Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].BrBr>C(O)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:7]2[C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CN=C=S
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2cccc(C(=O)O)c2s1
Temperature: 95 °C
Yield: 97 %

Procedure:
A solution of 39.2 g of methyl isothiocyanate and 50 g of 100% acetic acid is added dropwise to a suspension of 70 g of 3-amino-benzoic acid and 250 g of 100% acetic acid at 75-80° C. in the course of 50 minutes. A solution from which 3-(N′-methylthioureido)-benzoic acid slowly precipitates out in crystalline form is temporarily formed. After the mixture has been allowed to react completely for 2 hours, it is cooled to 50° and a solution of 81.5 g of bromine and 50 g of 100% acetic acid is added dropwise at 45-50° C. in the course of 2 hours. The mixture is then heated to 90-100° C. in the course of 2 hours and allowed to react completely for 2 hours, until the release of gas has ended. After 160 g of acetic acid have been distilled oft at 75-80° C. under reduced pressure, 200 g of water have been added to the residue, 67 g of 30% sodium hydroxide solution have been added dropwise, the mixture has been filtered with suction at 75-80° C. and the residue has been washed with water, 73 g of product of melting point >330° C. are obtained. HPLC analysis shows a content of 97% of the title compound, in addition to 0.7% of isomeric 2-methylamino-benzothiazole-5-carboxylic acid. Yield: 68% of theory.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[C:9]([CH3:20])=[C:10]([CH:17]=[CH:18][CH:19]=1)[C:11](N(OC)C)=[O:12]>C1COCC1>[Br:7][C:8]1[C:9]([CH3:20])=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH:11]=[O:12]
Reactant: CON(C)C(=O)c1cccc(Br)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one portion to a −78° C. solution of 3-bromo-N-methoxy-2,N-dimethyl-benzamide ((Example 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h at −78° C., the hydride reagent was quenched with EtOAc (10 mL), and the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL). After separating the layers, the organic layer was washed with NaHCO3 (3×20 mL), water (20 mL), and brine (30 mL). The solution was dried (sodium sulfate) and the solvent was removed in vacuo, giving the title compound (813 mg, 96%) as a colorless oil which was used without further purification. 1H-NMR (CDCl3): δ 10.28 (s, 1H), 7.80 (m, 2H), 7.25 (m, 1H), 2.78 (s, 3H).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11]1(=O)[O:15][CH2:14][CH2:13][CH2:12]1>>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([N:6]3[CH2:11][CH2:12][CH2:13][C:14]3=[O:15])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C1CCCO1
Product: O=C1CCCN1c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 51 %

Procedure:
A mixture of 3,4-(methylenedioxy)aniline (200 g, 1.46 mole) and γ-butyrolactone (225 ml) was heated (in a dry nitrogen atmosphere) with stirring in a 200° oil bath for 2 days. Product was isolated from the reaction mixture by distillation under reduced pressure (b.p. 156°, 33 μ). Product was filtered over Silica Gel 60 (Trade Name) eluting with ethylacetate. The eluant was concentrated and the crystalline product was collected and washed with ether and petroleum ether affording 1-(1,3-benzodioxol-5-yl)-2-pyrrolidinone (153.4 g; 51%), m.p. 89°-91° which was one spot on tlc analysis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:21][CH2:22][CH3:23].[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][S:27][CH2:26][C:25]([N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:35])=[O:34]
Reactant: CCCCN(C)C(=O)CSCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CSCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
6.88 g of triphenyl phosphine were added to a solution of 5.27 g of the product of Step B in 52 ml of methylene chloride and the mixture was cooled to 0° C. to +5° C. under a nitrogen atmosphere. 8.68 g of tetrabromo methane were added with stirring for one hour at 0° C. The reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 2-1) to obtain 6.2 g of the expected product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01(s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:22]=[CH:21][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=4[C:14]([NH:16][CH3:17])=[O:15])[C:4]=3[CH:3]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 25 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-N3-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a brown solid (32 mg, 25%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1.CC(C)([O-])C.[K+]>CC(O)(C)C.O>[CH:30]([C:26]1[N:25]=[C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:42][CH2:41][CH2:40][N:37]6[CH2:38][CH2:39][O:34][CH2:35][CH2:36]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)[CH:29]=[CH:28][CH:27]=1)([CH3:31])[CH3:32]
Reactant: OCCN1CCOCC1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCOCC5)ccn34)c12
Temperature: 95 °C
Yield: 52.7 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.250 g, 0.565 mmol), 2-morpholinoethanol (0.371 g, 2.82 mmol), and potassium t-butoxide were combined in t-BuOH in a reaction tube. The tube was sealed and heated to 95° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were with 10% aqueous potassium carbonate, dried over sodium sulfate, and concentrated. The resulting crude product was triturated with ether to give 165 mg (53%) of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid. MS (APCI), positive scan, m/z=554.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=O.C(N(CC)CC)C.C(C(Cl)=O)C.[F:30][C:31]1[CH:50]=[CH:49][C:34]([CH:35]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl.C(OCC)(=O)C.CCCCCC.O>[F:30][C:31]1[CH:50]=[CH:49][C:34]([CH:35]([N:43]2[CH2:44][CH2:45][N:46]([C:15](=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:47][CH2:48]2)[C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:33][CH:32]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(C=CC=CC(=O)O)c(OC)c1
Agent: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To 7.50 g (32.0 mmol) of 5-(2,4-dimethoxyphenyl)-2,4-pentadienoic acid were added 300 ml of dry dichloromethane and 4.46 ml (32.0 mmol) of triethylamine in the atmosphere of argon. The mixture was stirred at 0° C. followed by addition of 3.06 ml (32.0 mmol) of ethylcarbonyl chloride. The resulting mixture was stirred for 1 hour followed by addition of 11.04 g (38.4 mmol) of 4,4'-difluorobenzhydrylpiperazine in 50 ml of dry dichloromethane. Temperature of the mixture was raised to room temperature followed by stirring for additional 16 hours. After addition of water, the mixture was extracted with dichloromethane. The organic layer was washed successively with aqueous 1N-hydrochloric acid solution, a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 11.9 g (23.6 mmol) of 1-(4,4'-difluorobenzhydryl)-4-(5-(2,4-dimethoxyphenyl)-2,4-pentadienoyl)piperazine from eluate of ethyl acetate-hexane (1:1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][CH:6]=2)[N:8]=1)(=[O:15])[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1nc(-c2ccccc2)cs1
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Temperature: 25 °C

Procedure:
N-(4-phenyl-thiazol-2-yl)-acetamide was added to chlorosulfonic acid (5 eq) at 0° C. and allowed to warm to room temperature. The mixture was heated at 70° C. for 1 h and carefully poured into ice. The solid was filtered, washed with water and dried under vacuum to give 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride. Characterized by derivatization as N-[4-(4-Isobutylsulfamoyl-phenyl)-thiazol-2-y]-acetamide, 1H NMR (400 MHz, CD3OD) 8.08 (d, 2H), 7.85 (d, 2H), 7.58 (s, 1H), 2.66 (d, 2H), 2.22 (s, 3H), 1.7 (m, 1H), 0.87 (d, 6H). LCMS (m/z): 354.
Reaction SMILES: P(Br)(Br)Br.[BrH:5].[CH2:6]([C@H:11]1[CH2:16][CH2:15][C@H:14](O)[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10]>O>[CH2:6]([C@H:11]1[CH2:16][CH2:15][C@H:14]([Br:5])[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Br
Reactant: CCCCC[C@H]1CC[C@H](O)CC1
Agent: BrP(Br)Br
Solvent: O
Product: CCCCC[C@H]1CC[C@H](Br)CC1
Reaction time: 1 h

Procedure:
To a mixture of 104 g of phosphorus tribromide and 5 drops of a 48% aqueous solution of hydrogen bromide, 138 g of trans-4-pentylcyclohexanol were added dropwise under stirring while the temperature was controlled below 10° C. After the completion of the dropwise addition, the reaction mixture was reacted for one hour at the same temperature and then at room temperature for additional 1 hour. After the completion of the reaction, the reaction mixture was added with 200 ml of water, followed by extraction with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The resultant mixture was filtered and the solvent was distilled off from the filtrate under reduced pressure, whereby trans-4-pentylcyclohexyl bromide was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH2:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:4]4[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:15][CH:16]=1)[CH3:10]
Reactant: CC1CNS(=O)(=O)C1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 9 %

Procedure:
Using 4-methylisothiazolidine 1,1-dioxide (202 mg) described in Preparation Example 9 and [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (500 mg) described in Preparation Example 133 and by the reaction and treatment in the same manner as in Example 1, the title compound (46 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COc1nc(Cl)ccc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C(N)=O
Temperature: 110 °C
Yield: 38.6 %

Procedure:
A mixture of 6-chloro-2-methoxy-nicotinamide (7.15 g, 38.3 mmol), 2-bromo-5-hydroxy-benzaldehyde (11.5 g, 57.5 mmol) and K2CO3 (15.9 g, 115 mmol) in dimethylformamide (60 mL) was heated to 110° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with H2O (800 mL) and extracted with ethyl acetate (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (50-80% ethyl acetate/hexanes) to give the title compound as a light brown solid (5.19 g, 39% yield).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[C:4]#[N:5].Cl.Cl[CH2:14][C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CN(C=O)C>[NH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:1]/[N:2]=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)\[C:4]#[N:5])[N:16]=1
Reactant: Nc1nc(CCl)cs1
Reactant: N#C/C(=N\O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (2Z)-(hydroxyimino)(phenyl)acetonitrile (7.3 g, 49.95 mmol, 1 eq.) in 280 ml of acetonitrile and 30 ml of DMF, was added 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (11.09 g, 59.94 mmol, 1.2 eq.) followed by potassium iodide (829 mg, 4.99 mmol, 0.1 eq.) and caesium carbonate (39.06 g, 119.88 mmol, 2.4 eq.). The reaction was stirred overnight at room temperature. The solvent was then evaporated and the residue dissolved in EtOAc, subsequently washed with H2O and brine. Ater separation, the organic phase was dried over MgSO4 then concentrated. The residue was purified by chromatography on silica gel to give (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (10.30 g, 80% yield, only 1 oxime isomer).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH:13]1([N:16]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:34])[N:27]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:26]=2)C(=O)OC(C)(C)C)[CH2:15][CH2:14]1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:39][O:38][CH2:37][CH2:36][CH2:35][N:27]1[C:28]2[C:33](=[C:32]([CH3:34])[CH:31]=[CH:30][CH:29]=2)[C:25]([CH2:24][NH:16][CH:13]2[CH2:14][CH2:15]2)=[CH:26]1
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(C)cccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: COCCCn1cc(CNC2CC2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (213 μL) was added to a solution of tert-butyl cyclopropyl{[1-(3-methoxypropyl)-4-methyl-1H-indol-3-yl]methyl}carbamate (175 mg and 2,6-lutidine (192 μL) in dichloromethane (7 ml) under ice-cooling and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of sodium bicarbonate and methanol were added successively to the reaction mixture and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: ethyl acetate/methanol=95/5 to 70/30) to give N-{[1-(3-methoxypropyl)-4-methyl-1H-indol-3-yl]methyl}cyclopropanamine (106 mg) as a colorless oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=[O:47])[C:35]([CH3:46])([S:37]([CH:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)(=[O:39])=[O:38])[CH3:36])[O:30][N:29]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[CH3:27][C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=[O:47])[C:35]([CH3:46])([S:37]([CH:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)(=[O:39])=[O:38])[CH3:36])[O:30][N:29]=1)([CH3:26])[CH:24]=[O:23]
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dess-Martin periodinane (950 g, 2.24 mmol) is added to a solution of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (600 mg, 1.60 mmol) (see Amide Method B1 or B2) in DCM (10 mL). The reaction mixture is stirred at room temperature for 40 minutes. After this time, the reaction mixture is quenched with 50 mL (1:1) saturated aqueous NaHCO3 solution and saturated aqueous sodium thiosulfate solution and stirred at room temperature for 3 h then extracted with DCM 3 times. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. Yield: quantitative. 1H NMR (400 MHz, DMSO-d) δ ppm 1.4 (6H, s), 1.65 (2H, m), 1.7 (6H, s), 1.8 (2H, m), 3.4 (2H, m), 3.9 (3H, m), 6.4 (1H, s), 9.6 (1H, s), 11.5 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:4][C:5]([NH:8][C:9]2[CH:27]=[CH:26][C:12]3[N:13](C(=O)C(F)(F)F)[CH2:14][CH2:15][C:16](=[O:19])[NH:17][CH2:18][C:11]=3[CH:10]=2)=[N:6][CH:7]=1>CCO>[Cl:1][C:2]1[C:3]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:4][C:5]([NH:8][C:9]2[CH:27]=[CH:26][C:12]3[NH:13][CH2:14][CH2:15][C:16](=[O:19])[NH:17][CH2:18][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(=O)C(F)(F)F)ncc1Cl
Solvent: CCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3)ncc1Cl
Temperature: 80 °C
Yield: 22.1 %

Procedure:
2-{5-Chloro-2-[4-oxo-1-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (23 mg, 0.05 mmol) was dissolved in 1/1 EtOH/30% NaOH (2 ml) and heated to 80° C. in the microwave for 10 min. Reaction mixture was neutralized, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated to afford title compound as an off-white solid (5 mg, 26%) mp 267-268° C.; LCMS: m/z=452.30 (M+H+), HPLC (98% purity); 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.21 (s, 1H), 8.72 (m, 2H), 8.16 (s, 1H), 7.73 (m, 1H), 7.47 (m, 2H), 7.32 (m, 2H), 7.11 (m, 1H), 6.73 (m, 1H), 5.74 (m, 1H), 4.18 (m, 2H), 3.23 (m, 2H), 2.73 (m, 3H), 2.65 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:10].Cl.N1C=CC=CC=1>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:10]
Reactant: COc1ccccc1C(=O)c1cccc2c1ccn2C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc2c(C(=O)c3ccccc3O)cccc21
Yield: 60.7 %

Procedure:
Using the procedure of Step C of Example 3, 29.9 g of the product of Step C and 300 g of pyridine hydrochloride were reacted to obtain using methylene chloride as eluant for the chromatography 17.2 g of the expected product melting at 80° C. which was used as is for the following step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:9][C:8](=[O:10])[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(Br)cc1O2

Procedure:
1-(4-Bromo-2-hydroxy-phenyl)ethanone (10.1 g, 47.0 mmol) was coupled with N—BOC-4-piperidone according to the procedure for preparation of Intermediate 1, Step A, giving 7-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (18 g) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>[Pt]=O.CO>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: Cc1cc2ccccc2cn1
Agent: O=[Pt]
Solvent: CO
Product: CC1Cc2ccccc2CN1
Yield: 107 %

Procedure:
3.0 g of 3-methylisoquinoline(21 mM) and 50 ml of methanol were mixed and 0.84 g of platinum oxide was added thereto. The mixture was subjected to hydrogenation at 40 psi and filtered. The filtrate was concentrated under a reduced pressure, to give 3.3 g of the title compound.