Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)CCO
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCCCCCC[Sn](CCCCCCCC)(OCCC(C)C)O[Sn](CCCCCCCC)(CCCCCCCC)OCCC(C)C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
700 g (1.94 mol) of dioctyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1700 g (19.3 mol) of 3-methyl-1-butanol (made by Kuraray Co., Ltd., Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 143° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, whereupon the liquid mixture boiled, and hence distilling off of a low boiling component began. This state was maintained for 7 hours, and then the purge valve was closed, and the pressure in the system was gradually reduced, and residual low boiling component was distilled off with the pressure in the system at from 76 to 32 kPa. Once low boiling component stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 864 g of reaction liquid was obtained in the flask. According to 19Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetraoctyl-1,3-bis(3-methylbutyloxy)-distannoxane was obtained at a yield of 99% based on the dioctyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetraoctyl-1,3-bis(3-methylbutyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:35][N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][NH:40][CH2:39]1.O(C(C)C)C(C)C>CCOC(C)=O>[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1
Reactant: CN(C)C1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
DIPEA (0.182 mL, 1.043 mmol) was added to 6-chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 70 mg, 0.174 mmol), N,N-dimethylazetidin-3-amine (60.1 mg, 0.348 mmol) and iPr2O (1 mL) in a vial, which was sealed and the RM was stirred at 110° C. for 5 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. phase was extracted with DCM (2×20 mL) and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title compound as white crystals. HPLC (Condition 7) tR=5.627 min, UPLC-MS (Condition 3) tR=0.75 min, m/z=447.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 6H) 2.90-3.05 (m, 1H) 3.49-3.62 (m, 2H) 3.70-3.87 (m, 2H) 6.36-6.51 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.92 (m, J=8.60 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.69-8.79 (m, J=2.30 Hz, 1H) 10.24 (s, 1H) 12.90-13.21 (m, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:15]([C:13]2[N:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][CH:12]=2)=[O:17])=[CH:44][CH:43]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc(C(=O)Nc3ccc(Cl)cc3)cs2)CC1
Yield: 29.1 %

Procedure:
A mixture of 29.1 mg (0.1 mmol) 2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid; hydrochloride, 35.3 mg (0.11 mmol) 2-(1H-benzotriazol-1-yl-1,1,3,3-tetramethyl uronium tetrafluoroborate, 14.03 mg (0.11 mol) 4-chloroaniline and 140 ul (0.5 mmol) N-ethyldiisopropylamine in 1 ml DMF was reacted at room temperature for a prolonged period of time. The mixture was treated with 50 μl triethylamine and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethyamine (0.05%). The product fractions were evaporated to dryness to yield 10.6 mg (29%) of the title compound. MS (m/e): 364.1 (MH+, 100%).
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([O:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20]>>[CH2:1]([S:17][CH2:20][CH2:19][CH2:18][O:21][CH2:22][CH2:23][CH2:24][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCOCC=C
Reactant: CCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCSCCCOCCCSCCCCCCCCCCCCCCCC

Procedure:
The procedure that is used for this example is similar to that set forth in Example 3, except that n-hexadecyl mercaptan (129.26g., 0.5 mole) is reacted with diallyl ether (24.54g., 0.25 mole).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].Cl.[N:12]([O-])=O.[Na+].[O:16]=[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1C(O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][N:12]=[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[O:16])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: O=C(O)C1CCCCC1=O
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCCCC1=NNc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
3,4,5-Trichloroaniline (1.6 g, 11.2 mmol) was dissolved in water (4 mL), cooled to 0° C., conc. HCl (1.5 ml) followed by a solution of NaNO2 (0.7 g, 11.2 mmol) in water (4 mL), was added dropwise and the resulting mixture was stirred for 30 min. followed by the addition of a solution of 2-oxocyclohexanecarboxylic acid. The reaction mixture was warmed to room temperature and stirred for 1 h during which time a solid precipitated out which was filtered and air dried to give the title compound (1.0 g, 29%). 1H NMR (500 MHz, CDCl3, δ in ppm) 13.5 (bs, 1H), 7.26 (s, 2H), 2.70 (s, 2H), 2.53 (s, 2H), 1.87 (s, 4H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[C:28](=[O:29])[CH2:27][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc2ccccc2c1
Product: [Br-]
Temperature: 100 °C
Reaction time: 1.17 h
Yield: 94.6 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (75 mg, 0.22 mmol) in acetonitrile (5 ml), was added 2-bromo-1-(naphthalen-2-yl)ethanone (55.5 mg, 0.22 mmol) and the reaction was stirred at 100° C. for 70 minutes under microwave irradiation (UPLC-MS: complete conversion). The solvent was evaporated and the crude was triturated with i-Pr2O-EtOAc (9/1) to obtain (R)-1-(2-(naphthalen-2-yl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (121.9 mg, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2cc(F)ccc21
Yield: 71 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) (2.52 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF14) (3.79 g, 71%). 1H NMR (CDCl3) δ 7.12 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.67-6.34 (m, 2H), 4.60 (q, J=14.8 Hz, J=25.4 Hz, 2H), 4.03 (dd, J=8.4 Hz, J=14.0 Hz, 1H), 3.82 (dd, J=5.6 Hz, J=14.0 Hz, 1H), 3.57 (dd, J=4.8 Hz, J=10.0 Hz, 1H), 3.45 (dd, J=7.0 Hz, J=9.8 Hz, 1H), 2.15-2.05 (m, 1H), 0.93-0.89 (m, 12H), 0.06 (s, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.7 Hz), 146.4 (d, J=11.6 Hz), 125.3 (d, J=3.0 Hz), 116.4 (d, J=9.6 Hz), 109.1 (d, J=22.7 Hz), 105.1 (d, J=25.8 Hz), 67.8, 66.0, 44.1, 34.5, 26.0, 18.4, 14.9, −5.3, −5.4.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NN1CCCCC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCCCC2)[nH]n1
Yield: 85 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (218 mg, 0.74 mmol) was converted, using 1-aminopiperidine instead of 4-aminotetrahydropyran, to the title compound (228 mg, 85%) which was obtained as a colorless oil. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1c2ccccc2oc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c(=O)c3ccccc3oc12
Yield: 88.6 %

Procedure:
A mixture of 4-nitroxanthen-9-one 2k (4.5 g, 18.7 mmol) and 10% palladium on carbon (200 mg) in ethanol (70 mL) was hydrogenated (hydrogen pressure: 55 psi) for 16 h. The catalyst was removed via filtration and the solvent was evaporated to yield 3.5 g (89%) of title compound 4-aminoxanthen-9-one 3k.
Reaction SMILES: C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=O.[CH3:17][C:18]1[NH:23][C:22](=[O:24])[C:21](C(O)=O)=[CH:20][C:19]=1[C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1.C>>[CH3:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][C:19]=1[C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1
Reactant: Cc1nc(-c2cc(C(=O)O)c(=O)[nH]c2C)cs1
Agent: CCOC(=O)c1ccccc1C(=O)OCC
Product: Cc1nc(-c2ccc(=O)[nH]c2C)cs1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a 100 ml portion of boiling diethyl phthalate was added 20 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid and the resulting dark solution was heated for about 15 minutes and then cooled to about 150° C., treated with decolorizing charcoal and filtered. The filtrate was diluted with 350 ml of n-hexane (no solid precipitated) and then extracted with 300 ml of 3% aqueous sodium hydroxide solution. The aqueous phase was separated and acidified with acetic acid, yielding no precipitate. The acidic solution was concentrated on a rotary evaporator to a volume of about 100 ml and allowed to stand at room temperature overnight. The resulting crystalline yellow solid that had separated was collected, washed with water, dried and then recrystallized from isopropyl alcohol-ether to produce 6.8 g of 6-methyl-5-(2-methyl-4-thiazolyl)-2-(1H)-pyridinone, m.p. 188°-190° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-])#N.Cl.O.C(=O)(O)[O-:14].[Na+]>C(Cl)Cl>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH:1]=[O:14])[CH:8]=1
Reactant: Cc1cc[n+]([O-])c(C#N)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(C=O)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a solution of 2-cyano-4-methylpyridine-N-oxide (3.29 g, 0.0279 mol) in 164 mL of methylene chloride at -78° C. was added 27.6 mL of DIBAL(H) and the mixture was stirred at -78 ° C. for 2 h. To the above mixture was added 13 mL of HCl (conc.) and 52 mL of water, and the mixture was warmed to room temperature. To the aqueous layer was added sodium bicarbonate solution, the solution was extracted with ether, and the combined organic layer was concentrated in vacuo. The residue was purified by chromatography on silica (ether) to afford 0.5 g (14.8%) of 4-methylpyridine-2-carboxaldehyde, as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=O)[CH:18]=[CH:19][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=[CH:27]/[C:25]#[N:26])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=O)c1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=C/C#N)c1

Procedure:
According to the method described for Reference Example 35, (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile as an oily product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.Cl[CH2:8][C:9]([O:11][CH3:12])=[O:10].[OH-].[K+]>CO>[CH3:12][O:11][C:9](=[O:10])[CH2:8][N:4]1[N:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: COC(=O)CCl
Reactant: Nc1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cn1nnc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
63.1 A solution of 8.5 g 5-amino-1H-tetrazole, 8.8 ml methyl chloroacetate and 5.8 g potassium hydroxide in 100 ml methanol was heated to reflux under an argon atmosphere and stirred for 18 h. A white solid slowly precipitated. The suspension was cooled to r.t. The white solid was filtered off and washed with methanol. The filtrate was concentrated. The residue was suspended in 100 ml EtOH and heated to reflux. After 1 h stirring at reflux, the mixture was filtered while hot. The filtrate was concentrated. The residue was recrystallized in 100 ml EtOH to give 1.8 g of (5-amino-tetrazol-2-yl)-acetic acid methyl ester as colorless crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][Cl:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CC(C)=O>[Cl-:22].[CH3:1][C:2]1[N:9]2[C:5](=[N+:6]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Cc1csc2nc3ccccc3n12
Solvent: CC(C)=O
Product: Cc1csc2n1c1ccccc1[n+]2Cc1ccc([N+](=O)[O-])cc1
Product: [Cl-]
Reaction time: 18 h

Procedure:
204 mg of 3-methyl[1,3]thiazolo[3,2-a]benzimidazole were solubilised in acetone (3 mL). Then 558 mg (3 eq) of 4-nitrobenzyl chloride were added and the solution stirred under reflux. After 18 h, 3-methyl-9-(4-nitrobenzyl)[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride was recovered as a pale yellow powder (363 mg, 94%) by filtration. Mp 241° C.; 1H NMR (300 MHz, MeOD) δ=2.95 (3H, d, J=1.3, CH3), 5.97 (2H, s, CH2), 7.30 (1H, q, J=1.3, H5), 7.68-7.82 (4H, m, Ar), 7.96-8.03 (1H, m, Ar), 8.27-8.36 (3H, m, Ar); 13C NMR (75 MHz, MeOD) δ=14.11, 50.56, 112.76, 113.82, 115.08, 125.37 (2C), 126.63, 128.64, 129.12, 131.04 (2C), 135.43, 137.72, 140.44, 149.92, 156.37; HRMS m/z C17H14N3O2S [M−Cl]− calcd: 324.0801, found: 324.0802.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[O:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Nitro-1,2,3,4-tetrahydronaphthalen-1-ol (1.0 g, 5.2 mmol) was dissolved in a mixture of DCM (10 mL) and pyridine (10 mL). Then, the reaction mixture was cooled to 0° C. and methane sulphonyl chloride (0.44 mL, 5.7 mmol) was added dropwise, and the reaction mixture was stirred at 60° C. for 2 hours. Next, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate, and washed with 1N HCl, saturated NaHCO3, and brine. The organic solution was dried (Na2SO4) and concentrated to give methanesulfonic acid 7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl ester. Yield 1.34 g (95%). LCMS (ESI): calc. C11H13NO5S=271; obs. low ionization.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([NH:20][C:21]1[C:40]([F:41])=[CH:39][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=O)[O:34]C(C)=C)[CH:27]=2)=[C:23]([F:42])[CH:22]=1)=[O:19])C.[CH3:43][NH2:44].C[N:46]1[CH2:50]CCC1>>[F:42][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[CH:8]=[CH:9][C:4]=2[NH:46][CH3:50])=[O:19])[C:40]([F:41])=[CH:39][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([NH:44][CH3:43])=[O:34])[CH:27]=1
Reactant: CN1CCCC1
Reactant: CN
Reactant: C=C(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OCC)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Product: CNC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(NC)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
Prop-1-en-2-yl (4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)pyridin-2-yl)carbamate (0.14 g, 0.24 mmol) was treated with a solution of N-methylamine (2.0 M in THF, 4 mL, 8 mmol) and N-methylpyrrolidine (0.021 g, 0.24 mmol), and was stirred at RT for 3 h. The solid was collected by filtration and further purified by silica gel chromatography (EtOAc). The purified residue was treated with MeCN/H2O (1:1, 4 mL), frozen and lyophilized to obtain 1-(4-(2,5-difluoro-4-(1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-3-methylurea (23 mg, 18% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 10.35 (d, J=6.0 Hz, 1H), 9.13 (s, 1H), 8.48 (dd, J=12.9, 7.2 Hz, 1H), 8.06 (d, J=5.9 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.48 (m, 3H), 7.34 (t, J=8.5 Hz, 2H), 6.92 (s, 1H), 6.57 (dd, J=6.0, 2.4 Hz, 1H), 6.24 (d, J=7.9 Hz, 1H), 3.01 (d, J=5.0 Hz, 3H), 2.66 (d, J=4.6 Hz, 3H); MS (ESI) m/z: 539.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].C[N:26]([C:28]1[CH:33]=[CH:32]C=CN=1)C.C(S(N)(=O)=O)CC.CO.ClCCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:28]([NH:26][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:19])[CH2:33][CH3:32]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Reactant: CN(C)c1ccccn1
Agent: CCCS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCCNC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCC)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(N-[5-Bromo-2-propoxvbenzyl]-N-ethylamino)pyridazine-3-carboxylic acid (example 18) (500 mg, 1.27 mmol) was dissolved in dichloromethane (50 ml), (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC),(365 mg, 2.07 mmol), dimethylaminopyridine, (DMAP) (465 mg, 3.81 mmol) and propanesulfonamide (190 mg, 1.54 mmol) was added. The mixture was stirred at ambient temperature under argon overnight, after which TLC (5% methanol/dichloromethane) suggested the reaction was complete. The reaction mixture was loaded directly onto a MPLC column (silica) and the title compound obtained by elution 5% methanol/dichloromethane as a foam (380 mg, 60%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 10 g. 3-(α-naphthyloxy)propyl bromide and 12.5 g. ethyl 4-aminobenzoate in 100 ml. hexamethylphosphoramide is stirred at 110° for 15 hours. The cooled solution is diluted with 200 ml. water and extracted 3 times with 100 ml. portions of ether. The combined extracts are washed with brine, dried and evaporated to an orange residue. The product is crystallized from ethanol to yield a solid which is crystallized from ethanol to yield white crystals, m.p. 93°-94° C.