Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH:12]1[CH2:15][N:14]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([CH:12]1[CH2:13][N:14]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:15]1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1SC1CN(C(=O)c2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1S(=O)C1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To an ice-cold stirred solution of (3-(2-tert-butylphenylthio)azetidin-1-yl)(phenyl)methanone (0.18 g, 0.55 mmol) in methylene chloride (10.0 mL) was added m-CPBA (0.15 g, 0.61 mmol). After 10 min a saturated solution of sodium thiosulfate and sodium hydrogen carbonate was added to the reaction mixture and the resulting reaction mixture was warmed to room temperature. After 30 min the reaction mixture was diluted with methylene chloride and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide (3-(2-tert-butylphenylsulfinyl)azetidin-1-yl)(phenyl)methanone (0.17 g, 66%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[CH2:21][C:20]2[C:15](=[N:16][C:17]([S:22][CH3:23])=[N:18][CH:19]=2)[N:14]([CH3:24])[C:13]1=[O:25].Cl>CCO.[Fe]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH2:21][C:20]3[C:15](=[N:16][C:17]([S:22][CH3:23])=[N:18][CH:19]=3)[N:14]([CH3:24])[C:13]2=[O:25])[CH:4]=1
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)C2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(N)c(F)cc1Cl)C2
Temperature: 50 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
To a solution of 3-(2-chloro-4-fluoro-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.4 g, 3.7 mmol) in EtOH (30 mL) was added conc. HCl (0.75 g, 9 mmol), followed by active iron power (2 g, 36 mmol). The reaction was stirred at 50° C. for 6 hours. The reaction was filtered and the filtrate was diluted with water and treated with saturated aq Na2CO3 solution until pH 8. The aqueous mixture was extracted with EtOAc (3×80 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.08 g, 84% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1 H), 7.30 (d, J=11.2 Hz, 1 H), 6.84 (d, J=8.8 Hz, 1 H), 5.50 (s, 2 H), 4.66 (d, J=14.6 Hz, 1 H), 4.53 (d, J=14.6 Hz, 1 H), 3.27 (s, 3 H), 2.51 (s, 3 H); MS (ESI) m/z: 354.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.Br[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:27][C:28](=[O:30])[CH3:29])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCC(C)=O
Yield: 63 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 10 ml of methyl ethyl ketone, and 0.15 g (1.10 mmol) of bromoacetone as a reaction reagent (XII) and 0.30 g (2.20 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate1:2) to give 0.29 g (yield 63%) of 4-methoxy-5-methyl-6-(5-acetylmethyloxy-1-ethylpyrazol-4-yl) carbonylthiochroman-1,1-dioxide (Compound No. 59) as an end compound which comes under the general formula (XI). Table 20 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: [Na].[O:2]=[C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]2[C:5](=[O:19])[CH2:4]1.Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][C:4]1([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3](=[O:2])[N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[N:6]2[C:5]1=[O:19])=[O:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CC(=O)N12
Reactant: CCOC(=O)CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)OCC)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Yield: 18.2 %

Procedure:
(b) 0.43 g of sodium was dissolved in 20 ml of ethanol. A solution of 2.27 g of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in 20 ml of ethanol was added and the mixture was heated under reflux for 2 hours. 5 g of ethyl 3-bromopropionate were added and the mixture was heated under reflux for an additional 2 hours. The solvent was removed and the residue was partitioned between dichloromethane and 2N hydrochloric acid. The organic layer was separated and evaporated. The residue was chromatographed on silica gel to give 0.37 g (9%) of tert.butyl 2,2-bis(2-ethoxycarbonylethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O.[CH3:21][S:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])=[O:23].[Na]>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:26]([CH3:27])[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Yield: 29.1 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-trifluoromethyl-phenyl)-methanone (compound of example A.3) (4 g, 11.6 mmol), methanesulfonylacetone (2.37 g, 17.4 mmol) and sodium tetrachloroaureate(III) dihydrate (0.23 g, 0.58 mmol) were heated at reflux in ethanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), NaOH (2×) and NaCl (1×). The crude product was purified by chromatography on silica gel in heptane/ethyl acetate 70:30. One obtained a light yellow solid (1.5 g, 29%). MS: m/z=444 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[C:27]([O:32][CH3:33])=[CH:28][C:29]=1[O:30][CH3:31]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:36])[C:27]([O:32][CH3:33])=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc(OC)c(N=C=O)cc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1Cl
Yield: 100.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-4,6-dimethoxyphenyl isocyanate (76 mg) was added, and the admixture was refluxed with heat for 18 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 93 mg of the title compound (yield: 100%)
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CCN(CCc1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: CCN(CCc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 95.8 %

Procedure:
Synthesized from 4-{2-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol (302 mg) and 1-(2-chloroethyl)piperidine hydrochloride (168 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (364 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](I)[CH2:13][CH3:14]>[Na].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: CCCI
Reactant: Cc1ccc(O)c(C(N)=O)c1
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(C)cc1C(N)=O

Procedure:
5-Methylsalicylamide (30.2 g; prepared as described in French Pat. No. M21) was dissolved in a solution of sodium (4.6 g.) in ethanol (200 ml.). Propyl iodide (37.4 g.) was added with stirring, and the mixture was stirred for 1 hour at room temperature and then under reflux for a further 19 hours. The mixture was concentrated to about 75 ml. and poured into water (300 ml.). The precipitated solid was filtered off and stirred with 2N sodium hydroxide solution (100 ml.). The insoluble solid was filtered off and washed with water to give crude 5-methyl-2-propoxybenzamide (37.5 g.), m.p. 112°-115° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5]OC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12). Title compound: ES-MS: 360.0 [M+H]+; single peak at tR=6.16 min (System 1); Rf=0.12 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=2)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[C:7]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:3])=[O:21])=[CH:16][CH:15]=2)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Temperature: 63 °C
Reaction time: 21 h

Procedure:
Thionyl chloride (18.8 mL, 257.1 mmol) is added dropwise to a mixture of 2-{p-[(3,5-dichloro-2-pyridyl)oxy]phenoxy}propionic acid (21.1 g, 64.3 mmol) in chloroform (220 mL). When the addition is complete, dimethylformamide (1.5 mL) is added and the reaction mixture is stirred for 21 hours at 63° C., concentrated in vacuo and chased with chloroform to obtain the title product as a yellow syrup which is identified by 1H NMR spectral analysis.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1.O>CN(C=O)C>[N:1]([C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(N=[N+]=[N-])ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium azide (0.25 g) was added to a solution of (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g) in DMF (30 ml). The reaction mixture was stirred for 2 hours at room temperature, then for 6 hours at 50° C. After cooling, the reaction mixture was poured into water and extracted with ether (3×100 ml). The combined extracts were washed with brine, dried and concentrated to give (E)-methyl 2-[2-(6-azidopyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.02 g, 99%) as an oil; 1H NHR: δ 3.51 (3H, s), 3.65 (3H, s), 6.12 (1H, s), 7.0-7.35 (4H, m), 7.37 (1H, s), mass 8.47 (1H, s) ppm; IR maxima (film): 2135, 1711, 1635 cm−1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[O:25])[N:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:21]1[C:20](=[O:22])[N:19]([CH2:23][C:24](=[O:25])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[N:18]=[C:17]1[C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O

Procedure:
92.6 mg (0.475 mmol) of tert.-butyl bromoacetate are added to 150.0 mg of (0.365 mmol) 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenylmethyl]-acetamide from Example 242A and 178.5 mg (0.548 mmol) of caesium carbonate in 5.0 ml of acetone and heated for 5 hrs under reflux. For the workup, the reaction mixture is concentrated after cooling, the residue is partitioned between water and ethyl acetate, the organic phase separated and the aqueous phase extracted several times more with ethyl acetate. The combined organic phases are concentrated and the residue purified by preparative HPLC [Method 12]. 139 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>C(Cl)Cl>[CH2:33]([O:40][NH:41][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)=[CH:19][CH:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NOCc1ccccc1)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (1.58 g, 6 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and O-benzylhydroxyamine hydrochloride (1.05 g, 6.6 mmol) was stirred in methylene chloride (150 mL). N-methylmorpholine (1.82 g, 18 mol) was added dropwise and the mixture was stirred overnight. The mixture was then washed with 0.05 N hydrochloric acid and water. The resulting solution was dried with magnesium sulfate and concentrated. The residue was crystallized from methylene chloride/hexanes to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.67 (t, J=5.6 Hz, 4H), 3.42 (t, J=5.6 Hz, 4H), 3.91 (s, 4H), 4.89 (s, 2H), 6.97 (d, J=9.0 Hz, 2H), 7.30-7.50 (m, 5H), 7.62 (d, J=9.0 Hz, 2H); MS (ES) m/z: 369.3 (MH+); HRMS Calcd. for C21H24N2O4 (M+): 368.1736. Found: 368.1744.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of Boc-Phe-OH (2.65 g), N-methylaniline (1.09 g) and HOBT (1.35 g) in DMF (25 ml) was added WSC.HCl (1.92 g) under ice-cooling. The mixture was stirred for 5 hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride solution, and dried over magnesium sulfate. The evaporated residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of chloroform and methanol (100:1). The fractions containing the object compound were combined and evaporated to give Boc-Phe-NMePh (2.17 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH:34]1(C=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH:34]1([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=CC1CCCCC1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (0.138 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 17 mg; HRMS (FAB+, NBA) (M+H)+ 449.3163, C29H41N2O2 requires 449.3168; LC-MS: (M+H)+ 449.2, tr 7.92 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH2:17]Cl.[CH3:19][C:20]1([CH3:28])[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([NH2:27])[CH2:21]1>C(Cl)Cl>[CH3:15][N:14]([CH:13]=[N:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:17][NH:27][CH:22]2[CH2:23][CH:24]([CH3:26])[CH2:25][C:20]([CH3:28])([CH3:19])[CH2:21]2)[CH:5]=1)(=[O:11])=[O:10])[CH3:16]
Reactant: CC1CC(N)CC(C)(C)C1
Reactant: COc1ccc(S(=O)(=O)N=CN(C)C)cc1CCl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N=CN(C)C)cc1CNC1CC(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.2 g of 4-methoxy-3-chloromethyl-N-dimethylaminomethylenephenylsulfon-amide, 0.37 ml of 3,3,5-trimethylcyclohexylamine and 5 ml of methylene chloride is stirred at RT for 24 hours and then concentrated in vacuo.
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].[N:32]1([C:38]2[N:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]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:44]([C:41]6[CH:42]=[N:43][C:38]([N:32]7[CH2:33][CH2:34][O:35][CH2:36][CH2:37]7)=[CH:39][CH:40]=6)(=[O:46])=[O:45])[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(N2CCOCC2)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(N5CCOCC5)nc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

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 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (21 mg, 80 μmol) and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added and the resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 18.7 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[C:27]([CH:28]=O)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[S:23]1[C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:25]2[S:30][CH:31]=[CH:32][C:24]1=2
Reactant: O=Cc1cc2sccc2s1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5sccc5s4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 6 mL of a chloroform solution containing 270 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 135 mg of thieno[3,2-b]thiophene-2-carbaldehyde, 54 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 284 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.31 g of 1-(2-(4-((thieno[3,2-b]thiophen-2-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.