Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH:32]([CH3:34])[CH3:33])[CH:19]=3)[CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:35]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:30][C:27]([CH3:28])([CH3:29])[C:26](=[O:31])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:35][C:9]=3[CH:10]=2)[CH2:14][CH3:15])[CH3:17])=[CH:19][C:20]=1[CH:32]([CH3:33])[CH3:34]
Reactant: CCC(c1cc2cc(C(=O)OC)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1cc2cc(C(=O)O)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-isopropyl-phenyl]-ethylpropyl}-benzofuran-5-carboxylic acid methyl ester (1.55 g, 3.24 mmol) in methanol (5.0 mL) and THF (5.0 mL) is treated with NaOH (2.0 M, 10 mL). The resulting mixture is stirred at RT for 12 h. The mixture is concentrated and neutralized with HCl (5 N) till pH˜3, and extracted with EtOAc (3×30 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (1.49 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:7]=1C=O)#[N:2].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:11]([Cl:21])=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15]=2[Cl:16])[C:7]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25])#[N:2]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Yield: 56.7 %

Procedure:
By the method of Example 5, Step H, 1.5 g (0.0045 mole) of 4-cyano-5-formyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole and 1.0 g (0.0096 mole) of malonic acid were reacted in the presence of 5 mL of pyridine and 10 drops of piperidine, yielding 0.96 g of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum of this solid was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:11][CH:10]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1O[Si](C)(C)C(C)(C)C
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (>99%). LCMS (m/z): 423.2 (MH+); LC Rt=3.78 min.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:16][C:17]1[N:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21](=[O:29])[C:20]([Cl:30])=[N:19][CH:18]=1>C(Cl)Cl>[Cl:30][C:20]1[C:21](=[O:29])[N:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:17]([CH2:16][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][N:19]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)Cn1c(CBr)cnc(Cl)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(CSc2ccccc2)cnc(Cl)c1=O

Procedure:
THIOPHENOL (1.28 ML, 12.5 MMOL) WAS ADDED DROPWISE TO A STIRRED SOLUTION OF TRIETHYLAMINE (3.0 ML, 21.5 MMOL) AND 6-BROMOMETHYL-3-CHLORO-1-ETHOXYCARBONYLMETHYLPYRAZINONE (3.86 G, 12.5 MMOL) IN METHYLENE CHLORIDE (20 ML). AFTER 15 MIN THE MIXTURE WAS PARTITIONED BETWEEN METHYLENE CHLORIDE AND WATER. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID WHICH WAS CARRIED FORWARD TO THE NEXT STEP:
Reaction SMILES: C[CH:2]1[CH2:8][CH2:7][N:6]2[C:9](=[O:21])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1.[CH3:22]C1CCC2C3C(=O)N4CCCCCC4=NC=3SC=2C1>>[CH3:22][CH:18]1[CH2:17][CH2:16][C:15]2[C:10]3[C:9](=[O:21])[N:6]4[CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][C:5]4=[N:12][C:11]=3[S:13][C:14]=2[C:19]1=[O:20]
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Reactant: CC1CCc2c(sc3nc4n(c(=O)c23)CCCCC4)C1
Product: CC1CCc2c(sc3nc4n(c(=O)c23)CCCCC4)C1=O

Procedure:
Compound 28 was synthesized by the method described for compound 17 using compound 27 as a starting material.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]I>CN(C)C=O.O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH3:23])[C:12](=[O:16])[CH:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCCN(Cc2ccccc2)C1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(Cc2ccccc2)C(c2ccccc2)C1=O
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
15.3 g of sodium hydride (65% dispersion in mineral oil, 0.414 moles) was suspended in 250 ml of N,N-dimethylformamide at 10° C. To this suspension, 100 g of 4-benzyl-2-oxo-3-phenylpiperazine (0.376 moles) was added portionwise over a period of 30 min and stirred for 15 min. A solution of 64 g of methyl iodide (0.45 moles) in 50 ml of N,N-dimethylformamide was added slowly in 45 min maintaining the temperature below 25° C. and maintained for 1 hour. After completion of the reaction, mass was poured slowly in 1000 ml of cold water (15° C.). The product was extracted with toluene (1×500 ml, 1×300 ml) from aqueous phase. Toluene layer was washed with water (2×200 ml) and concentrated. To the residue, 250 ml of cyclohexane was added and cooled to 10° C. with stirring. Filtered the product and washed with precooled cyclohexane to obtain 98.5 g of 4-benzyl-1-methyl-2-oxo-3-phenylpiperazine product (yield: 93.8%, purity: 99.15 by HPLC)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].N1C=CC=CC=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12>ClCCl>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 2-fluoro-4-trifluoromethyl-1-benzenecarbonyl chloride (0.87 g, 3.83 mmol) in dichloromethane (5 mL) was added into a mixture of pyridine (15 mL) and 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (1.00 g, 2.56 mmol) in dichloromethane (5 mL) at 0° C. over 5 minutes. The mixture was stirred at 0° C. for 10 minutes and at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was washed with saturated aqueous ammonium chloride twice and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica using Isco system to provide N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo [3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.95 g, 1.76 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.90 (dd, 1H), 8.30(d, 1H), 8.28 (s, 1H), 7.99 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 6.90 (br, 2H), 5.27 (m, 1H), 3.94 (s, 3H), 2.70 (m, 2H), 2.47 (m, 4H), 2.17 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.23 min. MS: MH+ 543.
Reaction SMILES: [F:1][C:2]([C:18](OC)=[O:19])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([CH2:18][OH:19])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 79.1 %

Procedure:
The method of Example 9 was repeated using 1-(2-fluoro-2-(methoxycarbonyl)ethenyl)1-(4-trifluoromethoxyphenyl)cyclopropane (Example 3) (0.39 g), diethyl ether (10 ml) and lithium aluminium hydride (0.11 g) to yield the title compound (0.28 g, 80%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH:10]([OH:22])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]=O.C>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:19][CH:18]=1
Reactant: OCc1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Agent: O=[Pd]
Solvent: CCO
Product: OCc1ccc(C2CCNCC2O)cc1
Yield: 79 %

Procedure:
A solution of 2.0 g (6.72 mmol) of (3RS,4RS)-l-benzyl-4-(4-hydroxymethyl-phenyl)-piperidin-3-ol in 100 ml of ethanol was hydrogenated at room temperature and 3 bar for 4 hours in the presence of 1.0 g of palladium oxide/charcoal (20%). For the working-up, the catalyst was filtered off under suction over Dicalit and the residue was washed twice with 50 ml of ethanol each time. The ethanol solution was evaporated under reduced pressure and the residue was chromatographed on silica gel using a 65:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 1.1 g (79% of theory) of (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-piperidin-3-ol as a colourless solid; MS: 207 (M)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]2([N:29]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=1)[S:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]2([N:29]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[CH:20]=1)[S:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Sc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Sc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 110 °C
Yield: 50.5 %

Procedure:
To a solution of 2-amino-6′-bromo-1-methyl-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one TFA salt (70 mg, 0.14 mmol), 3-cyanophenylboronic acid (51 mg, 0.34 mmol), and Cs2CO3 (250 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). Then the system is degassed by sweeping with N2. The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro-[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (30 mg) as a TFA salt. MS ESI+ve m/z 425 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:26]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)c2ccc(Cl)cc2Cl)c1)OC(C)C

Procedure:
Ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2,4-dichlorobenzoic acid were treated in the same manner as in Example 19d), to give ethyl 3-(3-{[(2,4-dichlorobenzoyl)amino]methyl}-4-methoxyphenyl)-2-isopropoxypropanoate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([CH2:21]O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1([CH2:21][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC1CCCC1)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
Trifluoromethanesulfonic anhydride (6.72 mL, 39.94 mmol) is dissolved in DCM (40 mL) and cooled to −40° C. To this is added dropwise cyclopentanemethanol (4.00 g, 39.94 mmol) dissolved in DCM (10 mL) and anhydrous pyridine (3.23 mL, 39.94 mmol). The reaction is stirred at −40° C. for 45 min. The reaction is diluted with hexanes (30 mL) and run through a plug of silica using hexanes (300 mL) as the eluent. Concentration without heating gives trifluoromethanesulfonic acid cyclopentylmethyl ester as a clear, colorless oil that is used immediately.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([Cl:19])[CH:11]=2)=[N:6]1)[CH3:4].[CH3:20][C:21]1[NH:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:19][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@@H:3]([CH3:4])[CH2:2][NH:1][C:26]([C:24]3[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=3)=[O:27])[N:6]=2)[CH:17]=[C:16]([F:18])[C:13]=1[C:14]#[N:15]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Yield: 8.2 %

Procedure:
(S)—N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propyl)-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.498 g, 3.95 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 8.2%. 1H-NMR (400 MHz; DMSO): δ 1.45 (d, 3H), 2.27 (s, 3H), 3.50-3.74 (m, 2H), 4.62-4.77 (m, 1H), 7.02 (d, 1H), 7.45 (s, 1H), 7.88-8.04 (m, 4H), 12.11 (s, 1H).
Reaction SMILES: ClC1N=NC(NC)=C(C2C=CC=CC=2)C=1.[Cl:16][C:17]1[N:22]=[N:21][C:20]([N:23]([CH3:40])[C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:26]=2)=[C:19]([C:41]2[CH:46]=[CH:45][C:44](F)=[CH:43][C:42]=2OC)[CH:18]=1>CCCCCCC.C(OCC)(=O)C>[Cl:16][C:17]1[N:22]=[N:21][C:20]([N:23]([CH3:40])[C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([S:35]([CH3:38])(=[O:36])=[O:37])[CH:26]=2)=[C:19]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:18]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CNc1nnc(Cl)cc1-c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1nnc(Cl)cc1-c1ccccc1
Yield: 20 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-phenyl-pyridazin-3-yl)-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) gave the desired compound as a colorless solid (20%). MS (ESI+): m/z=470.054 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH:9]([CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(CC#N)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(C(C#N)Cc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
The solution of 2.3 g of diisopropylamine in 30 ml of dry tetrahydrofuran was cooled to -35 to -40° C., followed by addition of 1.5M n-butyl lithium in 15 ml hexane in solution, and stirred for 30 minutes, to produce lithium diisopropylamide. To the solution was added the solution of 2.0 g of 4-methoxymethyloxybenzyl cyanide in 15 ml of dry tetrahydrofuran at -78° C., and stirred at the same temperature for 30 minutes, followed by addition of 3-picolyl chloride hydrochloride (1.9 g) at -78° C., and stirred overnight to room temperature. The reaction solution was poured into saturated aqueous sodium chloride solution, which was then extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, followed by the distillation of the solvent to obtain residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform-methanol (50:1 v/v) to produce 0.67 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][S:56]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)(=[O:58])=[O:57])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:39][CH2:40]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NS(=O)(=O)c4ccccc4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.037 mmol) in CH2Cl2 (1 mL) was added DIEA (0.00617 mL, 0.035 mmol) and benzenesulfonyl chloride (1.5 mg, 8.49 μmol). The reaction solution was stirred at room temperature for 30 min, concentrated and then treated with TFA (1.132 mL, 14.69 mmol) at 70° C. for 1 hr. The reaction mixture was concentrated and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)-6-((trans)-4-(phenylsulfonamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.6 mg, 12.54% yield) as a white solid (13.0 mg, 44.4%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.910 minutes. [M+H]=565.25. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36-11.55 (1H, m), 8.13-8.33 (1H, m), 7.89-8.01 (1H, m), 7.76-7.91 (3H, m), 7.47-7.70 (5H, m), 7.20-7.38 (1H, m), 6.78-6.96 (1H, m), 5.83-6.02 (1H, m), 3.48-3.72 (1H, m), 2.92-3.13 (1H, m), 1.83-2.12 (2H, m), 1.53-1.80 (2H, m), 0.99-1.41 (5H, m), 0.66-0.85 (2 H, m), 0.41-0.67 (2H, m), 1.80-2.05 (2H, m), 1.39-1.70 (2H, m), 1.14-1.41 (2H, m), 0.77 (2H, d, J=4.77 Hz), 0.63 (2H, d, J=3.01 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(N2CCOCC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of ethyl 4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.06 g, 0.23 mmol) in THF/MeOH/water (3:1:1) (5 mL) was added sodium hydroxide (0.095 g, 2.3 mmol). The reaction mixture was allowed to stir at rt for 20 h and was concentrated. The residue was acidified to pH 1-2 with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (0.048 g, 88%). LCMS: (FA) ES+ 239.1. 1H NMR (400 MHz, d6-DMSO) δ:7.67 s, 1H), 3.72-3.75 (m, 4H) and 3.52-3.55 (m, 4H).