Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:6]=2[N:18]=1.C1CCC([N:28]=[C:29]=[N:30]C2CCCCC2)CC1.C(OC(NC(NC(OC(C)(C)C)=O)=S)=O)(C)(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:17][C:29]([NH2:30])=[NH:28])[CH3:16])[C:6]=2[N:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=N)N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30, 100 mg, 0.350 mmol) in methylene chloride (3 mL) was added PL-DCC resin (394 mg, 0.575 mmol) and the mixture was stirred at room temperature for 15 min. N,N′-bis-tert-butoxycarbonylthiourea (112 mg, 0.406 mmol) was added and the reaction mixture was stirred at room temperature overnight. PS-trisamine resin (4.12 g, 3.6 mmol/g, 14.8 mmol) was subsequently added and the resulting mixture was stirred at room temperature overnight. The resins were removed by suction filtration and the filtrate was concentrated under reduced pressure. Purification of the crude material by reverse phase C-18 silica gel chromatography [0-70% acetonitrile in water (containing 0.1% TFA)] afforded 2-amino-9-((2S)-2-{[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide (71, 48 mg 26%). NH4OAc standard conditions. DAD Retention time=4.98 min. M+H=326.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Si@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: CC(C)CCBr
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
2.5 g (20 mmol) of 3-methylbutyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (21 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,4-difluorobiphenyl to obtain 4'-(trans-4-(3-methylbutyl)-4-silacyclohexyl)-3,4-difluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.5 g of the trans isomer (yield 90%). The results of its analysis are shown below.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:19]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Reactant: CC1(C)OB(c2ccncc2-c2ccccc2)OC1(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3-c3ccccc3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate O instead of Intermediate B and with 3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Boronic Acid 2) instead of pyridin-4-ylboronic acid. LCMS: 386.2 m/z (M+H)+; ret. Time: 6.04 min (Analytical Method C).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])([CH2:13][OH:14])[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[OH:14][CH2:13][C:10]1([NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCCCc1nnc(C(=O)NC2(CO)CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(C(=O)NC2(CO)CCNC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL) at 0° C., and the reaction was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (3-hydroxymethyl-pyrrolidin-3-yl)-amide dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:22]1[CH:23]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:22]2[CH:23]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH:6]=1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Temperature: 21 °C

Procedure:
A solution of [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester from Step 2 (4 g, 14 mmol), 8-bromo-6-isopropylquinoline (3 g, 12 mmol), Na2CO3 (2M, 18 mL, 36 mmol) and Pd(PPh3)4 (692 mg, 0.6 mmol) in DMF (250 mL) was heated at 80° C. under N2 for 18 h. The resulting reaction mixture was cooled to 21° C. and diluted with water and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20) provided the [3-(6-Isopropyl-quinolin-8-yl)-phenyl]-acetic acid methyl ester compound.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:37])[N:11]([CH3:36])[C:12]([CH:27]([OH:35])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:37])[N:11]([CH3:36])[C:12]=2[CH:27]([OH:35])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:16]=1
Reactant: Cn1c(C(O)Cc2ccccc2)c(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(C(O)Cc2ccccc2)c(-c2cccc(-c3ccccc3)c2)cc(O)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31.2 %

Procedure:
To a solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (100 mg, 0.205 mmol) in 5 mL methanol, was added 10% palladium on charcoal (21.83 mg, 0.02 mmol). The resulting mixture was stirred at room temperature under hydrogen (1 atm) for 45 min. The mixture was filtered to remove charcoal, concentrated and purified by reversed-phase HPLC to afford 5-(biphenyl-3-yl)-3-hydroxy-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (25.4 mg, 0.064 mmol, 31.2% yield). ES-MS (M+H)+=398. High resolution mass spec (ESI) calc (M+H)+=398.1751 found 398.1754
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1>CO>[ClH:1].[ClH:1].[N:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccncc3)C2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(N2CCCC3(CCNCC3)C2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 15.9 ml) was added to tert-butyl 2-(pyridin-4-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (0.66 g, 1.991 mmol) and the mixture was refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in ethanol (5 ml) and the mixture was cooled. Acetone (20 ml) was added and the mixture was stirred at 0° C. for 30 min. Diethyl ether (50 ml) was added and the precipitate was filtered out with suction, washed with diethyl ether and dried in vacuo. Yield: 0.42 g (69%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].BrC1C=CC(N=[C:22]=[O:23])=CC=1N=C=O>>[CH3:22][O:23][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13]
Reactant: O=C=Nc1ccc(Cl)c(N=C=O)c1
Reactant: O=C=Nc1ccc(Br)c(N=C=O)c1
Product: COc1ccc(N=C=O)cc1N=C=O

Procedure:
4-chloro-1,3-phenylene diisocyanate; 4-bromo-1,3-phenylene diisocyanate;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.CN(C)C1C=CC=CC=1.[C:19]([Cl:22])(Cl)=[O:20].CN(C=[O:27])C>C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[Cl:22][C:19]([O:20][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:27]
Reactant: CN(C)C=O
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: COc1ccccc1OC(=O)Cl
Yield: 50 %

Procedure:
A solution of 2-methoxyphenol (2 g, 16.1 mmol), N,N-dimethylaniline (1.95 g, 16.1 mmol), phosgene (8.34 mL of a 1.93 M solution in toluene, 16.1 mmol) and a catalytic amount of DMF in chlorobenzene (5 mL) was stirred in a pressure tube for 2 h at 80° C. The organic layer was separated and concentrated in vacuo. The residue was distilled (Buchi Kugelrohr; bp=115° C. @ 10 mm Hg) to provide 2-methoxyphenyl chloroformate (1.5g; 50%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:24]([NH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:26])[CH3:25]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:31]2[CH2:32][CH2:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:29][CH2:30]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C2c3ccccc3C(=O)N2C)CC1
Product: Cl
Yield: 83.2 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.375 g) was coupled to 4-acetamido-4-phenylpiperidine (0.28 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (0.263 g); mp 185°-192° C.; MS: m/z=550(M+1); NMR(CD3SOCD3): 1.91 (s,3), 2.3 (m,2), 3.06 (s,3), 3.15 (m,2), 4.87 (d,1, J=3.5), 6.8 (d,1, J=8), 7.0 (d,1, J=1.8), 7.23 (m,1), 7.34 (m,5), 7.48 (m,2), 7.65 (m,1), 7.90 (d,1, J=7.6), 8.1 (s,1). Analysis for C31H33Cl2N3O2.1.5 HCl: Calculated: C, 60.64; H, 6.07; N, 6.84; Found: C, 60.98; H, 5.91; N, 6.75.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([CH2:21][CH3:22])[CH2:19][OH:20])=[C:15]([CH:25]=[CH2:26])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([CH2:21][CH3:22])[CH:19]=[O:20])=[C:15]([CH:25]=[CH2:26])[CH:14]=1
Reactant: C=Cc1cc(OC)ccc1C[C@@H](CC)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(OC)ccc1C[C@H](C=O)CC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
DMSO (4.9 mL, 68.8 mml) is added to a solution of oxalyl chloride (4.5 mL, 51.6 mmol) in dry DCM (100 mL) at −78° C. and the mixture is stirred at −78° C. for 10 min. A solution of (R)-2-(4-methoxy-2-vinylbenzyl)-butan-1-ol (5.70, 25.9 mmol) in DCM (30 mL) is added. The mixture is stirred at −78° C. for 15 min and then at −40˜−30° C. for 1 h. Triethylamine (18 mL, 129 mmol) is added slowly. The mixture is stirred at −10˜0° C. for 15 min. The mixture is partitioned between DCM and aq. NH4Cl. The organic extract is dried with MgSO4 and concentrated to give the title compound as an orange oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([OH:17])[CH2:15][CH2:14][CH:13]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCC3)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4c(c3)OCC4)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(2,3-dihydro-benzofuran-6-yl)-4-hydroxy-cyclohexanone (as prepared in Example 3, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH:16]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH:15]3[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].Cl>C(OCC)(=O)C>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH3:36])[O:28][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH:16]2[CH:15]([CH2:20][NH:19][CH2:18]2)[CH2:14]1
Reactant: COc1ccc(OC(CCCN2CC3CN(C(=O)OC(C)(C)C)CC3C2)c2ccc(C#N)cc2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(OC(CCCN2CC3CNCC3C2)c2ccc(C#N)cc2)cc1OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
tert-Butyl 5-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.9 g, 1.7 mmol; from step (d) above) was dissolved in ethyl acetate (25 mL). The solution was cooled to 0° C. Ethyl acetate (25 mL) saturated with gaseous HCl was added and the mixture was stirred at rt for 4 h. The mixture was evaporated and then dissolved in CH3CN. K2CO3 (1 g) and water (0.05 mL) were added and the mixture was stirred for 2 h. The salts were filtered of and the solvent was evaporated, giving 0.71 g (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:22][CH2:23][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccccn1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccn3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(pyridine-2-carbonyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[NH2:9][C:10]1[C:11]([C:25](O)=[O:26])=[N:12][C:13]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[C:14]([F:16])[CH:15]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN1C(=O)CCC1>[NH2:9][C:10]1[C:11]([C:25]([NH:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:26])=[N:12][C:13]([C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[C:14]([F:16])[CH:15]=1
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
To a solution of 4-chloropyridin-3-amine (1.0 equiv.) and 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.0 equiv.) in NMP (1 M) was added HOAt and EDCI sequentially. The reaction mixture was stirred at room temperature for 2 days. The crude reaction was purified by prep HPLC to give 3-amino-N-(4-chloropyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (14%). LCMS (m/z): 379.0 (MH+); LC Rt=3.49 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[CH:27]=[N:26][CH:25]=2)[C:5]([F:8])=[N:6][CH:7]=1.Cl.CC(O)C>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[CH:25]=[N:26][CH:27]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)[N:29]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cc(Cl)cnc5F)cc34)n2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ncc(Cl)cc1-c1ccc2[nH]nc(-c3cncc(O[C@@H]4CCCNC4)n3)c2c1
Temperature: 65 °C

Procedure:
(3R)-tert-butyl 3-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate 10a (270 mg, 0.48 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (97 mg, 0.56 mmol) (Combi-Blocks, Catalog# BB-3818), potassium phosphate tribasic (308 mg, 1.45 mmol) (Sigma-Aldrich, Catalog# P5629-25G, Lot#069K0110), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.8 mg, 0.03 mmol) (Strem, Catalog#15-1149, Batch# A0183078), and Pd2(dba)3 (13.3 mg, 0.02 mmol) (Strem, Catalog#46-3000, Lot# A8761089) were weighed into a 10 mL glass microwave vial. The vial was purged with argon, the solids were treated with dioxane (4 mL) and water (1 mL) and the vial was sealed. The contents were heated in Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 115° C. for 30 min. The reaction mixture was treated with 2 mL of water and extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated, affording (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate as a light yellow solid. MS (ESI, pos. ion) m/z: 609.2 (M+1). The material was used without purification. To a solution of (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (292 mg, 0.48 mmol) in THF (2.2 mL) and EtOH (2.2 mL) was added HCl, 5-6N in IPA (0.8 mL, 26.40 mmol). The solution was heated in an oil bath at 65° C. for 1 h. The crude reaction was concentrated to a yellow solid that was dissolved in 5 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in ACN] in [0.1% TFA in water]. The desired fractions were collected, concentrated, and basified with 1 N NaOH, extracted with EtOAc. The EtOAc solution was washed with brine, dried with Na2SO4 and concentrated to afford (R)-5-(5-chloro-2-fluoropyridin-3-yl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indazole as an off white crystalline solid. MS (ESI, pos. ion) m/z: 425.1 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][CH2:28][CH2:29][NH2:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][CH2:28][F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCCF
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCCF)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.54 g, 1.39 mmol) in CH3CN, was added neat 2-fluoroethanamine (0.28 g, 2.79 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2-fluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.358 g, 57% yield). 1H NMR (500 MHz, CDCl3) δ 1.23 (t, 2H, J=7.3 Hz), 2.02 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 3.85-3.88 (m, 2H), 4.07-4.12 (m, 1H), 4.25 (dd, 1H, J=4.6, 12.5 Hz), 4.47-4.53 (m, 1H), 4.54-4.63 (m, 1H), 5.14 (t, 1H, J=9.7 Hz), 5.25 (t, 1H, J=5.4 Hz), 5.73 (d, 1H, J=8.6 Hz), 6.50 (d, 1H, J=9.3 Hz), 6.68 (t, 1H, J=5.4 Hz).
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(O)(=O)C>C1C=CC=CC=1>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:2]([CH3:13])=[CH:3][C:4]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:5])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=CC(=O)OCC[Si](C)(C)C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 3.75 g (1.5 mmol) of the compound of Example 39A in 55 ml benzene are added 3 g (18.5 mmol) 3-(trifluoromethyl)aniline and 1.1 g (18.5 mmol) acetic acid. The mixture is stirred under reflux overnight using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 6). The product containing fractions are combined and concentrated in vacuo.