Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:13][C@H:14]([CH2:16][O:17][S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:24])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into the suspension of cis-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (1322 mg, 3.842 mmol) in CH2Cl2 (55 mL) was added dropwise pyridine (6749 μL, 21.7 eq.) at −78° C. under N2 over 10 min followed by the addition of a solution of Ts2O (1568 mg, 1.25 eq.) in CH2Cl2 (35 mL) over 20 min. After stirring at rt for 3 h, the reaction mixture was treated with saturated NaHCO3, and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (50 mL). The combined organic phases were washed with H2O (2×100 mL) and brine (100 mL), and dried over MgSO4. After removing the solvent, a brown paste (2050 mg) was obtained. The brown paste was purified by chromatography on silica gel (50 g pre-packed column) and eluted with CH2Cl2 (600 mL), 2% MeOH/CH2Cl2 (600 mL), and 4% MeOH/CH2Cl2 (600 mL) to obtain the title compound as a light-brown foam. 1H NMR (CDCl3, 400 MHz): δ=2.20-2.28 (m, 2H), 2.47 (s, 3H), 2.47-2.52 (m, 1H), 2.57-2.64 (m, 2H), 4.12-4.13 (d, 2H, J=5.2 Hz), 5.07-5.11 (m, 1H), 5.63 (brs, 2H), 7.14 (s, 1H), 7.37-7.39 (d, 2H, J=7.6 Hz), 7.81-7.84 (m, 2H), 8.22 (s, 1H). MS (ES+): m/z 498.9 (100) [MH+]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH3:36])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cncc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-methoxy-pyridine.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1)(C)(C)C>Cl.CCOC(C)=O>[CH3:6][NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCOc2cc(CN3CCCCC3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of methyl-(7-piperidin-1-ylmethyl-chroman-4-yl)-carbamic acid tert-butyl ester (567 mg, 1.58 mmol, 1.0 eq) in saturated HCl/EtOAc (15 mL) was stirred at RT for 7 h. The solvent was removed with a rotary evaporator. The crude was diluted with saturated Na2CO3 (60 mL), and extracted with EtOAc (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The title compound was obtained as orange oil. MS (ESI, pos. ion) m/z: 261 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1>CO>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C)sc(C)c1N
Solvent: CO
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Yield: 6.4 %

Procedure:
A mixture of 18.5 g (0.1 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 15.76 g (0.1 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) is heated in a wax bath at 168°-186° C. for one hundred ten minutes and then at 185°-186° C. for ninety minutes under nitrogen. The mixture is cooled, suspended in hot methanol, cooled and 4.2 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 1.75 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid; mp 336° C. (dec) after recrystallization from pyridine.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:8][C:3]1[C:2]([C:14]2[CH:13]=[CH:12][C:11]([C:25]3[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=3)=[C:10]([F:9])[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3N)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 3-bromopyridin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C15H12FN5, 281.11; m/z found, 282.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.64-8.54 (m, 1H), 8.00-7.89 (m, 1H), 7.74-7.64 (m, 1H), 7.46-7.36 (m, 1H), 7.09-7.03 (m, 1H).
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:19][B-](F)(F)F.[H+].N([O-])=O.[Na+]>C(O)(=O)C>[CH2:16]([C:12]1[C:13]([F:15])=[CH:14][C:9]([O:8][C:7]2[C:2]([F:19])=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([OH:18])[CH:11]=1)[CH3:17]
Reactant: F[B-](F)(F)F
Reactant: CCc1cc(O)c(Oc2cccnc2N)cc1F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(O)c(Oc2cccnc2F)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.6 %

Procedure:
To a stirred solution of 2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol (45 mg, 0.18 mmol) in glacial acetic acid (2.5 ml) was added 0.36 ml of tetrafluoroboric acid (48% in water). The reaction mixture was cooled to 0° C. and sodium nitrite (18 mg, 0.27 mmol) was added at 0° C. and stirred at 0° C. for 1.5 hours until reaction was complete on TLC. The reaction mixture was quenched by adding ice and sodium bicarbonate solution and stirred for 10 minutes before extracting the aqueous solution with ethylacetate. The combined ethyl acetate fraction was washed with saturated sodium bicarbonate solution, water, followed by brine, dried over anhydrous sodium sulfate and concentrated in vacuo to get the crude compound. The crude material was column purified over silica gel using Petroleum ether/ethyl acetate 9:1 as eluant and then further purified by preparative HPLC using 0.1% TFA in water and acetonitrile as solvent system to get 8 mg (17.6%) of 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 31 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), pyrrole (0.42 g) and dimethylformamide (25 ml), the title compound (0.60 g) was obtained as an amorphous solid, MS, m/z: 388.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([OH:12])[CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1OCc1ccccc1

Procedure:
2-(benzyloxy)benzaldehyde (5g, 23.6 mmol) was reacted with vinylmagnesium bromide in THF (90 ml) at 0 C. The reaction was quenched with 2 N HCl and the product was extracted in i-PrOAc, dried over Na2SO4 and purified by flash chromatography with EtOAc:toluene 2.5:97.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:15][CH:16]([F:28])[O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[F:28][CH:16]([F:15])[O:17][C:18]1[CH:19]=[C:20]([S:24]([NH:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: CN1CCN(c2cc(N)ccn2)CC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc(NS(=O)(=O)c3cccc(OC(F)F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of 200 mg of 2-(4-methyl-piperazin-1-yl)-4-amino-pyridin (1.04 mmol) in 5 ml of pyridine 272 mg of (1.12 mmol) of 3-difluoromethoxybenzene sulfonylchloride (1.66 mmol) were added and the reaction mixture was stirred for 15 h at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. This mixture was washed with aqueous NaHCO3. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography with ethyl dichloromethane/methanol (0-15%) as eluent, yielding 231 mg of the purified product.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:12][CH2:13][C:14](=S)[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:2].[CH:27]([O:30][CH2:31][C:32]([NH:34][NH2:35])=O)([CH3:29])[CH3:28]>C(O)CCC>[CH2:1]([S:3]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[N:12][CH2:13][C:14]3[N:15]([C:32]([CH2:31][O:30][CH:27]([CH3:29])[CH3:28])=[N:34][N:35]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:2]
Reactant: CCS(=O)c1cccc2c1C(c1ccc(C(F)(F)F)cc1)=NCC(=S)N2
Reactant: CC(C)OCC(=O)NN
Solvent: CCCCO
Product: CCS(=O)c1cccc2c1C(c1ccc(C(F)(F)F)cc1)=NCc1nnc(COC(C)C)n1-2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-ethylsulfinyl-5-[p-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with isopropoxyacetic acid hydrazide to give 7-ethylsulfinyl-1-(isopropoxymethyl)-6-[p-(trifluoromethyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([OH:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].N1C=CC=CC=1.C(OC(=O)C)(=O)C.[CH:30](=[N:36]/O)/[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[F:1][C:2]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([O:8]/[N:36]=[CH:30]\[C:31]2[O:35][CH:34]=[CH:33][CH:32]=2)[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: O/N=C\c1ccco1
Reactant: CC(C)OC(=O)C1(F)C(=O)NC(=O)NC1O
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)OC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
In 50 ml of acetone was dissolved 20.0 g (85.4 mmol) of isopropyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, and 8.78 g (111.0 mmol) of pyridine and 8.65 g (93.9 mmol) of acetic anhydride were added to the solution, followed by stirring under ice-cooling for 3 hours and subsequently at room temperature for 16 hours. The solvent was disttiled off under reduced pressure, and the acetylated compound, which precipitates after the addition of water, was recovered by filtration, washed with water and dried. One-half its amount and 5.70 g (51.2 mmol) of (Z)-furfuraldoxime were dissolved in 30 ml of pyridineacetone (pyridine:acetone=2.1), and the solution was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane-ethyl acetate changing gradually the mixing ratio from (9:1) to (1:2) to yield 5.5 g of 5-fluoro-6-[(Z)-furfurylideneaminooxy]-5-isopropyloxycarbonyl-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine. m.p. 131°-134° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.[CH3:22][NH2:23]>C1(C)C=CC=CC=1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH3:22])[C:3]=2[N:10]=[N:9]1
Reactant: CN
Reactant: Fc1ccccc1Cn1nnc2c(Cl)ncnc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1ncnc2c1nnn2Cc1ccccc1F
Reaction time: 15 h

Procedure:
A solution of 9.22 g (35 mmol) of crude 7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine in 150 ml of toluene is added dropwise, while stirring, to a mixture of 750 ml of ethanol and 200 ml of 40% aqueous methylamine solution. The whole is left to stand for 15 hours at room temperature and then the solvent is distilled off under reduced pressure. 500 ml of water are added to the residue. The precipitated product is filtered off with suction and recrystallised from methanol. In this manner 3-(2-fluorobenzyl)-7-(N-methylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 180°-182° is obtained.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1)(OC(C)(C)C)=O.[ClH:23]>C(O)C>[ClH:22].[ClH:23].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCOc1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(OCC[C@@H]2CCCN2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 124 mg (0.40 mmol) of the compound from step 104a above in 3 mL of ethanol was added 10 mL of satd HCl in ethanol, and the reaction mixture was stirred for 1 hour at room temperature. The volatiles were removed under vacuum, and the residue was acidified and extracted with methylene chloride. The aqueous solution was made basic and extracted with methylene chloride. The extract was dried over MgSO4 and concentrated. The residue was purified on a column of silica gel, eluting with 10970 methanol in methylene chloride. The compound was converted to the salt by the HCl in ether according to Example 14c to afford the title compound. MS (DCI/NH3) m/e: 227 (M+H)+. 1H NMR (D2O, 300MHz) δ: 1.69-1.85 (m, 1H), 1.91-2.18 (m, 2H), 2.21-2.37 (m, 3H), 3.23-3.43 (m, 2H), 3.67-3.81 (m, 1H), 4.15-4.46 (m, 2H), 7.47 (m, 2H), 8.06 (d, J=3.5 Hz, 1H). Anal. Calc. for C11H15N2OCl.2 HCl: C, 45.09; H, 5.71; N, 9.34; Found C, 45.04; H, 6.01; N, 9.05. [α]25D =+19.00° (c=0.15, H2O).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(COC)OC>[N+:16]([C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:2]([C:20]([CH3:24])=[CH2:19])=[N:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1NCc1ccccn1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1cc(NCc2ccccn2)c([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-4-amine E-2.17″ (125 mg; 0.47 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (200 μl; 1.06 mmol), cesium carbonate (300 mg; 0.90 mmol) and [1,1′-Bis[diphenylphosphino]-ferrocene]dichloropalladium (30 mg; 0.04 mmol) are suspended in 7.5 ml dimethoxyethane and 2.5 ml water and heated for 1 h at 100° C. The solvent of the reaction mixture is removed under reduced pressure and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.O[CH2:18][CH:19]([CH2:21]O)O.II.OS(O)(=O)=O.[OH-].[Na+]>O>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][N:7]1[C:6]2[CH:16]=[C:2]3[N:1]=[CH:21][CH:19]=[CH:18][C:3]3=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: OCC(O)CO
Reactant: CN(C)CCN1CCOc2ccc(N)cc21
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(C)CCN1CCOc2cc3cccnc3cc21
Temperature: 180 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
6-Amino-3,4-dihydro-4-(2-dimethylaminoethyl)-2H-1,4-benzoxazine (D3, 4.66 g, 21 mmol), glycerol (2.9 g, 31 mmol) and iodine (0.135 g, 0.5 mmol) were stirred as conc. H2SO4 (3.2 ml, 60 mmol) was cautiously added. The mixture was stirred at 180° C. for 2 h, cooled, dispersed in water (300 ml), basified (40% NaOH), and extracted with dichloromethane. The extract was dried (Na2SO4) and evaporated to an oil, which was chromatographed on silica, eluting with 20% methanol/dichloromethane. This gave the title compound (0.50 g, 9%) as a dark oil.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12]CC)=[O:11])[NH:7][C:8]=1[CH3:9]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([OH:12])=[O:11])[NH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Aqueous lithium hydroxide (2 M, 4 ml) was warmed to 50° C. and a solution of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 28, 0.30 g, 1.60 mmol) in MeOH was added to it. The reaction was heated to 80° C. and stirred for two hours. The MeOH was removed and the aqueous solution was cooled to 0° C. and acidified with 30% HCl. The precipitated product (0.23 g, 92%) was filtered and dried. MS (ES): 160 (M+1) for C6H6ClNO2; NMR (CDCl3): 2.25 (s, 3H), 6.85 (s, 1H), 8.98 (brs, 1H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:43]12[NH:49][CH:46]([CH2:47][CH2:48]1)[CH2:45][CH2:44]2>>[CH:46]12[N:49]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[C@@H:23]4[CH2:32][CH2:31][C:30]5[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=5[CH2:24]4)=[CH:40][CH:41]=3)[CH:43]([CH2:48][CH2:47]1)[CH2:44][CH2:45]2
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: C1CC2CCC1N2
Agent: Cl
Product: COc1cc(NCCCc2ccc(CCN3C4CCC3CC4)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 13.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: [Na].[OH:2][CH:3]([C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[N:22][NH:23][N:24]=2)[CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[OH:2][CH:3]([C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[N:22][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:24]=2)[CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(O)c1cccc(OCc2cccc(-c3nn[nH]n3)c2)c1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2cccc(-c3nnn(CC(=O)OCC)n3)c2)c1
Yield: 85.7 %

Procedure:
To a solution of 0.3 g of sodium in 60 ml of ethanol was added 4.3 g of 5[3-[3-(1-hydroxyhexyl)phenoxymethyl]phenyl]-2H-tetrazole and 2.0 g of ethyl bromoacetate. The mixture was refluxed for 18 hours. The solvent was evaporated and the residue was partitioned between ether and water. The ether layer was dried and evaporated to give 4.5 g of a viscous oil. This was passed through a short silica gel column and eluted with chloroform:methanol (4:1). The product (2.3 g) was obtained as a light amber oil.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19].CC[N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.C([O-])(O)=O.[Na+]>>[CH2:4]([C:5]1([CH3:6])[CH2:28][CH2:26][N:25]([C:2]2[N:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([CH3:16])[C:3]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH2:29][CH2:31]1)[CH2:3][CH:17]=[CH2:18]
Reactant: CCOC(=O)c1cn2c(Cl)c(C(=O)C(=O)OC)c(C)cc2n1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCCC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reaction time: 2 h

Procedure:
A solution of ethyl 5-chloro-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.40 g, 1.23 mmol, 1 equiv), DIPEA (0.52 mL, 2.96 mmol, 2.4 equiv), and 4-(but-3-en-1-yl)-4-methylpiperidine, HCl (0.23 g, 1.23 mmol, 1 equiv). After 2 h, the reaction was added to saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to provide the product (0.44, 81%) as a viscous yellow oil that slowly crystallized. 1H NMR (400 MHz, CDCl3) δ 8.28-8.13 (m, 1H), 7.37 (br. s., 1H), 5.96-5.78 (m, 1H), 5.08 (d, J=17.6 Hz, 1H), 5.00 (d, J=10.5 Hz, 1H), 4.57-4.43 (m, 2H), 3.97 (s, 3H), 3.62-3.28 (m, 2H), 3.01-2.87 (m, 2H), 2.34 (d, J=0.8 Hz, 3H), 2.14-2.04 (m, 2H), 1.62-1.38 (m, 9H), 1.14-0.99 (m, 3H); LCMS (ESI, M+1): 442.25.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.Cl>O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
28.05 kg (16 l) of chlorosulfonic acid are initially introduced and 4.4 kg of 4-chlorobenzoic acid were added in the course of 10 minutes with stirring (no heat effect). In the course of 90 minutes, the mixture was heated to 130°-135° C., during which evolution of HCl was to be observed. The mixture was subsequently stirred for 3 hours at the stated temperature, and allowed to cool and to stand overnight. The reaction mixture was then allowed to run with stirring onto a mixture of 70 kg of ice and 30 kg of water, during which the temperature must not climb above 10° C. The product was filtered off with suction, washed with 40 kg of water and dried in vacuo at 40° C.