Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCCC1=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 105 °C
Yield: 90.1 %

Procedure:
Sulfone 9.1 (2.24 g, 5.4 mmol) was combined with N-tert-butoxycarbonyl-4-aminomethylpiperidine (5.6 g, 16.2 mmol) and 1-methyl-2-pyrrolidinone (9 mL). The mixture was heated to 100-110° C. for 2 hours at which time it was cooled to room temperature and ethyl acetate was added. The resultant white solid was filtered and washed with ethyl acetate to give 2.3 g of 3-(2-chlorophenyl)-7-[(1-tert-butoxycarbony-piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (MH+=473). Hydrogen chloride gas was bubbled into 2.1 g of the protected amine which was suspended in 1,4-dioxane (22 mL), and the suspension stirred for 1 hour, concentrated in vacuo and dried to give the intermediate 3-(2-chlorophenyl)-7-[(piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21](O)[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19]2
Reactant: OC1CCc2cc(F)ccc21
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OC2CCc3cc(F)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 5-fluoro-2,3-dihydro-1H-inden-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.39-2.46 (1H, m), 2.59-2.64 (1H, m), 2.90-2.98 (1H, m), 3.13-3.20 (1H, m), 5.72-5.75 (1H, m), 5.84 (1H, d, J=1.6 Hz), 6.89-6.94 (1H, m), 6.98 (1H, d, J=8.8 Hz), 7.34-7.37 (2H, m), 7.62 (1H, d, J=1.6 Hz), 7.86 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H13FN4O, 321. Found, 321.
Reaction SMILES: [CH:1]1([CH:7]([C:9](C(Br)C2CCCCC2)=O)Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[NH2:22][C:20]1[S:21][CH:9]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]=1
Reactant: O=C(C(Br)C1CCCCC1)C(Br)C1CCCCC1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(C2CCCCC2)cs1
Temperature: 25 °C

Procedure:
Cyclohexylbromomethylketone (49 g., 0.24 mole) was added to a slurry of thiourea (20.1 g., 0.26 mole) in 250 ml. of ethanol and the mixture heated to reflux. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated in vacuo to an oil. The oil was taken up in 100 ml. of water, the solution made basic with concentrated ammonium hydroxide and crude product recovered in two crops by filtration. Crude product was recrystallized from cyclohexane to yield purified 2-amino-4-cyclohexylthiazole (20.4 g.; m.p. 141°-143° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([N:17]=CC3C=CC=CC=3)[C:9]2=[O:25])=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[C:9]1=[O:25]
Reactant: O=C1N(N=Cc2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NN1C(=O)C(Cc2ccncc2)(Cc2ccncc2)c2ccccc21
Temperature: 0 °C
Yield: 40.4 %

Procedure:
To a solution consisting of 3,3-bis-(4-pyridinylmethyl)-1,3-dihydro-1-[(phenylmethylene)amino]-2H-indol-2-one (7.84 g) and absolute ethanol (68 ml) was added hydrazine hydrate (6.4 ml). The resulting mixture was heated at reflux for 5.75 hours, followed by cooling to 0° C. The product crystallized upon cooling. Filtration and washing with ether-pentane afforded 2.50 g of 1-amino-3,3-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][OH:14])[CH:6]=[C:5]2[CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:12]([OH:15])[CH2:13][O:14][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[CH3:22]
Reactant: Cc1cn([C@@H](c2ccccc2)[C@H](O)CO)c2ccc(F)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine(11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Reaction time: 0.25 h
Yield: 108.7 %

Procedure:
To a solution of the nitro compound 53 (256 mg, 0.57 mmol) in a mixture of MeOH (12 mL) and THF (4 mL) at 0° C. was added NiCl2.6H2O (279 mg, 1.14 mmol), followed by portion wise addition of NaBH4 (87 mg, 2.27 mmol). The reaction mixture turned black after 15 min, and was filtered through a celite pad; the filtrate concentrated under reduced pressure. The residue was suspended in 2N HCl and the solids were removed by filteration. The filtrate was basified with NH4OH to pH˜10 then extracted with EtOAc. The organic phase was concentrated to afford the title compound 54 (260 mg, crude, >100% yield, HPLC pure) as yellowish foam. MS (m/z): 420.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[CH3:20]O.S(=O)(=O)(O)O>O>[CH3:20][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[S:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Sc2ccc(C)cc2CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc(C)ccc1Sc1ccc(C)cc1

Procedure:
47 g. of crude 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid are dissolved in 170 ml. of methanol. 19 Ml. of concentrated sulfuric acid are added dropwise with stirring and the mixture is subsequently heated at reflux for 3.5 hours. After cooling, the mixture is diluted with water and extracted several times with benzene. The benzene extracts are washed with water, sodium bicarbonate solution and again with water. After evaporation of the solvent, there remains a residue which is chromatographed on 400 g. of silica gel. By elution with benzene, there is obtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid methyl ester, which ester is dissolved in 73 ml. of methanol, treated with 18.8 g. of potassium hydroxide and 73 ml. of water and subsequently heated at reflux for 1 hour. Thereafter, the methanol is removed in vacuo and the residue acidified with hydrochloric acid. The mixture is extracted with benzene, the benzene extract washed with water and concentrated in vacuo. The residue is crystallized from cyclohexane, and there is obtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid having a melting point of 81°-83° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([OH:18])=[O:17])[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([OH:18])=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC2CC(C(=O)O)C1C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC2CC(C(=O)O)C1C2
Reaction time: 0.5 h

Procedure:
A solution of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid, 72g, in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the resulting product was dissolved in 2 mL TFA and added to a stirring 1N HCl in Et2O solution. After stirring the mixture for 0.5 hour, the resulting precipitate was filtered and washed with dry Et2O to give 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1.N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccco1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccco1
Temperature: 65 °C

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-2-yl)pyrazole (0.081 g) in tetrahydrofuran (2 ml) was added t-butyl nitrite (74 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with hexane containing increasing amounts of ether (up to 10%). Combination and evaporation of appropriate fraction gave the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:11])[N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[N:4]1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:9][C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH:2]([F:1])[F:11])[N:4]=1)=[O:10]
Reactant: O=C(O)c1ccn(C(F)F)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccn(C(F)F)n1

Procedure:
A solution of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid (CAS 925179-02-8) (500 mg, 3.1 mmol) in methanol (18 ml) was cooled to 0° C. and treated with sulphuric acid (98%, 0.2 ml, 3.1 mmol). The mixture was heated to reflux for 2 hours. For the workup, the solution was cooled and concentrated at reduced pressure. The residue was partitioned between ethyl acetate (25 ml) and water (30 ml). The organic layer was separated, washed with water until the water phase showed a neutral pH. After drying over sodium sulphate, the organic layer was evaporated at reduced pressure. The 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester was obtained as a colorless liquid (535 mg, 99% of theory) pure enough to be engaged in the next step without further purification. MS (ISP): m/z=177.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:13])=[N:7][NH:8]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH3:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:8][N:7]=1
Reactant: Cc1n[nH]c2cccc(O)c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (0.452 g of a 60% dispersion in mineral oil, 11.3 mmol) in DMF (30 mL) was added 4-hydroxy-3-methylindazole (1.52 g, 10.3 mmol) (prepared in a similar manner to that described in J. Med Chem., 2000, 2672) in DMF (20 mL) via a cannula. The mixture was stirred at room temperature for 10 minutes and then benzyl bromide (1.223 mL, 10.3 mmol) was added and stirring was continued at room temperature for 2 hrs. The mixture was quenched with ammonium chloride solution and the DMF was evaporated. Ethyl acetate and water were added and the product was extracted into ethyl acetate and the extracts were dried (Na2SO4) and evaporated. Chromatography (0-100% ethyl acetate in hexane) gave the title compound (D30) as an orange solid (1.774 g, containing ˜10% dibenzylated material).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:10][CH2:11][CH2:12][CH:13]([OH:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:5][CH:4]=1.[C:46]1(=[O:52])[O:51][C:49](=[O:50])[CH2:48][CH2:47]1.[CH2:53]([N:55]([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:54].CN1C=CN=C1>C(Cl)Cl>[CH2:53]([N:55]([CH2:58][CH3:59])[CH2:56][CH3:57])[CH3:54].[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:10][CH2:11][CH2:12][CH:13]([O:31][C:46](=[O:52])[CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:43][CH:42]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCC(O)CCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(CCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1-(bis(4-methoxyphenyl)(phenyl)methoxy)icosan-3-ol (6.8 g, 11.0 mmoles), succinic anhydride (1.1 g, 11.0 mmoles), triethylamine (4.6 mL, 33.0 mmoles) and 1-methylimidazole (0.44 mL, 5.5 mmoles) are dissolved in methylene chloride (68 mL). The reaction is stirred at ambient temperature for five days, during which time the solution darkened. The solution is then diluted with methylene chloride (100 mL) and washed twice with ice-cold aqueous citric acid (10% [w/v], 50 mL) and once with saturated aqueous sodium chloride (50 mL). The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and evaporated to a dark resin. The crude product is purified on silica gel (200 mL bed volume) eluting with methylene chloride:triethylamine (95:5 [v/v/v], 500 mL), then methylene chloride:methanol:triethylamine (93:2:5 [v/v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a resin. The resin is dried well in vacuo. The yield is 2.4 g (30%).
Reaction SMILES: ClC1C=CC2SC=C([CH2:9][N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)[C:11]3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.Cl.CNC>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([N:10]([CH3:11])[CH3:9])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CNC
Agent: Cl
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)N(C)C
Yield: 34 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with dimethylamine hydrochloride, the title compound was obtained as a colorless solid in 34% yield: mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.06-7.01 (m, 2H), 4.45 (s, 2H), 4.06 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 3.07 (s, 6H), 2.34 (s, 3H); MS (ES+) m/z 363.3 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:28][O:27][C:24]1[N:23]=[C:22]([O:29][CH3:30])[C:21]([C:20]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:6][CH:7]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:31])=[CH:17][CH:16]=[C:15]([OH:32])[CH:14]=3)=[CH:26][N:25]=1
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Reactant: C1CCNCC1
Product: COc1ncc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCCC3)cc2)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and piperidine as the starting material.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (430 mg, 0.95 mmol) in ethanol (10 mL) and water (2 mL) was treated with lithium hydroxide (46 mg, 1.9 mmol). The reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was diluted with water (20 mL) and then washed ethyl acetate (1×20 mL). The aqueous layer was then acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×40 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid (386 mg, 96%) as a white solid which was used without further purification: mp 172-176° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
3-Indolebutyric acid (1.7 g, 8.2 mmole), 1-hydroxybenzotriazole hydrate (1.3 g, 9.8 mmole) and 1,3-diisopropylcarbodiimide (1.5 ml, 9.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (2.0 g, 8.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Product fractions were concentrated and washed with a minimum amount of THF to remove a by-product and give 3.0 g (82%) of the desired product, (7-methylsulfonylamino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oily white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13](Cl)[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:34]=[CH:35][C:36]([C:13]3[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]4[N:7]=[C:8]5[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=[CH:9]5)=[C:5]4[N:14]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 21 %

Procedure:
1 g (2.9 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-2), 1.09 g (2.9 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 322 mg (0.28 mmol) tetrakis(triphenylphosphine)palladium and 886 mg (8.4 mmol) sodium carbonate in 30 mL dioxane and 4.2 mL water were heated over night at 105° C. The reaction mixture was poured on water/dichloromethane and vigorously stirred for 30′. The organic phase was separated, washed with brine, dried, filtered, and the solvent was evaporated. The residue was purified by HPLC yielding 346.4 mg (20.6%) of the title compound.