Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:37])([F:38])[F:36])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.4 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.17 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.1 g, 55%). MS (ISP) 505.1, 507.1 [(M+H)+]; mp 234° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[Cl:16].[OH-].[Li+]>CO>[NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:16]
Reactant: CCOC(=O)c1cc(Cl)c(N)n2ccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(C(=O)O)c2nccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a stirred solution of ethyl 5-amino-6-chloroimidazo[1,2-a]pyridine-8-carboxylate (Example 1, METHOD A, Step 3, 217 mg, 0.91 mmol) in methanol (5 mL) was added 1N aqueous lithium hydroxide (500 μL) and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and acidified with 1N hydrochloric acid. The resultant precipitate was collected by filtration to give 165 mg (86%) of the title compound as a white solid.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37]C)=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.O.C1COCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([OH:37])=[O:36])[C:23]([C:39]([F:41])([F:42])[F:40])=[CH:22][N:21]=2)=[CH:17][CH:18]=1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiOH.H2O (94 mg, 2.2 mmol) was added to a solution of methyl 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A14) (306 mg, 0.562 mmol) in MeOH (1 mL), water (1 mL) and THF (10 mL) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant oil partitioned between EtOAc (150 mL) and 2 M aqueous NaOH (100 mL). The organic layer was separated, washed with water (2×100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to yield the title compound A15 as a yellow oil (0.25 g, 83%); LCMS-A: rt 6.267 min; m/z 531 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([NH:22][CH3:23])[CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=O)=[N:29][CH:30]=1>>[C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH2:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)[CH:19]=[N:18][CH:17]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(Cl)cn1
Reactant: CNc1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Product: CN(C(=O)Cc1ccc(Cl)cn1)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 1 using (7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Preparation 187) and (5-chloro-pyridin-2-yl)-acetic acid (see Preparation 90) to afford the title compound as off white solid in 21% yield, 25 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.78 (s, 9H), 3.32 (s, 3H), 3.77 (brs, 2H), 7.26 (br, 1H), 7.83 (br, 1H), 8.21 (s, 1H), 8.32 (s, 1H), 8.48 (s, 1H), 8.85 (s, 1H), 8.97 (s, 1H), 9.02 (s, 1H), 9.51 (s, 1H); LCMS (system 10): Rt=3.29 min; m/z 463.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][OH:6])=[O:4].[CH3:9][N:10]=[C:11]=[O:12].CCCCCC>C(N(CC)CC)C.C(Cl)Cl>[CH3:9][NH:10][C:11]([N:5]([O:6][C:11]([NH:10][CH3:9])=[O:12])[C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])=[O:12]
Reactant: CN=C=O
Reactant: CC(C)(C)C(=O)NO
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON(C(=O)NC)C(=O)C(C)(C)C

Procedure:
(2,2-dimethyl)propiohydroxamic acid (5.9 grams), methyl isocyanate (6.5 grams), and a few drops of triethylamine were stirred in about 50 ml of methylene chloride over a period of about 48 hours. This mixture was then concentrated under vacuum leaving a colorless, oily residue. Trituration of this oil with hexane left a sticky solid which was recrystallized from a solution of methylene chloride and hexane. Subsequent recrystallization from a minimal amount of methylene chloride and toluene left the desired, N-((methylamino)carbonyl)-N-((methylamino)carbonyl)oxy)(2,2-dimethyl)propionamide as white crystals, m.p. 117°-119° C. (with slight sintering from about 116° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[CH3:23][N:24](C=O)C>[Zn].[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:23]#[N:24])=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(C#N)cc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of [1-(4-Bromo-phenyl)-3-hydroxy-3-methyl-cyclobutyl]-carbamic acid tert-butyl ester 2-1 (prepared according to WO2008/070041; 3.56 g, 10 mmol), Zn (1 g, 15 mmol), Zn(CN)2 (1.76 g, 15 mmol), Pd2(dba)3 (0.5 g, 0.5 mmol) and DPPF (300 mg, 0.5 mmol) in 30 mL of DMF was stirred at 100° C. for 2 hrs under N2. After the mixture was cooled to rt, 100 mL of water was added and product was extracted with ethyl acetate 100 mL×3. The organic layer was combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using EA/PE (1:2) as eluant to give compound 2-2.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)=[O:25])[CH:15]=[C:16]([Sn](C)(C)C)[CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[N:38]([S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=12>CN(C=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)=[O:25])[CH:15]=[C:16]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]5[N:38]([S:41]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)(=[O:42])=[O:43])[CH:39]=[CH:40][C:33]=45)[CH:17]=3)[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)c1cc(NC(=O)c2ccco2)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1ccco1

Procedure:
A stirred solution of N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-2-furancarboxamide (216 mg) and 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (182 mg) with Solvias catalyst (11 mg) in DMF (3 ml) was heated at 120° C. for 20 min in the microwave. The solvent was evaporated and the residue was purified on 20 g silica cartridge using ether and then 10% ethyl acetate:ether. The appropriate fractions were evaporated to dryness and triturated with ether to give the title compound, 90 mg as an off-white solid.
Reaction SMILES: NC[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N+]([O-])(O)=O.[C:18]([N:21]1C(C)=CC(C)=N1)(=[NH:20])[NH2:19].C(N(CC)C(C)C)(C)C.Cl>O1CCCC1>[NH:20]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)[C:18]([NH2:21])=[NH:19]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NCc1ccc(CCC(=O)O)cc1
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)Nc1ccc(CCC(=O)O)cc1
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
3.70 g (19.14 mmol) of the oily methyl ester of 3-(4-aminomethylphenyl)propionic acid was dissolved in 150 ml of tetrahydrofuran. To the solution were added 5.80 g (28.71 mmol) of 1-amidino-3,5-dimethylpyrazole nitrate and 4.70 g (36.37 mmol) of N,N-diisopropylethylamine, and the mixture was heated overnight under reflux. The reaction mixture was concentrated under vacuum to give an oil. This oil was reacted with 70 ml of 5% HCl for 3 hours under reflux. The reaction mixture was passed through a filter and the filtrate was ice-cooled. The pH of the filtrate was adjusted to 6.4 by addition of 10% aqueous NaOH. The so adjusted filtrate was stirred for 30 minutes under ice-cooling. The precipitating crystal was recovered by filtration and washed successively with distilled water and tetrahydrofuran. Upon drying, 2.85 g of a pale yellow crystal was obtained (yield: 67.4%). m.p.≥300° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: OCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of (3,5-difluorophenyl)methanol (1.98 g, 13.7 mmol) in THF (20 mL) at 0° C. was added sodium hydride (1.0 g, 25 mmol) in portions. The mixture was stirred at 0-5° C. for 1 h, and then methyl iodide (4.3 mL, 69 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were concentrated and the resulting residue was columned on 40 g silica gel, eluting with 0-40% EtOAc in hexanes, to give a colorless oil (2.1 g, 97%). 1H NMR (300 MHz, CDCl3) δ 6.86 (m, 2H), 6.71 (m, 1H), 4.43 (s, 2H), 3.38 (s, 3H) ppm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (4.09 g, 10.0 m mole) was added to methylene dichloride (40 ml) and triethyl amine (2.02 g, 20.0 m mole), was added thereto while stirring and cooling with ice. After that, ethanesulfonyl chloride (1.29 g, 10.0 m mole)-methylene dichloride (10 ml) solution was added dropwise over 1 hour thereto. The reaction solution was allowed to stand overnight at room temperature and then washed with two 20 ml portions of hydrochloric acid, 10% aqueous sodium chloride (20 ml), two 20 ml portions of 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride (20 ml) in order. A methylene dichloride layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a syrupy N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline benzylester (3.85 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:28]([CH:30]2[CH2:33][C:32](=[CH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)=[O:29])=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:28]([CH:30]2[CH2:31][CH:32]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33]2)=[O:29])=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: COc1ccc2c(c1)CCN(C(=O)C1CC(=CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C(=O)C1CC(CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of tert-butyl 2-(3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutylidene)acetate (138 mg, 0.24 mmol) and 10% palladium-carbon (25.1 mg, 0.24 mmol, 50%, wet) in MeOH (20 mL) was stirred overnight at room temperature under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give tert-butyl (R)-2-(3-(1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (118 mg, 0.201 mmol, 85%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([N:6]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]=[CH:7]1)(=[O:5])=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[OH:12][CH2:11][C:9]1[N:8]=[CH:7][N:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[CH3:16])[CH:10]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)N(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CN(C)S(=O)(=O)n1cnc(CO)c1

Procedure:
Crude ethyl 1-(dimethylsulphamoyl)imidazole-4-carboxylate, from method 1, was reduced with diisobutylaluminium hydride to give 4-hydroxymethyl-1-(dimethylsulphamoyl)-imidazole. A mixture of this product (1.09 g) in methylene chloride (10 ml), dihydropyran (1.0 ml), pyridinium tosylate (1.26 g) and a few crystals of tosic acid was stirred at room temperature for 60 hours. Solvent was removed and the residue worked up to give 1-(dimethylsulphamoyl)-4-(tetrahydropyran-2-yloxy)imidazole, as an oil. This was cyanated with tosyl cyanide and butyllithium as described above to give 2-cyano-1-(dimethylsulphamoyl)-4-(tetrahydropyran-2-yloxy)imidazole, as an oil. A solution of this (150 mg) in ethanol (3 ml) was heated under reflux for 5 minutes after addition of a few milligrams of pyridinium tosylate. Solvent was removed and the residue purified by silica gel chromatography to give the starting material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.6 %

Procedure:
3-Hydroxybenzaldehyde (1.0 g, 8.2 mmol) was dissolved in dichloromethane (50 mL). (4-Methylphenyl)boronic acid (2.2 g, 16.4 mmol), triethylamine (5.7 mL, 41.0 mmol) and copper acetate(II) (1.5 g, 8.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (324 mg, yield 19%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]=[C:31]=S)=[O:29])=[CH:26][CH:25]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C1COCC1>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28](/[N:30]=[C:31]2/[N:10]([C@H:11]3[CH2:12][CH2:13][C@@H:14]([C:17](=[O:18])[NH:19][CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16]3)[C:3]3[CH:4]=[C:5]([O:8][CH3:9])[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:29])=[CH:33][CH:34]=1
Reactant: COc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. cooled solution of cis-4-(5-amino-2-methoxypyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (211 mg, 0.689 mmol) in 1 mL THF, was added a suspension of 4-fluorobenzoyl isothiocyanate (250 mg, 1.377 mmol) in THF (3.4 mL). The resulting reaction mixture was stirred at 0° C. for 15 minutes. The ice bath was removed, and the mixture was stirred for 15 minutes at RT. To the mixture were added EDC (396 mg, 2.066 mmol) and DIPEA (0.433 mL, 2.479 mmol), and the flask was heated at 60° C. for 1 hour. The resulting mixture was allowed to cool to RT, and the solvents were removed. The residue was dissolved in 10% IPA in DCM and was washed with water and brine. The organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 5% of 1% NH4OH in MeOH in DCM. The title compound was collected as an off-white solid. The solid was partitioned with 10% IPA/EtOAc and was washed with 1 mL:2 mL saturated aqueous NH4Cl/water, and brine. The organic layer was dried over Na2SO4, filtered and the solvents were removed to afford the title compound as an off-white solid (212 mg, 68%). M/Z calc'd for C24H28FN5O3: 453.51. found 454 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([CH2:32]O)=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:36])=O>O1CCOCC1>[Cl:36][CH2:32][C:29]1[S:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:13]([CH2:12][C:8]3([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10][CH2:9]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:25]=2)=[N:31][CH:30]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CO)s2)nn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CCl)s2)nn1
Yield: 72 %

Procedure:
To a solution of t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate (44.1 g, 93.8 mmol) in dioxane (235 mL) was added thionyl chloride (27.3 mL, 375.3 mmol). The reaction was stirred until it was homogeneous. The reaction was then slowly quenched by pouring into a mixture of saturated potassium carbonate solution and ethyl acetate. The organic layer was then separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 33.1 g of t-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:44]=[CH:43][C:10]2[NH:11][C:12]([CH2:14][CH2:15][CH:16]3[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[CH:41]=[N:40][C:39]6[C:34]5=[N:35][CH:36]=[N:37][C:38]=6[NH2:42])[O:24]4)[CH3:21])[CH2:17]3)=[N:13][C:9]=2[CH:8]=1)([CH3:6])[CH3:5].Cl.[CH3:46]O>>[NH2:42][C:38]1[N:37]=[CH:36][N:35]=[C:34]2[C:39]=1[N:40]=[CH:41][N:33]2[C@H:25]1[C@H:26]([OH:30])[C@H:27]([OH:28])[C@@H:23]([CH2:22][N:20]([CH:18]2[CH2:19][CH:16]([CH2:15][CH2:14][C:12]3[NH:11][C:10]4[CH:43]=[CH:44][C:7]([C:4]([CH2:5][CH3:46])([CH3:6])[CH2:3][O:2][CH3:1])=[CH:8][C:9]=4[N:13]=3)[CH2:17]2)[CH3:21])[O:24]1
Reactant: COCC(C)(C)c1ccc2[nH]c(CCC3CC(N(C)C[C@H]4O[C@@H](n5cnc6c(N)ncnc65)[C@@H]5OC(C)(C)O[C@@H]54)C3)nc2c1
Reactant: CO
Agent: Cl
Product: CCC(C)(COC)c1ccc2[nH]c(CCC3CC(N(C)C[C@H]4O[C@@H](n5cnc6c(N)ncnc65)[C@H](O)[C@@H]4O)C3)nc2c1
Reaction time: 2.5 h
Yield: 53 %

Procedure:
9-[(3aR,4R,6R,6aR)-6-{[(3-{2-[5-(1-Methoxy-2-methylpropan-2-yl)-1H-1,3-benzodiazol-2-yl]ethyl}cyclobutyl)(methyl)amino]methyl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (0.485 g, 0.706 mmol, 88% pure) was dissolved in MeOH (20 ml) and conc. HCl (4.9 ml, 10 vol) was added at r.t. and the reaction left for 2.5 h. The reaction was concentrated in vacuo and the residue dissolved in the minimum amount of MeOH (˜2 ml). The reaction was quenched by addition of sat. NaHCO3 solution (10 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM and 20% 2M NH3 in MeOH:80% DCM as eluent to give the product as a white foam (0.213 g, 53%): MS (ESI+) for C29H40N8O4 m/z 565.4 [M+H]+; LC purity 100% (ret. time, 2.11 min) (7 min); 1H NMR (500 MHz, d4-MeOD) δH 8.28 (d, J=4.1 Hz, 1H), 8.22 (d, J=3.2 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J=8.5, 2.1 Hz, 1H), 7.29 (dd, J=8.5, 1.5 Hz, 1H), 6.01 (t, J=3.9 Hz, 1H), 4.84-4.74 (m, 1H), 4.41-4.29 (m, 1H), 4.29-4.19 (m, 1H), 3.48 (s, 2H), 3.30 (s, 3H), 3.14-2.98 (m, 1H), 2.99-2.89 (m, 1H), 2.90-2.73 (m, 2H), 2.39 (s, 3H), 2.37-2.30 (m, 1H), 2.28-2.10 (m, 2H), 2.08-1.86 (m, 4H), 1.70-1.51 (m, 1H), 1.38 (s, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[O:15]C)=[CH:6][C:5]=1[F:31])#[N:2].[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[OH:15])=[CH:6][C:5]=1[F:31])#[N:2]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2OC)nc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2O)nc1
Yield: 57.2 %

Procedure:
Combined 6-(4-(4-(cyanomethyl)-3-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (27 mg, 0.064 mmol) and lithium chloride (27.0 mg, 0.638 mmol) in DMA (1.0 mL) and heated at 60° C. for 24 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (formic acid conditions) to give the title compound (15 mg, 57.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.7 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.3 Hz, 2H) 4.03 (s, 2H) 7.42 (br. s., 1H) 7.52-8.06 (m, 2H) 8.41 (br. s., 1H) 8.50-8.82 (m, 3H) 8.91 (d, J=1.5 Hz, 1H) 13.28 (br. s., 1H). MS m/z 410 [M+H]+.