Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](=[NH:5])[NH2:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[H-].[Na+]>O1CCCC1>[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:3](=[NH:5])[NH2:4]
Reactant: CSC(=N)N
Reactant: NCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(N)OCCCCCN

Procedure:
S-Methylisothiourea is reacted with 5-aminopentanol and sodium hydride in tetrahydrofuran to give O-(5-aminopentyl)isourea, which is reacted with 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone in refluxing ethanol to give 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [C:1]([NH:4][C:5](=S)[NH:6][NH:7][C:8]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10](=[O:25])[CH:9]=1)(=[O:3])[CH3:2]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:9]2[C:10](=[O:25])[N:11]([CH2:22][CH2:23][CH3:24])[C:12](=[O:21])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[NH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCCn1c(=O)cc(NNC(=S)NC(C)=O)n(Cc2ccccc2)c1=O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC(C)=O)n[nH]c2n(Cc2ccccc2)c1=O

Procedure:
A solution of 6-(4-acetylthiosemicarbazido)-1-benzyl-3-propylpyrimidine-2,4(1H,3H)-dione (3.0 g) in dimethylformamide (50 ml) was heated at 100° to 110° C. for 60 hours. The reaction mixture was concentrated and dissolved in 90% methanol. The solution was left standing for cooling to give pale brown crystals, followed by recrystallization from ethanol to obtain colorless crystals, m.p. 108° to 110° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][C:55]1[O:59][N:58]=[CH:57][C:56]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:56]2[CH:57]=[N:58][O:59][C:55]=2[CH3:54])=[O:61])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1oncc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 91 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 91% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z=559.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=4)=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[C:34]#[N:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:42][C:43](=O)[NH:44][C:45]2[S:46][CH:47]=[CH:48][N:49]=2)C=CC=CC=1>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][C:43]([NH:44][C:45]5[S:46][CH:47]=[CH:48][N:49]=5)=[O:42])=[CH:29][CH:28]=4)=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[C:34]#[N:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)cc4)c3cc2C#N)CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Nc5nccs5)cc4)c3cc2C#N)CC1

Procedure:
4-(4-(4-Aminophenoxy)-6-cyanoquinolin-7-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (225 mg) was heated in dimethylsulfoxide together with thiazol-2-yl-carbamic acid phenyl ester at 80° C. in the same manner as Example 713 to obtain the title compound (240 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC(OC)=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: COc1cc(Br)cc2cc[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)c2[nH]ccc2c1
Yield: 50 %

Procedure:
3-(7-Methoxy-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester CVI (120 mg, 50% yield) was prepared from 5-bromo-7-methoxyindole using the procedure described above for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])(=O)=O.C(O)(=O)C>O>[C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=[O:22])[CH2:21][Cl:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g.), sulfuryl chloride (13.5 g.) and acetic acid (30 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (200 ml.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer) (29 g.).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C1C=CC=CC=1.[CH3:48][Si:49]([C:52]#[CH:53])([CH3:51])[CH3:50]>C(OCC)C.[Cu](I)I.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>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[C:53]#[C:52][Si:49]([CH3:51])([CH3:50])[CH3:48])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccccc1
Product: C[Si](C)(C)C#Cc1c2ccccc2cc2ccccc12

Procedure:
To a solution of 9-bromoanthracene (1.35 g, 5.25 mmol), triphenylphosphine (138 mg, 0.53 mmol), copper iodide (50 mg, 0.26 mmol), and bis(triphenylphosphine)palladium dichloride (74 mg, 0.11 mmol) in 1:1 triethylamine/benzene (35 mL) was added trimethylsilylacetylene (1.11 mL, 7.85 mmol) and the solution was heated at reflux 1 h. The cooled solution was diluted with ethyl ether (100 mL) and filtered. The organic was washed with H2O (3×100 mL), dried over Na2SO4, and filtered. Solvents were removed under reduced pressure to yield crude 9-anthracenyltrimethylsilylacetylene. The crude oil was dissolved in methanol (150 mL) and 3.5 M KOH(aq) (2 mL) was added and stirred 1 h. The reaction was quenched with H2O (150 mL) and the product was extracted with hexane (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and solvents were removed under reduced pressure to yield crude 9-anthracenylacetylene. The crude oil was dissolved in benzene (10 mL) and added to a solution of 4-bromophthalic anhydride (0.908 g, 4.0 mmol), triphenylphosphine (105 mg, 0.40 mmol), copper iodide (39 mg, 0.20 mmol), and bis(triphenylphosphine)palladium dichloride (56 mg, 0.08 mmol) in 2:1 triethylamine/benzene (30 mL) by cannula transfer and heated at reflux 1 h. The cooled solution was filtered and the precipitate was diluted with 0.5 M NaHCO3(aq) (100 mL) and stirred vigorously 1 h. The mixture was diluted with acetone (50 mL) and filtered. The crude product was recrystallized from toluene and dried under reduced pressure to yield 4-(9-anthracenylethynyl)phthalic anhydride (1.03 g, 73.8%) as a deep red solid. 1H NMR (DMSO-d6, 300 MHz) δ7.77 (t, J=7.1 Hz, 2H), 7.88 (t, J=7.2 Hz, 2H), 8.29-8.34 (m, 3H), 8.56 (d, 7.8 Hz, 1H), 8.75 (s, 1H), 8.83 (d, J=8.7 Hz, 2H), 8.92 (s, 1H).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:38][CH2:39][CH2:40][OH:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:41][CH2:40][CH2:39][NH:38][C:26]([N:12]1[CH2:13][CH:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH2:15][CH:10]([NH:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:8])[CH2:11]1)=[O:28]
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NCCO)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 29 mg (0.47 mmol) of 2-aminoethanol and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 10 mg (15% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:25][CH3:26])(=[O:24])/[CH:18]=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:19]([CH2:18][C:17]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: COC(=O)/C=C\C(=O)OC
Solvent: CCN(CC)CC
Product: COC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OC
Yield: 79.6 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 14.41 grams of dimethyl maleate, and 0.5 grams of triethylamine. The product is recrystallized from heptane to give 30.44 grams (80% yield) of white solid, m.p. 94°-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3nn[nH]n3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3nn[nH]n3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].O1CC[CH2:20][CH2:19]1>[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:19][CH3:20])=[O:4])=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: CCCC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: CCCC(C)(C(=O)OCC)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
2.6 g of 2-methyl-2-(4-nitrophenyl)pentanoic acid are dissolved in 30 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 2.2 g (95%) of ethyl 2-(4-aminophenyl)-2-methylpropanoate; LC-MS retention time: 1.99 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[O:16]=[C:17]1[CH2:21][CH2:20][S:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[C:18]1[C:17](=[O:16])[CH2:21][CH2:20][S:19]1
Reactant: COC(=O)C(C)c1ccc(C=O)c(Cl)c1
Reactant: O=C1CCSC1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c(Cl)c1
Yield: 21.4 %

Procedure:
By using methyl 2-(3-chloro-4-formylphenyl)propionate (170 mg) obtained in Example 62 and 3-oxothiolane (115 mg), the title compound (50 mg, 21%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:36]([C:38]1[CH:39]=[C:40](OB(O)O)[CH:41]=[CH:42][CH:43]=1)#[N:37].[ClH:48].C(OCC)(=O)C>C(OCC)C>[ClH:48].[C:36]([C:38]1[CH:43]=[C:42]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:18]([C:19]3[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=3)[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:35])[S:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:37]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Reactant: N#Cc1cccc(OB(O)O)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cccc(C#N)c3)cc2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 402-1 and 3-cyanophenylboric acid as starting materials and by an operation similar to that of Example 407 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2cc(F)ccc2F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=S)Nc2cc(F)ccc2F)cc1
Yield: 149.3 %

Procedure:
36.7 g of 4-methyl-2',5'-difluorobenzanilide was dissolved in 170 ml of toluene, and 36 g of Lawesson's reagent was added. The mixture was refluxed for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from 100 ml of benzene to give 35.0 g of the captioned compound as yellow needle-like crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH:18]C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH2:18])[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 96.8 %

Procedure:
A solution of 3-(2-acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.06 g) in acetonitrile (100 cc) is stirred with methanesulphonic acid (6 cc) for 30 minutes at 20° C., then diluted with ethyl acetate (200 cc) and stirred with a saturated sodium bicarbonate solution (300 cc). The aqueous layer is extracted with ethyl acetate (100 cc) and the combined organic solutions are washed with a half-saturated sodium chloride solution (2×250 cc), then dried over magnesium sulphate, and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.9 g) is obtained in the form of a yellow froth. This product is redissolved in dry tetrahydrofuran (75 cc). The solution, cooled to about 0° C, is treated successively with phenylacetyl chloride (1.54 g) and triethylamine (1.4 cc) and then stirred for 1 hour at between 0° and 4° C. The reaction mixture is diluted with ethyl acetate (100 cc) and a half-saturated sodium bicarbonate solution (200 cc). The organic layer is decanted, washed with water (100 cc) and then with a half-saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up in methylene chloride (25 cc). The precipitate is filtered off and then taken up in boiling acetonitrile (80 cc). After the mixture has cooled, the precipitate is filtered off, washed with acetonitrile (10 cc) and dried under reduced pressure (2 mm Hg; 0.27 kPa) at 25° C. 3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-phenylacetamido-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.65 g) is thus obtained in the form of a white solid.
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc2nc(-c3ccc(I)cc3)sc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.7 %

Procedure:
Boron tribromide (1 M in CH2Cl2, 6 mL) was added to an anhydrous CH2Cl2 (20 mL) solution of 4 (550 mg, 1.5 mmol). After stirring at room temperature for 24 h, the reaction mixture was quenched with ice water (10 mL) and neutralized with solid NaHCO3 (1.51 g, 18.0 mmol). The mixture was diluted with pH 7 buffer solution (Fisher, 20 mL) and extracted with dichloromethane-methanol (4:1, 3×100 mL). The extracts were combined, dried with anhydrous Na2SO4, and evaporated. The residue was treated with CH2Cl2/MeOH, to give pure 2-(4-iodophenyl)-1,3-benzothiazol-6-ol (5) as a white solid (295 mg, 55.8%).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(C#CC(C)(C)O)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 65 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (292 mg, 0.61 mmol) in DMF (3 mL) were added triethylamine (0.255 mL, 1.83 mmol), copper iodide (23 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol), and 2-methyl-3-butyn-2-ol (0.179 mL, 1.83 mmol). The solution was degassed by bubbling nitrogen gas and heated to 65° C. for 14 hr. The solution was diluted with EtOAc and washed with water, dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) provided 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(3-hydroxy-3-methylbut-1-yn-1-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as a mixture of enantiomers. The enantiomers were separated on Chiral Technology AD 2×25 cm column at 12 mL/min using 1:1 iPrOH/Heptane in a 25 min run. First enantiomer has a retention time of 7.57 min and the second enantiomer has a retention time of 15.74 min. For both enantiomers: 1H NMR (500 MHz, CD3OD) δ 9.80 (d, 1H), 7.60 (d, 1H), 7.50-7.40 (m, 3H), 7.34 (d, 1H), 3.90 (m, 1H), 1.48 (s, 3H), 1.47 (s, 3H), 1.12 (d, 3 H). LRMS (ESI) calc'd for C25H22Cl2N3O3 [M+H]+, 482.1; found 482.1.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:35][CH:34]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
60% sodium hydride (240 mg, 6.0 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (20 ml). After stirring at room temperature for 50 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (1.20 g, 6.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes and then at 50° C. for 60 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-methoxyphenethyl)pyrrolidine (734 mg, 2.45 mmol) in dimethyl sulfoxide (10 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with a mixture of the same solvents (3:1) and finally with a mixture of them (2:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl) pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (0.36 g, 36%).