Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([Br:11])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH:45]([CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)CO)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(OCC)C>[C:58]([O:57][C:55]([N:52]1[CH2:51][CH2:50][CH:49]([CH2:48][CH:45]([CH2:7][Br:11])[CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:39][CH2:40]2)[CH2:54][CH2:53]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CO)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(CBr)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
After pyridine (0.090 ml; 1.1 mmol), carbon tetrabromide (716 mg; 2.2 mmol) and triphenylphosphine (567 mg; 2.2 mmol) were added to a solution in diethyl ether (5 ml) of 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]ethyl alcohol (476 mg; 1.1 mmol) synthesized by the above process under ice cooling, the ice bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 465 mg (yield: 86%) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-(bromomethyl)propane as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[CH:5][C:6]([Cl:22])=[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[N:10]2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:6]1[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[N:10]2)=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([F:23])[CH:5]=1
Reactant: NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-83 by using 2-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-5-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one (0.400 g, 0.900 mmol), pivaloyl chloride (0.2 mL, 1.35 mmol), DIPEA (2 mL), and THF (10 mL) to afford 0.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.10 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.42-7.44 (m, 1H), 7.62-7.66 (m, 3H), 7.88-7.91 (br d, 1H), 8.14 (m, 1H); MS (m/z): 529.42 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[C:3]1=[O:15]>C(O)C.O1CCCC1.[Ni]>[NH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:15])[N:2]([CH3:1])[C:10]2=[O:11]
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(N)cc2C1=O

Procedure:
A solution of give 2-methyl-5-nitro-isoindole-1,3-dione (1.1 g, 5.3 mmol) in ethanol/tetrahydrofuran (1:1, 50 mL) is hydrogenated at 45 psi over Raney nickel catalyst. The reaction mixture is filtered through a pad of diatomaceous earth and concentrated to give 5-amino-2-methyl-isoindole-1,3-dione as a yellow cottony solid (0.85 g, 91%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (15.0 g, 0.065 mol), benzylamine (15.6 ml, 0.14 mol) and DMSO (100 ml) is heated at 80° C. overnight. The reaction mixture is poured into ice/water and the gummy solid which formed is collected by filtration. The solid is dissolved in ethyl acetate, dried over MgSO4, filtered and concentrated. The residual oil is crystallized from ethyl acetate to afford 18 g (92%) of 1-ethyl-N-(phenyl methyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 130°-132° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][C:4]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)NC1CCCCC1

Procedure:
β-Chloropropionyl chloride (31.7 g.) is added dropwise to a stirred solution of cyclohexylamine (24.8 g.) and triethylamine (28.2 g.) in toluene (250 ml.). The mixture is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. There is thus obtained as residue β-chloro-N-cyclohexylpropionamide, m.p. 77°-80° C. β-Chloro-N- 2-furfurylpropionamide may similarly be obtained from furfurylamine.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:7][C:8]1[S:12][N:11]=[C:10]([C:13](=[N:17][O:18][CH:19]2[CH2:23][CH2:22][CH:21]=[CH:20]2)[C:14]([OH:16])=O)[N:9]=1.[NH2:24][CH:25]1[C:57](=[O:58])[N:27]2[C:28]([C:41]([O:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])=[C:29]([S:32]/[CH:33]=[CH:34]\[C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:30][S:31][C@H:26]12.C[Si](NC(=O)N[Si](C)(C)C)(C)C>C(Cl)Cl>[NH2:7][C:8]1[S:12][N:11]=[C:10]([C:13](=[N:17][O:18][CH:19]2[CH2:23][CH2:22][CH:21]=[CH:20]2)[C:14]([NH:24][CH:25]2[C:57](=[O:58])[N:27]3[C:28]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:29]([S:32]/[CH:33]=[CH:34]\[C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[CH2:30][S:31][C@H:26]23)=[O:16])[N:9]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reactant: Nc1nc(C(=NOC2C=CCC2)C(=O)O)ns1
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of phosphorus pentachloride (455 mg) in methylene chloride (15 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetic acid (syn isomer) (557 mg) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The resultant mixture was added to a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1 g) and bis(trimethylsilyl)urea (2 g) in methylene chloride (20 ml) at -20° C. The mixture was stirred at -20~-10° C. for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of water (100 ml), sodium bicarbonate (920 mg), ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, concentrated in vacuo, and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-cyclopenten-1-yl)oxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)C(=O)C3C=NN(C4C=CC=C(C)C=4S)C=3N=2)=[CH:4][CH:3]=1.BrC1C=CC(C(Cl)=[O:39])=CC=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1S
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzamide (4) used is prepared by the following procedure. To a solution of 4-chloroaniline (2, 66.0 g, 517.4 mmol) and 4-bromobenzoyl chloride (3, 109.0 g, 497.5 mmol) in dichloromethane (1200 mL) is added triethyl amine (83.2 mL, 597.0 mmol). The reaction mixture is then poured into 0.05 N sodium hydroxide solution and the resulted suspension is stirred at rt for 1 h. The solid formed is filtered and washed well with water. It is dried in vacuo and used for the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O>CC(O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[N:6]([CH:13]=2)[C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[S:3]3)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc2ccc(O)cc2s1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Temperature: 0 °C
Yield: 65 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36]O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36][NH:8][CH3:1]
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Reactant: COc1c(CCc2ccccc2)cc(F)c2c1c(CCO)cn2C
Product: CNCCc1cn(C)c2c(F)cc(CCc3ccccc3)c(OC)c12
Yield: 62 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 23-3 was used as starting material, giving compound 23-4 in 62% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 8.62 (br, 2H), 7.18-7.31 (m, 5H), 7.15 (s, 1H), 6.87 (d, J=13.4 Hz, 1H), 3.85 (d, J=1.7 Hz, 3H), 3.69 (s, 3H), 3.05-3.13 (m, 4H), 2.88 (br, 4H), 2.57 (s, 3H). LRMS: calc 340.2 found 341.1[MH]+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20](Br)=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:36]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([OH:36])=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1cc2c(cc1Br)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1O)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of (R)-6-(5-bromo-3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (0.54 g, 0.97 mmol), bis(pinacolato)diboron (0.5 g, 2.0 mmol), PdCl2dppf-CH2Cl2 complex (16 mg, 0.02 mmol) and potassium acetate (0.40 g, 4.0 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate and filtered through a silica-celite pad. The filtrate was concentrated, dissolved in acetone (10 mL) and cooled to 0° C. Into this solution was added an aqueous solution of Oxone (10 mL, 1.0 M). The mixture was stirred at room temperature for 15 min and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic extractions were combined and washed with aq. NaHSO3 and brine, dried over Na2SO4, and concentrated. Purification on silica gel eluting with 40% ethyl acetate in hexane gave (R)-6-(3-cyano-1-cyclopentyl-5-hydroxy-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as a yellow solid (0.40 g, 84%); Melting point: 239-240° C.; MS m/z 493.2 M+H+; 1H NMR (500 MHz, CD3COCD3) δ 9.24 (dd, J=2.30, 0.65 Hz, 1H), 8.50 (dd, J=8.25, 2.35 Hz, 1H), 8.42 (s, 1H), 8.10 (dd, J=8.25, 0.85 Hz, 1H), 7.47 (bs, 1H), 7.54 (s, 1H), 7.15 (s, 1H), 5.30-5.26 (m, 1H), 4.40-4.35 (m, 1H), 2.40 (s, 3H), 2.34-2.31 (m, 2H), 2.16-2.14 (m, 2H), 2.10-2.07 (m, 2H), 1.74-1.72 (m, 2H), 1.21 (d, J=2.25 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([N:2]2[CH2:1][C:3](=[O:4])[N:2]([CH3:1])[C:3]2=[O:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccccc1
Reactant: CN=C=O
Product: CN1C(=O)CN(c2ccccc2)C1=O
Reaction time: 7 h
Yield: 35 %

Procedure:
A mixture of n-phenyl glycine (22.3 grams, 0.15 moles), methylisocyanate (14.2 grams, 0.25 moles) and 30 ml of toluene was stirred at 40°-45° C. for 7 hours and allowed to stand overnight at room temperature (21° C.). The product was collected and washed with toluene, crystallized from toluene and yielded 10.5 grams (35% yield) of the above-identified product having a melting point of about 168°-170° C.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CN1C(=O)CCC1>[O:13]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nnc2ccc(Oc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 200 mg) were initially charged dissolved in NMP (4 ml). Thereafter, sodium phenoxide (185 mg) was introduced at RT. After stirring at RT for one hour, the reaction was completed by heating to 55° C. for 2 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The crude product was purified using silica gel with a dichloromethane/methanol gradient. 38 mg of the title compound were obtained in solid form. LC-MS rt: 0.80 min [M+H]+: 228.1 (met. a)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]3[CH2:19][CH2:20][OH:21])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccnc(-n2ccnc2)n1
Reactant: OCCC1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCCC1CCCCN1c1ccnc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
The above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and Hünig's base (0.536 g, 4.15 mmol). After heating at 80° C. for 5 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 349 mg (46%) of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)), (1H NMR (CDCl3) δ8.54 (s, 2), 8.11 (d, 1), 7.82 (t, 1), 7.11 (d, 1), 6.44 (d, 1), 3.60 (m, 2), 3.03 (m, 1), 1.77 (m); MS: 2.74 (M+H)+). To a solution of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (25 mg, 0.092 mmol) dissolved in DMF (5 ml) was added NaH (60% dispersion in oil, 5.5 mg, 0.14 mmol) followed by piperonyl chloride (17 mg, 0.10 mmol) and t-butyl ammonium chloride. After stirring for 16 hours at 80° C., the solvent was removed in vacuo and the residue was partitioned with saturated NH4Cl and CH2Cl2. The organic layer was separated, dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (CH2Cl2/MeOH, 19/1) to give 13 mg (35%) of 4-[2-[[(1,3-benzodioxol-5-yl)methoxy]ethyl]piperidin -1-yl]-2-(1H-imidazol-1-yl)pyrimidine (the compound of formula (Icc)); 1H NMR (CDCl3) δ8.52 (s, 1), 8.05 (d, 1), 7.80 (s, 1), 7.09 (s, 1), 6.73 (m, 3), 6.45 (d, 1), 5.93 (s, 2), 4.30 (s, 2), 3.45 (m, 2),2.95 (m, 1), 1.55 (m); MS: 408.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[IH:21]>>[CH3:10][C:6]12[CH:3]([I:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: I
Reactant: CC1=CCCC(C)=CCC1
Agent: CC1=CCCC=C(C)CC1
Product: CC12CCCC(C)(CC1)C2I
Yield: 80.6 %

Procedure:
A mixture of 13.6 g (0.1 mol) of 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene, ratio 80/20, was boiled under reflux while stirring for two hours with 100 ml 55% hydrogen iodide in the presence of 2 g AMBERLYST A15 ion-exchange resin. The reaction product was extracted with pentane after cooling. The pentane layer was washed with water and an aqueous sodium bicarbonate solution. Residual free iodine present in the solution was washed away with a diluted sodium thiosulfate solution. The resulting pentane solution was dried over anhydrous sodium sulfate and pentane was flashed off. Fractional distillation under reduced pressure gave 17 g of 1,5-dimethyl-8-iodobicyclo[3,2,1]octane (b.p. 106° C./7 mm Hg). Yield 80.6% calculated on the amount of 1,5-dimethyl-1,5-cyclooctadiene added to the reaction. The purity of the product according to gas-liquid chromatography was more than 95%. The product appeared to be sensitive to day-light.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) were dissolved in 50 mL of DCM. Ethanesulfonyl chloride (0.170 mL, 1.78 mmol) was added dropwise and the solution was stirred at rt for 2.5 h. The solution was washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.155 mL, 2.06 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 565 mg (78%). 1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7.42 Hz, 3 H), 1.48-1.60 (m, 2 H), 1.64 (s, 9 H), 1.66-1.72 (m, 2 H), 1.73-1.82 (m, 2 H), 1.99-2.09 (m, 2 H), 2.18 (m, 1 H), 3.11 (m, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 7.38 (dd, J=9.08, 2.05 Hz, 1 H), 7.72 (d, J=2.15 Hz, 1 H), 7.85 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 414.0.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[CH2:11].[C:18](OOC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>C(C(C)=O)C(C)C>[CH3:17][CH2:16][CH2:15][CH2:14][O:13][C:9]([CH:10]=[CH2:11])=[O:12].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:1]=[CH:2][C:3]1[C:8]([CH:18]=[CH2:19])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: C=CC(=O)OCCCC
Solvent: C=Cc1ccccc1
Solvent: CC(=O)CC(C)C
Product: C=Cc1ccccc1C=C
Temperature: 90 °C

Procedure:
40 parts by weight of methyl isobutyl ketone were put into a flask with a stirrer, and heated to 90° C. with stirring in a stream of nitrogen gas. A mixture of 95 parts by weight of styrene, 10 parts by weight of butyl acrylate and 25 parts by weight of benzoyl peroxide was added dropwise over a period of 6 hours to the methyl isobutyl ketone which was maintained at 90° C. Subsequently, the above-mentioned mixture was subjected to polymerization at 90° C. for 10 hours, whereby a styrene-butyl acrylate copolymer solution was obtained.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:25](Cl)(Cl)=[O:26]>C(Cl)Cl>[C:12]([C@H:9]1[CH2:10][O:11][S:25](=[O:26])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[C@@H](CO)NCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (5.77 g, 27.8 mmol) in dry DCM (100 mL) was cooled down to −20° C., DIEA (19.39 ml, 111 mmol) was added, followed by thionyl chloride (2.228 ml, 30.6 mmol) in DCM (10 mL). The reaction mixture was stirred for 1 h at this temperature, then concentrated. The residue was purified by column chromatography to give the title compound (6.26 g) as a diastereomeric mixture. LCMS m/z=254.0 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)C#CC(=Nc1ccccc1)SCC1CC1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(SC=CC(=Nc2ccccc2)SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.91 g) was dissolved in methanol (15 mL), a small amount of potassium carbonate was dissolved thereto at room temperature, and the mixture was stirred for 1 hour. 4-fluorothiophenol (0.35 mL) was added thereto and further stirred for 5.5 hours. The reaction mixture was concentrated under reduced pressure, then the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1), medium pressure HPLC(hexane/ethyl acetate=99.2/0.8-98.5/1.5) to obtain cyclopropylmethyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.84 g).