Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([NH:44][C@@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37](=[O:38])[NH:44][C@@H:45]([C:49]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:50])[CH:46]([CH3:47])[CH3:48])([CH3:41])([CH3:43])[CH3:42]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 96.9 %

Procedure:
Following general amide formation method 1, 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 0.123 mmol, 1.0 eq) was combined with BOC-D-Valine (26.7 mg, 0.123 mmol, 1.0 eq) which gave ((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (82 mg) in 92% yield. HRMS m/z, (M+H)+: 688.3961.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][O:22][CH3:23])[C:15]([O:24][CH:25]([CH3:27])[CH3:26])=[N:14][C:13]([NH:28][C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][N:30]=2)=[CH:12]3)[CH2:4][O:3]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:25]([O:24][C:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[C:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:17]=2)[CH:12]=[C:13]([NH:28][C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][N:30]=2)[N:14]=1)([CH3:27])[CH3:26]
Reactant: COCCOc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCC(O)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.2 %

Procedure:
A solution of 30 mg of [6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-isopropoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine in 5 ml THF and 1 ml 1NHCl was stirred at room temperature for 3 h, and sent to Prep. LC-MS after neutralized with NaHCO3. 5 mg of 3-[1-Isopropoxy-7-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yloxy]-propane-1,2-diol was produce as solid. LC-MS: m/e 447 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:10]([OH:12])=O)=[C:6]([CH2:8][CH3:9])[N:7]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[CH2:1]([C:3]1[S:4][C:5]([C:10]([Cl:14])=[O:12])=[C:6]([CH2:8][CH3:9])[N:7]=1)[CH3:2]
Reactant: CCc1nc(CC)c(C(=O)O)s1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1nc(CC)c(C(=O)Cl)s1

Procedure:
In accordance with the method of Synthesis Example 2, 2,4-diethylthiazole-5-carboxylic acid and phosphorus pentachloride were reacted to give 2,4-diethylthiazole-5-carboxylic acid chloride quantitatively. The 2,4-diethylthiazole-5-carboxylic acid chloride was used in the following reaction without purification.
Reaction SMILES: C[O:2][C:3]1([O:35]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[C:23]([O:31]C)([O:29]C)[C:22]5=[O:33])[CH:14]=3)[CH:9]=2)[C:4]1=[O:34].C(O)(=O)C.Br>O>[OH:31][C:23]1([OH:29])[C:22](=[O:33])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:34])[C:3]([OH:2])([OH:35])[C:11]5=[O:12])[CH:14]=3)[CH:20]=2)[C:24]1=[O:28]
Reactant: COC1(OC)C(=O)c2ccc(-c3cccc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)c3)cc2C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3cccc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)c3)cc2C(=O)C1(O)O
Temperature: 115 °C
Yield: 54.8 %

Procedure:
1,3-bis(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (33) (119 mg, 0.25 mmol) was suspended in a solvent mixture of 3 ml of acetic acid and 3 ml of water, and the suspension was mixed with 3 ml of 47% hydrobromic acid. This mixture was refluxed at 115° C. over night. After it was cooled to room temperature, the reaction solution was filtered to obtain a solid, which was then dried at a reduced pressure, to obtain 59 mg (56%) of 1,3-bis(2,2-dihydroxy-1,3-dioxoindan-5-yl)benzene (34) in the form of a beige solid. The readings for this compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([CH2:22][S:23][CH2:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:27])[CH3:26])[C:4]=1[CH3:33].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36]>CO>[CH3:34][S:35]([O-:38])(=[O:37])=[O:36].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([CH2:22][S:23][CH2:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:27])[CH3:26])[C:4]=1[CH3:33]
Reactant: CS(=O)(=O)O
Agent: COCCOC(C)(C)CSCc1c(C)c(OC)cc[n+]1-c1nc2ccc(C(F)(F)F)cc2[nH]1
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
483.5 mg of intramolecularly deprotonized 4-methoxy-2-[[[2-(2-methoxyethoxy)-2-methylpropyl]thio]methyl]-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation were dissolved in 5 ml of methanol, whereupon 96 mg of methanesulfonic acid were added thereto, the solution was concentrated and the residue was dissolved several times in ethyl acetate and the solution was concentrated each time. The resinous residue was dried in a high vacuum, whereby 4-methoxy-2-[[[2-(2-methoxyethoxy)-2-methylpropyl]thio]methyl]-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]-pyridinium methanesulfonate was obtained as a foam. The microanalysis showed the following values:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O-:13])=O)=[N:3]1.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: CN
Reactant: Cn1nc(C(=O)[O-])c2ccccc21
Solvent: CO
Product: CNC(=O)c1nn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A suspension of methyl (1-methyl-1H-indazolecarboxylate (3.88 g, 20.4 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (5 mL) was stirred at RT for 4 hr. During that time the suspension became a solution. The mixture was concentrated to approximately ⅓ by volume at which time the product precipitated as a pale yellow solid. The solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.42 g, 89%) which was sufficiently pure for use in the next step: 1H NMR (300 MHz, CDCl3) δ 8.24 (m, 1 H), 7.47 (m, 2 H), 7.34 (m, 1 H), 6.95 (bs, 1 H), 4.19 (s, 3 H), 3.05 (d, J=12.0 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([NH:27][C:28](=[O:42])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:21][CH3:22])[CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:26]=[C:25]([NH:27][C:28](=[O:42])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][C:32]=2[Cl:41])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:21][CH3:22])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.180 g (0.284 mmol) of tert.butyl 4-[(2-{2-chloro-4-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-phenoxy}-ethyl)-ethyl-amino]-piperidine-1-carboxylate (from Example 97) were dissolved in 5.0 mL dichloromethane. After the addition of 0.44 mL (5.680 mmol) of trifluoroacetic acid the mixture was stirred for 2 hours at RT. The reaction solution was evaporated down i. vac. and the residue combined with sat. aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with EtOAc. The org. phase was dried over magnesium sulphate, filtered and evaporated down i. vac. Further purification was carried out by column chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[CH:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1.Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:25][C:15]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22](=[O:24])[C:23]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)c3ccccc3C(=O)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
A Grignard solution, consisting of 85.5 g (0.5 mol) of 4-bromotoluene and 11.5 g of magnesium filings, is added dropwise to 104 g (0.5 mol) of anthraquinone in 2,000 ml of absolute toluene and 500 ml of absolute tetrahydrofurane at 80° C. After the dropwise addition has ended, the mixture is subsequently stirred for 6 hours at 80° C. The reaction mixture is then hydrolysed in 2,000 ml of ice water, containing hydrochloric acid. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue is recrystallised from acetonitrile. 32.5 g (21% of theory) of 9,10-dihydro-9-hydroxy-9-(4-methylphenyl)-10-oxoanthracene of melting point 203°-209° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(C3CCNCC3)cncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A mixture of 0.57 gm (1.8 mMol) 1-tert-butoxycarbonyl-4-(isoquinolin-4-yl)piperidine and 6 mL trifluoroacetic acid in 6 mL dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10% to 40% methanol and a trace of ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.242 gm (63%) of 4-(isoquinolin-4-yl)piperidine as a tan solid. A portion of this material was converted to the oxalate salt to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[CH3:10].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])=[C:3]([C:9]([OH:11])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:4]=1
Reactant: CC(O)(c1ccccc1)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Product: CC(O)(c1ccccc1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-phenylethanol and chloroacetyl chloride according to the acylation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.42 (s, 1H), 7.93 (d, J=8.71 Hz, 1H), 7.64 (d, J=1.86 Hz, 1H), 7.52 (dd, J=1.77, 8.71 Hz, 1H), 7.33-7.18 (m, 5H), 6.99 (s, 1H), 4.17 (d, J=14.92 Hz, 1H), 3.99 (d, J=14.98 Hz, 1H), 1.84 (s, 3H); MS (ES) m/z 366/368/370 ([M−H]−, 100%); Anal. Calc. For C16H15BrClNO2: C, 52.13; H, 4.10; N, 3.80. Found: C, 52.18; H, 4.05; N, 3.77.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:12])[C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]1([CH2:7][O:8][C:9](=[O:12])[CH:10]=[CH:11][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC(=O)OCc1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](C=CC(=O)OCc1ccccc1)(CCCC)CCCC
Temperature: 65 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a stirring mixture of 2-propynoic acid phenylmethyl ester (2.46 g, 15.4 mmol) and tributyltin hydride (3.89 mL, 14.9 mmol, 97% purity) was added 2,2'-azobisisobutyronitrile (99.4 mg) and the reaction mixture was slowly warmed to 65° C. After stirring for 8 h at 65° C., the cooled reaction mixture was purified by flash chromatography, eluting with a mixture of hexane and EtOAc (50:1) to give 3-(tributylstannyl)-2-propenoic acid phenylmethyl ester (4.80 g, 10.65 mmol) as a mixture of E and Z isomers, in 69% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Br:8])[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Yield: 67.8 %

Procedure:
A mixture of 1,2-dibromobenzene (0.63 ml, 5.2 mmol), (3-ethoxycarbonylphenyl)boronic acid (506 mg, 2.6 mmol), tetrakis(triphenylphosphine)palladium(0) (640 mg, 0.6 mmol) and potassium carbonate (2.879 g, 20.9 mmol) was heated in toluene-ethanol (1:1, 10 ml at 90° C. for 3 hours. Upon cooling, the mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography using Biotage with iso-hexane containing a gradient of DCM (2-15%) to yield the title compound (538 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[S:14][C:15]1[S:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1.[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28]O)[CH3:24].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.CS(C)=O.CN1CCCC1=O.O1CCCC1>[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([S:14][C:15]3[S:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])[CH3:24]
Reactant: CCN(CC)CCCO
Reactant: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1OC
Reaction time: 10 h
Yield: 74.7 %

Procedure:
6-Methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolinol (500 mg), 3-diethylaminopropanol (290 mg), diethyl azodicarboxylate (390 mg), triphenylphosphine (590 mg), tetrahydrofuran (30 ml), 1-methyl-2-pyrrolidinone (2 ml) and dimethylsulfoxide (10 ml) were stirred together at 0° C. for 5 hours and then at room temperature for 10 hours. Water was added, extraction was performed with ethyl acetate, and the extract was back extracted with 2N aqueous hydrochloric acid. After adding 5N aqueous sodium hydroxide to the hydrochloric acid extract and performing extraction with ethyl acetate, the extract was washed with water and then with brine and dried over magnesium sulfate. NH type silica gel was coated onto a glass filter, the ethyl acetate layer was passed through the filter, and the solvent was distilled off under reduced pressure to obtain 500 mg of a reddish-brown oil.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:21][N:20]([C:22](=[O:39])[CH2:23][N:24]([CH2:32][CH2:33][C:34]3[N:35]=[N:36][NH:37][CH:38]=3)C(=O)OC(C)(C)C)[CH2:19][CH2:18][C:16]=2[N:17]=1>ClCCl.CO>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:21][N:20]([C:22](=[O:39])[CH2:23][NH:24][CH2:32][CH2:33][C:34]3[N:35]=[N:36][NH:37][CH:38]=3)[CH2:19][CH2:18][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N(CCc1c[nH]nn1)CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(CNCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Add hydrogen chloride (1M in ethyl ether; 2.55 mL; 8 equiv; 2.55 mmoles) to a 0° C. solution of tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-4-yl)ethyl]carbamate (0.165 g; 1.0 equiv; 0.318 mmoles) in dichloromethane (2 mL) and methanol (1 mL). After stirring for 1 hour at 0° C., concentrate the mixture. Redissolve the crude product in a 10:1 mixture of dichloromethane:methanol and wash with saturated sodium bicarbonate. Extract the aqueous layer with additional 10:1 mixtures of dichloromethane:methanol (4×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-{[2-(1H-1,2,3-triazol-4-yl)ethyl]amino}ethanone (0.136 g; 102%) as a brown foam: MS (m/z): 419 (M+1).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]2[C:27]([CH2:28][OH:29])=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[CH2:31]O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH:22]([C:23]3[CH:24]=[CH:25][C:26]([OH:30])=[C:27]([CH2:28][OH:29])[CH:31]=3)[O:2][CH2:1]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: OCc1ccc(O)c(CO)c1CNCCCCCCOCCCCc1ccccc1
Solvent: ClCCl
Product: OCc1cc(C2CN(CCCCCCOCCCCc3ccccc3)CO2)ccc1O

Procedure:
With stirring, 0.18 ml 36.5% aqueous formaldehyde are added at room temperature to a suspension of 0.589 g of (RS)-α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-4-hydroxy-1,3-dihydroxymethylbenzene (racemic mixture of R- and S-enantiomers) in 14 ml of methylene chloride. The mixture is stirred for 1 hour, diluted with methylene chloride and stirred for 14 hours at room temperature. The solution is washed with water (2×10 ml), dried over magnesium sulfate and concentrated by evaporation at 20 mbar and 30° C. The residue is dried at 0.1 mbar at 30° C. for 4 hours, giving the racemate of (SR)-3-[6-(4-phenylbutoxy)hexyl]-5-(4-hydroxy-3-hydroxymethylphenyl)oxazolidine in the form of a crystalline powder; m.p. 72°-75° C. [1H-NMR (400 MHZ, CD2Cl2)]: identical with the spectrum of the compound of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C@H:15]1[CH3:19].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C@@H:15]2[CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: CCc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCc1c(N2CC[C@H](O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-ethylbenzonitrile (1.01 g), (2S,3S)-3-hydroxy-2-methylpyrrolidine (8.25 mmol) and lithium carbonate (813 mg), the title compound was obtained as a colorless solid (yield: 147 mg) by an operation similar to that in Example 3.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(#N)C>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][S:8](=[O:11])(=[O:12])[C@H:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:6]1
Reactant: COc1cccc(C2CN(C[C@H](O)C(F)(F)F)CCS2(=O)=O)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: COc1cccc([C@@H]2CN(C[C@H](OC(=O)Nc3ccc(Cl)cc3)C(F)(F)F)CCS2(=O)=O)c1
Temperature: 85 °C
Yield: 13.7 %

Procedure:
In a 25 mL round-bottom flask, (S)-1,1,1-trifluoro-3-[2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-yl]-propan-2-ol (234 mg, 662 μmol) was combined with acetonitrile (5.00 ml) to give a colorless solution. 1-chloro-4-isocyanatobenzene (102 mg, 662 μmol) was added. The reaction mixture was warmed at 85° C. for 3 h, resulting in only a trace of product. Heating was continued at reflux overnight. The reaction was 50% complete by LCMS. An additional 60 mg of 1-chloro-4-isocyanatobenzene was added and the reaction mixture was heated at reflux for overnight. Reaction was not complete. Another 50 mg starting 1-chloro-4-isocyanatobenzene was added and the reaction mixture was stirred at reflux for 10 h. Reaction was complete by LCMS. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 30% EtOAc in hexanes gradient). The front end fractions of the product peak that was isolated from the column, that contained mostly one pure epimer (as determined by LCMS) were pooled to afford (4-chlorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl]-ethyl ester (46 mg) as a white foam. The absolute configuration was assigned based on analogy to Examples 1, 2, 11 and 12. (M+H)+=507 m/e.
Reaction SMILES: C1(N[C:5](=[O:37])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:36])CC1.Br.[OH2:39]>>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:18]1[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:15]2[N:16]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:37])=[O:39])=[C:7]([CH3:36])[CH:8]=3)=[CH:13][N:14]=2)[N:17]=1
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Reactant: O
Agent: Br
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)O
Yield: 9 %

Procedure:
A mixture comprising 50 mg (97 μmol) N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide and 0.5 mL hydrobromic acid was heated at 120° C. for 10 minutes under microwave irradiation. Water was added, the precipitate filtered off and purified by chromatography to give 30.0 mg (62%) of title compound A and 4.1 mg (9%) of title compound B.