Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]O)=[O:19])[CH:13]=1.CC[O:24]CC>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([O-:20])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N+:6]([OH:24])[CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CCOCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: O=C([O-])c1cccc(Cl)c1
Product: O[n+]1cc(Br)cc2cc[nH]c21

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (20 g, 0.1 mol) was suspended in 300 mL of NMP. A solution of 3-Chloroperbenzoic acid (40 g, 0.16 mol) in 100 mL NMP was added dropwise over 30 min. The solution was stirred at 23° C. for 1 h after which 600 mL of ether were added. The grey precipitate was filtered off and washed with ether to yield 18 g of 5-Bromo-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate. The filtrate was stirred with 250 mL saturated sodium bicarbonate solution and 250 mL water to give 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (4.3 g, 20.2 mmol). The filtered 5-Bromo-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate was suspended in 200 mL of water and 200 mL of saturated sodium bicarbonate solution and was vigorously stirred for 1 h. The grey solids were filtered and washed with water to give a second crop of 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (11.15 g, 52.3 mmol, 71% combined yield). 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 7.9 (d, J=1.5 Hz, 1H), 7.5 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H). MS: m/z 212.9 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(C(F)(F)F)cccc23)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1cccc2c(C3CCNCC3)noc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.00 g, 21.6 mmol), HCl (100 mL of a 1 M ether solution, 100 mmol), and methanol (50 mL) was stirred at room temperature under nitrogen overnight. The reaction was concentrated and the solid triturated with methanovether to afford 5.84 g (88%) of the desired product as a white powder, mp: 242–243° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C([O:15][C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.C(O)(=O)C>O1CCCC1.CCCCCC>[O:15]=[C:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Reaction time: 2 h

Procedure:
To a solution of dimethyl methylphosphonate (115.5 g.) in tetrahydrofuran (2.1 l.) at -65°, there is added 660 ml. of a 1.6 M solution of n-butyl lithium in hexane, and then there is added a solution of ethylhydrocinnamate (93.5 g.) in tetrahydrofuran (225 ml.). The mixture is stirred at -65° for 2 hrs. and then stirring is continued at 25° for 16 hrs. Acetic acid (70 ml.) is added, the solution is concentrated under reduced pressure and the residue is partitioned between methylene chloride and water. The organic layer is dried, concentrated, and distilled at 2 mm. to give 121.5 g. of the title compound; b.p. 184-195; mass spectrum 256 (M+).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([CH3:36])[CH:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:35]2)=[C:29]([CH3:36])[CH:28]=1)=[O:26]
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Reactant: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:11](Cl)[CH:12]=[CH:13][CH3:14].[Mg].[Cl-].[Na+]>CCOCC.O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([OH:10])([CH:13]([CH3:14])[CH:12]=[CH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC=CCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)C1(O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.94 g 1-acetyl-4-piperidone in a mixture of ether (80 ml) and tetrahydrofuran (40 ml), was added dropwise at 10° C. or lower 275 ml of a 0.5M Grignard reagent prepared by the usual way from crotyl chloride and magnesium, and the resulting mixture was stirred overnight at room temperature. To the ice-cooled reaction mixture, was slowly added 100 ml of saturated aqueous solution of sodium chloride, and the layers were separated. The aqueous layer was extracted with chloroform, the two organic solutions were each concentrated, and the combined concentrate was subjected to silica gel column chromatography using, as eluent, a mixed solvent of ethyl acetate/n-hexane (1:1 by volume) containing 3% methanol, giving 16.9 g of 1-acetyl-4-hydroxy-4-(1-methyl-2-propenyl)piperidine as oil.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:15]([O-])([O-])=[O:16].[Cs+].[Cs+].I[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CO>[Cu]I.C1(C)C=CC=CC=1>[CH3:15][O:16][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]
Reactant: N#Cc1cccc(I)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 83.4 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 3-iodobenzonitrile (229 mg, 1.0 mmol), methanol (162 μL, 4.0 mmol) and toluene (1 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 5:1) provided 111 mg (84% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:5]3[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14-7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:26][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3′-Amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (351 mg; 1 mmol) is dissolved in dimethylformamide (22.5 ml; dried over a molecular sieve), while gassing with argon, and potassium tert-butylate (172 mg; 1.5 mmol) is added at room temperature. After the mixture has been stirred for one hour, bromomethyl-cyclopropane (0.124 ml; 1.3 mmol) is added and stirring is continued for 1 hour at a bath temperature of 60° C. The reaction mixture is then cooled to room temperature and concentrateds The residue is taken up in water/ethyl acetate and the mixture is poured into a separating funnel and extracted by shaking. The aqueous phase is separated off and re-extracted once with ethyl acetate. The combined organic phases are washed with an aqueous saturated sodium chloride solution, dried over magnesium sulphate, filtered with suction and concentrated. The residue is chromatographed over silica gel (21 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). The pure fractions are concentrated and the residue is stirred with diethyl ether (10 ml) for 1 hour, filtered off with suction, rinsed with diethyl ether and dried under a high vacuum.
Reaction SMILES: [Li].[CH3:2][Si:3](Cl)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.II.[F:19][C:20](F)=[CH2:21]>O1CCCC1>[F:19][C:20]([Si:3]([CH3:2])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:21]
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C(F)F
Agent: II
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium wire (2.08 g, 300 mmol) in dry tetrahydrofuran (150 ml) was added methyldiphenylsilyl chloride (15.8 ml, 75 mmol) and a catalytic amount of iodine. The reaction mixture was sonicated for 40 min and then stirred overnight at room temperature. The reaction mixture was cooled to −78° C. and 1,1-difluoroethylene (approx. 225 mmol) was passed through the mixture for 30 min. The mixture was stirred at −78° C. for 2 h and then warmed to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with cyclohexane (×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 1 kg) eluting with hexane, followed by cyclohexane. The appropriate fractions were combined and concentrated to give Preparation 83 (7 g) as a colourless oil.
Reaction SMILES: C1(S[C:5]([F:23])([F:22])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])([OH:13])[CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)CC1.ClC1C=CC=[C:27]([C:31](OO)=O)[CH:26]=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1([S:35]([C:5]([F:22])([F:23])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])([OH:13])[CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)(=[O:39])=[O:37])[CH2:27][CH2:26]1
Reactant: O=S([O-])([O-])=S
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(C1CC1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.3 g, 6.63 mmol) in dichloromethane (200 ml), 85% m-chloroperbenzoic acid (3.6 g, 14.58 mmol) was added at room temperature, followed by stirring at room temperature for 12 hours. After the completion of the reaction, a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added and the resulting mixture was stirred. The dichloromethane solution was separated and after washing with water, dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 1-(cyclopropylsulfonyl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.9 g, yield: 76%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH2:34][CH2:35][CH2:36][OH:37].C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:34][CH2:35][CH2:36][OH:37])=[N:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(N=C(NCCO)Nc3c(C)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.107 g) was added to a mixture of 1-(2-chloro-6-methylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.118 g), 2-aminoethanol (0.03 ml), chloroform (5 ml) and methanol (5 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was thus obtained the title compound (0.128 g); NMR Spectrum: (DMSOd6+CD3CO2D) 1.47–1.62 (m, 2H), 1.85–2.11 (m, 5H), 2.29 (s, 3H), 2.67 (s, 3H), 2.87 (t, 2H), 3.33 (d, 2H), 3.59 (t, 4H), 3.79 (s, 3H), 4.0 (d, 2H), 7.08 (s, 1H), 7.19–7.32 (m, 3H), 7.4 (d, 1H), 8.43 (s, 1H), 10.5 (br s, 1H); Mass Spectrum: M+H+ 513 and 515.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([O-:37])=[O:36]>O1CCCC1.CCCCCC.O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]=[CH:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(CC=Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a suspension of [2-(4-methylphenyl)ethyl]triphenyl-phosphonium bromide (55.4 g) in anhydrous tetrahydrofuran (840 ml) kept at -50° C., a 1.5 N solution of n-butyl lithium in hexane (80 ml) was added, and the resultant mixture was stirred for a while. A solution of p-nitrobenzaldehyde (15.1 g) in anhydrous tetrahydrofuran (100 ml) was added thereto. The resulting mixture was allowed to stand at room temperature overnight, diluted with water and extracted with ethyl acetate. The extract was concentrated under reduced pressure and chromatographed on a column with silica gel, followed by eluting with a mixture of hexane and ethyl acetate to give 4-[3-(4-methylphenyl)-1-propenyl]nitrobenzene (21 g). nD24 1.5321.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.207 g, 1.03 mmol) in DCM (5 mL) was added oxalyl chloride (0.112 mL, 1.29 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h., the solvent was removed in vacuo and the 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.I[CH2:30][CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[CH2:30]([O:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)[CH3:31]
Reactant: CCI
Reactant: Oc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
A mixture of 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (80 mg, 0.20 mmol) from Example 147, iodoethane (47 mg, 0.30 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in NMP (3.5 mL) was stirred at rt for 5 h. The mixture was added to water and extracted with DCM. The organic layer was separated, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (35 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.14-7.19 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 5.41 (s, 2H), 4.72 (d, J=4.8 Hz, 1H), 3.97-4.04 (m, 2H), 3.43-3.54 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.60-1.65 (br m, 2H), 1.32 (t, J=13.8 Hz, 3H), 1.15-1.24 (m, 4H). LCMS (ESI) m/z 423 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:5]=[CH:6][CH:7]=1.ClCCl.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30]>C(OCC)(=O)C>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:3]=1)=[O:17]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cccc(NC(=O)c2ccccc2Br)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1cccc(NC(=O)c2ccccc2Br)c1

Procedure:
N-(3-Aminophenyl)-2-bromobenzamide (50 mg, 0.17 mmol), dichloromethane (1.7 mL), pyridine (17 μL, 0.21 mmol), and isovaleryl chloride (25 μL, 0.21 mmol) were added to a vial with stir bar and stirred for 20 h. The reaction was then diluted with ethyl acetate, then the combined organics were washed with 1 M aqueous HCl, then half-saturated aqueous NaHCO3, then brine. The crude solution was dried over Na2SO4, filtered, and concentrated to a colorless oil, then purified by column chromatography (EtOAc/hexanes gradient) after dry-loading on SiO2. The title compound was obtained as a white solid (53 mg, 82%). LRMS (ESI+) (M+H): 375.05.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:19])[CH3:18]
Reactant: NC1CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
A mixture of cyclopropylamine (1.39 g, 24.3 mmol) and triethylamine (3.5 g, 35 mmol) was added drop-wise to a 0° C. solution of ethyl chloro(oxo)acetate (3.5 g, 26 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 0° C. for 10 minutes and filtered; the filtrate was concentrated in vacuo to afford the product as a yellow solid Yield: 3.0 g, 19 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 7.14 (br s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.78-2.86 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 0.83-0.90 (m, 2H), 0.59-0.65 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([N:14]([C:24]([CH3:27])([CH3:26])[CH3:25])[O:15][CH:16]([C:18](=[O:23])[NH:19][CH2:20][CH2:21][OH:22])[CH3:17])[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].C(N(CC)CC)C>>[C:24]([N:14]([CH:9]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])[C:10]([CH3:13])([CH3:12])[CH3:11])[O:15][CH:16]([CH3:17])[C:18]([NH:19][CH2:20][CH2:21][O:22][C:28](=[O:31])[CH:29]=[CH2:30])=[O:23])([CH3:26])([CH3:25])[CH3:27]
Reactant: CCOP(=O)(OCC)C(N(OC(C)C(=O)NCCO)C(C)(C)C)C(C)(C)C
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCNC(=O)C(C)ON(C(C(C)(C)C)P(=O)(OCC)OCC)C(C)(C)C

Procedure:
In analogy to Example 3C) are reacted 8.43 g (0.0205 mol) (1-{tert-butyl-[1-(2-hydroxy-ethylcarbamoyl)-ethoxy]-amino}-2,2-dimethyl-propyl)-phosphonic acid diethyl ester, 2.08 g (0.025 mol) acryloylchloride and 3.2 ml (0.025 mol) triethylamine to afford the title compound as two diastereomers: 4.79 g of a colorless oil and 3.5 g of a white solid, mp 95-98° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4])(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCO/C(C)=N/O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of ethyl (1E)-N-hydroxyethanimidate (8.4 g, 81.5 mmol) in DMF (20 mL) is added triethylamine (12 mL, 86.24 mmol) and the mixture is stirred for 20 minutes. 2,4,6-Trimethylbenzene-1-sulfonyl chloride (20 g, 81.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are dried over sodium sulphate, filtered, and evaporated to dryness to give the title compound as white solid (15 g, 64%). The crude material is used without further purification.