Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C[O:13]C(OC)N(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) and dimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF (1.2 ml) was heated at 135° C. in a sealed tube for 15 h. The reaction mixture was cooled to rt and added dropwise to a 20° C. solution of NaIO4 (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After 3 h, the mixture was treated with water (20 ml) and extracted with EtOAc (3×15 ml). The extracts were washed with water (3×15 ml) and brine (15 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, a brown solid of 4-chloro-2-nitrobenzaldehyde was obtained (J. Org. Chem. 2003, 68, 4104-4107). 1H NMR (CDCl3, 400 MHz) δ 7.74-7.78 (m, 1H), 7.94-7.96 (m, 1H), 8.11-8.12 (m, 1H), 10.39 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Br:25]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:25][CH:9]([C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 95.4 %

Procedure:
1-(4-Chlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (5.0 g) was dissolved in a mixture of 100 ml of chloroform and 100 ml of acetic acid. To this solution, 2.2 g of bromine was added dropwise at 50° C. The mixture was kept at 50° C. for 3 hours and then washed with ice-water and an aqueous solution of sodium bicarbonate. The chloroform layer was evaporated and the solid residue was crystallized in a mixture of carbon tetrachloride and n-hexane. The crystals were collected by filtration and dried to give 5.8 g of the captioned compound. m.p. 167°-168° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:36])=[CH:24][CH:25]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
5.57 g (15 mmol) of N-benzyloxycarbonyl-tyrosine-tert-butyl ester is reacted with bromoacetic acid-tert-butyl ester to alkylated phenol analogously to Example 3a).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].C([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:17][CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCC1CCCCN1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCCCC2CO)cc1
Temperature: 120 °C
Yield: 9.2 %

Procedure:
In a screw cap pressure tube, 4-fluorobenzonitrile (354.0 mg, 3.15 mmol), piperidin-2-ylmethanol (363.4 mg, 3.15 mmol) and NaHCO3 were suspended in DMF (2.0 ml). The tube was sealed and the mixture heated to 120° C. for 3 days. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were washed with H2O, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH 98:2→96:4) affording 63 mg (9%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:22])[C@H:6]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](F)[N:9]=1)#[N:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:10]3[N:9]=[C:8]([NH:7][C@H:6]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:22])[CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:13]=[CH:12][N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: N#CCNC(=O)[C@H](CC1CCCCC1)Nc1ccnc(F)n1
Product: N#CCNC(=O)[C@H](CC1CCCCC1)Nc1ccnc(N2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
The title compound was prepared from the product of example 8 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine (0.66 g) by the method of example 1 step (iv). Yield 0.2 g.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[C@@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: C[C@H]1CNC(=O)c2cc3cc(O)ccc3n21
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CNC2=O)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 1, from (S)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow foam (52%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([CH:60]=O)=[N:56]1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH2:60][C:57]1[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cn1ccc(C=O)n1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1Cc1ccn(C)n1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (35 mg) was treated with 1-methyl-1H-pyrazole-3-carbaldehyde according to General Procedure D to give (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(1-methyl-1H-pyrazol-3-ylmethyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (25 mg). This was hydrolyzed according to General Procedure B to give the title compound (21 mg). LCMS (m/z): 830.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].[CH2:19](O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>CO.O>[CH3:19][O:12][C:11]([C@@:9]1([CH3:14])[CH2:8][CH2:7][C:6]2[C:15]([CH3:16])=[C:2]([OH:1])[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]=2[O:10]1)=[O:13]
Reactant: CCO
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A solution of 2 g(8 mmoles) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid; [α]D25 + 65.84° (c 1.18, C2H5OH) and 0.1 g of p-toluenesulfonic acid monohydrate in 40 ml of methanol was stirred and refluxed for 3.75 hr. After cooling, the solution was diluted with water and worked-up with ether in the usual manner (the ether extracts were additionally washed with saturated aqueous sodium bicarbonate solution) giving 2g (94.7%) of (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 132°-134.5°; [α]D25 +61.4° (c 4.91, CH3OH). The analytical specimen was obtained by recrystallization of a sample from aqueous methanol as a colorless solid, mp 133.5°-135°; [α]D25 +61.85° (c 5.07, CH3OH).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH:5]=1.CC[O:18][CH2:19][CH3:20].C([O:24]C(C)C)(C)C>>[O:3]1[C:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]=2[C:19](=[O:18])[C:20]1=[O:24]
Reactant: CCOCC
Reactant: CC(C)OC(C)C
Reactant: C[Si](C)(C)OC1=CCOc2ccccc21
Product: O=C1OC2=C(COc3ccccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a stirred solution of 4-[(trimethylsilyl)oxy]-2H-1-benzopyran (L. H. Hellberg, and A. Zuarez, Tetrahedron Letters, 40, 3553 (1974)) (205.8 g, 0.917 mole) in anhydrous ether (600 ml) oxalyl chloride (58.2 g, 0.458 mole) is added dropwise over a period of 40 minutes at room temperature under nitrogen. The suspension is stirred at room temperature for 18 hours and then diluted with isopropyl ether (~300 ml). The precipitate is collected by filtration and washed with isopropyl ether to give 80.2 g (86%) of orange-red solid, mp 146°-8° C. Recrystallization from tetrahydrofuranisopropyl ether gives an analytical sample, mp 146°-148° C.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].O>ClCCl>[CH2:1]([N:8]([C@H:9]([CH3:12])[CH2:10][OH:11])[C:15](=[O:16])[CH2:14][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Product: C[C@H](CO)N(Cc1ccccc1)C(=O)CCl
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
(R)-2-(Benzylamino)propan-1-ol (16.58 g, 100 mmol) was dissolved in dichloromethane (125 mL) and TEA (18.1 mL, 130 mmol) before being cooled to −10° C. in a methanol/ice bath. Chloroacetic acid chloride (8.78 mL, 110 mmol) was added dropwise and the mixture was stirred for 1.5 h at −10° C. A small amount of water was then added to remove the amine. The reaction mixture was poured into a separatory funnel, washed 2×50 mL with dichloromethane, separated, organic layers dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.C[Al](C)C.C[O:19][C:20]([C:22]1[N:23]=[C:24]([CH2:68][CH2:69][CH3:70])[N:25]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=2)[C:26]=1[C:27]([O:29][CH3:30])=[O:28])=O>C(Cl)Cl.CCOCC.C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]([C:26]1[N:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:36][CH:37]=2)[C:24]([CH2:68][CH2:69][CH3:70])=[N:23][C:22]=1[C:20]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:19])=[O:28]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(C(=O)N2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 0.72 g (4.4 mmol) of 1-(2-pyridyl)piperazine in 10 mL of anhydrous CH2Cl2 under N2 was added 4.4 mL (4.4 mmol) of a 1 N solution of HCl in ether. After 15 min., the suspension was cooled to 10° C. and treated with 2.2 mL (4.4 mmol) of 2.0 M Me3Al in toluene. Slow gas evolution was noted. After 30 min., a solution of 2.81 g (4.00 mmol) of 4,5-bis(methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole in 12 mL of CH2Cl2 was added. The reaction mixture was allowed to warm to room temperature and stir for 2 h, then partitioned between EtOAc and H2O. The water layer was washed with EtOAc and the combined organic extracts were washed with water and brine, then dried over MgSO4. After removal of solvents at reduced pressure, the residual tan foam (4.08 g) was purified using flash chromatography (eluent: 50/50 EtOAc-hexane to 1% MeOH-EtOAc) to give 2.36 g (71%)of the title compound as a white foam. 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J=7.5 Hz, 3H, CH3); 1.70 (sextet, J=7.5 Hz, 2H, CH2); 2.52 (t, J=7.5 Hz, 2H, CH2); 3.45 (m, 2H, piperazine); 3.54 (m, 2H, piperazine); 3.63 (m, 2H, piperazine); 3.71 (s, 3H, CO2CH3); 3.93 (m, 2H, piperazine); 5.46 (s, 2H, benzyl); 6.67 (m, 2H, aromatic); 6.82 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 6.94 (d, J=7.5 Hz, 6H, trityl); 7.11 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 7.2-7.4 (m, 10H, aromatic); 7.4-7.5 (m, 3H, aromatic); 7.91 (dd, J= 7.0, 6.0 Hz, 1H, tetrazolyl-phenyl); 8.19 (approx. dd, J=5.5, 2 . 0 Hz, 1H, pyridyl).
Reaction SMILES: [CH3:1][N:2]1[C:7](Cl)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].COCCOC.[Li+].[N:29]1[CH:34]=[CH:33][C:32](B([O-])[O-])=[CH:31][CH:30]=1.[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]1[C:7]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21]
Reactant: Cn1c(Cl)c(-c2ccccc2)nc(-c2ccccc2)c1=O
Reactant: [O-]B([O-])c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(-c2ccncc2)c(-c2ccccc2)nc(-c2ccccc2)c1=O

Procedure:
To a solution of 1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one (0.5 g) in 3:1 ethylene glycol dimethylether:water (30 cm3), under nitrogen, was added sequentially 4-pyridyl boronic acid lithium salt (0.42 g), sodium carbonate (0.72 g) and tetrakis-triphenylphosphine palladium (0.07 g). The reaction was heated at reflux, under nitrogen, overnight. The solvents were evaporated and the residue partitioned between water and 5% methanol/dichloromethane. The organic phase was separated, dried over magnesium sulphate and evaporated in vacuo. The residue was subjected to silica gel chromatography using 2% methanol/dichloromethane as eluant. The product was treated with hydrogen chloride in methanol and recrystallised from ethyl acetate/diethyl ether to afford1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one hydrochloride(0.2 g; 32%) as yellow crystals. Found C, 70.50; H, 4.90; N, 11.20% C22H17N3O.HCl requires C, 70.30; H, 4.83; N, 11.18%.m/e (ES+) 340 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][N:8]2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1nn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a mixture of methyl 6-bromo-1H-indazole-3-carboxylate (0.50 g, 1.96 mmol) and potassium carbonate (1.28 g, 9.29 mmol) in acetonitrile (15 mL) is added methyl iodide (1.31 g, 9.29 mmol) at room temperature. The reaction mixture is stirred at room temperature for 15 h. Remove the solvent under vacuum, dilute with water, and extract with ethyl acetate (3×10 mL). The combined organics are dried over sodium sulfate and concentrated under reduced pressure. The crude is purified by flash chromatography eluting with 8:2 hexane/ethyl acetate to give 0.35 g (70%) of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 4.14 (s, 3H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.66 (s, 1H), 8.08 (d, J=8.8 Hz, 1H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([C:28]4[CH:27]=[CH:26][O:25][C:24]=4[CH3:23])=[O:30])=[N:37][CH:36]=3)=[O:39])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cc1occc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 0.296 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine and 624 μL of triethylamine in 3 ml of dichloromethane is added a solution of 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride in 4 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaHCO3 and the mixture extracted with ethyl acetate. The extract is washed with H2O, 1M NaHCO3 brine and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C>CO.Cl.O1CCOCC1>[CH3:19][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H]1CCC[C@H](C(=O)c2ccc(Br)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of trans-3-(4-bromobenzoyl)cyclohexane-1-carboxylic acid (500 mg, 1.61 mmol, obtained from Rieke Metals Inc., Lincoln, Nebr., USA) and 2,2-dimethoxypropane (669 mg, 6.43 mmol) in methanol (20 mL), 5 drops of 4 M HCl in dioxane was added, and this reaction mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation to give the product 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester as a brown oil (500 mg, yield 95.7%). 1H NMR (300 MHz, DMSO) δ 7.80 (d, 2 H), 7.60 (d, 2 H), 3.70 (s, 3 H), 3.25 (m, 1 H), 2.50 (m, 1 H), 2.20-1.90 (m, 4 H), 1.70-1.50 (m, 4 H); LC-MS ret. time 3.30 min, m/z 324.9 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])#[N:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13].C1(O)C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:3]2[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=2[O:10][S:12](=[O:14])(=[O:13])[N:15]=1
Reactant: N#Cc1c(O)cccc1F
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: NC1=NS(=O)(=O)Oc2cccc(F)c21
Temperature: 50 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
8.0 g (58.3 mmol) of 2-cyano-3-fluorophenol are dissolved in 100 ml of anhydrous toluene. With exclusion of moisture and under protective argon gas, a solution of 8.489 g (60 mmol) of chlorosulphonyl isocyanate is added dropwise, in the course of which slight exothermicity occurs. The mixture is stirred at 50° C. for 16 hours; phenol is no longer detectable by thin-layer chromatography. The mixture is heated under reflux for 16 hours; no further evolution of HCl gas takes place. The mixture is concentrated under reduced pressure, taken up in acetonitrile and admixed with aqueous acetonitrile. After stirring at room temperature for 1 hour, the mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 13 g of a reaction mixture are obtained, which is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 1.3 g of a fraction are isolated, which consists of two components at log P=0.76 and 1.06. After separating this mixture by means of HPLC, 0.8 g of 4-amino-5-fluoro-1,2,3-benzoxathiazine 2,2-dioxide is obtained as a white solid.
Reaction SMILES: [SH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Cl)[O-].N1CCOCC1.[ClH:33]>>[Cl:33][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl
Reactant: [O-][N+](=Nc1ccccc1Cl)c1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [SH-]
Solvent: C1COCCN1
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Temperature: 75 °C
Yield: 79 %

Procedure:
84 Parts of an aqueous solution of technical sodium hydrosulfide, free from sodium thiosulphate, were added to a mixture comprising 53.4 parts of 2,2'-dichloroazoxybenzene in 140 parts of morpholine at 60° C - 65° C within 90 minutes. Subsequently, the reaction temperature was raised to 75° C and maintained at that temperature for 2 1/2 hours. Next the temperature was further raised to 90° C and maintained at that temperature for 1 hour. The pH of the reaction mixture varied between 9.5 to 10. After this period the absence of the starting material was confirmed. Then the reaction mixture was cooled to 20° C and neutralized cautiously with 400 parts of hydrochloric acid of 15 percent strength at a temperature below 20° C. Then the reaction mixture was cooled to 0° C to 5° C, and the resulting precipiatate filtered off and washed with water until free of chloride. After drying below 70° C, 40.1 parts of 2,2'-dichlorohydrazobenzene of a melting point of 85° C to 87° C were obtained, this representing a yield of 79 percent of the theory.