Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:35]([O:37][CH:38]1[CH2:41][NH:40][CH2:39]1)[CH3:36]>CN1C(=O)CCC1>[CH2:35]([O:37][CH:38]1[CH2:41][N:40]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:39]1)[CH3:36]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCOC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC1CN(c2cc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)ccn2)C1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-ethoxy-azetidine hydrochloride in NMP. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].O>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
64.8 μL (0.50 mmol) of 4-ethynyl-1-methoxybenzene (12), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 12 hours at 800 rpm (reversed every 30 minutes). After the lapse of 12 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 47.0 mg (0.35 mmol) of 4-ethyl-1-methoxybenzene (13). The yield was 69%. The reaction is expressed by the following scheme.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]([F:46])([O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:46][C:2]([F:1])([O:37][C:38]1[CH:39]=[CH:40][C:41]([S:44][CH3:45])=[CH:42][CH:43]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:16][SH:17])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c2ccc(F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CS)C(=O)O)c2ccc(F)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)-ethylamino]-3-tritylsulfanylpropionic acid (0.69 g, 1.04 mmol) in DCM (0.8 ml), TFA (0.322 ml, 4.18 mmol) and triethylsilane (0.332 ml) were added. After stirring 3 h, solvent and excess of TFA were evaporated under vacuum. The residue was dissolved in benzene and evaporated again on rotary evaporator to give 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanyl-phenoxy)ethylamino]-3-mercaptopropionic acid. The residue was dissolved in 1N NaOH (4 ml) and the solution was used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:4]1[CH:5]=[N:6][N:7]([CH3:8])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccnn1C
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: COc1c(Br)cnn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of 5-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in 647 mg, 76% yield of the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=3.33 min (polar—5 min, ZQ3).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31].[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:44])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
A solution of triphenylphosphine (99 mg, 0.37 mmol) and N-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26 mL) cooled to 0° C. was treated with 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (85 mg, 0.25 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03 mL, 0.37 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. At this time, the reaction was diluted with water (50 mL) and extracted with chloroform (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (69.3 mg, 65.6%) as an off-white solid: mp 163-165° C.; EI-HRMS m/e calcd for C21H28N2O3S2 (M+) 420.1541 found 420.1535.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[F:39][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH2:13][C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:38])[CH2:11]1
Reactant: [F-]
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CC(=O)c2ccc3c(c2)C(F)CC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: C(OC(=O)[NH:5][CH:6]([CH3:31])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17](=[O:19])[NH2:18])[CH:16]=1)[N:13]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:12][CH2:11]2)C.[OH-].[K+]>C1(C)C=CC=CC=1>[NH2:5][CH:6]([CH3:31])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17]([NH2:18])=[O:19])[CH:16]=1)[N:13]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:12][CH2:11]2
Reactant: CCOC(=O)NC(C)Cc1cc2c(c(C(N)=O)c1)N(CCCO[Si](C)(C)C(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(N)Cc1cc2c(c(C(N)=O)c1)N(CCCO[Si](C)(C)C(C)(C)C)CC2
Yield: 78.3 %

Procedure:
(2-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-7-carbamoyl-2,3-dihydro-1H-indol-5-yl}-1-methyl-ethyl)-carbamic acid ethyl ester (VI), (3 g, 0.006 mole) was heated to reflux in toluene (25 ml) with KOH (2 g:0.03 mole) for 3 h. Reaction mixture was quenched with water and toluene layer was separated and washed with water. The organic layer was dried over sodium sulphate. The solvent was evaporated under reduced to give 1.84 g of (VII) as brown oily mass.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: Nc1cccc(Cl)c1C(=O)NCCC12CC3CC(CC(C3)C1)C2

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (CN 26482-53-1) (0.105 g) and 2-amino-6-chlorobenzoic acid (0.132 g) and purified by supercritical fluid chromatography eluting with CO2 in ethanol to give the title compound, contaminated with 0.35 mol equivalents of imidazole, as a white solid (0.046 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([CH3:10])[CH:4]=1.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:12].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH2:16][CH:15]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([CH3:10])[CH:4]=1)[C:14]([O:13][CH2:11][CH3:12])=[O:30]
Reactant: Cc1ccc(CBr)cc1C
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCOC(=O)C(N)Cc1ccc(C)c(C)c1

Procedure:
A mixture of 18.6 g (93.5 mmol) 4-bromomethyl-1,2-dimethyl-benzene, 25.0 g (93.5 mmol) ethyl(diphenylmethylidene-amino)-acetate, 3.29 g (10.0 mmol) tetrabutylammonium bromide, 41.3 g (250 mmol) K2CO3×1.5H2O and 600 mL acetonitrile was refluxed overnight. The reaction mixture was filtered, the filtrate was evaporated down under reduced pressure, the residue was taken up in 500 mL diethyl ether and combined with 250 mL semiconc. HCl with vigorous stirring. Then the organic phase was separated off, the aqueous phase was extracted twice with diethyl ether and neutralised by the addition of solid NaHCO3. The aqueous phase was extracted by shaking three times with 200 mL EtOAc, the combined organic phases were washed once with water, dried over Na2SO4, filtered and evaporated down under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccccc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (100 mg, 0.17 mmol) in EtOH (4 mL)/H2O (1 mL) were added phenylboronic acid (50 mg, 0.35 mmol), potassium carbonate (100 mg, 0.7 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>ClC1C=CC=CC=1>[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[C:5]([NH:18][C:7](=[O:17])[C:6]3[CH:15]=[CH:2][C:3]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:5]=3)=[CH:4][C:3]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1cc(N)c2c(c1N)C(=O)c1ccccc1C2=O
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: Clc1ccccc1
Product: CCCCc1ccc(C(=O)Nc2cc(CCCC)c(NC(=O)c3ccc(CCCC)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 20 °C

Procedure:
1,4-Diamino-2-butylanthraquinone (0.30 g, 0.001 mole) and p-butylbenzoic acid chloride (0.48 g, 0.0024 mole) are refluxed in 20 ml chlorobenzene for 0.5 hrs. The reaction mass is cooled to 20° C. and chromatographed with chloroform on Silica gel. 1,4-Bis(4-butylbenzamido)-2-butylanthraquinone is obtained in amount 0.36 g (60%). Found, %: C 76.74, H 8.31, N 4.53; C40H52N2O4. Calculated, %: C 76.89, H 8.39, N 4.48; λmax =475 nm, S=-0.22. M.p.=180°-181.3° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[CH3:16]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-ethylaniline (60 μl, 0.243 mmol) similar to Example 13 and isolated as an tan oil (69 mg, 98%). 1H NMR (CDCl3): 8.81-8.79 (m, 1H), 8.48-8.45 (m, 1H), 7.84-7.78 (m, 1H), 7.42 (s, 1H), 7.37-7.29 (m, 2H), 7.18 (s, 1H), 7.16 (d, J=1.5 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 2.66 (q, J=7.5 Hz, 2H), 2.47 (s, 3H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[N:11]=1.[CH3:23][NH2:24]>CCO>[CH3:23][NH:24][C:16](=[O:18])[CH2:15][CH2:14][S:13][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:22])[F:21])[S:8][CH:9]=1
Reactant: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (0.5 g.) in EtOH (20 ml.) was treated with 33% w/v ethanolic methylamine (7 ml.) and stirred for 18 hours at room temperature. The solution was evaporated and the residue crystallised from aqueous EtOH to give N-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionamide (0.35 g.), m.p. 152°-154° (73%).
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CS(C)=O>[CH2:20]([N:12]1[C:13]2[C:14](=[O:15])[NH:16][CH:17]=[N:18][C:19]=2[N:10]=[CH:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnc2ncn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.23 g of inosine was dissolved in 90 ml of dimethyl sulfoxide, and 16 ml of benzyl bromide was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was poured into 3 L of ethyl acetate. The resulting supernatant was removed and the precipitated oil was dissolved in 10% hydrochloric acid (135 ml). The solution was heated at 70° C. with stirring for 4 hours. The solution was cooled to room temperature, and then neutralized to pH 7 using a 5N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, and dried to give 12.748 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C1CCCCO1)[N:15]=[CH:14]2.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CCO.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:37][CH3:38])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:36])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: CC/C(=C(/c1ccc(/C=C/C(=O)NS(C)(=O)=O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (0.26 g, 0.5 mmol; Compound 407), DMAP (92 mg, 0.75 mmol), methane sulfonamide (0.19 g, 2 mmol) and EDC (0.14 g, 0.75 mmol) in THF (2.5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl, diluted with water, and extracted with ethyl acetate (2×50 mL). The combined organic layers were concentrated to give the crude product that was purified on a silica gel column using 5% methanol in DCM to afford a pale yellow solid. This solid was redissolved in EtOH (5 mL), and then HCl (1 mL, 1.25 N HCl in ethanol) was added. The reaction was heated at 70° C. for 3 h, cooled to room temperature, diluted with water, and then extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a RP-C18 column using 40-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 11.80 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.63-7.53 (m, 2H), 7.39-7.30 (m, 4H), 7.21-7.12 (m, 2H), 7.00 (d, 2H), 6.49 (d, 1H), 3.28 (s, 3H), 2.36 (q, 2H), 0.89 (t, 3H). LCMS: 524 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:18]([NH:17][CH2:13][CH2:14][CH2:15][CH3:16])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CCCCN=C=S
Solvent: CCOC(C)=O
Product: CCCCNC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and butyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 267-269° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (t, 3H, CH3), 1.24-1.60 (m, 4H, CH2CH2), 3.21 (q, 2H, NHCH2), 7.2-7.4 (m, 3H, ArH+NH), 7.68 (d, 1H, ArH), 10.55 (br.s, 1H, NH); MS: m/e 287-289 (M+); (C11H14N3Cl1O2S1) calc. C, 45.91; H, 4.91; N, 14.60; found C, 45.92; H, 5.12; N, 14.46.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)=[O:7].Br[CH2:45][CH2:46][OH:47].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:37]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[N:18][N:17]([CH2:45][CH2:46][OH:47])[CH:16]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)=[O:7]
Reactant: OCCBr
Reactant: COCCOCOc1cc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3cnn(CCO)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 100 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[(1H-pyrazol-4-yl)methyl]piperazine (254 mg), 2-bromoethanol (259 mg), potassium carbonate (228 mg) and tetrabutyl ammonium bromide (13 mg) in N,N-dimethylformamide (2.5 ml) was stirred at 100° C. for 2 days. After cooling, the mixture was evaporated in vacuo and water and ethyl acetate were added to the residue. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on alumina with a mixture of methylene chloride and methanol (100:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine (185 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH3:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH:35][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 88.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.24 g, 0.54 mmol) obtained in Example 128, step 2 and 2,5-dimethylaniline (0.098 g, 0.81 mmol), the title compound (0.25 g, 86%) was obtained.