Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([CH2:5][N+]1C=CC=CC=1)(=[O:4])[NH2:3].[CH:12]([C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:15]#[N:16])=O.C(N(CC)CC)C.[Cl-].ClC=[N+](C)C>CO>[OH:4][C:2]1[CH:5]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:14]([C:15]#[N:16])=[CH:12][N:3]=1
Reactant: Cc1ccccc1C=C(C#N)C=O
Reactant: NC(=O)C[n+]1ccccc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1cc(O)ncc1C#N
Temperature: 45 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
1.726 g (10.0 mmol) 1-carbamoylmethyl-pyridinium chloride and 1.712 g (10.0 mmol) 2-formyl-3-o-tolyl-acrylonitrile in 24.8 ml methanol were treated with 1.05 g (10.4 mmol) triethylamine at 20-30° C. The reaction mixture was stirred for 2 hours and concentrated in vacuo (rotary evaporator at 40° C. and 20 mbar). The residue was taken up in 50 ml dichloromethane, treated with 2.56 g (20.0 mmol) (chloromethylene)dimethylammonium chloride (Vilsmeiers Reagent) and heated at 45° C. for 1 hour. In order to remove all volatile matter, the mixture was concentrated in vacuo (rotary evaporator at 45° C. and 20 mbar). The residue was heated to 180-190° C. for 15 minutes, cooled down to 20-25° C. and distributed in 80.0 ml dichloromethane and 80.0 ml water. The layers were separated. Evaporation of the organic phase in vacuo gave 1.37 g of amorphous product of 6-hydroxy-4-o-tolyl-nicotinonitrile.
Reaction SMILES: C1(S(C=C(SC)SC)(=O)=O)C=CC=CC=1.C[C:17]1[N:18]=CN[C:21]=1[CH2:22]SCCN.[C:27]1([S:33]([CH:36]=[C:37](SC)[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N)C#C>>[C:27]1([S:33]([CH:36]=[C:37]([NH:18][CH2:17][C:21]#[CH:22])[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C
Agent: C#CCN
Agent: CSC(=CS(=O)(=O)c1ccccc1)SC
Product: C#CCNC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C

Procedure:
Reaction of methylphenylsulfone with carbon disulphide under strongly basic conditions and treatment of the product with methyl iodide yields 1-benzenesulphonyl-2,2-bis(methylthio)ethylene. When 1-benzenesulfonyl-2,2-bis(methylthio)ethylene is reacted with 2-[(4-methyl-1H-imidazol-5-yl)-methylthio]ethylamine according to the procedure of Example 6, Step A, the product is 1-benzenesulfonyl-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene. Reaction of this methylthio compound with propargylamine by the procedure of Example 6, Step B, yields the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](B2OC(C)(C)C(C)(C)O2)=[N:25]1>>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(Cl)nc21
Product: Cn1ncc2c(NCc3cccc(S(C)(=O)=O)c3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methanesulfonyl-benzyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 128. NMR (CDCl3) 3.03 (s, 3H, CH3), 4.20 (s, 3H, CH3), 5.13 (d, H, ArH, J=5.95 Hz), 5.84 (sbr, H, NH), 7.51-7.65 (m, 3H, 3×ArH), 7.79 (d, H, ArH, J=7.72 Hz), 7.91 (d, H, ArH, J=7.77 Hz), 7.93 (s, H, ArH), 8.09 (s, H, ArH), 8.39 (d, H, ArH, J=7.28 Hz), 9.04 (s, H, ArH), 10.13 (sbr, H, NH). MS: (ESI+) MH+=434.10
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(/C=C/C1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 37.5 %

Procedure:
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid, and then 0.20 g of platinum oxide was added thereto. Thereafter, the mixture was stirred in a hydrogen stream at room temperature for 7.5 hours. After the reaction, the catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.69 g of the title compound as pale yellow crystal.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500+4×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2-bromoethoxy)-3-methoxybenzaldehyde. M.p. 61-64° C.
Reaction SMILES: [ClH:1].F[C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10](F)[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28]C(=O)C)([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.Cl>CO.O1CCOCC1>[ClH:1].[OH:34][C@@H:4]1[C@H:3]2[C@@H:8]([CH2:9][CH2:10][C:11]3[C@:16]2([CH3:17])[CH:15]=[CH:14][C:13](=[O:18])[CH:12]=3)[C@@H:7]2[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][OH:28])([C@@:6]2([CH3:33])[CH2:5]1)[CH2:24][NH:23][CH2:22]3
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@H]1CNC[C@]12C(=O)CO
Temperature: 25 °C
Reaction time: 240 h
Yield: 100 %

Procedure:
In a closed vessel compound 20 (300 mg, 0.600 mmol) is dissolved in MeOH, HCl (0.045 ml, 0.180 mmol) in dioxane is added and the mixture is stirred at room temperature for 10 days, then further HCl (0.045 ml, 0.180 mmol) is added and the reaction mixture is stirred for further 2 days. The reaction mixture is concentrated to dryness affording the title compound (253 mg, 0.600 mmol, 100% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].CO.[CH:21](=O)[CH2:22][CH3:23]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH:21][CH2:22][CH3:23])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CCC=O
Solvent: O
Solvent: CO
Product: CCC=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 58 μl of propanal were added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 127 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-propylidenehydrazine ((40-b)-(15)-3).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])(=O)=O)=CC=1>CN(C=O)C>[N:1]([CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:23][CH3:24])=[N+:2]=[N-:3]
Reactant: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](C#CCCN=[N+]=[N-])(CC)CC
Temperature: 60 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
Sodium azide (1.80 g; 27.65 mmol) was added to a solution of 4-(triethylsilyl)but-3-ynyl 4-methylbenzenesulfonate (3.12 g; 9.22 mmol) in DMF (15 mL) and stirred at 60° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure and the residue was partitioned between saturated ammonium chloride and ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford 2.0 g (quantitative yield) of (4-azidobut-1-ynyl)triethylsilane as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.23 g), 2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine (4.88 g) were suspended in monochlorobenzene (40 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[NH+:15]=3)Br)=[CH:10][C:5]=2[O:4][CH2:3]1.[NH2:22][C:23]([NH2:25])=[S:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:22]=[C:23]([NH2:25])[S:24][C:12]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)[nH+]1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(-c2sc(N)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-(2-benzo[1,3]dioxol-5-yl-1-bromo-2-oxo-ethyl)-6-methyl-pyridinium bromide (30 mg, 0.072 mmol), thiourea (7.5 mg, 0.094 mmol, 1.3 equiv), and potassium carbonate (0.11 mmol, 1.5 equiv) in ethanol (1 mL) was heated to 80° C. overnight. The resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo. Reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided 4-Benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-thiazol-2-ylamine (15.6 mg, 70%).[MS: M+H=312.0].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=1[S:15](=[O:24])(=[O:23])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([NH2:31])CCCCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[N:31]([CH3:25])[C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:15](=[O:24])(=[O:23])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCNS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Reactant: CCCCCCN
Product: CCCCCCNS(=O)(=O)c1cc(C2(O)CCC(=O)N2C)ccc1Cl

Procedure:
The 4-(4-chloro-3-n-hexylsulfamoylphenyl)-4-oxobutanoic acid required is obtained analogously to the instructions indicated in Example 15(a) using 7.5 g of n-hexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](I)[CH:3]=1.[NH2:11][NH2:12]>C(O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: N#Cc1ccc(Cl)cc1I
Solvent: CCO
Product: Nc1n[nH]c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
A mixture of 10.0 g. of 4-chloro-2-iodobenzonitrile, 5 ml. of 95% hydrazine and 50 ml. of ethanol is allowed to stand for 24 hours at 50° C. Working up as in Example 1 gives 3-amino-6-chloroindazole.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[O:22][C:23](=[O:73])[C@@H:24]([NH:40][C:41]([C@@H:43]1[CH2:52][C:51]2[CH:50]=[C:49]3[O:53][CH2:54][C@H:55]([C:57]4[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=5)=[CH:59][CH:58]=4)[O:56][C:48]3=[CH:47][C:46]=2[CH2:45][NH:44]1)=[O:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:28][CH:27]=1>C(Cl)Cl>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([N:44]2[C@H:43]([C:41]([NH:40][C@@H:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=4[CH3:39])=[CH:30][CH:31]=3)[C:23]([OH:73])=[O:22])=[O:42])[CH2:52][C:51]3[CH:50]=[C:49]4[O:53][CH2:54][C@H:55]([C:57]5[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]6[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=6)=[CH:59][CH:58]=5)[O:56][C:48]4=[CH:47][C:46]=3[CH2:45]2)=[O:20])[CH2:14]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)[C@@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Reaction time: 0.67 h

Procedure:
EDC (3 eq.) and (1R,3S)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (25 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 950.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]COC)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.Cl.[OH-].[Na+].O>O1CCCC1>[OH:29][C:28]1[CH:27]=[CH:26][C:5](/[CH:6]=[CH:7]/[C:8]2[N:16]([CH3:17])[C:15]3[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(OC)c3)n2C)n(CCC)c1=O
Yield: 71.4 %

Procedure:
Compound d (3.00 g, 6.78 mmol) obtained in Reference Example 4 was suspended in 60 ml of tetrahydrofuran, and 2N hydrochloric acid (17 ml) was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was neutralized by adding 2N sodium hydroxide under ice-cooling. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from hexane/ethyl acetate to give 1.93 g (72% yield) of Compound e as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>CC(N(C)C)=O.ClCCl>[CH:21]1([NH:24][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1Cl
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6-(4-methylpiperazinyl)-3-pyridine-carboxylate (Example D-2, 1.00 g, 3.314 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 60 hours. The reaction mixture was diluted with dichloromethane (30 mL), washed with water, and dried on sodium sulfate. Flash chromatography on silica gel column using dichloromethane as eluent provided compound 0.85 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][C:6]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])=[CH:5][N:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (28 mg, 0.072 mmol) in DMF (5 mL), ethyl bromoacetate (0.110 mL, 1 mmol) and potassium carbonate (138 mg, 1 mmol) were added. The mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (20 mL) and extracted (2×20 mL ethyl acetate). The combined extracts were washed with brine, dried on MgSO4, and filtered. The residue was further purified by silica gel chromatography, eluting with PE/EtOAc (2:3, v/v) to afford pure product as a white solid (24.2 mg, 70%). 1H-NMR (CDCl3): δ 3.85 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 3.90 (d, 2H, J=2.8 Hz, CH2), 4.00 (s, 3H, OCH3), 4.15 (s, 2H, CH2), 4.27 (q, 2H, CH2), 6.10 (s, 2H, Ph-H), 6.74 (d, 1H, J=2.0 Hz, Py-H), 7.04 (d, 1H, J=15.6 Hz, CH), 7.44 (d, 1H, J=2.0 Hz, Py-H), 7.811 (d, 1H, J=15.6 Hz, CH); HR-MS (ESI+) m/z: 481.1364 [M+H]+; C22H28N2O8S requires 480.1566,
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C([N:25]4[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])CC4)C=CN=3)=C(C3C=CC=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.N1CCC(O)C1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[N:51]=[C:52]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:32]3)[CH:53]=[N:54][CH:55]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Reactant: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Agent: OC1CCNC1
Product: OC1CCN(c2cncc(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)n2)C1

Procedure:
The title compound was prepared according to the experimental for compound 187 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and pyrrolidin-3-ol. M/e+ 406 for C22H21ClN5O (M+H)−; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.71 (d, J=10.6 Hz, 2H), 7.59 (dd, J=9.1, 0.7 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.16 (m, 1H), 6.77 (t, J=6.9 Hz, 1H), 4.56 (s, 1H), 4.32 (s, 2H), 4.06 (m, 1H), 3.53 (m, 3H), 3.00 (bs, 1H), 2.04 (m, 2H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([OH:30])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: O=C(O)c1ccccc1S
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)O)cc1
Yield: 95.5 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.23 g (1.5 mmol) of thiosalicylic acid. The product was washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 276°-278° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(=O)CC(C)=O)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=[O:27])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(=O)CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h
Yield: 65 %

Procedure:
0.48 g (1.2 mmol) of t-butyl 4-hydroxy-3-{[4-(trifluoromethyl)benzoyl]amino}piperidin-1-carboxylate (product of step 1) was dissolved in 10 mL of methylene chloride, and 5.24 g (1.9 mmol) of Dess-Martin periodinane was dropwise added thereto. After stirring for 5 hours, 50 mL of ethylacetoacetate was dropwise added thereto, and the resulting solution was washed with water. An organic layer dried over anhydrous magnesium sulfate. The reaction solution was filtered off and distilled off under reduced pressure, then the residue was purified by column chromatography to give 0.30 g (0.78 mmol) of the title compound in a total yield of 65%.