Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[N:3]=1.[C:21]1([N:27]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC([O-])=O.[K+]>C(O)CCC.O>[CH3:10][O:9][C:6]1[C:7](=[O:8])[C:2]([C:31]2[N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:28]=[CH:29][CH:30]=2)=[N:3][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:5]=1
Reactant: COc1cn(-c2cccc3cccnc23)nc(Br)c1=O
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: COc1cn(-c2cccc3cccnc23)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 81.5 %

Procedure:
A mixture of 3-bromo-5-methoxy-1-quinolin-8-ylpyridazin-4(1H)-one (70 mg, 0.217 mmol), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88.1 mg, 0.326 mmol), KOAc (42.6 mg, 0.434 mmol) and PdCl2{P(t-Bu)2(Ph-p-NMe2)}2 (7.7 mg, 0.0109 mmol) in BuOH (1.1 mL) and water (0.1 mL) was heated to reflux for 16 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with AcOEt/hexane to yield the title compound (69.9 mg, 81% yield) as a white solid: mp 189-192° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 6.98 (1H, s), 7.31-7.49 (6H, m), 7.58-7.73 (2H, m), 7.78 (1H, d, J=1.9 Hz), 8.14 (1H, d, J=8.3 Hz), 8.54 (1H, d, J=7.9 Hz), 8.67 (1H, s), 8.99 (1H, d, J=4.1 Hz). Anal. Calcd for C23H17N5O2: C, 69.86; H, 4.33; N, 17.71. Found: C, 69.61; H, 4.37; N, 17.57.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:32])[C:23]=2[N:33]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.CO.C1COCC1.Cl>[Pd].O>[NH2:11][C@H:12]([C:16]([O:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:32])[C:23]=2[N:33]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a hydrogenation bottle was added (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl N-[(benzyloxy)carbonyl]-L-valinate (1.5 g, 2.5 mmol) followed by a mixture of methanol (30 mL), THF (15 mL) and water (5 mL) and conc HCl (5 mL). To this was added Pd/C (90 mg) and the reaction was hydrogenated at 40 psi (2.8×105 Pa) overnight. To the reaction mixture was added conc. HCl (5 mL) and Pd/C (90 mg) and the reaction was hydrogenated at 40 psi (2.8×105 Pa) for 18 hours. The reaction was filtered through CELITE filter aid and the filtrate was evaporated to afford a clear oil. The product was isolated by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-8% methanol in dichloromethane with 1% ammonium hydroxide) to provide (4-amino-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl L-valinate (0.495 g) as an off white solid, mp 161-163° C.; MS (ESI) m/z 463 (M+H)+; Anal. Calcd for C21H30N6O4S: C, 54.53; H, 6.54; N, 18.17. Found C, 53.96; H, 6.62; N, 17.85, delta C=0.57.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[Cl:35]N1C(=O)CCC1=O.O.C(Cl)Cl>C(#N)C>[NH2:1][C:2]1[C:33]([Cl:35])=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1cc(Cl)c(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 95 °C
Yield: 28 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-methyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (60 mg, 0.128 mmol) was dissolved in acetonitrile (2 ml) and N-chlorosuccinimide (23 mg, 0.128 mmol) was added. The reaction was heated to 95° C. for 4 h. The reaction mixture was cooled to RT and partitionated between water and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (heptane/ethyl acetate 7:3) to yield the desired product (18 mg, 28%) as a brown gum. MS (ISP) 503.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16])[CH:6]=[CH:7][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OC)=O.[Cl-].[NH4+].[Al]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCCCCCc1cccc(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Al]
Agent: [Cl-]
Solvent: COC=O
Solvent: ClCCl
Product: COc1cccc(CCCCCCC=O)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Methyl 7-(3-methoxyphenyl)heptanoate (0.259 g, 1.04 mmol) was dissolved in dry dichloromethane (10 mL) under an atmosphere of argon and cooled to −78° C. A 1 M solution of diisobutylaluminum hydride (in hexanes) (1.19 mL, 1.19 mmol) was added and the reaction was allowed to proceed over 45 minutes. The reaction was quenched with methyl formate (0.0710 g, 1.04 mmol). The quenched reaction solution was allowed to warm to 0° C. and saturated ammonium chloride was added (2.8 mL) at which point aluminum salts precipitated from the solution. These salts were broken up with the addition of saturated sodium potassium tartrate (excess) and stirring for 18 hours at room temperature. The aqueous and organic layers were separated and the aqueous layer was washed twice with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate then brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The aldehyde product was isolated as a clear oil (80%, 0.181 g) following flash column chromatography with silica (0-8% ethyl acetate:hexanes gradient mobile phase): 1H NMR (600 MHz, CDCl3) δ 9.75 (s, 1H), 7.19 (t, 1H), 6.73 (d, J=7.2 Hz, 1H), 6.72 (m, 2H), 3.80 (s, 3H), 2.58 (t, 2H), 2.42 (t, 2H), 1.63 (m, 4H), 1.36 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 202.78, 159.56, 144.25, 129.17, 120.80, 114.17, 110.84, 55.09, 43.84, 35.88, 31.10, 28.99, 28.96, 21.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH:46][CH3:47].C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:10]([C:11](=[O:12])[N:46]([CH3:47])[CH3:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C(=O)OC(C)(C)C)c3)cc12
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C(=O)OC(C)(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of (tert-butoxycarbonyl-methyl-amino)-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid, (100 mg, 0.16 mmol), dimethylamine (2 N in THF, 0.12 mL, 0.24 mmol), and diisopropylethylamine (31 mg, 0.24 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 646 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](C(F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Cl:32]C1C=CC=CC=1N1CCNCC1>>[Cl:32][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:12]2[C:11](=[O:31])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH2:1][CH3:2])[CH2:16][CH2:17]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2ccccc2Cl)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2-chlorophenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19]>[B-](F)(F)(F)F.[Ag+].O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil with the properties described in Example 121.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CC(C)(OC(=O)[NH:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52](O)=[O:53])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[NH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52]([N:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:22]2[CH:23]=[C:19]([C:16]3[S:15][C:14]([C:12]([NH:11][CH2:10][C:7]4[CH:8]=[CH:9][N:4]5[CH:3]=[CH:2][N:1]=[C:5]5[CH:6]=4)=[O:13])=[CH:18][CH:17]=3)[CH:20]=[N:21]2)([CH3:31])[CH2:26][CH2:27]1)=[O:53]
Reactant: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCN(C(=O)CCOCCOCCOCCOCCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.139 g, 0.274 mmol), 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (0.100 g, 0.274 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.105 ml, 0.958 mmol) was stirred at room temperature for 3 hours. The reaction mixture was purified directly by normal phase chromatography and the resulting material was treated with HCl/dioxane (4 M) then concentrated to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 9.58 (t, J=6.0 Hz, 1H), 8.89 (d, J=7.0 Hz, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 2H), 8.06 (s, 3H), 7.92 (d, J=3.9 Hz, 1H), 7.83 (s, 2H), 7.50 (dd, J=7.0, 1.2 Hz, 1H), 7.26 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.05 (s, 2H), 3.80 (dd, J=11.8, 6.8 Hz, 2H), 3.66-3.58 (m, 4H), 3.55 (dd, J=9.2, 4.4 Hz, 4H), 3.50 (t, J=7.5 Hz, 8H), 3.37-3.26 (m, 1H), 3.23-3.13 (m, 1H), 2.99-2.90 (m, 2H), 2.55 (t, J=6.6 Hz, 2H), 1.53-1.19 (m, 4H), 0.95 (s, 3H); MS (ESI(+)) m/e 682 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:34])C(=O)C1>CC#N>[Br:34][C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (4.40 g, 11.9 mmol) in CH3CN (25 mL), was added NBS (3.60 g, 20.2 mmol). The resulting solution was stirred for 30 minutes at 80° C. before being concentrated in vacuo. The reaction was diluted with ethyl acetate (200 mL), washed with water (×3), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 2-6% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 5-bromo-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LRMS (ESI) calc'd for C18H22N4O3SiBr [M+H]+: 449, found 449.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](OCC)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].[O-]CC.[Na+].[Na]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][CH:18]([CH3:20])[CH3:19])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C
Reactant: CC(C)N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)NC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C

Procedure:
A mixture of crude 7-chloro-3-ethoxy-2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (0.45 g) and isopropylamine (4 ml) in an ethanolic sodium ethoxide solution, prepared by dissolving 0.4 g of sodium in 10 ml of ethanol, was refluxed for 3 hours and then neutralized with 4M acetic acid. The mixture was evaporated to dryness and partitioned between 25 ml of water and 25 ml of dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column with a 7:3 mixture of n-heptane and ethyl acetate as solvent to give the title compound;
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[CH3:25])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:32]>CO.[OH-].[OH-].[Pd+2]>[ClH:32].[CH3:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CC1CCCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCCCN1c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a solution of 8-benzyl-3-(2-methylpiperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (0.65 g) in methanol (20 mL) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2.5 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (628 μL) and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.40 g, 73%) as a pale-yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH:6]2[CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)=[N:2]1>C(O)C.[Pd]>[NH:1]1[CH:5]=[N:4][C:3]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc[nH]n2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1nc(C2CCNCC2)n[nH]1
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (7.3 g, 25 mmol) in ethanol (100 mL) was added 10% palladium on carbon (500 mg) and the reaction vessel was purged with hydrogen and stirred over an atmosphere of hydrogen for 3 hours. The reaction was filtered and concentrated to give 21-1 as a solid. MS (M+Hf): 153.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 2.98-2.94 (m, 2H), 2.82-2.74 (m, 1H), 2.57-2.50 (m, 2H), 1.82-1.78 (m, 2H), 1.60-1.50 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=S.[NH2:13][C@@:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20]([O:22]C)=O.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@:14]12[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20](=[O:22])[N:2]([CH3:1])[C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[N:13]2
Reactant: COC(=O)[C@@H]1[C@@H](C)OC[C@@]1(N)c1ccccc1F
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1OC[C@]2(c3ccccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
tert-Butyl (methylcarbamothioyl)carbamate (2.13 g, 11.2 mmol) was added to a stirred mixture of (2R,3S,4S)-methyl 4-amino-4-(2-fluorophenyl)-2-methyltetrahydrofuran-3-carboxylate (2.27 g, 9.0 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (3.9 mL, 22.4 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1:1) (2.15 g, 11.2 mmol) in dry DMF (18 mL) at RT under nitrogen. The mixture was stirred at RT for 3 days, then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 10% to 25% EtOAc in n-hexane) to give the title compound (3.15 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (d, J=6.06 Hz, 3H) 1.54 (s, 9H) 3.28 (s, 3H) 3.40 (dd, J=9.09, 2.02 Hz, 1H) 4.31 (d, J=10.11 Hz, 1H) 4.36-4.45 (m, 2H) 7.10-7.24 (m, 3H) 7.33-7.40 (m, 1H) 10.53 (br. s., 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([N:40]([CH2:47][CH3:48])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][CH:41]([N:40]([CH2:47][CH3:48])[CH2:38][CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(CC)CC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with diethyl-4-piperidinylamine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C38H50Cl2N5O2 [(M+H)+] 678.3336, observed 678.3335.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]([CH3:32])[C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH2:11]2)=[O:8])[N:3]=[CH:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([N:12]2[CH2:13][CH2:14][C@@H:10]([N:9]([CH3:32])[C:7](=[O:8])[CH2:6][C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)[CH2:11]2)=[N:20][CH:19]=1
Reactant: CN(C(=O)Cc1c[nH]cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)Cc1c[nH]cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)-2-(1H-imidazol-4-yl)-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)acetamide (0.11 mmol) in TFA (1 mL) and DCM (2 mL) was stirred at room temperature for 1.5 hours. The volatiles were removed under reduce pressure. The residue was dissolved in MeOH (2 mL) and treated with ethane-1,2-diamine (0.2 mL) at room temperature overnight. The volatiles were then removed under reduced pressure and the residue was purified by flash chromatography to give the title compound. MS (m/z): 326 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:28](=[O:29])[C:27]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:20]=4[C:11]3=[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:9]=2[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>O1CCOCC1.C(OCC)C>[CH:1]([N:4]1[C:28](=[O:29])[C:27]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:19][C:20]=4[C:11]3=[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CCCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reaction time: 1 h

Procedure:
To a suspension of 110 mg of 14d in 300 μl of dioxane was added 400 μl of a solution of 4N HCl in dioxane. A clear solution readily formed. The reaction mixture was stirred for 1 h. Then, 3 ml of a 1/1 mixture of ethyl acetate and diethyl ether was added. The precipitate was filtered and dried, to give 95 mg of white crystalline 14e; Mp 242-243° C. MS-ESI: [M+1] 480.14. NMR (CDCl3+CD3OD) δ 1.13 (d, 6,0-isoC3H7), 1.33 (d, 6, isoC3H7), 3.85 (s, 3, OCH3), 3.95 (m, 1, isoC3H7), 4.65 (m, 1, isoC3H7), 6.67 and 6.72 (2×s, H7 and H10), 7.18, 7.21 and 7.44 (3×m, 3, thiophene). hFSHRago (CHO luc) pEC50=7.03.