20]=2)=[CH:21][CH:22]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethyl-amino]benzonitrile (3.79 g), sodium azide (0.9 g) and ammonium chloride (1.4 g) in N,N-dimethylformamide (30 mL) was heated and stirred at 120° C. for 18 hours. The reaction mixture was allowed to cool and was poured into water (100 mL). The precipitate was filtered and dried. On crystallization from acetic acid there was obtained 5-[4-[N-(2- benzyloxy-5-bromobenzyl)-N-ethylamino)phenyl]tetrazole, yield 1.2 g, mp 206°-208° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:14][CH2:13][CH:12]1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)C1C=CC=CC=1.[ClH:21].O1CCOCC1>CO.[Pd]>[ClH:21].[N:15]1([CH:12]2[CH2:13][CH2:14][CH:11]2[NH2:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NC1CCC1N1CCCC1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCC1N1CCCC1

Procedure:
(2-Pyrrolidin-1-yl-cyclobutyl)-carbamic acid benzyl ester (intermediate AA, 475 mg, 1.7 mmol) was dissolved in 25 mL methanol and 4N HCl in dioxane (870 mL, 3.4 mmol) and palladium on charcoal (10%, 184 mg, 0.17 mmol) were added. The reaction mixture was hydrogenated at room temperature with a H2-balloon over night. The palladium on charcoal was filtered off and the solvent was evaporated. The crude product was used without any further purification, light yellow semisolid (525 mg, 99%). The 2 diastereomers were not separated.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1.[N+](C1C=CC=CC=1S([O:26][C:27]1[C:28]([O:36][CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2)(=O)=O)([O-])=O.O>CN(C)C=O>[CH3:37][O:36][C:28]1[C:27]([OH:26])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[N:31][NH:32]2
Reactant: COc1c(OS(=O)(=O)c2ccccc2[N+](=O)[O-])ccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)ccc2[nH]ncc12
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
Cesium carbonate (45 mg, 0.137 mmol) and thiophenol (24 ml, 0.229 mmol) were added to a solution of 4-methoxy-1H-indazol-5-yl 2-nitrobenzenesulfonate (40 mg, 0.115 mmol) in N,N-dimethylformamide (1 ml) at 0° C. After 30 minutes, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-methoxy-1H-indazol-5-ol (19 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23].CC(C)([O-])C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2[NH:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23]
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(Nc2nc3ccc(F)cc3c3c(Cl)nccc23)c1
Temperature: 25 °C

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthytidine (Example 1, Step 5) (500 mg, 1.87 mmol) and methyl 3-amino-4-methylbenzoate (340 mg, 2.06 mmol) in THF (9.3 mL) was added sodium tert-butoxide (396 mg, 4.12 mmol). The reaction stirred at room temperature for ten minutes and was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-30% EtOAc/heptane) afforded the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[CH:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO>[OH:3][CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[CH:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c1C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(C(C)O)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a cloudy solution of 7-acetyl-4-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (62 mg, 0.123 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) at 0° C. was added sodium borohydride (23.25 mg, 0.614 mmol) in one portion. The mixture was stirred at room temperature for 30 min and then the reaction was quenched with ice cold water (15 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with dichloromethane (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (24.8 mg, 0.047 mmol, 38.6% yield) as a white solid. LCMS (M+H)+=507.24. 1H NMR (500 MHz, DMSO-d6) δ: 11.77 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.83 (d, J=11.6 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J=6.9 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.54 (m, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.32 (m, 1H), 7.27-7.23 (m, 2H), 7.08 (dd, J1=12.9 Hz, J2=8.5 Hz, 1H), 5.26 (m, 1H), 4.85 (m, 1H), 4.96 (d, J=16.9 Hz, 1H), 4.86 (d, J=16.9 Hz, 1H), 3.86 (s, 3H), 1.88 (s, 3H), 1.38 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41]>>[OH:1][CH:2]([C:3](=[O:5])[NH:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1)[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCc1ccccn1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1ccccn1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with pyridin-2-ylmethylamine; ESI-MS [M+H]+: 533.2
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O>COCCOC>[C:9]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:4])[CH3:5])([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.02 h
Yield: 86.5 %

Procedure:
In 5 ml of 1,2-dimethoxyethane (DME), 1.086 g of Boc-Val-OH was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and a solution of 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 879 mg of the title compound.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])[CH2:2][CH2:3]C.N1CCC[C:12]1=O>>[CH3:12][CH:2]([CH3:3])[CH2:1][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10]
Reactant: O=C1CCCN1
Reactant: CCCCC1CCNC1=O
Product: CC(C)CC1CCNC1=O

Procedure:
3-butyl-2-pyrrolidinone (Sinnerich J, Elad D (1968) "The light-induced addition of 2-pyrrolidinone to olefins" Tetrahedron, 24, 4509-4516);
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.Cl.[NH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH2:15]>C(O)C>[NH2:10][C:9]1[N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=[C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCOC(=O)CNN
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1N
Yield: 91.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (5 g, 30.7 mmol) and ethyl hydrazinoacetate hydrochloride (4.74 g, 30.7 mmol) in ethanol (50 mL) was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo. The crude reaction mixture was partitioned between CH2Cl2 and concentrated aqueous ammonia. The aqueous phase was extracted with CH2Cl2 and the organic phases combined, dried over MgSO4, filtered and evaporated to give ethyl 2-(5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate as a solid (7.4 g), which was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18](OC([O-])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][C:7]1=[O:11])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 88 h
Yield: 48.3 %

Procedure:
A mixture of 6-chloro-1,3-dihydro-indol-2-one (11.35 g, 67.7 mmol), sodium carbonate (35.9 g, 338.5 mmol), tert-butyl dicarbonate (36.7 g, 168.2 mmol) and THF (300 mL) was stirred at 20° C. for 88 h then solids were removed by filtration and the filtrate evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 5-25% EtOAc in petrol) gave the title compound (8.746 g) as an oil. MS: [M−H]−=266.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](N)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 93.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=458.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)O
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948:360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-benzyloxyaniline (999 mg, 5 mmol) and N,N-dimethylaniline (1.209 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL), and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-benzyloxyanilino)quinazoline hydrochloride (1.675 g, 82%) as a mustard yellow solid; mp 246°248° C. Calculated for C21H16N4O3.HCl: C, 61.69; H, 4.19; N, 13.71%. Found: C, 61.72; H, 4.22; N; 13.52%. 1H NMR (DMSO-d6): δ11.98 (1 H, brs), 9.85 (1 H, d, J=2.2 Hz), 8.94 (1 H, s), 8.76 (1 H, dd, J=2.3, 9.1 Hz), 8.15 (1 H, d, J=9.3 Hz), 7.65 (2 H, d, J=9.0 Hz), 7.48 (2 H, d, J=7.0 Hz), 7.41 (2 H, t, J=7.4 Hz), 7.31 (1 H, t, J=7.4 Hz), 7.15 (2 H, d, J=9.1 Hz), 5.16 (2 H, s). Mass spectrum (APCI) 373 (100 MH+).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)s1
Yield: 90.4 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol) with 5-amino-4-bromo-3-methylisoxazole (127 mg, 0.72 mmol) yielded 273 mg (90%) of the crude sulfonamide. After passing through a small plug of silica gel, a portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a white powder, m.p. 161-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br>C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Yield: 103.3 %

Procedure:
4-methylbenzophenone (10.0 g; 51.0 mmol) was dissolved in benzene (60 mL) and the solution was warmed to reflux. Solution of bromine (8.39 g; 52.5 mmol) in benzene (15 mL) was added to the reaction mixture over 10 h. The reaction was refluxed for a further 6 h until a light orange solution in obtained and all bromine is consumed. The benzene solvent was evaporated and crude product was obtained as an off-white solid. Recrystallisation from methanol (130 mL) provided 4-(bromomethyl)benzophenone (14.5 g; 69% yield) as a white crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:27]([O:29][P:30]([O:34]CC)[O:31][CH2:32][CH3:33])[CH3:28]>>[CH2:27]([O:29][P:30]([CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O:31][CH2:32][CH3:33])=[O:34])[CH3:28]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(Cc1ccccc1CCCBr)(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C(Cc1ccccc1CCCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Yield: 49 %

Procedure:
A solution of 7.5 g (17.5 mmol) of ethyl 3-[2-(3-bromopropyl)phenyl]-2-acetamido-2-carboethoxypropanoate in 20 mL of freshly distilled triethylphosphite was stirred at reflux for 6 h. The excess P(OEt)3 and the volatile by-products were removed from the mixture by distillation under vacuum. The remaining viscous oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure to yield 4.2 g (49%) of the product as a viscous yellow oil. IR(neat): 1746, 1680 cm-1 (C=O). 1H NMR(CDCl3) δ 1.1-2.1 (complex m, 19H); 2.4-2.7 (t, 2H); 3.6 (5, 2H); 3.8-4.3 (m, 8H); 6.55 (s, 1H); 6.9-7.2 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]1([N:34]=[C:35]=[S:36])[CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH:31]2[CH2:33][CH2:32]2)=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: S=C=NC1CC1
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC2CC2)CC1
Yield: 41.1 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.2 ml (1.8 mmol) of cyclopropyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. The crude product obtained after purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) was crystallized from methanol/diethyl ether. 195 mg (41%) of the title compound were obtained as a colorless solid.