Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:27]([CH3:26])[C:31]=2[CH3:32])=[O:34])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(CO)Oc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC(C)(C)CO)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Yield: 76.2 %

Procedure:
To a solution of 2-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-1-ol (2.84 g, 8.3 mmol) in DCM (30 mL) was added 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.97 g, 8.4 mmol), EDCI (1.92 g, 10.0 mmol) and HOAT (0.23 g, 1.7 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated in vacuo. The residue was stirred in 95% EtOH (50 mL)/water (30 mL), and then filtered to give the title compound as a light yellow solid (3.52 g, 76.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O1CCCC1>[OH-].[Na+]>[C:15]1([O:14][C:12]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)O)c1)Oc1ccccc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
After 274.3 g of 3-aminobenzoic acid was dissolved in 4L of a 0.5N aqueous solution of sodium hydroxide, a solution of 328.8 g of phenyl chloroformate in 1L of tetrahydrofuran was added dropwise at 10° C. The reaction mixture was stirred at the same temperature for 1 hour, and then at room temperature for 1 hour. Crystals so precipitated were collected by filtration with suction, washed with water, dried and then recrystallized from ethanol to obtain 412 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[CH3:18][S:19]SC.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:19][CH3:18])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Brc1ccc2ccc(Br)cc2c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc2ccc(Br)cc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.8 %

Procedure:
A stirred solution of 189 (5.72 g, 20.0 mmol) in THF (80 mL) was treated dropwise at −78° C. with n-BuLi (2.5 M in hexanes, 8.40 mL, 21.0 mmol) under N2. The mixture was stirred at −78° C. for 20 min, then treated slowly with dimethyl disulfide (2.16 mL, 24 mmol) and allowed to warm to room temperature. The solvent was removed under reduced pressure to give a residue that was shaken with water, and the resulting solid was crystallised fom petroleum ether to give 2-bromo-7-(methylsulfanyl)naphthalene (199) (4.14 g, 82%): mp 80-81° C.; 1H NMR [(CD3)2SO] δ 8.11 (d, J=1.9 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.54 (dd, J=8.72, 2.0 Hz, 1H), 7.44 (dd, J=8.6, 2.0 Hz, 1H), 2.58 (s, 3H). Anal. (C11H9BrS) C, H, S.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].Cl>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-nitrophenol (30.0 g) and 1,1′-carbonyldiimidazole (47.34 g) were dissolved in THF (300 mL). The mixture was refluxed over night. The reaction mixture was cooled, poured into ice/water and acidified with 1M aqueous HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Methanol (150 mL) was added to the resulting precipitate and the mixture was stirred for 30 minutes at r.t. The resulting solid was filtered off and dried in vacuo. The title compound was obtained as a yellow solid (32.32 g, 88%). MS (neg. ion, m/e)=179.0 [(M−H)−].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22].Br.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22])[CH3:25]
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Reaction time: 0.5 h

Procedure:
1.6 g of 60% sodium hydride was suspended in 50 ml of dimethylformamide, and under ice cooling, 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was added. After stirring for 30 minutes, 2.8 g of 2-diethylaminoethylbromide hydrobromide was added. The mixture was stirred for 2 hours. The reaction mixture was poured into cold water, and extracted with ethyl acetate. The extract was purified by silica gel column chromatography, and then subjected to thin-layer chromatography to give 5-(2-diethylaminoethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.ClCCl>O>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=2[C:14]=1[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:33])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2cc(Cc3ccccc3)sc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Tin tetrachloride (2.0 mL, 17.09 mmol) was added dropwise over a 10 minute period to a stirred, -78° C. solution of 2-benzyl-6-methoxy-benzo[b]thiophene (2.71 g, 10.65 mmol), anisoyl chloride (1.93 g, 11.29 mmol) and dichloromethane (41 mL) under a dry nitrogen atmosphere. After 1 hours at -78° C., the reaction mixture was slowly warmed to room temperature and stirred for 16 h period. The reaction mixture was added to water and extracted with ether. The ether phase was washed with brine and silica gel was added to it. The solvent was removed and the adsorbate was flash chromatographed (eluent: 9:1 petroleum ether: ethyl acetate) to provide the title compound as a white solid (2.42 g, 58%): mp 110-112° C.: NMR (CDCl3); δ 7.84 (d, J=9 Hz, 2H), 7.31-7.18 (m, 7H), 7.92 (d, J=9 Hz, 2H), 6.97 (dd, J=9, 2 Hz, 1H), 4.17 (s, 2H), 3.88 (s, 3H), 3.883 (s, 3H); MS (FAB+): 389 (80%, M+H); Anal. Calc. for C24H20O3S: C, 74.20, H, 5.19, N, 0.00. Found: C, 74.94, H, 5.10, N, 0.03.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(Cl)(Cl)Cl>CC#N>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:16]([F:31])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C=C[C@@H](F)[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R,3E)-2-benzyl-5-(trimethylsilyl)pent-3-enoyl]-1,3-oxazolidin-2-one (0.88 mmol, 370 mg) in CH3CN (8 mL) was added [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (referred to hereafter as Selectfluor) (0.88 mmol, 310 mg). The reaction was allowed to stir at RT for 48 hr. The solvent was removed in vacuo. The crude product was purified by column chromatography to yield a mixture of diastereoisomers de=10% (250 mg, 95%). 1H NMR (400 MHz, CDCl3): δ=6.98-7.3 (m, 10H), 6.0 (m, 1H), 5.5 (dm, J=17, 1H), 5.42 (d, J=10.6, 1H), 5.1 (ddd, J=7.1, 8.1, 47.2, 1H), 4.85 (m, 1H), 4.64 (m, 1H), 3.98-4.12 (m, 2H), 2.84-3.0 (m, 3H), 2.2 (m, 1H); 13C NMR (100 MHz, CDCl3): δ=172.5, 152.9, 137.2, 135.1, 133.7, 133.6, 129.5, 129.3, 128.9, 128.5, 127.2, 126.8, 120.6, 120.5, 94.4 (d, J=175), 65.6, 55.1, 48.1 (d, J=21), 37.3 34.8 (d, J=6); 19F {1H} NMR (376.5 MHz, CDCl3): δ=−175.7; IR (CHCl3): v 3444, 2957, 1645, 1367, 1235, 1205 cm−1; [α]D20=−18.4° (c, 0.5 CHCl3); HMRS required for C22H23NO3F 368.1662 ([M+H+]) found 368.1669.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C=C>>[CH2:22]([N:7]1[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[C:6]1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=1)[CH:21]=[CH2:20]
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Agent: [K+]
Solvent: C=CCBr
Product: C=CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.3 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1M solution, 1.08 mmol) and allyl bromide (0.041 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.3%).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:29]1[CH:31]([CH:32](O)C#N)[CH2:30]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:32][CH:31]3[CH2:29][CH2:30]3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Reactant: N#CC(O)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccccc1N(CC1CC1)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 49 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.18 g, 0.47 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (6.0 mL). The solution was treated with cyclopropylcarboxaldehyde (0.10 mL, 1.3 mmol) and then sodium cyanoborohydride (35 mg, 0.55 mmol) and the reaction was stirred at room temperature for 7 hours. 1M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compounds (0.1 g) as an oil.
Reaction SMILES: NC1C=CC=CC=1.[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1Cl)(=[O:13])=[O:12].[CH2:24]([CH2:26][NH2:27])[OH:25]>CO>[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[NH:27][CH2:26][CH2:24][OH:25])[NH2:20])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Reactant: NCCO
Solvent: Nc1ccccc1
Solvent: CO
Product: Nc1ccc(NCCO)c(S(=O)(=O)CCO)c1
Reaction time: 6 h

Procedure:
The aniline compound employed under (a) with the β-sulfatoethylsulfonyl group can be prepared, for example, as follows: 132.8 parts of 2-(β-hydroxyethylsulfonyl)-4-nitrochlorobenzene are added slowly to a solution of 76.5 parts of ethanolamine in 500 parts by volume of methanol at a temperature of 65° C., and the reaction batch is stirred for a further 6 hours at this temperature. 400 parts by volume of methanol are subsequently distilled off from the reaction batch while simultaneously and continuously adding water. 2-(β-hydroxyethylsulfonyl)-4-nitro-1-(β-hydroxyethyl)aminobenzene crystallizes on cooling from the now aqueous medium in high purity. This compound can be employed for the conversion of the nitro group to the amino group during catalytic hydrogenation. For this, 58 parts of this nitro compound are dissolved in 400 parts by volume of methanol and hydrogenated in an autoclave in the presence of a nickel catalyst at a temperature of 100° C. and pressure of 50 bar of hydrogen. The catalyst is subsequently filtered off and the filtrate allowed to crystallize out by cooling of the methanolic solution. 3-(β-hydroxyethylsulfonyl)-4-(β-hydroxyethylamino)aniline is obtained in good yield and high purity.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[CH:14]=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.CC[O:21]C(CCl)=O>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]([CH3:16])[C:14]([OH:21])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C=O)c1cccc(Oc2ccc(F)cc2)c1
Reactant: CCOC(=O)CCl
Product: CC(C(=O)O)c1cccc(Oc2ccc(F)cc2)c1

Procedure:
2-[m-(p-fluorophenoxy)phenyl]propionaldehyde, which has been synthetically prepared in accordance with Example 1 from 3-(p-fluoro-phenoxyphenyl)acetophenone (boiling point: 137° - 138° C./0.5 mmHg) and ethyl ester of chloroacetic acid, is subjected to oxidation in the manner described in Example 1. There is thus obtained the purposed product in a form of oily substance having the melting point of 175° - 176° C./0.5 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[CH:10]=[C:6]3[O:7][CH2:8][O:9][C:5]3=[CH:4][C:3]=2[CH:11]=1
Reactant: Nc1cc2c(cc1C=O)OCO2
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cc3c(cc2nc1N)OCO3

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 6-amino-1,3-benzodioxole 5-carbaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:14]Br>CO>[Br:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)nn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCO3 (5.2 g, 62 mmol). The reaction mixture was stirred for 30 minutes at RT then Br2 (4.9 g, 31 mmol) was added drop wise. Then the resulting reaction mixture was stirred additionally for 16 h at RT. After completion of reaction, the reaction mass concentrated under reduced pressure, crude purified by silica gel (100-200 mesh) chromatography using EtOAc/Hexane (8:2) to afford 4-Bromo-6-chloro-pyridazin-3-ylamine (2.3 g, 36%) as a solid.
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Cl:10][Si:11](Cl)([Cl:13])[Cl:12]>C(OCC)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:5][CH:4]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: Cl[Si](Cl)(Cl)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
Freshly activated magnesium (8.5 g, 0.35 mol) was slowly added over a period of four hours to a solution of 1,4-dibromobenzene (80 g, 0.34 mol) in 200 mL of diethylether, keeping the temperature below 30° C. The reaction mixture was stirred for 8 hours and then slowly added to a mixture of tetrachlorosilane (100 mL, 0.87 mol) in diethylether (50 mL) within 12 hours. The mixture was stirred for 12 hours, and unreacted tetrachlorosilane and diethylether were removed in vacuum. The remaining liquid was fractionally distilled through a Vigreux column under reduced pressure to provide 4-bromophenyltrichlorosilane as an oil (350 μHg/85° C.-37 g/37%). 1HNMR(400 MHz, CDCl3): δ 7.69 (4H, dd). 13CNMR (100 MHz, CDCl3): δ 134.6, 131.9, 130.4, 128.2. GC-MS: 290 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:46])OC2C=CC=CC=2)[CH:32]=1>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:46])[NH:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 6 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][CH:14]=[CH2:15])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH3:17]O>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][CH:14]=[CH2:15])[C:8]([OH:12])=[CH:9][C:10]=2[CH3:17])[O:5][C:4](=[O:16])[CH:3]=1
Reactant: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Reactant: CO
Product: C=CCc1c(O)cc(C)c2c(C)cc(=O)oc12

Procedure:
In a manner analogous to example 23, from 4-methyl-7-hydroxy-8-allylcoumarin (XII) 4-methylangelicin (XXIX; m.p. 194°-5° C. (from MeOH)) was obtained: ##STR32## and from 4,5-dimethyl-7-hydroxy-8-allylcoumarin (XIV) the 4,5-dimethylangelicin (XXX; m.p. 211°-2° (MeOH)) was obtained: ##STR33##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Procedure NN: 4′-Nitro-biphenyl-4-carboxylic acid 200 mg (0.82 mmol), 152 mg of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.99 mmol), 515 mg of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (0.99 mmol) and 100 mg of triethylamine (0.99 mmol) are put into 5 ml of dichloromethane and stirred at room temperature for overnight. The reaction mixture is diluted with dichloromethane, washed by brine, dried over Na2SO4 and evaporated. The crude product is applied to silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1), followed by SCX column to give the product. 163 mg (52%) Observed mass; 380 (M+1)
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:26](=[O:27])[CH2:25][C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)Cc1cccs1
Product: CCc1noc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=[C:22]2[NH:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14]
Reactant: O=C1CNC(=S)N1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)C)c1O
Yield: 32.9 %

Procedure:
Prepared according to the procedure described in Example 1 using 4-hydroxy-3,5-bis(1-methylethyl)benzaldehyde (3.0 g, 15 mmoles), 2-thiohydantoin (1.6 g, 14 mmoles), sodium acetate (4.2 g, 51 mmoles), and acetic acid (35 ml), filtered off, dried, and recrystallized from acetonitrile to afford the pure product (1.4 g), mp 225°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:18]1[CH2:23][CH2:22][NH:21][C@@H:20]([CH3:24])[C:19]1=[O:25])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].CN1CCOCC1.[Cl:34][C:35]1[CH:40]=[C:39]([N:41]=[C:42]=[O:43])[CH:38]=[CH:37][C:36]=1[O:44][C:45]([F:48])([F:47])[F:46]>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:42](=[O:43])[NH:41][C:39]2[CH:38]=[CH:37][C:36]([O:44][C:45]([F:47])([F:48])[F:46])=[C:35]([Cl:34])[CH:40]=2)[C@@H:20]([CH3:24])[C:19]1=[O:25])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN[C@@H](C)C1=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 30, (S)-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-((S)-3-methyl-2-oxo-piperazin-1-yl)-5-oxo-pentanoic acid methyl ester (intermediate 29) with 3 eq. of 4-methylmorpholine and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 67% yield as white foam. MS: 605.20 (MH+, Cl).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C:13]([CH3:16])=[C:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2].[H][H]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[CH3:18])=[CH:6]/[C@@H:7]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]2[C@@H:8]1[C@@H:9]([OH:17])[CH2:10][CH2:11]2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C(C)=C/[C@@H]1CCC(C)=C2CC[C@H](O)[C@@H]21
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/[C@@H]1CC[C@@H](C)[C@H]2CC[C@H](O)[C@@H]21
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of compound (10a) (223.8 mg, 0.8466 mmol) and degassed DCM (34) was cooled to 0° C. The flask was flushed with hydrogen over a period of 2 minutes before hydrogen was bubbled through the solution itself for one additional minute. After adding Crabtree catalyst (68.0 mg, 0.0845 mmol) the flask was once again flashed with hydrogen for 3 minutes before hydrogen was bubbled through the solution for 2 minutes until it became colorless. The icebath was removed and the mixture stirred for 2¼ hours. Argon was bubbled through the reaction mixture and the solvent was evaporated. Chromatography (hexane/EtOAc 7/1 to 3/1) of the residue furnished 162.7 mg of compound of (11a) as white solid with 72% yield.