Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]1=[O:42].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[C:1]([C:4]1[C@@H:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[C:36]2[CH:37]=[CH:38][N:33]([CH3:32])[C:34](=[O:42])[CH:35]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cn1ccc(B(O)O)cc1=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1-c1ccn(C)c(=O)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(300 mg, 0.61 mmol) and (1-methyl-2-oxo-4-pyridyl)boronic acid (121 mg, 0.79 mmol) are suspended in acetonitrile (9 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 914 μL, 1.83 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (9.95 mg, 0.012 mmol) are added and the reaction is shaken at 75° C. overnight. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 142 mg; ESI mass spectrum [M+H]+=521; Retention time HPLC: 0.99 min (HPLC method Z018_S04).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH2:27]([N:29]([CH:39]([O:44][CH3:45])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[CH3:28].[CH3:46][Si:47](Cl)([CH3:49])[CH3:48]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Si:47]([CH3:49])([CH3:48])[CH3:46])[C:31]=1[C:30]([N:29]([CH2:27][CH3:28])[CH:39]([O:44][CH3:45])[C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38]
Reactant: CCN(C(=O)c1ccccc1Cl)C(OC)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 59.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (3.53 mL, 4.59 mmol) was added to a dry ice/acetone cooled solution of TMEDA (639 mL, 4.23 mmol) and N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chlorobenzamide (1.0 g, 3.53 mmol) in THF (7 mL). The resulting mixture was stirred at -78° C. for 45 min, then TMSCl (671 mL, 5.29 mmol) was added in a single portion. The reaction was allowed to warm to 0° C., and partitioned between ether and 10% HCl. The ether solution was then extracted with sat aq NaHCO3, dried (MgSO4), and purified by RC with 1:49 EtOAc/hexanes to afford 750 mg of the title compound as a white solid, a 60% yield. m.p. 82°-83° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCCS(=O)(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 30 ml of dioxane, 60 ml of acetone, 1.6 g (120 mmol) of anhydrous potassium carbonate and 1.6 g (10 mmol) of butane-sulfonyl chloride was refluxed for about 10 hours. The mixture was then freed from dioxane and acetone by distillation in vacuo and then added with ethylether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation and then recrystallization was effected from methanol to give 2.8 g (86%) of the desired white crystalline compound. m.p. 59°-61° C.
Reaction SMILES: [CH2:1]([N:17]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:18](=[O:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.CN([CH:34]=[O:35])C>>[CH:34]([C:23]1[S:22][C:21]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18](=[O:20])[CH3:19])=[CH:25][CH:24]=1)=[O:35]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCCCN(C(C)=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
27 g of N-Hexadecyl-N-(2-thienyl)-acetamide are dissolved in 22 cc. of anhydrous DMF and 14 g of phosphorus oxychloride are added dropwise thereto under cooling with ice, thereby avoiding increase of the temperature of the reaction mixture above 20° C. Stirring is continued for 1 hour at 20° C. and the reaction mixture finally is stirred for 3 hours at 80° C. Ice is added to the reaction mixture and 5 N soda lye is added thereto until reaching a pH of 6. The resulting mixture is extracted with ether, the ethereal phase is separated, washed with water and dried over Na2SO4. The ether is separated and the residue is purified chromatographically on a column of silicic acid gel using hexane/ethyl acetate as eluant.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:15]C(OCC3C=CC=CC=3)=O)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4].[H][H]>CO.C1COCC1.[C].[Pd]>[CH3:1][N:2]([CH3:27])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26])=[O:4]
Reactant: CN(C)C(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)C1Cc2ccc(N)cc2NC1=O
Yield: 92.2 %

Procedure:
To a suspension of N,N-dimethyl-7-benzyloxycarbonylamino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (820 mg) in methanol (8 ml) and THF (8 ml) was added 10% palladium-carbon (100 mg). The reaction mixture was stirred under one atmospheric pressure of hydrogen at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The precipitated crystals were washed with combined solution of IPE and THF to obtain the entitled compound (480 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([O:33][CH:34]1[CH:39]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])=[CH:42][CH:41]=2)[CH2:38][CH2:37][NH:36][CH2:35]1)[C:12]1[C:20]2[N:19]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[N:17](COCC[Si](C)(C)C)[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([O:8][C:9]([CH:11]([O:33][CH:34]1[CH:39]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])=[CH:44][CH:45]=2)[CH2:38][CH2:37][NH:36][CH2:35]1)[C:12]1[C:20]2[N:19]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2c(C(OC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)C(=O)OCc3ccccc3)cccc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc2c(C(OC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)C(=O)OCc3ccccc3)cccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The mixture of 1.03 g of methyl 4-(1-benzyloxycarbonyl-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxymethyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole-2-carboxylate, 10 ml of methanol and 10 ml of 2M HCl is stirred at 50° C. over 2 hours. The reaction mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (70 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (2:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-4-trifluoromethyl-pyrimidine (0.1 g, 0.55 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 150° C. in a microwave for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate and hexane to provide (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 395 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (d, 1H), 7.37-7.32 (m, 5H), 6.72 (d, 1H), 5.08 (s, 2H), 4.67 (bs, 1H), 4.22 (m, 2H), 3.49 (m, 2H), 2.08 (m, 2H), 1.68-1.60 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:2]1.BrC1C=NC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:8][C@@H:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C@H:3]1[O:4][CH2:5][CH2:6][NH:1][CH2:2]1
Reactant: OC(c1cccnc1)C1CNCCO1
Reactant: Oc1ccccc1F
Solvent: Brc1cccnc1
Product: Fc1ccccc1O[C@@H](c1cccnc1)[C@@H]1CNCCO1

Procedure:
(S)-2-[(S)-(2-Fluorophenoxy)-pyridin-3-yl-methyl]-morpholine was synthesized via morpholin-2-yl-pyridin-3-yl-methanol from 3-bromopyridine and 2-fluorophenol according to general procedure C and was isolated as a gummy oil (mixture of diastereoisomers). MS (APCI): 289 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([Cl:22])=[CH:13][C:14]=1[C:15]1[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=1)C)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:22][C:12]1[N:11]=[CH:10][C:9]([NH:7][CH3:6])=[C:14]([C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnc(Cl)cc1-c1cccnc1C
Reaction time: 1.5 h

Procedure:
To a solution of the obtained (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-carbamic acid tert-butyl ester in dichloromethane is added 0.40 ml trifluoroacetic acid at room temperature. The reaction mixture is stirred at this temperature for about 1.5 h. After addition of an aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane. The combined organic layers are dried and concentrated to give the compound (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine of formula IX.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH2:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11]([O:13][CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:7].[ClH:41]>O1CCOCC1>[Cl-:41].[CH2:27]([O:26][C:24]([NH:23][C@H:10]([C:11]([O:13][CH2:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:9][O:8][C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][NH2+:1]1)=[O:7])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Reactant: Cl
Solvent: C1COCCO1
Product: O=C(N[C@@H](COC(=O)[C@@H]1CCC[NH2+]1)C(=O)OCC(=O)c1ccccc1)OCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31.5 g (56.8 mmol) of the compound from example 2A are dissolved in 200 ml of 4M hydrogen chloride solution in dioxane under argon and stirred overnight at RT. The reaction solution is concentrated, and taken up once using ethyl acetate and concentrated again, and concentrated twice using dichloromethane. The residue is dissolved in ethanol (100 ml), diethyl ether (400 ml) is slowly added with stirring, the mixture is cooled and the precipitate is filtered off with suction. 25.2 g (86% of th.) of the product are obtained, which is reacted further without further purification.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1([CH2:33][CH2:34][OH:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:1]([O:35][CH2:34][CH2:33][C:20]1([OH:19])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 21.50 ml (82.50 mmol) of tert-butyldiphenylsilyl chloride in 15 ml of dichloromethane is added dropwise, under an inert atmosphere, to a solution of 18.4 g (75 mmol) of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in step 12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml of dichloromethane, cooled to about 0° C. The mixture is allowed to warm to room temperature and stifling is then continued for 12 hours. Saturated aqueous ammonium chloride solution is added to the reaction medium. The aqueous phase is separated out and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 10/90 and then 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH2:2][CH3:3].[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)[CH:13](Cl)[CH2:14][CH2:15][CH3:16])[CH3:9].N1C=CC=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[N:7]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[S:6][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:19])[CH3:9]
Reactant: CCCNC(N)=S
Reactant: CCCC(Cl)C(=O)C(=O)OCC
Solvent: c1ccncc1
Solvent: CCO
Product: CCCNc1nc(C(=O)OCC)c(CCC)s1
Yield: 68.3 %

Procedure:
n-Propylthiourea (270 mg), 3-chloro-2-oxohexanoic acid ethyl ester (441 mg), and pyridine (0.28 ml) were added to ethanol (10 ml), and the solution was refluxed for 3.5 hours. The solvent was evaporated. The residue was extracted with chloroform (20 ml), and washed with dilute hydrochloric acid solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (eluent:chloroform/methanol=100/1), 2-n-propylamino-5-n-propyl thiazole-4-carboxylic acid ethyl ester (400 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)CCC1.[CH:39]([OH:42])(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C@H:17]([OH:18])[CH2:19][NH:38][CH2:28][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([O:42][CH3:39])[CH:32]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H]1CO1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (1S)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiranyl]ethylcarbamate (V, 1.58 g, 4.28 mmol) and 3-methoxybenzylamine (VI, 825 microliter, 6.42 mmol) in isopropanol (45 mL) is heated to 90 degrees C. for 4 hours. Upon cooling to 20–25 degrees C., the reaction mixture is concentrated under reduced pressure. Purification by flash chromatography (silica; methylene chloride/methanol/ammonium hydroxide 98/1/1 to 95/:4/1) gives tert-butyl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, 1.97 g), NMR (300 MHz, MeOH-d4): δ 7.41–6.79, 5.05, 4.33–3.33, 3.74, 3.54, 3.03–2.46 and 1.29; ESI-MS (m/z) [M+H]+=507.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([S:39]([C:36]6[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=6)(=[O:41])=[O:40])[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(F)cc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 4-fluoro-benzenesulfonyl chloride (16 mg, 80 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by reverse phase chromatography (Method C) to afford 7 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:25][C:26]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)[N:3]=[CH:4][C:5]=2[C:19]2[CH:18]=[N:17][C:16]([CH3:15])=[CH:21][CH:20]=2)[N:10]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Solvent: O
Product: Cc1ccc(-c2cnc(Nc3nc(C)cs3)c3nc(C)ccc23)cn1

Procedure:
The title compound, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-methylpyridine-5-boronic acid hydrate and 2-amino-4-methylthiazole.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)[C:22](Cl)=[O:23].[I:27][C:28]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:29]=1C(O)=O>C(Cl)(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:22](=[O:23])[C:36]4[CH:35]=[C:34]([O:37][CH3:38])[C:33]([O:39][CH3:40])=[CH:29][C:28]=4[I:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)CCCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)O)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c(C(=O)N(CCCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Yield: 79 %

Procedure:
Prepared from N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,3-diamine (273 mg, 1.0 mmol), in 79% yield with a reaction time of 12 h, from the acid chloride prepared using 4.0 mmol of oxalyl chloride and 1.36 mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 7e had: IR (CHCl3) 1650; 1H NMR (CDCl3) δ 1.93 (m, 1H), 2.16 (m, 1H), 2.34 (s, 6H), 2.58 (m, 1H), 3.31 (s, 3H), 3.47 (m, 1H), 3.75 (s, 3H), 3.95 (m, 1H,), 4.55, (m, 1H), 6.16 (s, 1H), 6.39 (s, 1H), 704 (s, 1H), 7.28 (d, 1H, J=5.0), 7.31 (s, 1H), 7.38 (s, 1H), 8.56 (d, 1h, J=5.0); 13C NMR (CDCl3) δ 25.8, 45.1, 47.2, 55.5, 56.1, 26.9, 82.7, 98.1, 102.3, 107.0, 110.1, 120.1, 121.5, 122.5, 133.5, 145.5, 148.1, 148.4, 148.6, 149.2, 149.7, 151.1, 170.1; HRMS calcd for C24H26IN3O5H: 564.0995; found 564.0990.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:12]([N:15]([CH2:17][CH3:18])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[ClH:24]>>[Cl:24][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:12]([N:15]([CH2:17][CH3:18])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cl
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)CC
Product: CCC(C(c1ccc2nc(Cl)sc2c1)n1ccnc1)N(C)CC
Reaction time: 1 h

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine (5 mg, 0.1 mmol) and 2N HCl (5 mL) was stirred at Rt for 1 h. The mixture was filtered and evaporated to afford 1-(2-chlorobenzo[d]thiazol-6-yl)-N-ethyl-1-(1H-imidazol-1-yl)-N-methylbutan-2-amine. MS ESI: m/z 349.2 [M+H+].
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:17][CH2:18][CH2:19]CC>>[C:1]([N:5]=[N:6][C:18]([CH3:19])=[CH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC
Reactant: CC(C)(C)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)N=NC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 6.75 g. (0.077 m.) tert.-butylhydrazine in 50 ml. of methylene chloride containing 2 g. of anhydrous sodium sulfate, was added 3.0 g. (0.0326 m.) chloroacatone. The addition was carried out dropwise holding the reaction temperature below 10° C. with an ice bath. The reaction was stirred an additional 45 minutes and filtered. The filtrate was washed with cold water (10° C.), dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off using a rotating evaporator and a 20° C. water bath. A yellow oil containing some solids suspended in it was obtained. The crude material was slurried in cold pentane and filtered. The pentane was then evaporated off from the filtrate on the rotating evaporator. The yield was 1.9 g. (47%) of a yellow oil. The infra-red spectrum was consistent with the structure of the proposed compound. 2-tert.-butylazopropene is a thermally unstable compound and evolves nitrogen at room temperature and is therefore a very low temperature blowing agent.