Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:20])[CH2:19][CH2:18][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCC2)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of 2-bromo-5-iodoanisole (400 mg, 1.28 mmol) in tetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M in hexane, 0.62 mL, 1.55 mmol) dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then treated with neat cyclobutanone (0.1 mL, 1.3 mmol) dropwise over 10 minutes and stirred at −78° C. for an additional 1.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 27 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (40 mg, 12% yield). GCMS 256/258 (M)+; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.29 Hz, 1 H), 7.09 (d, J=1.95 Hz, 1 H), 6.98 (dd, J=8.17, 1.83 Hz, 1 H), 3.94 (s, 3H), 2.51-2.61 (m, 2H), 2.35-2.46 (m, 2 H), 2.02-2.10 (m, 1 H), 1.66-1.79 (m, 1 H).
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)([Cl:20])=O.N1[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]>>[ClH:20].[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([N:27]3[CH2:25][CH2:24][CH2:23][CH2:26]3)=[O:17])[CH2:14][C:9]=2[NH:8][CH:7]=1
Reactant: N#CC1=NC=C1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: O=S(=O)(O)O
Product: Cl
Product: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
In 53 ml of azetonitrile were added 5.3 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 2.9 ml of thionyl chloride, and the mixture was stirred at 53° to 55° C. for 1.5 hours. The mixture was distilled under reduced pressure to remove 10 to 15 ml of the solvent. After 15 ml of acetonitrile was added thereto, the mixture was further distilled under reduced pressure to remove 10 to 15 ml of the solvent. The residual solution was added dropwise to a solution of 14.2 g of pyrrolidine in 50 ml of acetonitrile at 2° C. or lower. After the addition, the temperature was returned to room temperature, and the mixture was stirred for 1 hour, followed by concentration under reduced pressure. To the residue was added 30 ml of a saturated sodium chloride aqueous solution, and the mixture was extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, treated with hydrochloric acid in ethanol, and recrystallized from ethanol/ethyl acetate to obtain 4.25 g (82.9%) of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride.
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22](O)=[O:23])[CH2:20][CH2:19][N:18]2[C:25](OCC2C=CC=CC=2)=O)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][O:65][C:66]1[C:67]([NH2:72])=[N:68][CH:69]=[CH:70][N:71]=1>C(#N)C.CN(C=O)C>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:72][C:67]3[C:66]([O:65][CH3:64])=[N:71][CH:70]=[CH:69][N:68]=3)=[O:23])[CH2:20][CH2:19][N:18]2[CH3:25])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1nccnc1N
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1nccnc1NC(=O)[C@@H]1CCN(C)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
4-Methylmorpholine (47.4 μl, 0.431 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (150 mg, 0.359 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (141 mg, 0.431 mmol) in acetonitrile (5.94 ml). The resulting solution was cooled to 0° C. and stirred at 0° C. for 15 min. To the reaction mixture was added 3-(methyloxy)-2-pyrazinamine (67.4 mg, 0.539 mmol). The reaction mixture was stirred for 2 days at rt. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM, washed with saturated NaHCO3 solution, followed by brine. The solution was dried over sodium sulfate and filtered. The solvent was removed to give a residue which was redissolved in DMF (3.75 ml) and purified by RP-HPLC to afford (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-[3-(methyloxy)-2-pyrazinyl]-3-pyrazolidine carboxamide (96 mg, 0.183 mmol, 51% yield) as a white solid. LC-MS (ES) m/e 525.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.C(Cl)(Cl)Cl.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:24]
Reactant: NN
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
12.3 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine are stirred in 40 cc of hydrazine hydrate at a bath temperature of 90° for 3 hours. The mixture is cooled with ice, 100 cc of chloroform are added, and the excess hydrazine is separated. Upon concentrating the chloroform phase, the crude title compound is obtained as an oil. This is converted to bis[3-hydrazino-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine]trisfurmarate by boiling with 4 g of fumaric acid in 50 cc of absolute ethanol. M.P. 132°-134° (decomp., from absolute ethanol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCCCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=467.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and cyclohexanone.
Reaction SMILES: BrC1C=CC([N:8]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=CC=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)CCC.[C:44]1(C)[C:45](C)=[CH:46][CH:47]=[CH:48][CH:49]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:33]1[CH:32]=[CH:31][C:30]([C:44]2[CH:45]=[CH:46][C:47]([C:21]3[CH:22]=[CH:23][N:24]=[C:19]([NH:8][CH:9]4[CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]4)[N:20]=3)=[CH:48][CH:49]=2)=[CH:35][CH:34]=1
Reactant: CC1(C)CC(N(c2ccc(Br)cc2)c2ncccn2)CC(C)(C)N1
Reactant: Cc1ccccc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccncc4)cc3)n2)CC(C)(C)N1

Procedure:
[4-(4-Bromophenyl (pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (116 mg; 0.3 mmol), PdCl2(PPh3)2 (21 mg; 0.03 mmol) and 4-tributylstannanyl-pyridine (221 mg; 0.6 mmol) were heated in xylene (3 ml) at 100° C. for 1 hour. The reaction mixture was filtered, evaporated and purified by preparative HPLC to give the title compound as a white solid. Yield: 20 mg (17%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][C:12]1C=C[CH:20]=[C:14]2[C:15]([NH:17][C:18](=[O:19])[C:13]=12)=O.[Na].[CH2:24]([OH:26])[CH3:25].O>C(O)C>[C:18]1(=[O:19])[N:17]([CH2:15][CH2:14][CH2:20][S:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:24](=[O:26])[C:25]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:13]12
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: CCO
Reactant: Sc1ncccn1
Agent: [Na]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCSc1ncccn1

Procedure:
A mixture of 2-mercaptopyrimidine (5.6 g.) and 3-bromopropylphthalimide (13.4 g.) in ethanol (100 ml.) containing sodium (1.15 g.) was heated under reflux for 20 hours to give 2-(3-phthalimidopropylthio)pyrimidine, m.p. 81.5°-82.5° (from ethanol-water). Reaction of the phthalimido compound (3.7 g.) and hydrazine (1.86 g.) followed by reaction of the product directly with N-cyanoN',S-dimethylisothiourea by the procedure of Example 3(a) gives N-cyano-N'-methyl-N"-[3-(2-pyrimidylthio)propyl]guanidine.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:24]1([CH2:30][O:31][CH2:32][CH2:33][CH2:34][Br:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br-:35].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][CH2:32][O:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCOCc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 66.4 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and 3-bromopropyl phenylmethyl ether (0.050 mL, 0.283 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0579 g, 66.6%). EI-MS m/z 451(M+) Rt (2.28 min).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:38][C:39]([CH2:41]Cl)=[CH2:40]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:3]([N:10]1[CH2:24][CH2:25][CH2:26][N:27]([S:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:29])=[O:30])[CH2:41][C:39](=[CH2:38])[CH2:40][N:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(CCl)CCl
Reactant: O=S(=O)(NCCCN(CCCNS(=O)(=O)c1ccccc1)Cc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1CN(S(=O)(=O)c2ccccc2)CCCN(Cc2ccccc2)CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 24 h
Yield: 77.4 %

Procedure:
In a 500 mL three-necked round-bottomed flask equipped with a rubber septum and a gas inlet, 0.92 g of a 60% (w/w) dispersion of sodium hydride in mineral oil (0.55 g NaH, 23 mmol) was washed with hexane (3×15 mL) under N2. A solution of 5.78 g (11.5 mmol) of N-benzylbis(3-benzenesulfonamidopropyl)amine in 220 mL of DMF was added slowly with stirring. The resulting clear solution was stirred under N2 while a solution of 1.44 g (11.5 mmol) of 3-chloro-2-chloromethyl-l-propene in 8 mL of DMF was added dropwise over 10 h. Stirring at room temperature under N2 was continued for an additional 24 h. The solvent was removed by rotary evaporation evaporation using a hot water bath. A solution of the residue in 50 mL of CHCl3 was washed with water (3×30 mL) and saturated aq. NaCl (2×30 mL) then dried (MgSO4). Removal of the drying agent by filtration and concentration of the filtrate by rotary evaporation gave the crude product as a thick yellow oil. The oil was dissolved in 100 mL of 1:1 (v/v) ethyl acetate/hexane and filtered through a pad of 16 g of basic alumina (Act 1, 80-200 mesh) washing with an additional 50 mL of 1:1 ethyl acetate/hexane. Concentration of the combined filtrates under vacuum afforded 4.93 g (77 %) of 9-benzyl-3-methylene-1,5-dibenzenesulfonyl-1,5,9-triazacyclododecane as a bubbly film that was converted to the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.F[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:31]#[N:32].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([NH:1][C:2]2[N:7]=[C:6]3[N:8]([C@@H:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH:29]=1)#[N:32]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3[N+](=O)[O-])nc21
Temperature: -15 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of (R)-tert-butyl 5-amino-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (94 mg) and 3-fluoro-4-nitrobenzonitrile (225 mg) in DMF (6 mL) was cooled to −25° C. and treated with NaH (60% w/w in mineral oil, 75 mg) and slowly allowed to warm to −15° C. The mixture was stirred for four hours between −20° C. and −15° C., then diluted with EtOAc and quenched with saturated ammonium chloride solution. The organic phase was washed three times with brine, separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2% MeOH in methylene chloride) provided 100 mg (R)-tert-Butyl 5-(5-cyano-2-nitrophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (70).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1.O1CCC(OC2N=CC(C(OCC)=O)=CC=2)CC1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:9]2[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CN1CCC(O)C1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Product: CCOC(=O)c1ccc(OC2CCN(C)C2)nc1
Yield: 24.5 %

Procedure:
Ethyl 6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate was prepared from 1-methylpyrrolidin-3-ol (0.161 g, 1.59 mmol) and ethyl 6-chloronicotinate (0.269 g, 1.45 mmol) according to the method described for Intermediate 236. The crude material was purified by FCC, eluting with a gradient of 0-20% MeOH in EtOAc to afford the title compound as a colourless oil (0.089 g, 25%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.82 (1H, m), 8.13 (1H, dt), 6.74 (1H, m), 5.43 (1H, m), 4.39 (2H, dq), 2.82 (3H, m), 2.40 (3H, s), 2.39 (2H, m), 2.04 (1H, m) and 1.40 (3H, dt).
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[CH3:14][N:15]([CH2:19][CH2:20]O)[CH2:16][CH2:17][OH:18].[OH-].[Na+]>>[CH2:5]([O:4][CH2:20][CH2:19][N:15]([CH2:16][CH2:17][OH:18])[CH3:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(CCO)CCO
Reactant: CCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCCN(C)CCO
Temperature: 200 °C
Reaction time: 3 h

Procedure:
318 grams (1.377 moles) of n-octyl sulfate, Na salt, 491.5 grams (4.130 moles) of N-methyl diethanolamine and 55.1 grams (1.377 moles) of sodium hydroxide were heated with stirring for 3 hours under a nitrogen atmosphere to 200° C. After cooling to 80° C., the mixture was washed four times with saturated sodium chloride solution and then dried at 80° C. under a vacuum in a rotary evaporator. Sodium chloride precipitated from the product was filtered. A red-brown liquid having an amine number of 238 was obtained in a quantity of 254 grams.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[NH2:34]C1C=CC(C#N)=CN=1>>[C:20]([C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[N:17][CH:18]=1)#[N:34]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: N#Cc1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (113 mg, 0.34 mmol) and 2-amino-5-cyanopyridine (41 mg, 0.34 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (61 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.48 (broad s, 1H); 8.24 (d, J=8.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.82 (broad s, 1H), 7.70 (d, J=7.6 Hz, 1H); 7.49-7.45 (m, 1H), 7.33 (m, 2H), 7.23 (t, J=8.6 Hz, 1H); 7.04 (t, J=8.5 Hz, 2H); 5.24 (d, J=15 Hz, 1H), 4.72 (m, 1H), 4.28 (d, J=15 Hz, 1H), 2.61-2.56 (m, 1H); 2.53-2.46 (m, 1H); 2.00-1.95 (m, 2H). MS: m/z (MH+) 433.
Reaction SMILES: N1C=CN=C1.C1CCN2C(=NCCC2)CC1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[C:29]=1[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C1COCC1.O>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[C:29]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[C:28]([NH:27][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:32][N:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1onc(-c2cccc(F)c2F)c1-c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1onc(-c2cccc(F)c2F)c1-c1ccncc1
Reaction time: 1.5 h
Yield: 44.8 %

Procedure:
In 3 mL of THF, 68 mg of imidazole and 152 mg of DBU were dissolved, into which 155 mg of phenylacetyl chloride was dropped under cooling with ice and stirring, followed by 1.5 hours' stirring at room temperature. Then a solution of 137 mg of 5-amino-3-(2,3-difluorophenyl)-4-(4-pyridyl)isoxazole and 152 mg of DBU in 3 mL of THF was added dropwise, followed by 26 hours' stirring at room temperature. After addition of water, the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was washed first with saturated aqueous NaHCO3 solution and then with brine, dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation. The resultant residue was purified by thin-layer silica gel chromatography (developer, hexane:ethyl acetate=1:1) to provide 88 mg (yield: 45%) of the title compound as colorless crystal.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>ClCCl>[C:16]([O:15][C:13]([NH:12][CH:9]([CH2:10][CH3:11])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([NH:30][NH:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:34])[F:33])=[CH:32][CH:31]=1)=[O:8])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)O
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)C(=O)NNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.03 h
Yield: 64 %

Procedure:
(S)-2-acetoxy-3-tert-butoxycarbonylamino-pentanoic acid (1.82 mmol, 0.5 g, A) is dissolved in 30 mL dichloromethane. N-Cyclohexylcarbodiimide-N′-methylpolystyrene (3.64 mmol, 1.92 g, B) is added and the resulting reaction mixture stirred for 2 min. 4-(trifluoromethoxy)benzoic acid hydrazide (1.65 mmol, 0.363 g, C) is added and the reaction mixture stirred over night. After 16 hours LC/MS analysis still showed hydrazide. Polystyrene methyl isocyanate (1.65 mmol, 1.15 g) is added and stirring continued for eight hours. The reaction mixture is filtered under suction and the filtrate concentrated under reduced pressure. To give acetic acid (S)-2-tert-butoxycarbonylamino-1-[N′-(4-trifluoromethoxy-benzoyl)hydrazinocarbonyl]-butyl ester as a foam (0.5 g, 64%). According to LC/MS still some hydrazide present. MS: m/z=500 (M+Na+), 478 (M+H+)
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][C:17]([CH:20]2[CH2:22][CH2:21]2)([F:19])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[CH:20]1([C:17]2([F:19])[CH2:18][NH:15][CH2:16]2)[CH2:22][CH2:21]1
Reactant: FC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC1(C2CC2)CNC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To wet 10% palladium on carbon (Degussa catalyst) under nitrogen was added ethanol (100 ml). A solution of 1-Benzhydryl-3-cyclopropyl-3-fluoroazetidine hydrochloride (6.74 g, 21.23 mmol) in ethanol (50 ml) was added to the catalyst and the mixture hydrogenated at 60 psi on the Parr shaker hydrogenation apparatus for 5 hrs. The reaction was filtered through celite and concentrated to an oil. Ether (50 ml) was added and the mixture cooled to 0° C. and stirred until a precipitate formed. The suspension was filtered and the filter cake was washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as an off white solid (3.00 g, 93%). 1H NMR d6-DMSO δ 0.52-0.56 (2H, m), 0.59-0.64 (2H, m), 1.35-1.40 (1H, m), 3.91-4.10 (4H, m), 4.01-4.23 (4H, m), 9.50 (1H, brs), 9.63 (1H, brs).
Reaction SMILES: [C:1]([O:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[CH2:2][CH2:3][CH2:4]CC.C(OCC=C)(=O)CC>>[C:1]1(=[O:7])[O:8][CH2:9][CH2:10][CH2:11]1.[CH:3]([CH2:2][C:1]([OH:8])=[O:7])=[CH2:4]
Reactant: C=CCOC(=O)CCCCC
Agent: C=CCOC(=O)CC
Product: C=CCC(=O)O
Product: O=C1CCCO1

Procedure:
The reaction was carried out as described in Example 11, with the exception that 156 grams of allyl caproate were used instead of allyl propionate. 16.6 grams of γ-butyrolactone and 11.8 grams of vinyl acetic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CS(=O)c1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 140 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
A mixture of 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.0 g, 2.7 mmol), (1R,2R)-2-aminocyclohexanol (0.93 g, 8.1 mmol) and DIEA (697 mg, 5.4 mmol) in NMP (40 mL) was stirred for 2 d at 140° C. The mixture was cooled to rt and water (150 mL) was added. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH to afford (1R,2R)-2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (530 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, J=9.6 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.12 (dd, J=1.5, 8.4 Hz, 1H), 4.73 (d, J=5.1 Hz, 1H), 4.29 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 414 (M+H)+.