Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([C:12]2[N:16]3[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]3=[C:14]([Br:22])[N:13]=2)[CH2:9]1.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:22][C:14]1[N:13]=[C:12]([CH:10]2[CH2:9][N:8]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH2:11]2)[N:16]2[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]=12
Reactant: Cc1nccn2c(C3CNC3)nc(Br)c12
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nccn2c(C3CN(C4CCOCC4)C3)nc(Br)c12
Yield: 5.8 %

Procedure:
To tetrahydro-4-h-pyran-4-one (3.74 mmol, 0.346 ml) in dichloromethane (5 ml) and acetic acid (0.306 ml) was added 3-(azetidin-3-yl)-1-bromo-8-methylimidazo[1,5-a]pyrazine (1.872 mmol, 500 mg) in dichloromethane (10 ml) and after stirring for 20 minutes under a nitrogen atmosphere at room temperature sodium cyanoborohydride (3.74 mmol, 235 mg) was added in portions. After one hour the reaction mixture was quenched with water, a saturated aqueous sodium hydrogencarbonate solution was added (pH of reaction mixture ˜7) followed by 2M sodium hydroxide until the pH reached 11 and extracted three times with dichloromethane. The organic layers were combined, filtered through a phase separation filter and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) gave 1-bromo-8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)imidazo[1,5-a]pyrazine (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:22]=1>C(O)(=O)C>[ClH:1].[O:30]=[C:29]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])[CH2:28][CH2:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCc1cccnc1
Solvent: CC(=O)O
Product: Cl
Product: O=C(CCc1cccnc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
The experiment described above in Example 7 was repeated on a five mmol scale with 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, and 3-(3-pyridyl)propionic acid. The yield of the reaction product was 0.75 g (34%). The free base was dissolved in 5 mL of acetic acid (HOAc) and filtered. To the filtrate was added 5 mL of 6N HCl/dioxane. The hydrochloride salt was precipitated from the reaction by the addition of Et2O. The resultant solid product was collected by filtration and dried in an Abderhalden drying pistol. Analysis calculated for C22H20N4O3Cl2 : C, 57.53; H, 4.39; N, 12.20; Cl, 15.44. Found: C, 57.35; H, 4.45; N, 12.08; Cl, 15.58.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[CH3:6][C:7]1([CH3:31])[O:12][C:11](=[O:13])[C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:9](=[O:30])[O:8]1.[NH4+].[Cl-]>C1COCC1>[CH3:6][C:7]1([CH3:31])[O:12][C:11](=[O:13])[CH:10]([CH:14]([C:15]2[CH:16]=[CH:17][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:19][CH:20]=2)[C:1]#[C:2][CH3:3])[C:9](=[O:30])[O:8]1
Reactant: CC#C[Mg]Br
Reactant: Cc1ccccc1CSc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 15 %

Procedure:
An oven-dried 100 mL pear-shaped flask, fitted with an oven-dried stir bar, was charged with a 0.5 M solution of 1-propynyl magnesium bromide in THF (12.5 mL, 6.27 mmol) via cannula. The solution was cooled to 0° C., and then a solution of 28.2 (1.05 g, 2.85 mmol) in anhydrous THF (6 mL) was added over 3 minutes via cannula. The reaction was stirred at 0° C. for 5 minutes and then stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated NH4Cl(aq) and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) followed by recrystalization from hot ethyl acetate and hexanes to yield 162 mg (15%) of 2,2-Dimethyl-5-{1-[4-(2-methyl-benzylsulfanyl)-phenyl]-but-2-ynyl}-[1,3]dioxane-4,6-dione (28.3). LC/MSD m/e: 409.1 (M+H).
Reaction SMILES: S([O-])(=O)(=O)C.[CH3:6][C:7]1[O:11][N:10]=[C:9]([CH2:12]OS(C)(=O)=O)[CH:8]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1.CCN(CC)CC>CC#N>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH2:12][C:9]4[CH:8]=[C:7]([CH3:6])[O:11][N:10]=4)[CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Reactant: Cc1cc(COS(C)(=O)=O)no1
Agent: CS(=O)(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN2CCN(c3nc(N)n4nc(-c5ccco5)nc4n3)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mesylate derivative from subpart (a) above (0.28 mmol) was added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C@@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].C([N:19](CC)CC)C.ClC(OCC(C)C)=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.C(OCC)(=O)C>[N:32]1([NH:19][C:14](=[O:16])[C@H:5]([CH2:4][S:3][CH2:1][CH3:2])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCN(CC)CC
Reactant: C1CCNCC1
Reactant: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)NN1CCCCC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.46 g (21.9 mmole) of S-ethyl-N-t-butoxycarbonyl-L-cysteine and 3.05 ml (21.9 mmole) of triethylamine was added thereto. Upon cooling to -15° C., 2.87 ml (21.9 mmole) of isobutyl chloroformate was added dropwise and the mixture was stirred for 20 minutes at that temperature. Upon cooling to -30° C., a solution of 2.79 g (32.9 mmole) of piperidine in 5 ml of tetrahydrofuran was added in one portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the mixture was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated in vacuo to give 6.66 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine piperidylamide as an oil, 96% yield. ##STR14## A solution of 6.55 g (20.7 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine piperidylamide in 100 ml of ethyl acetate was added dropwise over 20 minutes to 80 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate. After stirring for 3 hours at room temperature, the reaction mixture was concentrated in vacuo, resulting in the formation of crystals. The crystals were collected, washed with ethyl acetate and then with ethyl ether and dried to give 3.66 g of S-ethyl-L-cysteine piperidylamide hydrochloride, 74% yield.
Reaction SMILES: CC1C=CC2CCCCC=2[N:3]=1.C1([Li])C=CC=CC=1.C(=O)=O.C[O:23][C:24]([CH:26]1[C:35]2[N:34]=[C:33]([CH3:36])[CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)=O.N1C2CCCCC=2C=CC=1CC(OC)=O>>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH:26]([C:24]([NH2:3])=[O:23])[C:35]=2[N:34]=1
Reactant: Cc1ccc2c(n1)CCCC2
Reactant: COC(=O)C1CCCc2ccc(C)nc21
Agent: COC(=O)Cc1ccc2c(n1)CCCC2
Agent: O=C=O
Agent: [Li]c1ccccc1
Product: Cc1ccc2c(n1)C(C(N)=O)CCC2
Yield: 30 %

Procedure:
Reaction of 2-methyl-5,6,7,8-tetrahydroquinoline with phenyl lithium and carbon dioxide followed by esterification according to the general method described in Examples 1B and 6B gave an inseparable mixture of methyl-2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and methyl 5,6,7,8-tetrahydroquinoline-2-acetate which was converted without purification to a mixture of 2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide and 5,6,7,8-tetrahydroquinoline-2-acetamide by reaction with ammonia using the method described in Example 2. Fractional recrystallisation from diisopropyl ether gave the title compound as colourless needles m.p. 114° (overall yield 30%) (Found: C, 69.31, H, 7.45, N, 14.7, C11H14N2O requires: C, 69.45, H, 7.42; N, 14.72%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COc1ccc(O)cc1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(OC)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (56 mg), p-methoxyphenol (78 mg), and triphenylphosphine (69 mg) in THF (1 ml) was added a solution of diethyl azodicarboxylate (45, mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:4) and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (68 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH:26]=5)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=5)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-[1-(3-Methyl-3H-benzoimidazol-5-yl)-ethyl]-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 185.1, 600 mg, 1.018 mmol) was dissolved in DCM (10 mL) and MeOH (2.5 mL). HCl in dioxane (4 N, 1.272 mL) was added and the RM was stirred 1 h at rt. The solvent was totally evaporated and the residue taken in water /acetonitrile. It was basified with NaHCO3. the mixture was cooled down with dry ice and sonicated to afford a suspension. It was filtered and collected, and dried under high vacuum overnight to afford the title compound as a white solid (tR 2.04 min (conditions 8), MH+=388, 1H-NMR in DMSO-d6: 8.39 (s, 1H); 8.07 (d, 2H); 8.01 (d, 1H); 7.69 (s, 1H); 7.61 (s, 1H); 7.51 (d, 1H); 7.47 (d, 1H); 7.23 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.78 (s, 3H); 3.75 (q, 2H); 1.79 (d, 3H)).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:16](=[O:18])[CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[O:19][CH3:20])=[CH:25][CH:24]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(C(OC)C(=O)O)cc1OC1CCCC1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1OC1CCCC1

Procedure:
(RS)-(3-Cyclopentyloxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].[OH-:17].[Na+].[CH3:19][OH:20]>Cl.O>[C:4]([O:17][C:19]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH2:3][CH2:2]1)=[O:20])([CH3:5])([CH3:9])[CH3:3]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of indole-4-carboxylic acid (500 mg) in methanol (9 ml) and conc. hydrochloric acid (1.0 ml) was added a portion of sodium cyanoborohydride (487 mg) at 0° C. and the mixture was stirred at ambient temperature for 1 hour. The suspension was diluted with water (10 ml) and then the clear solution was neutralized with 2N sodium hydroxide aqueous solution. Methanol was removed and the aqueous solution was diluted with dioxane (15 ml) and 1N sodium hydroxide aqueous solution (10 ml). To the mixture was added portionwise di-tert-butyl dicarbonate (813 mg) and the solution was stirred at ambient temperature for 2 hours. The solution was neutralized with 1N hydrochloric acid and diluted with ethyl acetate (30 ml). The resulting solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The solid was triturated with diethyl ether:n-hexane (1:9) to give 1-tert-butoxycarbonylindoline-4-carboxylic acid (727 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][N:24]([CH3:43])[C:25](=[O:42])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=3[CH3:32])[C:25]([N:24]([CH3:43])[CH3:23])=[O:42])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: Cc1ccc(C(=O)N(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(-c2cc(C(=O)N(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.102 g, 0.298 mmol), N,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide from above, (0.129 g, 0.447 mmol), and K2CO3 (0.123 g, 0.894 mmol), were taken up in dioxane (6 mL) and water (1.2 mL). The mixture was degassed with argon for 30 min and tetrakis(triphenyl-phosphine)palladium(0) (0.026 g, 0.022 mmol) was added. The mixture was then heated under argon at 95°C. for 18 h. The solvents were pumped off, and after aqueous workup, the crude material was flashed on silica gel (15 g), eluted with a EtOAc/CH2Cl2 gradient to give the title compound as a white amorphous solid. mp 144-147° C. LC-MS m/z 470 (M+H)+, 2.02 min (ret time).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[NH:11][C:10]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>C(Cl)Cl.CN(C=O)C>[C:31]1(=[O:41])[N:35]([CH2:7][CH2:8][C:9]2[CH:13]=[C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[NH:11][C:10]=2[C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Agent: CS(=O)(=O)Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A solution containing 0.75 g of methanesulfonyl chloride in 25 mL of CH2Cl2 was added to a stirred solution containing 0.8 g (3.3 mmol) of 3-(2-hydroxyethyl)-2,5-dithienylpyrrole (XX) and 3 mL of triethylamine in 25 mL of methylene chloride (CH2Cl2) maintained at 0° C. under an inert argon gas atmosphere. The mixture was stirred for 2 hours at 0° C., followed by treatment with a solution containing 8 g (40 mmol) of potassium phthalimide in 50 mL of DMF. The resulting mixture was heated at 40° C. overnight. After cooling to room temperature, the mixture was filtered, and the solvents of the filtrate evaporated in vacuo in the presence of with 20 g of SiO2 -60. The solid absorbed on the SiO2 was chromatographed on a 100 g column of SiO2 -60 that was equilibrated and eluted with a 1% dioxane-toluene solvent mixture. Fractions having volumes of 20 mL were collected, and fractions numbered 10 through 25, containing the product (XXI), were combined, then concentrated to yield 860 mg of an oil (64% yield). An analytical sample of compound XXI (mp 174°-175° C.) was recrystallized from diethyl ether.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cc2ncc[nH]2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A suspension of 500 mg (1.23 mmol) of N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28 (iv)], 847 mg (12.3 mmol) of imidazole and 277 mg (1.9 mmol) of sodium iodide in 10 ml of N,N-dimethylformamide was stirred at 90° C. for 2 hours and then the temperature was lowered to room temperature. The resulting mixture was diluted with ethyl acetate. The diluted mixture was washed several times with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with a mixture of diethyl ether and hexane, and the resulting crystallized product was collected to give 471 mg (yield 88%) of the title compound as crystals, melting at 193°-195° C. (after recrystallization from a mixture of methanol, diethyl ether and hexane).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[Br:43]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:43][C:32]1[N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:26]=[C:27]2[CH:33]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.610 mL, 4.25 mmol) in tetrahydrofuran (2.0 mL) at −78° C., n-butyllithium (2.5 M in hexanes, 1.70 mL, 4.25 mmol) was added dropwise. After the white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting resulted solution was added to a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.30 g, 3.07 mmol) in tetrahydrofuran (10 mL) at 78° C. After 30 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.10 g, 3.38 mmol) in tetrahydrofuran (6 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (1.30 g, 84%). LCMS calculated for C22H21BrN3O4S (M+H)+: m/z=502.0. Found: 502.0; 1H NMR (400 MHz, CDCl3): δ 8.15-8.12 (m, 3H), 7.68-7.58 (m, 1H), 7.51-7.47 (m, 2H), 6.88 (s, 1H), 6.31 (d, J=2.0 Hz, 2H), 6.28 (t, J=2.5 Hz, 1H), 3.72 (s, 6H), 3.16-3.12 (m, 2H), 2.99-2.96 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]3)[CH2:10][C:9](=[O:18])[O:8][C:5]2=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC.O1CCCC1>[OH:18][CH:9]1[CH2:10][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[O:8]1
Reactant: O=C1NC(=O)C2(CC(=O)Oc3ccc(F)cc32)N1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(CC(O)Oc3ccc(F)cc32)N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 640 mg. (0.002 mole) of 6-fluorospiro[chroman-4,4'-imidazolidine]2,2',5'-trione in 40 ml. of toluene at -78° C. was added 852 mg. (0.006 mole) of diisobutylaluminum hydride in hexane, and the reaction mixture allowed to stir at -78° C. for 30 minutes. The reaction was allowed to warm to 0° C. and was stirred for 24 hours. The reaction was recooled to -40° C., 6 ml. of dry tetrahydrofuran was added and the reaction warmed to 0° C. Additional diisobutylaluminum hydride (1.0 ml) was added in 0.2 ml. portions. The reaction mixture was added to 10% hydrochloric acid and the mixture extracted with ethyl acetate. The combined extracts were washed dried and concentrated to dryness. The residue was chromatographed to give 67 mg. of the desired compound, m.p. 247°-251° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4](CC2C=CC=CC=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([NH:1][CH2:2][C:3]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][NH:4]1)=[O:30]
Reactant: NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Reactant: O=C=NCCCl
Solvent: CCOC(C)=O
Product: O=C(NCCCl)NCC1(Cc2ccccc2)CC(=O)C(OCc2ccccc2)=CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 185.7 %

Procedure:
To a suspension of 48.0 g (0.15 mol) of 2-(aminomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 1.5 l of ethyl acetate was added 12.8 ml (0.15 mol) of 2-chloroethylisocyanate. The mixture was stirred overnight at room temperature, the product filtered off by suction, washed with ethyl acetate, and dried in vacuo, yielding 59.6 g of the title compound, melting point 130° C.