Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][C:8]([CH:10]=O)=[CH:7][CH2:6][CH2:5]1)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1>[N+:1]([CH:4]1[CH2:9][C:8]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=CC1=CCCC([N+](=O)[O-])C1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C=CC1=CCCC([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
To a solution of 5-nitro-cyclohex-1-enecarbaldehyde (18 g, 0.116 mol) in pyridine (36 ml) was added malonic acid (41 g, 0.394 mol). The resulting suspension was heated to 60° C. for about 7 hours. After cooling to a temperature between 15° C. and 20° C., 6N HCl (72 ml) was slowly added into the reaction mixture to adjust the pH to between 1.5 and 2 while maintaining the temperature between 20° C. and 25° C. The mixture was then extracted with methylene chloride three times (1×180 ml, 2×90 ml). The combined extracts were washed with 1N HCl (48 ml), water (48 MI) and concentrated to a volume of 36 ml. The concentrate suspension was cooled to 0° C. and 5° C. for 1 hour. Light yellow solid was obtained after filtration and drying under vacuum. Yield: 10 g, 60%. Mp 158-160° C. 1HNMR (400 MHz, DMSO-d6): δ 2.10-2.33 (m, 4H), 2.73 (m, 2H), 4.96 (m, 1H), 5.83 (d, J=20 Hz, 1H), 6.28 (s, 1H), 7.27 (d, J=20 Hz, 1H), 12.3 (s, 1H).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:11][C:8]1[CH:7]=[N:6][C:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCC2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC2)nc1

Procedure:
A suspension of 11.5 g (64.18 mmol) of 2-(azetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 1 g of Pd/C at 10% in 400 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad and then concentrated at reduced pressure. We thus obtain 9.3 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [C:1]([N:8]([CH2:21][CH2:22][C:23]#[CH:24])[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:25]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1I)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[C:4]([O:3][C:1]([N:8]([CH2:21][CH2:22][C:23]#[C:24][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[NH:38][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reactant: C#CCCN(C(=O)OC(C)(C)C)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 93.8 %

Procedure:
A warm (45° C.) solution of N-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide (347 g, 0.885 mol), dichlorobis(triphenylphosphine)palladium (II) (3.50 g, 4.99 mmol), and DMF (700 mL) was added slowly over 8 h to a warm (55° C.), stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (350 g, 0.833 mol), dichlorobis(triphenylphosphine)palladium (II) (3.5 g, 4.99 mmol), copper (I) iodide (20.0 g, 0.105 mol), triethylamine, (259 g, 2.56 mol), and DMF (250 mL). The reaction mixture was stirred and maintained at 55° C. for 30 m after complete addition. The reaction mixture was distilled at reduced pressure using a heating bath temperature of 40-45° C. to remove triethylamine. The reaction mixture was filtered through a celite pad. The pad was washed with DMF (40 mL). 2-Propanol (280 mL) was added to the filtrate. The mixture was warmed to 55° C. Water (280 mL) was added slowly over 1 h to the stirred mixture. The stirred mixture was maintained at 55° C. for 30 m after complete water addition. The mixture was cooled to 10° C. The solid product was collected by filtration and washed with cold 1/1 (v/v) IPA/water (2×300 mL). The solid was vacuum dried at <50° C. to give N-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide (534.5 g, 94%) with 98% purity (as determined by HPLC).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=[N:31][O:32][CH3:33])[C:26]([N:28]([OH:30])[CH3:29])=[O:27])[C:13]=1[F:34].[C:39](Cl)(=[O:41])[CH3:40].O>O1CCCC1>[C:39]([O:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:14]1[C:13]([F:34])=[C:12]([O:11][C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]=2[Cl:8])[N:17]=[CH:16][N:15]=1)=[N:31][O:32][CH3:33])(=[O:41])[CH3:40]
Reactant: CON=C(C(=O)N(C)O)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(C(=O)N(C)OC(C)=O)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g (0.0012 mol) of triethylamine is initially added to a mixture of 0.4 g (0.0009 mol) of 2-(2-{[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy}phenyl)-N-hydroxy-2-(methoxyimino)-N-methylacetamide in 20 ml of tetrahydrofuran, and 0.08 g (0.00099 mol) of acetyl chloride is then added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into 100 ml of water and extracted 3 times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (4:1). This gives 0.18 g (41.1% of theory) of N-(acetyloxy)-2-(2-{[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy} phenyl)-2-(methoxyimino)-N-methylacetamide.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:21]=2)[CH2:6][CH2:5]1
Reactant: CC(C)N(c1nnc2ccc(F)cn12)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 136 mg, 3.39 mmol) in DMF (5 mL) was added Intermediate A (138 mg, 0.85 mmol) and the reaction mixture was stirred for 15 min at RT. A solution of Intermediate 103b (200 mg, 0.85 mmol) in DMF (3 mL) was added and the reaction mixture was heated at 60° C. for 1 h. The reaction mixture was quenched by careful addition of MeOH and then loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (220 mg, 68%). LCMS (Method 4): Rt 2.07 min, m/z 380 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=O)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Cl>[Pd].O=[Pt]=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[C@@H:13]([C:14]=2[CH:15]=1)[CH2:12][CH2:11][CH2:10][NH:9]3
Reactant: COc1ccc2c(c1)-c1cccnc1C2=O
Agent: O=[Pt]=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-methoxy-indeno[2,1-b]pyridin-9-one (2.00 g), 10% palladium on carbon (0.30 g), 4 M aqueous hydrochloric acid (6 mL), and methanol (100 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 4 h. PtO2 (0.20 g) is then added and shaking is continued under hydrogen atmosphere (1 bar) at room temperature for another 36 h. The catalysts are separated by filtration and the filtrate is concentrated. The residue is basified by the addition of 2 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 90:10→75:25) to give the title compound as a colorless oil. Yield: 1.00 g (52% of theory); LC (method 1): tR=1.50 min; Mass spectrum (ESI+): m/z=204 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[CH:9]=[C:8]([C:11]([CH3:24])=[CH:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)[S:7][C:6]=2[C:5]([CH3:26])([CH3:25])[CH2:4][CH2:3]1.[OH-].[K+].S(=O)(=O)(O)O>C(O)C.O>[CH3:1][C:2]1([CH3:27])[C:10]2[CH:9]=[C:8](/[C:11](/[CH3:24])=[CH:12]/[C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=3)[S:7][C:6]=2[C:5]([CH3:26])([CH3:25])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2cc3c(s2)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(s1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
3.0 g of ethyl p-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]benzoate are dissolved in 100 ml of ethanol and the solution is treated with a solution of 3.9 g of potassium hydroxide in 20 ml of water. After stirring at 50° C. for 3 hours, the mixture is cooled, poured into ice-water and acidified with 2N sulphuric acid. The mixture is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there are obtained 2.4 g of p-[(E)-2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]benzoic acid in the form of pale yellowish crystals, m.p. 236°-238° C.
Reaction SMILES: [CH3:1][C:2]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:3]=1[O:4][CH2:5][C@H:6]([OH:37])[CH2:7][NH:8][C:9]1[N:10]=[CH:11][NH:12][C:13](=[O:36])[C:14]=1[C:15]1[NH:16][C:17]2[C:25]([N:26]=1)=[CH:24][C:23]1[C:22](=[O:27])[N:21]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:20](=O)[C:19]=1[CH:18]=2>CC(O)=O.[Zn]>[CH3:1][C:2]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:3]=1[O:4][CH2:5][C@H:6]([OH:37])[CH2:7][NH:8][C:9]1[NH:10][CH2:11][NH:12][C:13](=[O:36])[C:14]=1[C:15]1[NH:26][C:25]2[C:17](=[CH:18][C:19]3[CH2:20][N:21]([CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)[C:22](=[O:27])[C:23]=3[CH:24]=2)[N:16]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2nc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(OC[C@H](O)CNC2=C(c3nc4cc5c(cc4[nH]3)C(=O)N(C3CCN(C)CC3)C5)C(=O)NCN2)c(C)c1
Temperature: 90 °C

Procedure:
2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (60.1 mg, 0.105 mmol) was mixed with zinc dust (300 mg) in AcOH (12 mL) resulting a mixture which was heated at 90° C. for 1 h, then cooled to the room temperature and filtered. The filtrate was evaporated, the residue was basified with NH3 in EtOH (2 M) and purified by chromatography with CH2Cl2/MeOH/28% aqueous NH4OH (60:10:1) to furnish a fluorescent product which was subjected to HPLC purification to afford the title compound in TFA salt form (42 mg, 60%). 1H NMR (DMSO-d6) δ 1.90-2.15 (4H), 2.13 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.81 (s, 3H, CH3), 3.20 (m, 2H), 3.40-3.60 (4H), 3.97 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 4.40 (s, 2H), 4.46 (s, 2H), 6.83 (d, J=6 Hz, 1H), 6.93 (d, J=6 Hz, 1H), 6.96 (s, 1H), 7.53 (br s, 1H), 7.75 (s, 1H), 9.75 (br s, 1H); ESI-MS m/z 560.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Oc1cc(Cl)c(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1Cl
Temperature: 25 °C
Yield: 85137 %

Procedure:
A stirred solution of 5.8 grams (0.029 mmole) of 3,4,5-trichlorophenol (commercially available), 3.8 mL (0.032 mole) of benzyl bromide and 4.45 grams (0.032 mole) of potassium carbonate in 75 mL of DMF was warmed to 80° C. where it was maintained during a two-hour period. After this time the reaction mixture was allowed to cool to ambient temperature and then 150 mL of water was added. The mixture was extracted with three 50 mL portions of diethyl ether and the combined extracts were washed with one 50 mL portion of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 7.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:23]([NH2:25])=[O:24].C(O)=O>O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([NH:25][CH:23]=[O:24])[CH3:2])=[CH:5][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: NC=O
Reactant: CC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Solvent: O=CO
Solvent: O
Product: CC(NC=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 7.25 g of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml, of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth (final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:34]([C@H:31]3[CH2:32][CH2:33][C@@H:28]([O:27][CH3:26])[CH2:29][CH2:30]3)=[O:35])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CO[C@H]1CC[C@@H](C(=O)O)CC1
Product: CO[C@H]1CC[C@@H](C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(cis-4-methoxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cis-4-methoxycyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light yellow oil. MS m/e: 523.4 [M]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC2CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NCC2CC2)cc1
Yield: 7.7 %

Procedure:
4-[N-(Cyclopropylmethyl)sulphamoyl]nitrobenzene (Method 53; 12.58 g) was reduced by hydrogenation in ethanol (300 ml) over 10% palladium on carbon (1 g) at 3 bar pressure. The catalyst was removed by filtration and the volatiles evaporated. 2 g of this crude product was purified by chromatography eluting with DCM increasing in polarity to 10% MeOH/DCM to give the title compound (850 mg). NMR: 0.08 (m, 2H), 0.25 (m, 2H), 0.83 (m, 1H, 2.80 (t, 2H), 4.15 (br s, 2H), 4.50 (br t, 1H), 6.65 (d, 2H), 7.62 (d, 2H); m/z: 226.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][C:23]([O:25]CC)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-].O.Cl>[Cl-].[Na+].O.C(O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][C:23]([OH:25])=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CC(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of ethyl 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoate (130 mg, 0.30 mmol), LiOH (63 mg, 1.5 mmol), water (1 mL) and ethanol (2 mL) was stirred at room temperature overnight. The aqueous layer was acidified with 2 N HCl to PH<1. Brine (30 mL) was added to the solution. The aqueous layer was extracted with a mixture of DCM:IPA (4:1) twice. The organic layer was dried over sodium sulfate, filtered and then concentrated under vacuum to give 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (88 mg, 75%). LC-MS m/z 390 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:32]=[O:33]>>[CH2:7]([CH:8]1[O:29][C:32](=[O:33])[N:10]([CH:11]([CH3:28])[CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:15]=2)[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)Cc1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(Cc2ccccc2)OC1=O

Procedure:
Following a procedure similar to that described in Example 4, 300 mg of 5-{4-[2-(3-phenyl-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 7), 120 mg of N,N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide were used. The resulting crude product was applied to a silica gel chromatography column, which was then eluted with a 3:2 by volume mixture of ethyl acetate and hexane, to give 200 mg of the title compound, melting at 60° C. to 70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])=[O:18])[CH:14]=[CH2:15]>O1CCCC1.CCCCCC>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:26])[CH3:27])[CH2:21][C@H:20]1[CH:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:33])=[O:18])[CH:14]=[CH2:15]
Reactant: Brc1ccccn1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccccn1
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of 2-bromopyridine (21.9 g) in tetrahydrofuran (310 ml) was added dropwise n-butyl lithium (1.65N) in hexane (78 ml) under -60° C. After stirring for 15 minutes, (2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (31 g) was added dropwise under -60° C. After stirring for 30 minutes, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(pyridin-2-yl)methanol (13.3 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:20](CC2C=CC(OC)=CC=2)[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>C(Cl)Cl>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)nc1
Temperature: 160 °C

Procedure:
To a 2 dram vial was added 6-chloro-8-((4-methoxybenzyl)(5-methylpyridin-2-yl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (32 mg, 0.064 mmol) and (trans)-cyclohexane-1,4-diamine (146 mg, 1.280 mmol). The reaction mixture was heated neat at 160° C. for 1 hour. The solution was diluted with DCM and washed with water. The organic layer was concentrated to dryness and then dissolved in neat TFA and heated to 80° C. for 2 hours. The solution was concentrated in vacuo and the residue was purified via preparative HPLC to give 6-((trans-4-aminocyclohexyl)amino)-8-((5-methyl-2-pyridinyl)amino)-N-4-pyridinylimidazo[1,2-b]pyridazine-3-carboxamide (14.2 mg, 0.031 mmol, 48.5% yield). HPLC Rt=2.19 minutes (Waters Sunfire C18 column 4.6×50 mm):0%-100% B. Solvent B: 90% MeOH, 10% H2O, 0.1% TFA). Solvent A: 10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min) [M+H]=458.