Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3OCCO3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(C2OCCO2)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (106 mg) in tetrahydrofuran (2 ml) was stirred with 2 N hydrochloric acid (0.2 ml) for 1/2 h at room temperature. The mixture was treated with piperidine (0.5 ml), stirred at room temperature for 1 h, and then treated with sodium borohydride (75 mg). After a further 1 h, the mixture was diluted wit water, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo. The resulting oil was crystallized from a mixture of benzene and cyclohexane to yield the title compound (60 mg) m.p. 93°-4°. TLC silica (methanol:ammonia 80:1) Rf 0.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OCCC(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCCC(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3,3-trifluoropropanol. Off-white solid. MS (m/e): 276.3 ([M+H—Me2C═CH2]+, 100%)
Reaction SMILES: [C:1]1([CH2:6][NH2:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:16][Si:17]([CH3:25])([CH3:24])[O:18][Si:19]([CH2:22]Cl)([CH3:21])[CH3:20].C1(C)C=CC=CC=1>O>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:6][N:7]1[CH2:20][Si:19]([CH3:22])([CH3:21])[O:18][Si:17]([CH3:25])([CH3:24])[CH2:16]1
Reactant: NCc1cccs1
Reactant: C[Si](C)(CCl)O[Si](C)(C)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si]1(C)CN(Cc2cccs2)C[Si](C)(C)O1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To a solution containing 22.6 g. (0.2 mole) of 2-thenylamine, 44.4 g. (0.44 mole) of triethylamine and 50.0 g. of acetonitrile dried over molecular sieves there is added 46.2 g. (0.2 mole) of 1,3-bis-chloromethyl-1,1,3,3-tetramethyl-disiloxane. The resulting homogenized solution is allowed to stand for 3 days and then heated in a bath at 90° C. for 36 hours. After cooling the mixture is then equiliberated between toluene and water, the organic phase is then washed with two more portions of water and concentrated to give 61.5 g. of a crude oil. Vacuum distillation through a Vigreux column gives 4-(2-thienylmethyl)-2,2,6,6-tetra-methyl-1-oxa-4-aza-2,6-disilacyclohexane; b.p. 78° to 80° C. at 0.1 to 0.11 mm.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][OH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:33]([O:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCc3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.075 g, 0.202 mmol), 2-phenylethanol (0.025 g, 0.202 mmol) and sodium hydride (0.010 g) in 5 mL of toluene was stirred at room temperature for 1 hour, and then refluxed overnight. The reaction mixture was cooled to room temperature, added 20 mL of water, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (58 mg, 62.9%). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.22-7.30, 7.20-7.24, 7.02, 6.86, 4.64, 3.91-3.98, 3.57, 3.48-3.52, 3.32, 3.11.
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1.Br[CH2:17][CH:18]([CH3:20])[CH3:19].O>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:17][CH:18]([CH3:20])[CH3:19])[N:10]=1
Reactant: CC(C)CBr
Reactant: Cc1cccc(Br)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)CCc1cccc(Br)n1
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
A 2.5M solution of n-buthyllithium (0.44 mL, 1.1 mmol) was added dropwise to a stirred solution of diisopropylamine (0.16 mL, 1.15 mmol) in THF (2 mL) at −78° C. The mixture was stirred for 15 minutes and 2-bromo-6-methylpyridine (0.11 mL, 1 mmol) was added dropwise. The mixture was stirred for 15 minutes and 1-bromo-2-methylpropane (0.21 mL, 2 mmol) was added dropwise. The mixture was stirred for 1 hour at this temperature and at room temperature for 60 hours. The mixture was treated with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-bromo-6-(3-methyl-butyl)-pyridine (82 mg, 36% yield) as a colourless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[CH3:18].C(OC(C)(C)C)(C)(C)C.[K].O>CN(C)C=O>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1cc(N)ccc1Br
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a mixture of 4-fluorobenzonitrile (12.61 g, 104 mmol) and 4-bromo-3-methylaniline (15.36 g, 82.56 mmol) in N,N-dimethylformamide (160 mL) on an ice water bath under a nitrogen balloon was added potassium tert-butyloxide (18.53 g, 165.12 mmol) portionwise. The reaction was stirred at room temperature overnight. Then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to get crude product. The crude was then recrystallized from ethyl acetate to give 4-(4-bromo-3-methylphenylamino)benzonitrile (5.675 g, 24%).
Reaction SMILES: [C:1]1([C:7]2[C:16]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I.Cl>C1COCC1>[CH3:32][N:17]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:26]([OH:28])=[O:27])=[CH:11][CH:10]=2
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N[C@@H](C)c3ccccc3)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (S)-methyl 2-phenyl-3-(1-phenylethylamino)quinoxaline-6-carboxylate (110 mg, 0.29 mmol, 1.00 equiv) in THF (9 mL), sodium hydride (137.9 mg, 5.74 mmol, 20.00 equiv, 60%). The resulting solution was stirred for 1 h at room temperature in an ice/salt bath. This was followed by the addition of a solution of CH3I (407.8 mg, 2.87 mmol, 10.00 equiv) THF (1 mL) dropwise with stirring at 0° C. The resulting solution was stirred for overnight at 20° C. in an ice/salt bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 40 mg (36%) of (S)-3-(methyl(1-phenylethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]([N:11]2[CH2:10][CH:9]([N:13]([C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)[CH3:28])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12]2)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown foam. MS m/e: 624.3 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19](Cl)[N:18]=[N:17][C:16]=2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1CCN2C(=NCCC2)CC1.C1C[O:54][CH2:53]C1>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:53]([C:19]2[N:18]=[N:17][C:16]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH:20]=2)=[O:54])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: C1CCOC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nnc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 150 °C

Procedure:
A 5.0 mL vial was charged with 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.3 g, 0.85 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.51 g, 2.5 mmol), Mo(CO)6 (0.22 g, 0.85 mmol), (trans-di-μ-acetobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (0.08 g, 0.085 mmol) and THF (3.0 mL). DBU (0.16 g, 1.06 mmol) was added, and the vial was immediately sealed. The reaction mixture was then exposed to microwave heating for 15 min at a pre-selected maximum temperature of 150° C. The reaction was thereafter cooled to room temperature. The mixture was filtered through a small plug of celite, and the plug was washed with DCM. The combined fractions were evaporated under reduced pressure, and the crude product was purified by column chromatography (silica gel) eluting first with DCM and then 5% methanol in DCM. The combined fractions were evaporated and purified by column chromatography (silica gel) eluting with 30% ethyl acetate in hexane to get 4-{[5-(4-benzyloxy-phenyl)-6-butyl-pyridazine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.120 g). LCMS: m/z 546.4 [M+2].
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1.[CH3:22][O:23][CH:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:27][CH:26]([O:41][CH3:42])[O:25]1>CO>[CH3:22][O:23][CH:24]1[CH:28]([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[CH2:27][CH:26]([O:41][CH3:42])[O:25]1
Reactant: COC1C=C(c2ccc(-c3ccncc3)cc2)C(OC)O1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CO
Product: COC1CC(c2ccc(-c3ccncc3)cc2)C(OC)O1
Yield: 99.2 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran, 2,5-dihydro-2,5-dimethoxy-3-(4-(pyridin-4-yl)phenyl)furan (300 mg, 1.06 mmol) was hydrogenated in MeOH after 6 hours to furnish 300 mg (100%) of 2,5-dimethoxy-3-(4-(pyridin-4-yl)phenyl)tetrahydrofuran as a yellow oil, which was a mixture of diastereomers by NMR, and which was used without further purification. 1H NMR (CDCl3): δ 8.68 (bs, 2H), 7.76-7.36(m, 6H), 5.34-4.94 (m, 2H), 3.72 -3.20 (m, 7H), 2.75 (ddd, 0.15H, minor isomer, J=5.9, 10.0, 13.7 Hz), 2.35 (ddd, 0.74H, major isomer, J=5.6, 12.8, 12.8 Hz), 2.20 (dd, 0.0.19H, minor isomer, J=6.9, 12.0 Hz), 2.12 (ddd, 0.16H, minor isomer, J=3.7, 5.9, 13.7 Hz); Anal. Calculated for C17H19NO3•0.2 H2O: C, 70.66; H, 6.77; N, 4.85. Found: C, 70.49; H, 6.74; N, 4.76.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH:21][C:28]([NH2:29])=[NH:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(N)n1cccn1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C
Yield: 33.1 %

Procedure:
C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (1.0 g, 3.5 mmol), 1H-pyrazol-1-carboxamidine hydrochloride (0.5 g, 3.5 mmol) and 1.2 mL of diethyl isopropylamine (7.0 nnol) were dissolved in 10 mL of DMF. The reaction mixture was heated to 100° C. for three hours and then cooled and diluted by addition of 75 mL of water. The aqueous mixture was extracted twice with 100 mL of EtOAc, and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure, and the resulting oil was purified by medium pressure chromatography (silica gel, MeOH/CHCl3/NH4OH 10:89:1) to yield 0.4 g (1.16 mmol, 33%) of N-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-guanidine, MS: 344 (M+H)+.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.CO>CS(C)=O>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.2 %

Procedure:
A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (2.0 g, 4.44 mmol), 3-(1,2,3,6-tetrahydropyridin4-yl)-1H -indole (1.01 g, 5.09 mmol) and diisopropylethyl amine (0.86 g, 6.65 mmol) in DMSO (10 mL) was heated to 80-83° C. After 10 h, the reaction mixture was cooled to 65-70° C. before CH3OH (3 mL) was added. The resulted suspension was cooled to room temperature, filtered, washed with CH3OH and dried in a vacuum oven to give 1.3 g (71%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.O[C@@H]1CCNC1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:31]5[CH2:32][CH2:33][CH:29]([OH:28])[CH2:30]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OC1CCNC1
Agent: O[C@@H]1CCNC1
Product: OC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-3-hydroxypyrrolidine. A yellow solid 116 was obtained (0.0353 g, 75%). 1H-NMR (CDCl3, 400 MHz) δ 2.15–2.23 (m, 1H), 2.25–2.31 (m, 1H), 3.78–3.84 (m, 2H), 3.87–3.95 (m, 2H), 4.28–4.34 (m, 4H), 4.72–4.76 (m, 1H), 6.77 (s, 1H), 6.91 (dd, J=1.1 Hz, 6.6 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.05 (dd, J=2.1 Hz, 8.1 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.54 (dd, J=1.4 Hz, 8.5 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H), 8.15 (d, J=6.6 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](I)[CH3:16].O.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C([Li])(C)(C)C>[CH2:15]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)[CH3:16]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a cooled solution (−78° C.) of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (960 mg, 4.57 mmol) in THF (19 mL), tert.-butyllithium (8 mL, 1.5 M solution in pentane) is added. The mixture is stirred at −78° C. for 10 min before ethyliodide (3.80 g, 24.37 mmol) is added. The reaction mixture is stirred at −78° C. for 3 h. Water/methanol 1:1 (8 mL) followed by 10% aq. citric acid solution is added and the mixture is extracted with EA. The combined organic extracts are washed with brine, dried over Na2SO4 and evaporated. The remaining solid is suspended in acetonitrile (6 mL), heated to 60° C., cooled to rt, filtered and dried to give 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (640 mg) as a slightly beige solid; LC-MS: tR=1.01 min, [M+1+CH3CN]=280.10.
Reaction SMILES: [OH:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C:2]([CH3:36])([CH3:37])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.3 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide (121 mg, 0.22 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.7 ml, 9.0 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane (1 ml) and ethylenediamine (0.9 ml, 13.3 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, rinsed with hot water and ethyl acetate then dried under high vacuum to provide 53 mg (58%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as an off-white powder. MS: (M+H)+=413; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.83 (br. s., 1H), 9.14 (s, 1H), 8.75 (d, J=8.7 Hz, 1H), 8.42 (s, 1H), 8.16 (d, J=9.4 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.36 (dd, J=8.7, 1.1 Hz, 1H), 4.78 (s, 1H), 4.17 (s, 3H), 4.03-4.16 (m, 1H), 1.22-1.28 (m, 6H), 1.16 (s, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:30])([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[NH:25][O:26][C:27](=[O:29])[N:28]=2)[CH:19]=1)[C:14]([F:17])([F:16])[F:15].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[N:31]1([C:36]([N:28]2[C:27](=[O:29])[O:26][N:25]=[C:24]2[C:20]2[CH:19]=[C:18]([C:13]([F:12])([F:30])[C:14]([F:15])([F:17])[F:16])[CH:23]=[CH:22][N:21]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=c1nc(-c2cc(C(F)(F)C(F)(F)F)ccn2)[nH]o1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)C(F)(F)F)ccn2)noc1=O
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To 2 ml of pyridine were added 0.16 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.14 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-(1-pyrrolidinecarbonyl)-3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (63)).