Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[NH3:18]>>[NH2:18][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Reactant: N
Product: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-amino-2′-deoxyuridine was prepared from 5-bromo-2′-deoxyuridine according to the procedure of Roberts and Visser, J. Am. Chem. Soc. 14:665-669 (1952). 5-bromo-2′-deoxyuridine (2 g, 6.2 mmol) dissolved in liquid ammonia (20 ml) was scaled in a glass tube and heated at 50° for 5 days. The tube was opened, and the ammonia was evaporated. 5-amino-2′-deoxyuridine was recrystallized from 5 ml water and 75 ml hot isopropyl alcohol.
Reaction SMILES: [Si](O[CH:9]1[CH:22](O[Si](C(C)(C)C)(C)C)[C:21]2[C:20](=[O:31])[C:19](=[O:32])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[C:20]1(=[O:31])[C:21]2[CH:22]=[CH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][C:19]1=[O:32]
Reactant: CC(C)(C)[Si](C)(C)OC1C2=C(C=CC(=O)C2=O)c2ccccc2C1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1C=Cc2c(ccc3ccccc23)C1=O
Temperature: 25 °C
Yield: 105.2 %

Procedure:
In a 20 mL volume glass container, 187 mg of the above-prepared 9,10-bis(t-butyldimethylsilyloxy)-9,10-dihydrophenanthrenequinone trimer, 20 mL of tetrahydrofuran, 64 μL of acetic acid, and 2.3 mL of tetrabutylammonium fluoride were placed and stirred at room temperature in air. The resultant reaction mixture was allowed to stand. Thereafter, the precipitate was collected by filtration and washed, thereby to give 87 mg of a phenanthrenequinone compound represented by the following chemical structural formula (1b-2) (hereinafter referred to as a “phenanthrenequinone compound (1b-2)”) (yield 75%), as a reddish brown-colored solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Yield: 24.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-chlorophenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.087 g, 0.177 mmol) obtained in step 2 and methanesulfonamide (0.084 g, 0.855 mmol), the title compound (0.025 g, 25%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21](=[O:23])[CH3:22].[O:24]=[C:25]1[NH:34][C:33]2[N:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)[CH:30]=[CH:29][C:28]=2[CH:27]=[CH:26]1>>[C:21]([C:10]1[C:9]([Cl:8])=[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:31]3[N:32]=[C:33]4[C:28]([CH:27]=[CH:26][C:25](=[O:24])[NH:34]4)=[CH:29][CH:30]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc(N2CCN(CCCCOc3ccc4ccc(=O)[nH]c4n3)CC2)c1Cl

Procedure:
In a manner similar to that of other examples above, 1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 108–110° C. MS: APCI: M+1: 455.2 (Exact Mass: 454.18).
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1.[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[O:17][N:16]=1.[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O>[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=3)=[O:12])[CH2:30][CH2:31]2)=[O:23])[O:17][N:16]=1
Reactant: O=C(CCc1cc(O)no1)NCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCc1cc(O)no1)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3,5-dichlorobenzyl carbonochloridate (331 mg, 1.380 mmol) and 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide (step 2) (200 mg, 0.690 mmol) in DCM (7 ml) was added 2M NaOH solution (6.90 ml, 13.80 mmol) and the mixture stirred vigorously at RT for 16 hrs. The mixture was diluted with EtOAc (50 ml) and acidified with 2M HCl. The organics were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in MeOH/EtOAc and dry loaded onto silica (10 g). This was applied to a 12 g silica cartridge, eluting with 1% AcOH/EtOAc. The product fractions were combined and concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:11]=[N:12][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:14][CH:15]=2)=[CH:4][C:3]=1B(O)O.Br[C:32]1[N:33]=[CH:34][NH:35][CH:36]=1>>[F:1][C:2]1[C:3]([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)=[CH:4][C:5]([C:10]2[N:11]=[N:12][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:14][CH:15]=2)=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(B(O)O)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: Brc1c[nH]cn1
Product: COc1cc(F)c(-c2c[nH]cn2)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 100.1 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using (2-fluoro-4-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)boronic acid (50 mg, 0.12 mmol) and 4-bromo-1H-imidazole (35.3 mg, 0.24 mmol) afforded 6-(4-fluoro-5-(1H-imidazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (52.7 mg) MS [M+H+]=439.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([I:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[CH:9]=[O:10]
Reactant: OCc1cc(Br)cc(I)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(I)c1

Procedure:
A mixture of (3-bromo-5-iodophenyl)methanol from the previous step (1.0 eq.) and Dess-Martin periodinane (1.18 eq.) was stirred at RT in dichloromethane (0.1 M) for 45 min. The reaction mixture was diluted with ether, filtered through a plug of SiO2, and the silica washed with a 3:1 (v/v) mixture of hexanes:EtOAc. The filtrate was concentrated in vacuo and passed again through a plug of SiO2, eluting with a 3:1 (v/v) mixture of hexanes:EtOAc to afford the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[CH3:25])[C:16]3[C:12](=[N:13][N:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[C:15]=3[CH:26]([CH3:28])[CH3:27])[C:11]2=[O:37])[CH:9]=1)[C:5]#[N:6].Cl.[OH2:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[CH3:25])[C:16]3[C:12](=[N:13][N:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[C:15]=3[CH:26]([CH3:28])[CH3:27])[C:11]2=[O:37])[CH:9]=1)[C:5]([NH2:6])=[O:39]
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)cc(C#N)c1)C2=O
Reactant: O
Agent: Cl
Product: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)cc(C(N)=O)c1)C2=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the compound prepared in example 103 (100 mg, 0.188 mmol) and concentrated HCl (10 mL) was heated to 70° C. and stirred at this temperature overnight. The reaction mixture was allowed to cool to rt, diluted with water and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH, 99:1) to afford the title compound. tR: 6.02 min (HPLC 2); ESI-MS: 549 [M+H]+ (LC-MS 2); Rf=0.47 (CHCl3/MeOH, 9:1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10]C(=O)[NH:8][CH:7]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:2]1.[OH-].[Na+]>C(O)C>[NH2:8][CH:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)[CH:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[OH:10]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccoc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Yield: 86.3 %

Procedure:
To a solution of (4RS,5SR)-5-(3-furanyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (7.0 g, 22.5 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (14.0 ml, 112.5 mmol) and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (5.54 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10]OC(OC)OC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[N:1]=[CH:10][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,3-diaminotoluene (1.00 g, 8.2 mmol) in CH2Cl2 (82 mL) was added trimethylorthoformate (4.5 mL, 41 mmol) and trifluoroacetic acid (0.32 mL, 4.1 mmol) and the mixture stirred at room temperature for 24 h after which the reaction mixture was diluted with CH2Cl2 (200 mL), and washed consecutively with saturated aqueous NaHCO3 (40 mL) and H2O (40 mL). The aqueous layers were reextracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated to a rusty brown solid (1.07 g, 97%). 1H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.23–7.18 (m, 1H), 7.10 (d, 1H, J=7.5 Hz), 2.64 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[OH:11][C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-amino-2-indanol (2.0 g, 13.4 mmol) is suspended in 100 mL DCM and at RT it is combined with acetic anhydride (1.27 mL, 13.4 mmol). The reaction mixture is stirred for 1 h at RT, once the reaction is complete the solvent is eliminated using the rotary evaporator and the crude product B-1b (HPLC-MS: tRet.=0.81 min; MS (M+H)+=192) is used in the subsequent reactions without further purification.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]1.[OH-].[Na+]>CO>[C:11]([CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:15])=[O:2])[CH2:6][CH2:7]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)CC1CCC(C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C1CCC(CC(=O)O)CC1
Temperature: 25 °C

Procedure:
(4-tert-Butylcyclohexyl)acetic acid methyl ester (9.81 g, 46.5 mmol) was dissolved in methanol 950 ml) and cooled on an ice bath. 2M Sodium hydroxide solution (50 ml, 100 mmol) was added with stirring. When addition was complete the reaction mixture was allowed to warm to room temperature and was stirred overnight. The methanol was evaporated in vacuo and the remaining aqueous phase was acidified to pH1 with 1M hydrochloric acid. The aqueous phase was then extracted with ethyl acetate(3×). The organic extracts were combined, dried over magnesium sulphate, filtered and evaporated to give a white solid, (8.66 g, 94%). 1H-NMR δ (CDCl3) (as a mixture of cis-trans isomers), 2.43 (0.1 H, d, J=8 Hz), 2.24 (0.9H, d, J=7 Hz), 1.92-1.47 (5H, m), 1.18-0.90 (5H, m) and 0.87 (9H, s).
Reaction SMILES: [C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([O:21]C)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.Cl>ClCCl>[C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([OH:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C=CC(=O)c2ccccc2)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cc(O)c(O)c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution containing 0.32 g of the above product obtained in Example 85 in 10 ml of dichloromethane 3 ml of 1 molar BBr3 --CH2Cl2 was added. The mixture was stirred for 20 min at room temperature, acidified with 10 ml 2N hydrochloric acid and extracted with dichloromethane. The solvent was evaporated in reduced pressure and the residue crystallized from acetone-dichloromethane. Yield 0.07 g (23%), m.p. 196°-201° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:38][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCC2CCOCC2)CC(=O)N3)cc1
Temperature: 120 °C
Yield: 25.9 %

Procedure:
6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.250 g, 0.733 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0.192 g, 0.733 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.030 g, 0.037 mmol) were combined in dimethylformamide (1.0 mL). Sodium carbonate (0.311 g, 2.93 mmol) in water (0.2 mL) was added and the reaction solution was then heated in a Biotage Emrys Optimizer microwave reactor at 120° C. for 15 min. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. Filtrate and ethyl acetate wash were combined and solvent removed under reduced pressure. The resulting material was purified using Biotage column chromatography (0-5% methanol in ethyl acetate) followed by trituration with dimethylformamide and water to afford the title compound (0.074 g, 0.19 mmol, 25%) 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.39 Hz, 2H), 7.53 (d, J=8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, J=11.1, 2.39 Hz, 2H), 3.61 (t, J=7.59 Hz, 2H), 3.25 (t, J=9.59 Hz, 3H), 1.70 (s, 1H), 1.66 (s, 1H), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (ESI) m/z 397.2 [M+1]+; mp 210-212° C.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36]>ClCCCl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cccc2c(=O)[nH]cnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a suspension of methyl 4-oxo-3,4-dihydroquinazoline-8-carboxylate (150 mg, 0.73 mmol) in 4 mL of anhydrous DCE, POCl3 (80 μL, 0.87 mmol, 1.2 equiv.) was added followed by DIPEA (630 μL, 3.6 mmol, 5.0 equiv.). The resulting mixture was stirred at 90° C. for 1-2 h. After cooling down to rt, 3-(trifluoromethyl)benzylamine (97 μL, 0.81 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at 80° C. for 2-4 h. After work-up, the crude was purified by chromatography to yield the title compound in 66% yield. 1HNMR (in CDCl3): 3.19 (s, 3H), 4.90 (s, 2H), 7.41-7.45 (m, 2H), 7.53 (t, J=8.9 Hz, 2H), 7.58 (s, 1H), 7.97 (dd, J=1.5 and 8.4 Hz, 1H), 8.04 (dd, J=1.5 and 7.3 Hz, 1H). Mass: M+H+: 362.
Reaction SMILES: CS[C:3]([N:7]1[CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:10][CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]=[C:3]([NH:4][CH2:5][CH3:6])[N:7]2[CH:11]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[CH2:10][CH:9]=[N:8]2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: CCN=C(SC)N1N=CCC1c1ccsc1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1cccc(Cl)c1)N1N=CCC1c1ccsc1
Yield: 0.1 %

Procedure:
0.47 g (1 mol equiv.) N-Ethyl-5-thiophen-3-yl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.37 g (1.05 mol equiv.) 3-chlorobenzenesulfonamide were added to 7 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 0.44 g (49%) 3-chloro-N-[ethylamino-(5-thiophen-3-yl-4,5-dihydro-pyrazol-1-yl)-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.19 (t, J=7.2, 3H), 2.78 (ddd, J=18.6, 6.0, 1.4 Hz, 1H), 3.31 (ddd, J=18.6, 11.8, 1.4 Hz, 1H), 3.54-3.70 (m, 2H), 5.62 (dd, J=11.8, 6.0 Hz, 1H), 6.75 (d, J=4.3 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 7.02 (br.s., 1H), 7.17-7.23 (m, 2H), 7.36 (m, 2H), 7.54 (br.s., 1H).
Reaction SMILES: [NH2:1][C:2](=[S:18])[N:3]1[CH2:7][CH:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4]1.Cl[CH2:20][C:21]([C:23]1[CH2:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:25][N:24]=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:26]1[O:25][N:24]=[C:23]([C:21]2[N:1]=[C:2]([N:3]3[CH2:7][CH:6]4[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:10][CH:5]4[CH2:4]3)[S:18][CH:20]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(N)=S)CC2C1
Reactant: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Temperature: 90 °C

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-(aminothioxomethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (i.e. the product of Step A) (0.5 g, 18.42 mmol) in chloroform (20 mL) was added 2-chloro-1-[5-(2,6difluorophenyl)-4,5-dihydroisoxazol-3-yl]ethanone (i.e. the product of Step B) (0.478 g, 18.42 mmol) and pyridine (0.29 g, 37.12 mmol) at room temperature. The reaction mixture was heated at 90° C. for 5 h, cooled to room temperature and concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL) and concentrated under reduced pressure. The resulting material was purified by column chromatography (1% methanol/chloroform as eluant) to provide the title product as white solid (0.7 g) melting at 78.9-80.2° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([NH:8][CH3:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[O:13]1[CH2:37][CH:14]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[O:36][CH2:35]3)=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1>CO>[OH:13][CH:14]([CH2:37][N:8]([CH3:9])[CH:6]1[CH2:7][C:2]([CH3:1])([CH3:12])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]1)[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH:34]([OH:36])[CH2:35][N:8]([CH:6]3[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]3)[CH3:9])=[CH:30][CH:31]=2)([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CN(CC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CN(C)C3CC(C)(C)NC(C)(C)C3)cc2)cc1)C1CC(C)(C)NC(C)(C)C1

Procedure:
To 50 ml of methanol were added 3.4 g of 2,2,6,6-tetramethyl-4-methylaminopiperidine and 3.4 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a manner similar to that described in Example 1, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.50 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O-:13])=[O:12])=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>CS(C)=O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2
Reactant: O=C([O-])c1cc2cc(O)ccc2[nH]1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a suspension of 5-hydroxyindole-2-carboxylate (5 g, 28.2 mmol), Cs2CO3 (20 g, 62.1 mmol) in DMSO (56 mL) was added 2-chlorobenzthiazole (3.5 mL, 4.8 g, 28.2 mmol) and the resulting reaction mixture was heated (70° C., 2 d). The reaction mixture was cooled (rt) and partitioned with H2O and EtOAc (50 mL each). The aqueous layer was treated with concentrated HCl to form a solid. The suspension was filtered and the solid washed with H2O and dried in vacuo to provide the title compound as a brown solid (7.55 g, 86%). 1H NMR (500 MHz, DMSO-d6): 12.03 (s, 1H), 7.88 (d, J=7.5, 1H), 7.73 (d, J=2.4, 1H), 7.67 (d, J=7.5, 1H), 7.55 (d, J=8.9, 1H), 7.43-7.40 (m, 1H), 7.31-7.28 (m, 2H), 7.15 (d, J=1.4, 1H), the CO2H proton was not detected.