Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C@H:2]1[C@@H:6](Cl)[CH2:5][S:4](=[O:9])(=[O:8])[CH2:3]1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>O1CCOCC1>[NH:12]1[CH2:11][CH2:10][NH:13][CH:2]2[CH2:3][S:4](=[O:9])(=[O:8])[CH2:5][CH:6]12
Reactant: NCCN
Reactant: O=S1(=O)C[C@@H](Cl)[C@@H](Cl)C1
Solvent: C1COCCO1
Product: O=S1(=O)CC2NCCNC2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
cis-3,4-Dichlorotetrahydrothiophene 1,1-dioxide (5.0 g, 26.0 mmol) in dioxane (40 mL) was added dropwise to ethane-1,2-diamine (10.4 g, 173.0 mmol) in dioxane (25 mL) at 0° C. The mixture was heated at 100° C. for 3 h, followed by cooling to room temperature and continued stirring overnight. The two layers were separated and the bottom layer, containing ethylene diamine and amine salt, was washed twice with dioxane. The dioxane layers were combined and the solvent was removed in vacuo. The crude product was recrystallized from toluene to afford 2.7 g (59%) of the title compound as white crystals. HPLC 98%, RT: 0.292 (System B; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.76 (m, 2H) 2.86-2.96 (m, 2H) 3.13-3.20 (m, 2H) 3.33-3.44 (m, 2H) 3.63-3.70 (m, 2H). LC-MS 177 (M+H)+. *Previously described in U.S. Pat. No. 3,882,122.
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[N:8][C:9]=1Cl)([O-:3])=[O:2].C[CH2:13][O-:14].[Na+]>>[Cl:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([O:14][CH3:13])[N:8]=[CH:7][N:6]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: [Na+]
Product: COc1ncnc(Cl)c1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
100 g 5-nitro 4,6-dichloropyrimidine are heated in 1000 ml sodium ethylate solution (16.8 g sodium) for 10 hours to 50° C. Then the reaction mixture is evaporated under vacuum and the residue is stirred with water and vacuum treated. Subsequently, it is extracted several times with hot petroleum ether (boiling range 40° to 60° C.). After cooling, the crystals are vacuum treated and dried. 46 g 4-chloro-6-methoxy-5-nitropyrimidine are obtained having a melting point of 65° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([Mg]Br)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].I[CH:24]1[CH2:29][CH2:28][SiH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1.P(OCC)(OCC)OCC>[Cu]I.C1COCC1>[CH2:30]([SiH:27]1[CH2:28][CH2:29][CH:24]([C@H:18]2[CH2:19][CH2:20][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)[CH2:25][CH2:26]1)[CH2:31][CH3:32]
Reactant: CCC[SiH]1CCC(I)CC1
Reactant: Fc1ccc(-c2ccc(C3CCC([Mg]Br)CC3)cc2)cc1F
Agent: [Cu]I
Agent: CCOP(OCC)OCC
Solvent: C1CCOC1
Product: CCC[SiH]1CCC([C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
A 25 ml THF solution of 1.0M 4-(4-(3,4-difluorophenyl)phenyl)cyclohexyl magnesium bromide (25 mmol) was dripped into a mixed solution of 5.36 g (20.0 mmol) of 4-iodo-1-n-propyl-1-silacyclohexane, 50 mg of copper (I) iodide, 100 mg of triethyl phosphite and 50 ml of THF. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 1.49 g (yield 36%) of the target product, i.e. the trans, trans isomers. The obtained target product exhibited the same physical properties as the product of Example 1.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([C:6]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:7]=1[CH2:8]Cl)[CH3:5]>O.C(#N)C>[CH2:4]([C:6]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:7]=1[CH2:8][C:1]#[N:2])[CH3:5]
Reactant: CCc1cc(C)cc(CC)c1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C)cc(CC)c1CC#N
Temperature: 75 °C
Reaction time: 3 h
Yield: 115.5 %

Procedure:
In a mixture of 50 g of water and 99 g of acetonitrile was dissolved 27.98 g of sodium cyanide. To this mixture, a solution of 157.18 g of 2,6-diethyl-4-methylbenzyl chloride (GC-area: 71%) in acetonitrile (293 g) was added dropwise at 75° C. over 2.5 hours. This mixture was stirred at 75° C. for 3 hours. To the reaction mixture was added 99 g of water, and the mixture was separated. The organic layer was concentrated. To the residue were added 99 g of water and 198 g of hexane and the mixture was separated. The organic layer was washed with 99 g of an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated to obtain 123.46 g of 2,6-diethyl-4-methylphenylacetonitrile (GC-area: 71%) as a brown oil.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.O=P(Cl)(Cl)Cl.[C:25]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:38][CH:39]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC1C=CC(C)=CC=1>[CH:37]1[C:32]2[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH:39]=[N:38][C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=CNc1ccccc1Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(C)cc1
Product: C1=Nc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.1 %

Procedure:
P2O5 (516.5 g) was added portionwise to H3PO4 (247.5 ml) and stirred under a N2 flow at room temperature. The mixture was stirred for 2 hours at 120° C., then cooled to 50° C. p-Xylene (1810 ml) was added, and stirring was continued for 15 minutes. POCl3 (83.3 g) was added, and stirring was continued for 10 minutes. N-[2-(phenylmethyl)phenyl]formamide (prepared as described in Helv. Chim. Acta 47(5) 1163-72 (1964)) (37.2 g) was added portionwise. The mixture was stirred for 30 minutes at 60°-70° C. Another portion of N-[2-(phenylmethyl)phenyl]formamide (74.3 g) was added portionwise, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was cooled and the p-xylene layer was removed. Water (990 ml) was added slowly. The mixture was cooled with ice-water. A solution of KOH (1073 g) in water (2200 ml) was added over 2 hours. CH2Cl2 (500 ml) was added dropwise and the mixture was stirred vigorously during 15 minutes. The organic layer was separated. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried with MgSO4, filtered off and the solvent evaporated. The residue was purified by distillation yielding a mixed fraction. The mixed fraction was repurified twice by distillation, yielding 1.4 g of 11H-dibenz[b,e]azepine (interm. 9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][S:43][CH2:44][C:45](O)=[O:46]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:45](=[O:46])[CH2:44][S:43][CH3:42])=[N:6][CH:7]=1
Reactant: CSCC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.7 %

Procedure:
(1 g, 5.78 mmol) 5-Bromopyridin-2-amine was dissolved in DMF (40 ml) and HATU (2.64 g, 6.94 mmol, 1.2 equiv.) was added. After 15 minutes at room temperature Hunig's Base (6.0 ml, 34.7 mmol, 6 equiv.) and 2-(methylthio)acetic acid (736 mg, 6.94 mmol, 1.2 equiv.) were added. The mixture was stirred for 72 hours at room temperature. The reaction mixture was evaporated and extracted three times with saturated Na2CO3 solution and three times with ethyl acetate. The organic layers were extracted three times with 1N HCl solution and evaporated to dryness. The crude product was suspended in pentane, filtered and the solid evaporated to dryness. The desired N-(5-bromo-pyridin-2-yl)-2-methylsulfanyl-acetamide (312 mg, 21% yield) was obtained as a yellow solid, MS: m/e=258.9/260.8 (M+H+).
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH:9]([OH:11])[CH3:10])=[CH:7][N:8]=1>CC#N.O=[Mn]=O>[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1
Reactant: CC(O)c1cnc(Br)s1
Agent: O=[Mn]=O
Agent: N#N
Solvent: CC#N
Product: CC(=O)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanol (14.85 g, 71.37 mmol) in CH3CN (160 mL) was treated at rt with MnO2 (34.47 g, 356.84 mmol) and the reaction mixture was stirred for 20 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.54. LC-MS-conditions 02: tR=0.79 min.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)C(C)(C)C)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Yield: 98 %

Procedure:
10% Pd—C (0.1 g) was added to a solution of 4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 3-(2), Enantiomer B; 725 mg, 1.92 mmol) in ethyl acetate (10 mL), and the mixture was stirred in a hydrogen atmosphere for 40 minutes. The reaction mixture was filtered and then concentrated under reduced pressure to give the title compound (720 mg, 98%).
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]([N:38]1[CH2:43][CH2:42][CH2:41][CH:40]([NH2:44])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[NH:45]1[C:49]2=[N:50][CH:51]=[CH:52][C:53]([NH:54][C:55]3[S:56][CH:57]=[CH:58][C:59]=3[C:60](O)=[O:61])=[C:48]2[CH:47]=[CH:46]1>>[C:34]([O:33][C:31]([N:38]1[CH2:43][CH2:42][CH2:41][CH:40]([NH:44][C:60]([C:59]2[CH:58]=[CH:57][S:56][C:55]=2[NH:54][C:53]2[CH:52]=[CH:51][N:50]=[C:49]3[NH:45][CH:46]=[CH:47][C:48]=23)=[O:61])[CH2:39]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccsc2Nc2ccnc3[nH]ccc23)C1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-BOC-3-aminopiperidine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, br. s.) 11.64 (1H, s) 8.13 (1H, d, J=5.42 Hz) 7.99 (1H, d, J=6.30 Hz) 7.53 (1H, d, J=5.91 Hz) 7.35 (1H, dd, J=3.44, 2.46 Hz) 6.96 (1H, d, J=5.42 Hz) 6.90 (1H, d, J=5.81 Hz) 6.44 (1H, dd, J=3.47, 2.00 Hz) 3.82 (1H, td, J=8.59, 4.93 Hz) 2.78 (1H, br. s.) 1.82-1.94 (1H, m) 1.66-1.77 (1H, m) 1.53 (1H, d, J=11.42 Hz) 1.31-1.45 (10H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:32]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15][CH3:32])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of 2-(5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)aniline (Example 62) (25 mg, 0.06 mmol, 1 eq) in THF (2 mL) was added formaldehyde (13.64 of a 37% aqueous solution, 0.18 mmol, 3 eq). After 15 min, acetic acid (0.1 mL) and sodium cyanoborohydride (12 mg, 0.18 mmol, 3 eq) were added and the solution stirred 5 hrs. Aqueous saturated NaHCO3 was added, the solution extracted with DCM, the organics combined, dried over MgSO4 and concentrated. Purification by RP-HPLC, eluting with a linear gradient of 20%-100% CH3CN in 0.1% TFA/H2O followed by freebasing with aqueous MP-carbonate resin in DCM and concentration gave 8.6 mg (32%) the title compound.
Reaction SMILES: C(OC(=O)C1C=CC(NC([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=O)=CC=1)C.C(C1C=CC(C=CC(OC)=O)=CC=1)=O>>[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2nc3ccc(OC)cc3s2)cc1
Agent: COC(=O)C=Cc1ccc(C=O)cc1
Product: COc1ccc2nc(N)sc2c1
Yield: 93 %

Procedure:
The title compound 162 was obtained following the procedure described in J. Med. Chem., 1979, 22 (1), 28-32, starting from 2-amino-6-methoxybenzothiazole (93% yield). 1H NMR: (DMSO-d6) δ (ppm): 9.63 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.51 (m, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (q, J=6.8 Hz, 2H), 3.79 (s, 3H), 1.32 (t, J=7.2 Hz, 3H). m/z: 372.3 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][N:53]=2)[CH:48]=[C:47]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:47]1[NH:46][C:54]2=[N:53][CH:52]=[CH:51][CH:50]=[C:49]2[CH:48]=1)(=[O:20])=[O:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cccnc21
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4cccnc4[nH]3)c2c1
Yield: 45.9 %

Procedure:
2-Methylsulfonyl-N-[3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 47 from 157.7 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 122 mg of 1-(tert-butoxycarbonyl)-7-azaindole-2-boronic acid, 7 ml of dimethylformamide, 500 μl of a saturated aqueous sodium hydrogencarbonate solution and 6.7 mg of tetrakis(triphenylphosphine)palladium[0]. 50 mg of 2-methylsulfonyl-N-[3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of a creamy yellow solid which decomposes at approximately 200° C. (LC/MS analysis: Tr 2.88 minutes MH+=468).
Reaction SMILES: C([CH:8]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH2:9][N:10]([C:20]1[CH:29]=[CH:28][C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=1)[CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[O:24]1[CH2:25][CH2:26][O:27][C:22]2[CH:21]=[C:20]([N:10]([CH:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)[CH2:9][CH2:8][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)[CH:29]=[CH:28][C:23]1=2
Reactant: c1ccc(CC(CN(c2ccc3c(c2)OCCO3)C2Cc3ccccc3C2)C2CCCCN2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1ccc3c(c1)OCCO3)C2

Procedure:
To a stirred solution of compound 59 (1.55 g, 3.31 mmol) in methanol (30 mL) was added HCOONH4 (2.08 g, 33.11 mmol) and the solution was purged with nitrogen for 30 minutes. 10% Pd—C (0.4 g) was then added and the solution was refluxed for 6 hours. The reaction mixture was filtered through Celite® reagent and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide compound 60.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH3:13][NH:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: CN(C)S(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred together for 16 hours. 4-bromo-3-fluoro-N,N-dimethylbenzenesulfonamide (0.36 g, 89%) was provided after purification. HRMS: calcd for C8H9BrFNO2S, 280.95214; found (EI, M+.), 280.9516. HPLC purity 98.9% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11]C2C=CC(C)=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:23]>C1(C)C=CC=CC=1>[OH:23][C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][C:3]=1[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(OC(=O)CCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(=O)CCc2ccccc2)c1
Temperature: 178 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
p-Tolyl 3-phenylpropanoate (13.0 g, 54.1 mmol) was added to aluminium chloride (9.38 g, 70.3 mmol) and the mixture was heated under stirring to 178° C. for 2 h. Heating was removed and toluene was added (30 ml). Stirring was continued for 15 min to obtain a brown solution, which was cooled with an ice bath prior to the careful, dropwise addition of water (30 ml). The resulting biphasic mixture was further stirred until it reached room temperature, then diluted with toluene. The organic layer was washed 3 times with water, then twice with 1N aq. NaOH solution (50 ml). The organic layer was then neutralized by washing three times with half saturated aq. NaCl, then dried over MgSO4 and concentrated in a rotary evaporator to obtain 9.44 g (73%) of crude brown oil, which was short-path distilled at 129° C./0.05 mbar to obtain 1-(2-hydroxy-5-methylphenyl)-3-phenylpropan-1-one (4.39 g, 34%). The product was further purified by column flash chromatography on silica to obtain 3.68 g (28%) of product, which was finally recrystallized from hexane to yield 2.93 g (25%) of product as white crystals, melting point 40.3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[C:10]([CH2:9][CH2:8][C:4]=2[CH:3]=1)=[N:18][CH:17]=[CH:16][CH:15]=3
Reactant: O=C(O)c1cccnc1CCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccc(F)cc2CCc2ncccc21
Temperature: 0 °C
Yield: 0 %

Procedure:
Combine crude 2-[2-(3-fluoro-phenyl)-ethyl]-nicotinic acid (2.06 g, 15.0 mmol) and polyphosphoric acid (100 g) and heat the mixture to 160° C. for 6 h. Allow slow cooling of the reaction mixture over 12 h, then reheat the mixture to 160° C. and pour it into ice (200 g). Complete the transfer using water and adjust the pH of the aqueous mixture to ˜8.0 with 50% aqueous sodium hydroxide solution. Extract the product with methylene chloride. Dry the combined organic extracts with magnesium sulfate, filter and concentrate. Purify the crude product via flash chromatography (25% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to provide 1.54 mg (81%) of purified product. LCMS (APCI-pos): 228.1 (M+H). 1HNMR (CDCl3, 400 MHz): δ8.63 (dd, 1H), 8.39 (dd, 1H), 8.01 (dd, 1H), 7.31 (dd, 1H), 7.02 (dt, 1H), 6.95 (dd, 1H), 3.46-3.43 (m, 2H), 3.23-3.21 (m, 2H). (Literature reference: Journal of Heterocyclic Chemistry 1971, 73).
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Cn2cc(N)cn2)o1
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(5-methanesulfonyl-furan-2-ylmethyl)-4-nitro-1H-pyrazole (150 mg, 0.55 mmol), iron powder (94 mg, 1.66 mmol) and NH4Cl (149 mg, 2.77 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.37 min; [M+H]+=242.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)n1
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)c2cc(-c3ccc(OC)nc3OC)oc2c1
Yield: 53 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(2,6-dimethoxypyridin-3-yl)ethanone: Yield 53% following procedure A.2; m.p. 155-156° C.; IR 2937, 2961, 1605, 1504, 1475, 1460, 1272, 1107, 1011 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 8.12 (d, J=8.2 Hz, 1H), 7.18 (s, 1H), 6.66 (s, 1H), 6.41 (d, J=8.2 Hz, 1H), 6.32 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.85 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 161.9, 159.1, 158.7, 155.9, 153.7, 149.7, 137.4, 113.9, 106.7, 101.7, 101.5, 94.3, 88.4, 55.9, 55.8, 53.8, 53.7.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>O.C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:19]1([C:17]2[CH2:16][O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1O
Reactant: O=C(CBr)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: c1ccc(C2=Nc3ccccc3OC2)cc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To potassium carbonate (72 g, 521 mmol) in water (360 mL) and CH2Cl2 (400 mL) is added 2-aminophenol (10.05 g, 92.1 mmol) and tetra-n-butyl ammonium hydrogensulfate (0.156 g, 0.46 mmol). With vigorous stirring a solution of 2-bromoacetophenone (18.33 g, 92.1 mmol) in CH2Cl2 (150 mL) is added dropwise over a period of 45 min. The mixture is allowed to stir overnight. The layers are separated and the organic layer is washed 3 times with water (300 mL), dried over magnesium sulfate and concentrated to dryness. The resulting solid is recrystallized from absolute ethanol (50 mL) to yield 11.78 g (61%) of 3-phenyl-2H-1,4-benzoxazine; mp 108-111° C.