Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[N:27]([CH2:28][C:29]3[N:30](CC4C=CC=CC=4)[CH:31]=[CH:32][N:33]=3)[C:26]3[CH:41]=[CH:42][CH:43]=[CH:44][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]([CH2:11][CH:12]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([C:21]([C:23]2[N:27]([CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:26]3[CH:41]=[CH:42][CH:43]=[CH:44][C:25]=3[N:24]=2)=[O:22])[CH2:19][CH2:20]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2nccn2Cc2ccccc2)CC1)c1ccccc1)C(=O)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ncc[nH]2)CC1)c1ccccc1)C(=O)c1ccccc1
Reaction time: 18 h

Procedure:
Combine N-methyl-N-(4-(4-(1-(1-benzylimidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide (5 mmol) and 10% palladium-on-carbon (1.5 g) in methanol (50 mL). Add anhydrous ammonium formate (25 mmol). Heat to reflux. After 18 hours, filter, rinse with dichloromethane, and evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5](O)=[O:6].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:6])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCCC3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40.0 mg, 0.085 mmol) synthesized in Example (44a) was dissolved in tetrahydrofuran (5 mL), and pyrrolidine (21 μL, 0.26 mmol), HATU (64.9 mg, 0.171 mmol) and N,N-diisopropylethylamine (89 μL, 0.51 mmol) were added, followed by stirring at room temperature for 20 hours under nitrogen atmosphere. To the reaction solution, saturated brine (15 mL) was added, and extraction was carried out twice with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (32 mg, yield 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:32])[C:8]([C@H:13]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:14](O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)=[O:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:32])[C:8]([C@H:13]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:14][OH:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(Br)cc2c(O)c1[C@H](OC(C)(C)C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: CC[BH-](CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@@H](CO)OC(C)(C)C
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (4.56 g, 9.02 mmol) in THF (45 mL) was added lithium triethylborohydride solution (Super Hydride, 1.0 M in THF, 36 mL, 36 mmol). The reaction was stirred at 55° C. for 2.5 h. A saturated solution of NH4Cl was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 2.84 g. 1H-NMR: 400 MHz, (CDCl3) δ: 9.77 (s, 1H), 8.37 (s, 1H), 7.50 (m, 2H), 7.10 (s, 1H), 5.26 (dd, J=9, 4 Hz, 1H), 4.20 (m, 2H), 2.48 (s, 3H), 1.25 (s, 9H) 1.21 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]1CC1C=CC=CC=1)=[O:4].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(=O)OC)N1
Yield: 45 %

Procedure:
79 mg (0.3 mmol) of cis-N-benzylazetidine-2,4-dicarboxylic acid dimethyl ester and 25 mg of Pd(OH)2 (20% on C, 31% H2O, Aldrich) in 10 ml of methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 6 hours. The catalyst is filtered off and thoroughly washed, the solution evaporated, and the residue filtered over a short column to yield 23.4 mg (45%) of cis-azetidine-2,4-dicarboxylic acid dimethyl ester. 1H NMR (CDCl3): δ4.27 (dd, 2H, J=6.5, 8.5), 3.76 (s, 6H), 2.95 (dt, 1H, J=8.5 (t), 12 (d)), 2.60 (dt, 1H, J=6.5 (t), 12 (d)). IR (neat): 3345, 2955, 1740, 1437, 1231, 1042 cm-1. Mass spectrum: m/z 173 (7%), 114 (100), 82 (44), 59 (14), 55 (32), 54 (98). Calcd. for C7H11NO4 : 173.0688, found: 173.0688.
Reaction SMILES: CC1C=C([N+]([O-])=O)C(C)=CC=1C(=O)C=C(N(C)C)C.NN.[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-])=O)[C:26]([CH3:32])=[CH:25][C:24]=1[C:33]1[NH:37][N:36]=[C:35]([CH3:38])[CH:34]=1>C(O)C.CO.[Pd]>[CH3:32][C:26]1[CH:25]=[C:24]([C:33]2[NH:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[C:23]([CH3:22])=[CH:28][C:27]=1[NH2:29]
Reactant: Cc1cc(-c2cc(C)c([N+](=O)[O-])cc2C)[nH]n1
Agent: [Pd]
Agent: CC(=CC(=O)c1cc(C)c([N+](=O)[O-])cc1C)N(C)C
Agent: NN
Solvent: CCO
Solvent: CO
Product: Cc1cc(-c2cc(C)c(N)cc2C)[nH]n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one (100 mg, 0.38 mmol) and hydrazine (60 uL, 1.9 mmol) in ethanol (3 mL) was heated in a microwave at 100° C. for 15 min. The obtained 5-(2,5-dimethyl-4-nitrophenyl)-3-methylpyrazol was dissolved in methanol (10 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-Dimethyl-4-(3-methyl-1H-pyrazol-5-yl)aniline. ESMS m/z 202 (M+H+).
Reaction SMILES: [Si:1]([CH:18]([OH:25])[C@@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si](Cl)(C)(C)C.[C:41]1([Se:47]Br)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCOCC>[Si:1]([CH:18]([OH:25])[C@@H:19]1[O:23][C:22](=[O:24])[C@@H:21]([Se:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1CCC(=O)O1
Reactant: Br[Se]c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1C[C@H]([Se]c2ccccc2)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After being stirred at −78° C. for 1 h, Me3SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 30 min, the mixture was cooled to −78° C., and a solution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was added rapidly. The mixture was diluted with ether (50 mL), washed with water until the color of organic layer changed from dark brown to light yellow, dried (Na2SO4), filtered, and evaporated. The resulting oily residue [containing 3S (α, 5) and 3R (β) isomers; TLC: hexane/EtOAc, 10:1; Rf=0.42 and 0.28, respectively] was purified by flash chromatography on silica gel, eluting with hexane/EtOAc (99:1 to 95:5) to give the title compound 5 as a light yellow oil (4.093 g, 57%). 1H NMR (CDCl3) δ 7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.Cl[C:31]1[N:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[N:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1)=[O:20]
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-2,6-m dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.27 mmol), DIPEA (0.139 ml, 0.80 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 0.058 mg, 0.32 mmol) and dry NMP (0.9 ml). The resulting mixture was subjected to microwave irradiation at 250° C. for 20 minutes. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2N2C=C(C3(N)NC=NC4SC=CC3=4)N(C)C2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC([C:44]2[N:45]=[CH:46][N:47]([CH3:59])[C:48]=2[C:49]2[S:58][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=3[CH:50]=2)=CC=1>>[C:1]1([C:7](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:44]3[N:45]=[CH:46][N:47]([CH3:59])[C:48]=3[C:49]3[S:58][C:52]4[N:53]=[CH:54][N:55]=[C:56]([NH2:57])[C:51]=4[CH:50]=3)=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CN(c2ccccc2N=C(c2ccccc2)c2ccccc2)C=C1C1(N)NC=Nc2sccc21
Reactant: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(N)ncnc2s1
Product: Cn1cnc(-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 109 but using 6-[4-(4-iodophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 64) in place of 6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 49). Colourless solid (31 mg, 64%);
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH2:5][C:6]#[N:7].[OH-].[Na+].Cl.[NH2:14]O.Cl>C(O)C.O>[NH2:7][C:6]1[CH:5]=[C:4]([C:3]([CH3:10])([CH3:9])[CH2:2][OH:1])[O:8][N:14]=1
Reactant: CC(C)(CO)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)c1cc(N)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A mixture of 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile from Step B (1 g, 7.09 mmol), sodium hydroxide (378 mg, 9.45 mmol), and hydroxylamine hydrochloride (656 mg, 9.43 mmol) in a mixture of ethanol (100 mL) and water (100 mL), was heated at 60° C. for 22 h. After cooling to rt, concentrated HCl (1 g) was added and stirred at 50° C. for 2 h followed by 80° C. for a further 1 h. After concentration under reduced pressure, the mixture was treated with 30% sodium hydroxide solution and extracted with chloroform (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, and filtered. Concentrated under reduced pressure, followed by purification via recrystallisation from diethyl ether, afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H); LC-MS (ESI) m/z 156 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6](O)[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC1=C(O)N=C(CBr)S1=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC1=C(S(=O)(=O)c2ccc(C)cc2)N=C(CBr)S1=C=O
Yield: 70.1 %

Procedure:
2-Bromomethyl-5-ethoxy-carbonyl-4-hydroxy-thiazole (8 g, 0.03 mol) was dissolved in 80 ml of chloroform. The solution was then cooled down to 0° C. p-Toluenesulfonyl chloride (5.7 g, 0.03 mol) was added, followed by slow addition of triethylamine (3.64 g, 0.036 mol) at 0° C. The reaction was monitored by TLC and LCMS. After the reaction was done, solvent was evaporated and the crude product was then purified by column chromatography to give 8.5 g of title product (yield 67%; LC: Retention Time=2.05 min; MS: M+1=421).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[OH:22].[H-].[Na+].IC.[C:28](O)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:6][C:5]=1[O:22][CH3:28]
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-(3-(t-butyloxycarbonylamino)propyloxy)-2-hydroxybenzoic acid methyl ester (3.0 g, 9.2 mmol) from Step 1 in dry DMF (25 mL) was added sodium hydride (0.39 g of a 60% suspension in mineral oil, 9.7 mmol). The reaction was stirred at 0° C. for 1 h, when iodomethane (1.0 mL, 16 mmol) was added. The reaction was then warmed to ambient temperature. After 24 h, acetic acid (1 mL) was added and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 3:7 EtOAc:hexanes as eluant. 4-(3-(t-Butyloxycarbonylamino)propyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:6]([CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[N:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[N:6]([C:8]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([CH:11]=[O:12])[N:10]=2)[N:7]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cn2nc(Cl)cc(N3CCOCC3)c2n1
Product: O=Cc1nc2c(N3CCOCC3)cc(Cl)nn2c1-c1cccnc1

Procedure:
Compound 73e was a coupled with 3-bromopyridine (0.100 mL, 1.25 mmol) according to the procedures described in Example 20, Step A to afford compound 73f. Mass Spectrum (LCMS, ESI pos.): Calcd. for C16H14ClN5O2: 344.0 (M+H). found: 344.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:6]=1[Cl:7].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Cl:7][C:6]1[C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][S:3][C:2]=1[NH:1][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CC(C)S(=O)(=O)c1csc(N)c1Cl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)c1csc(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Yield: 35.5 %

Procedure:
2-Amino-3-chloro-4-isopropylsulfonylthiophene (260 mg) was stirred for 4 hours with 4-t-butylphenylisocyanate (119 mg) in 1 mL of pyridine at 60 ∞C. The pyridine was evaporated to dryness and the residue taken up in a mixture of ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed with water, saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. Concentration and crystallization of the residue from ethanol and water gave 100 mg of N-[3-chloro-4-(isopropylsulfonyl)thien-2-yl]-N'-(4-t-butyl-phenyl)urea, an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH2:31][O:32][CH3:33])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and 2-bromoethylmethyl ether (44 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 43 as a colorless oil (19 mg).
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:19]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[F:20][C:3]1[C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:28])=[CH:19][C:6]2[C:7]3[N:8]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: C#C[C@@](C)(O)c1ccccn1
Product: C[C@@](O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)c1ccccn1

Procedure:
Similar to as described in General Procedure F, reaction of 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide with (R)-2-(pyridin-2-yl)but-3-yn-2-ol gave the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]5)[N:16]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH2:12]1[C:10]2([CH2:9][NH:8][CH2:11]2)[CH2:14][N:13]1[C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]3)[CH:18]=[N:19][CH:20]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)n3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCc2cc(-c3cncc(N4CC5(CNC5)C4)n3)ccc21
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 6-[6-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyrazin-2-yl]-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (example 28, 0.231 g, 0.53 mmol) in DCM (3 mL) was added TFA (0.605 g, 5.3 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was evaporated several times with toluene and then the residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH—H2O (0.05% TEA) gradient to give the title compound (0.203 g, 99%) as a yellow solid (TFA salt). MS: 336.3 (M+H+).
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].[CH3:26][C:27]([C:30]([NH2:32])=[NH:31])([CH3:29])[CH3:28].Cl.C([O-])(=O)C.[Na+]>CN(C=O)C>[C:27]([C:30]1[N:32]=[C:17]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:4]([C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:6])=[C:1]([CH3:2])[N:31]=1)([CH3:29])([CH3:28])[CH3:26]
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)NCCCc1ccccc1
Reactant: CC(C)(C)C(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(C)C)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide was dissolved in 5 ml of DMF. 54.5 mg (0.399 mmol) of t-butyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate were added at room temperature and stirred at 80° C. for one day. After DMF was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].CN([CH:21]=[O:22])C1C=CC=CC=1.S(=O)(=O)(O)O>CCOCC>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:21]=[O:22]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CN(C=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=Cc1ccccc1C(F)(F)F
Reaction time: 3 h
Yield: 68.3 %

Procedure:
2.8 Grams of metallic magnesium, 25 g of 2-bromo-α,α,α-trifluorotoluene and 120 ml of ether were reacted to prepare a Grignard ragent by a conventional method, then 15 g of N-methylformanilide were added dropwise thereto, and the reaction mixture was allowed to stand for 3 hours. Under an ice-cooled condition, a dilute sulfuric acid was added to the reaction mixture. The ethereal layer was separated and was washed with a saturated sodium chloride aqueous solution and with a saturated sodium hydrogencarbonate aqueous solution, then was dried with anhydrous sodium sulfate, and was concentrated. The residue was purified by distillation under reduced pressure to yield 13.2 g of 2-trifluoromethylbenzaldehyde. Boiling point: 62°-65° C. (at 17 mm-Hg).