Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]([F:26])([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC(O)=CC=2)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:25])[F:26])=[CH:17][CH:16]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(I)nc1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Yield: 75.2 %

Procedure:
A mixture of 5-bromo-2-iodopyrimidine (88) (1.50 g, 5.27 mmol), 4-(trifluoromethoxy)phenylboronic acid (44) (1.185 g, 5.75 mmol) and Na2CO3 (1.11 g, 10.5 mmol) in toluene (120 mL) and water (15 mL) was purged with N2. Pd(PPh3)4 (60 mg, 0.05 mmol) was added and the mixture was refluxed under N2 for 17.5 h, then partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel (eluting with 4:1 hexanes/CH2Cl2) gave 5-bromo-2-[4-(trifluoromethoxy)phenyl]pyrimidine (89) (1.264 g, 75%) as a white solid: mp 107-108° C.; 1H NMR (CDCl3) δ 8.83 (s, 2H), 8.46 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H). APCI MS m/z 319, 321 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:25]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33]>>[CH2:9]1[O:8][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:25]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([F:33])=[C:27]([Cl:26])[CH:28]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1COC(c2ccccc2)(c2ccccc2)c2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1COC(c2ccccc2)(c2ccccc2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-diphenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 7.65 (dd, J=8.3, 2.44 Hz, 1H), 7.50 (dd, J=7.32, 2.44 Hz, 1H), 7.34-7.43 (m, 7H), 7.25 (d, J=8.3 Hz, 1H), 7.22-7.24 (m, 1H), 7.16-7.19 (m, 4H), 6.75 (d, 1.95 Hz, 1H), 4.26 (s, 2H); MS (ESI) m/z 442/444 ([M−H]−); Anal. calcd for C27H19ClFNO2: C, 73.06; H, 4.31; N, 3.16. Found: C, 72.67; H, 4.36; N, 2.89.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.O>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Morpholine (1.1 ml) was added to a solution of [4-bromo-2-(trifluoromethyl)phenyl]sulfonyl chloride (2.03 g) in DCM (7 ml) at 0° C. and stirred at 20° C. for 16 h. Water was added and the mixture was extracted with DCM. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound 2.10 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].[C]=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCCCCOC(C)=O
Reaction time: 3 h

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.396 g, 0.5 mmole), stannous chloride (0.190 g, 1 mmole), tetra-n-butylammonium chloride (0.278 g, 1 mmole) and n-amyl nitrite (25 ml, 171.0 mmole), together with monochlorobenzene (200 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 26.4 ml/min (1.18 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was performed at 90° C. for 3 hours. During the reaction, a further n-amyl nitrite (50 ml, 342.0 mmoles) was added dropwise to the reaction mixture over 2.5 hours. The reaction mixture was analyzed by gas chromatography, revealing that di-n-amyl malonate (125.6 mmoles, 59.1%) and n-amyl acetate (24.7 mmoles) were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[NH:11][C:10]=2[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7]1)=[O:5])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH2:31][CH2:32][F:33])(=O)=O.[H-].[Na+]>CN(C=O)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[N:11]([CH2:31][CH2:32][F:33])[C:10]=2[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7]1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccc(OC)cc3c21
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1cc(OC)ccc1n2CCF
Temperature: 80 °C
Yield: 45.5 %

Procedure:
To a solution of (+−)-8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene-6-carboxylic acid diethyl amide (51) (150 mg, 0.41 mmol; prepared according to Example 17(b)) in anhydrous DMF (4 ml) was added 2-fluoroethyl tosylate (166 mg, 0.82 mmol), prepared as described in L. Cronin et al (J. Org. Chem. 2004; 69: 5934-5946) followed by sodium hydride 60% dispersion in mineral oil (34 mg, 0.82 mmol) under nitrogen. The reaction mixture was heated at 80° C. for 1 h. After cooling, the solvents were removed in vacuo, the residue quenched with water (30 ml), extracted with DCM (2×30 ml), dried (MgSO4) and solvents removed in vacuo. The residue was purified by column chromatography on silica, eluting with 5-10% EtOAc/CH2Cl2. The crude solid was quenched with ether/pet.spirit, filtered, dried in vacuo (45° C.) to give the title compound (non-radioactive tetracyclic indole imaging agent) (77 mg, 46%) as a pale brown solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.12 (t, J=7.0 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H), 3.25-3.70 (m, 4H), 3.83 (s, 3H), 4.45-4.70 (m, 2H), 4.80 (t, J=5.2 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 5.09 (s, 1H), 6.84-6.93 (m, 2H), 7.13-7.32 (m, 3H), 7.46 (m, 1H), 7.58 (d, J=8.0 Hz, 1H).
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.[CH2:25]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:26][NH2:27].[Cl:35][C:36]1[CH:37]=[C:38]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:39][N:40]([CH3:60])[C:41]([C:43]1[CH2:47]N(CCC(NCCC(O)=O)=O)[C:45](=[O:58])[C:44]=1[OH:59])=[O:42]>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:39][N:40]([CH3:60])[C:41]([C:43]1[CH2:47][N:27]([CH2:26][CH2:25][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:45](=[O:58])[C:44]=1[OH:59])=[O:42]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Reactant: NCCC(=O)NCC(=O)O
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCC(=O)O)C1
Yield: 7 %

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and H-β-ala-gly-OH as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber powder (0.0158 g, 7% yield). 1H NMR (300 MHz, DMSO) δ: 2.45 (t, J=6.9 Hz, 2H), 2.98 (m, 3H), 3.60 (m, 2H), 3.73 (d, J=5.7 Hz, 2H), 4.06 (s, 2H), 4.57 (s, 2H), 7.23 (d, J=7.2, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.32 (m, 1H), 10.98 (bs, 1H), 12.50 (bs, 1H). HRMS (M−H) calcd for C18H19N3Cl2O6: 442.05727. found: 442.0584.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(Oc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-(naphthalen-2-yloxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 523 (M)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[H][H].C(N(CC)CC)C>[Pd].O.CO>[NH2:1][C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A suspension of 10.4 g of Z-Gln(Trt)-OH (20 mmol) in 180 ml of a 9:1 mixture of methanol and water and 20 ml of one-normal aqueous hydrochloric acid is hydrogenated at room temperature and under atmospheric pressure in the presence of 0.5 g of a 10% palladium on charcoal catalyst; after the uptake of hydrogen is complete the starting material has dissolved. The catalyst is filtered off and washed with methanol; the filtrate is concentrated to 200 g and, at 60°, 2.8 ml of triethylamine (20 mmol) are added, whereupon the product immediately starts to crystallize. The mixture is concentrated to 100 g and left to stand at about 4° for some time, and the crystals are filtered off and washed with a mixture of methanol and water until free of chloride. The H-Gln(Trt)-OH obtainable in this way contains 0.5 mole of water and melts at 233° (with decomposition).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.32 mmol), 1,1-dimethylethyl (4-hydroxyphenyl)carbamate (0.0737 g, 0.35 mmol) and ADDP (0.121 g, 0.48 mmol) in THF (3.5 mL) at rt was added tri-n-butylphosphine (0.12 mL, 0.48 mmol). The resulting mixture was stirred 1 hour at rt and diluted with EtOAc until homogeneous. The resulting solution was extracted with 1 N NaOH (×2), washed (water, brine), dried over Na2SO4 and filtered. The filtrate was adsorbed onto a minimal amount of silica gel and purified by flash chromatography (EtOAc/hexanes), affording 0.133 g of the title compound as a colorless gum: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=9.0 Hz, 1H), 7.26 (app. d, J=8.3 Hz, 2H), 7.16 (d, J=2.3 Hz, 1H), 6.98 (dd, J=9.0, 2.5 Hz, 1H), 6.80-6.75 (m, 2H), 6.38 (bs, 1H), 4.24-4.14 (m, 4H), 3.97 (t, J=5.1 Hz, 2H), 1.50 (s, 9H); MS (ESI) m/z 502 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14].Cl.[CH3:19][O:20][NH2:21]>CO>[CH3:19][O:20][N:21]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=O)c1ccc2ccccc2c1O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Yield: 76.9 %

Procedure:
69 g (0.26 mol) of methyl 1-hydroxy-2-naphthylglyoxylate and 44 g (0.53 mol) of O-methylhydroxylamine hydrochloride in 800 ml of methanol are stirred under reflux for 6 h. The mixture is then concentrated; the residue is taken up in ethyl acetate, and the solution is washed with H2O, dried over sodium sulfate and concentrated again. 52 g (0.20 mol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyloxime (77% yield) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>[H-].[Na+].C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(OC)c1O
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(OC)c1O
Temperature: -40 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a 500 mL flask fitted with a condenser, 2,6-dimethoxyphenol (10 g, 64.86 mmol) and 80 mL of anhydrous CHCl3 was added. The solution was cooled to −40° C. and NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) was added. Another 20 mL of anhydrous CHCl3 was added followed by rapid addition of N-bromo-succinimide (12.77 g, 71.35 mmol). The reaction mixture was stirred for 1 hour at −35° C., heated to room temperature over the next 30 minutes and heated to reflux for another 30 minutes. The solvent was evaporated under vacuum overnight. The tan solid was stirred with 100 mL ether, the mixture was filtered, and the residue was washed with ether. The solvent was evaporated under vacuum to yield a tan solid, which was then dissolved in boiling hexanes. The solution was decanted from the brown oil and filtered through a pre-heated celite pad into a heated flask. The light yellow solution was allowed to cool at room temperature for 3 hours. White wooly needles were filtered off and dried to yield 217 (3.22 g, 22 %). 1H NMR (CDCl3) δ 6.72 (s, 2H), 5.44 (s, 1H), 3.88 (s, 6H); 13C NMR (CDCl3) 147.47, 133.93, 110.88, 108.38, 56.33.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:14]#[N:15]>C(Cl)(Cl)(Cl)Cl.CCOCC.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:19][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[O:10][CH3:9]
Reactant: COc1cc(C#N)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc(C#N)ccc1CBr
Yield: 65 %

Procedure:
N-Bromosuccinimide (3.2 g.) and benzoyl peroxide (0.005 g.) were added to a solution of 3-methoxy-4-methylbenzonitrile (2.65 g.) in dry carbon tetrachloride (90 ml.). The mixture was heated to reflux for 15 minutes using a 250 watt tungsten lamp. The cooled reaction mixture was diluted with petrolum ether (b.p. 60°-80° C., 90 ml.), insoluble material removed by filtration, and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g., 65%) as a white solid, m.p. 87°-91° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (85 mg, 266 μmol; Intermediate 96) was suspended in acetone (5 mL) and treated with K2CO3 (73.6 mg, 532 μmol) and MeI (49.7 μL, 798 μmol) and stirred in a sealed tube at 65° C. for 1 h 30 min. The reaction mixture was cooled to rt and diluted with CH2Cl2, washed with H2O, dried (Na2SO4) and the solvent removed in vacuo to give 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde as an intense yellow, vitreous solid (72.3 mg), 65% pure according to LC/MS, which was directly used in the subsequent Grignard addition.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[OH:20][C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:21]
Reactant: CC(C)CC(O)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one (132 g) in methanol (1 L) was added Pd/C (20 g, 10% weight Pd on carbon). The reaction mixture was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. (R)-2-Hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one was obtained as an oil (68 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5.72 g (25.0 mmol, 1.0 eq.) of methyl-4-bromomethylbenzoate and 3.80 g (27.5 mmol, 1.1 eq.) of K2CO3 in 10 mL of DMF at ambient temperature was added a solution of 2.59 g (27.5 mmol, 1.1 eq.) of phenol in 10 mL of DMF dropwise, and the mixture stirred overnight. The reaction mixture was poured into 100 mL of water and extracted with 3×100 mL portions of 25% CH2Cl2 -hexanes. The combined organic phases were washed with 3×100 mL portions of water, dried (MgSO4), filtered and concentrated. The solid residue was recrystallized from ~50 mL of hexanes to give 5.31 g (88%) of the title compound as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 2H), 7.51 (d, 2H), 7.26-7.33 (m, 2H), 6.95-7.02 (m, 3H), 5.13 (s, 2H), 3.92 (s, 3H). MS (DCl) m/e 260 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[O:3][CH2:2][N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19]
Reactant: ClCOc1ccc(Cl)cc1Cl
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by the addition of a solution of 1-chloromethoxy-2,4-dichlorobenzene (see preparation 6) (5 mmol) in dichloromethane (25 ml) to a solution of 5-chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) in dichloromethane (75 ml). The mixture was stirred at room temperature for 2 h and at 40° C. for 7 h before being worked up as above; yield 1.30 g (80%), isomer ratio 3:1. The title compound crystallized from DMSO: m.p. 170° C. 1H NMR (TFA): δ 6.10 (CH2), 6.9-7.4 (Ph), 9.0-9.2 (H-4, H-6). IR (KBr): 1680 cm-1 (CO). MS (70 eV, m/z (% rel. int.)) 304 (l,M), 162 (3), 145 (35), 143 (100), 116 (28).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:23])[O:4]1.[P:24]([O-])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>N1C=CC=CC=1>[CH2:27]([O:26][P:24]([O:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:23])[O:4]1)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1nccn([C@@H]2O[C@H](COP(=O)(OCc3ccccc3)OCc3ccccc3)[C@H]3OC(C)(C)O[C@H]32)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.9 %

Procedure:
In 4 mL of pyridine was dissolved 0.22 g of methyl 4-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, 0.17 g of dibenzyl phosphate, 0.40 g of triphenylphosphine and 0.30 mL of diisopropyl azodicarboxylate were successively added and stirred at room temperature for 15 hours, and the solvent was removed under reduced pressure. By purifying the residue by column chromatography [eluent: ethyl acetate], 0.37 g of methyl 4-[(3aR,4R,6R,6aR)-6-({[bis(benzyloxy)phosphoryl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained as an orange-colored solid product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7].[K+].[Br-]>>[N:5]([C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([OH:19])[C:12]([OH:20])=[N:11]2)=[N+:6]=[N-:7]
Reactant: O=[N+]([O-])O
Reactant: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Agent: [Br-]
Agent: [K+]
Product: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15 ml 89% nitric acid was ice-cooled and then gradually added 1 g (4,2 mmol) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. After stirring at 0° C. for 15 min, the reaction mixture was poured into 100 ml ice-water. The crude product was recrystallized (acetone-methanol-water) to give 0,95 g (80%) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinooxaline. IR (KBr): 2450 cm1 (N3) NMR (DMSO-d6): 12.3 (2H, broad s), 7.07 (1H,s).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:10]2[CH:6]([CH2:7][N:8](C(OC=C)=O)[CH2:9]2)[C:5](=[O:16])[CH:4]=[CH:3]1.[ClH:18]>>[ClH:18].[CH3:1][C:2]1([CH3:17])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5](=[O:16])[CH:4]=[CH:3]1
Reactant: C=COC(=O)N1CC2C(=O)C=CC(C)(C)C2C1
Agent: Cl
Product: CC1(C)C=CC(=O)C2CNCC21

Procedure:
A solution of 5.83 g of (3aRS,7aRS)-7,7-dimethyl-2-vinyloxycarbonyl-2,3,3a,4,7,7a-hexahydro-1H-4-isoindolone in 80 cm3 of hydrochloric acid-saturated dioxane is stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is dissolved in 150 cm3 of ethanol and the solution is brought to reflux for 1 hour 30 minutes and is then concentrated to dryness under reduced pressure (2.5 kPa). 5.2 g of (3aRS,7aRS)7,7-dimethyl-2,3,3a,4,7,7a-hexahydro-1H-4-isoindolone hydrochloride are obtained in the form of a brown foam.