Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:28][C:25]2[S:26][CH:27]=[C:23]([S:22][CH3:21])[N:24]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CSc1csc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Temperature: 25 °C
Yield: 109 %

Procedure:
Into a solution of 510 (0.815 g, 4.10 mmol) and dry THF (20.0 mL) was added a solution of triethylamine (0.572 mL, 4.10 mmol) and dry THF (5.00 mL), followed by a solution of 508 (0.500 g, 3.42 mmol) dissolved in dry THF (15.0 mL). The reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo. The residue was partitioned between a saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was washed a second time with the saturated sodium bicarbonate solution and than twice with aq. 1 M HCl. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 512 (1.15 g, >100%) as a brown solid. The crude product was suspended in diethyl ether, stirred and filtered. The filter pad was washed with ether several times, and dried in vacuo to give 512 (0.692 g, 63%) as a light brown solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].C1CCN2C(=NCCC2)CC1.[O:24]=[S:25]1(=[O:50])[C:30]2[CH:31]=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43](=[N:45][OH:46])[NH2:44])=[CH:38][CH:37]=3)[CH:33]=[CH:34][C:29]=2[N:28]2[CH2:47][CH2:48][CH2:49][C:27]2=[N:26]1.Cl>CC#N>[O:50]=[S:25]1(=[O:24])[C:30]2[CH:31]=[C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([CH2:42][C:43]4[NH:44][C:1](=[S:2])[O:46][N:45]=4)=[CH:40][CH:41]=3)[CH:33]=[CH:34][C:29]=2[N:28]2[CH2:47][CH2:48][CH2:49][C:27]2=[N:26]1
Reactant: NC(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1)=NO
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3ccc(Cc4noc(=S)[nH]4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
348 mg (1.95 mmol) of 1,1′-thiocarbonyldiimidazole and then 530 μl (3.516 mmol) of DBU are added to a suspension of the product obtained in Step A (330 mg, 0.85 mmol) in 8 ml of CH3CN. The reaction solution is stirred at ambient temperature overnight. 20 ml of 1N HCl are added; extraction (CH2Cl2), washing (saturated NaCl), drying (MgSO4) and evaporating to dryness are carried out. The title product is obtained in the form of a yellow wax which is used in the crude state in the following Step.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(OB=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][C:26]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:27]=2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.COCCOC>[C:39]1([C:37]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([NH:25][C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:22][N:21]=3)=[O:24])[CH:38]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=BOc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Sodium carbonate (55 mg), phenylboranic acid (38 mg), water (0.35 mL), and bis(triphenylphosphine)palladium(II) dichloride (3.7 mg) were added to an ethylene glycol dimethyl ether (1.2 mL) suspension of tert-butyl 2-(5-bromopyridine-2-carboxamido)-4-phenylbenzoate (0.12 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then sodium carbonate (55 mg), phenylboranic acid (38 mg), and bis(triphenylphosphine)palladium(II) dichloride (3.7 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 0.11 g of tert-butyl 4-phenyl-2-(5-phenylpyridine-2-carboxamido)benzoate as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.Cl.[Cl-].[CH2:39]([N:41]1[CH:45]=[C:44]([CH2:46][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:43]=[CH:42]1)[CH3:40].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:39]([N:41]1[CH:45]=[C:44](/[CH:46]=[CH:24]/[C:23]2[C:19]([O:18][CH2:17][C:16]3[CH:32]=[CH:33][C:13]([O:12][CH2:11][C:9]4[N:10]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[O:7][C:8]=4[CH3:36])=[C:14]([O:34][CH3:35])[CH:15]=3)=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:43]=[CH:42]1)[CH3:40]
Reactant: CCn1cnc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cnc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.50 g), [(1-ethyl-1H-imidazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride (2.05 g), anhydrous potassium carbonate (1.07 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hrs. To the reaction mixture were added [(1-ethyl-1H-imidazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride (2.05 g) and anhydrous potassium carbonate (1.07 g), and the mixture was further stirred at room temperature for 16 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give an oily substance, which was then subjected to silica gel column chromatography and eluted with acetone-hexane (1:1 to 6:4, v/v) to give [4-({4-[({4-[(E)-2-(1-ethyl-1H-imidazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-2-(2-furyl)-5-methyl-1,3-oxazole as a pale-yellow oil (335 mg, yield 19%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.[OH-:15].[Na+]>Cl>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:2]=[C:3]([CH2:4][C:5]([OH:14])=[O:15])[C:12]=2[CH:11]=1
Reactant: Cc1ccc2oc(=O)cc(CCl)c2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2occ(CC(=O)O)c2c1
Yield: 94 %

Procedure:
4-chloromethyl-6-methyl-chromen-2-one (10.4 g, 50.0 mmol) is suspended in a 1.0 M aqueous NaOH solution (400 mL). The reaction mixture is heated under reflux for 30 min. until a clear solution is obtained. The reaction mixture is cooled in an ice bath and carefully neutralized with a 2 M aqueous HCl solution (200 mL). More of a 2 M aqueous HCl solution is added until a white precipitate formed (pH <5). The precipitate is collected by suction filtration, washed with a small amount of an 1 M aqueous HCl solution and dried in vacuo at 50° C. to afford the title compound as a white powder (9.94 g, 47 mmol, 94%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.63 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=8.3 Hz, 1H), 3.76 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1
Reactant: COC1(OC)CCCN1C
Reactant: CC(=O)C=C(C)N
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(n1)N(C)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution containing 1.20 g (12.1 mmol) of 4-amino-3-penten-2-one in 8 mL of toluene was added 3.00 g (20.7 mmol) of 2,2-Dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 2.38 g (24.8 mmol) of t-BuONa and 2 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 10 mL of sat aq. NH4Cl. The mixture was extracted with three 30-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:4→1:1 ethyl acetate-hexanes as eluent gave 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a brown oil: yield 0.62 g (32%); silica gel TLC Rf 0.15 (1:4 ethyl acetate-hexanes); 1H NMR (CDCl3) 1.91 (s, 3H), 2.20 (s, 3H), 2.65 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 3.23 (t, 2H, J=8.4 Hz), 5.98 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:27])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:35]1([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:37][CH2:36]1>CO>[CH:40]1([N:39]([CH2:38][CH:35]2[CH2:36][CH2:37]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:27])=[O:9])[CH:3]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: C1CCC(NCC2CC2)CC1
Solvent: CC(C)NC(C)C
Solvent: CO
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate (Intermediate 36, 123 mg; 0.30 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in methanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (45.3 mg; 0.37 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give methyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with concentrated HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:16][CH:12]([F:17])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and commercially available sodium chlorodifluoroacetate (5.57 g, 36.5 mmol) were dissolved in N,N-dimethylformamide (45 mL) and water (905 μL), and then sodium hydroxide (1.48 g, 37.0 mmol) was added at room temperature, and the mixture was heated and stirred at 120° C. for 2 hours. The solvent was evaporated under vacuum, the residue was cooled to 0° C., and 5 M hydrochloric acid and diethyl ether were added for partition. The organic layer was washed with water and a saturated saline solution, and then the solvent was evaporated. The residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate 9:1-7:3), and then the target fraction was concentrated under vacuum to obtain the title compound (2.66 g, 39%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C:29]1([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[NH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]1([C:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:36][C:2]2[S:6][C:5]([S:7]([N:10]3[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:11]3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(N=C(c2ccccc2)c2ccccc2)s1)N1CCN[C@@H](CC2CCOCC2)C1
Temperature: 100 °C
Yield: 69.1 %

Procedure:
In a sealed vial (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (540 mg, 1.32 mmol), diacetoxypalladium (14.81 mg, 0.066 mmol, Strem Chemicals, Newburyport, Mass.), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XantPhos) (38.2 mg, 0.066 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (279 mg, 2.90 mmol), and diphenylmethanimine (287 mg, 1.58 mmol, Sigma-Aldrich, St. Louis, Mo.) were combined and suspended in toluene (5 mL). Nitrogen gas was bubbled through the solution for 5 min and then the mixture was heated at 100° C. for 16 h. The solution was diluted with EtOAc (20 mL) and then washed with water (15 mL) and brine (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (465 mg).
Reaction SMILES: CN(C=O)C.[CH3:6][N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1.Br[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][N:28]2[C:31](=[O:48])[C@@H:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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]>[CH3:6][N:7]1[CH:11]=[C:10]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][N:28]3[C:31](=[O:48])[C@@H:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)[CH:9]=[N:8]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)N(C(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC3)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To DMF (11 ml, 225 μmol) in a sealed tube flushed with nitrogen was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47 mg, 0.225 mmol), (S)-tert-butyl 1-(6-bromoindolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (100 mg, 225 μmol), sodium carbonate solution (629 μl, 629 mmol), and 1,1′-dis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (Pd(dppf)Cl2) (9.2 mg, 11 μmol). The slurry was heated to 85° C. and stirred for three hours. LCMS indicated a trace of starting material remained. Another aliquot of Pd(dppf)Cl2 (9.2 mg, 11 μmol) was added and the slurry stirred for an additional eight hours. The reaction was then allowed to cool to room temperature. The reaction was diluted with water and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with 1M lithium chloride solution (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 0 to 60% ethyl acetate:hexanes) to give tert-butyl (S)-1-(6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (67 mg, 67%). MS ESI (pos.) m/e: 447.3 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:44])=[CH:46][CH:47]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NCCc1cccs1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiopheneethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamide was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J=7.9 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 7.24-7.13 (m, 3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (dd, J=5.0, 3.5 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.51-6.46 (m, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.97 (ABq, 2H), 4.83 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.78-3.57 (m, 2H), 3.13 (t, J=6.2 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 166.8, 161.8, 161.3, 141.7, 141.1, 139.2, 134.1, 132.5, 128.7, 127.5, 127.4, 127.0, 125.4, 123.9 (2C), 123.6, 119.9 (2C), 118.7, 109.0, 93.2, 80.5, 72.3, 57.6, 43.7, 41.2, 29.8, 28.9; MS (ES+) m/z 523.1 (M+1).
Reaction SMILES: [F:1][C:2]1([CH2:16][OH:17])[CH2:7][CH2:6][C:5]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].[NH4+].[Cl-]>CN(C)C=O>[F:1][C:2]1([CH2:16][O:17][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][C:5]2([O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11]2)[CH2:6][CH2:7]1
Reactant: OCC1(F)CCC2(CC1)Oc1ccccc1O2
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCC3(CC2)Oc2ccccc2O3)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 350C (495 mg) in N,N-dimethylformamide (6 mL) was added NaH (65% in mineral oil, 320 mg). The mixture was stirred for 30 minutes, and then 4-fluoro-3-nitrobenzenesulfonamide (457 mg) was added. The mixture was stirred overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (300 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a silica gel cartridge and was eluted with 30% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)#[N:4].C1(C)C=CC=CC=1.Cl[CH:27]([CH3:32])[CH2:28][N:29]([CH3:31])[CH3:30]>C(C(C)=O)C.C(OCC)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH:27]([N:8]1[C:7]2[CH:6]=[C:5]([C:3]#[N:4])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:32]
Reactant: CC(Cl)CN(C)C
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
Powdered potassium hydroxide (96.7 g) is added to a suspension of 2-cyanophenothiazine (242 g) in methyl ethyl ketone (2.2 liters). The temperature of the mixture rises spontaneously to 24° C. and the mixture is brought to 60° C. for half an hour while stirring. The toluene solution of 2-chloro-1-dimethylaminopropane prepared above is added in the course of 30 minutes. The mixture is heated under reflux for 12 hours. After cooling, the mixture is transferred to a separating funnel and washed with distilled water (2×2 liters). The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give an oil, which is diluted in ethyl ether (2 liters). The solution obtained is cooled and primed by scratching. The crystallized yellow precipitate is removed by filtration. The mother liquors are concentrated to dryness under reduced pressure (100 mm Hg; 13.3 kPa) at 30° C. to give a brown oil which is purified by chromatography on a column (height: 80 cm; diameter: 8.5 cm) of silica (0.2-0.06 mm), eluting with an 80:20 (by volume) mixture of cyclohexane and ethyl acetate and collecting 1-liter fractions. Fractions 7 to 16 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbonitrile (54.8 g) in the form of a brown oil.