Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O>[Fe].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Sc2ccc(Cl)cc2)nc1

Procedure:
6-(4-Chlorophenylthio)-3-nitropyridine (1.33 grams) was mixed with ammonium chloride (5.0 grams) in 5 ml. of water and about 50 ml. of 3A ethanol at 70°-80° C. Iron powder (3.0 grams) was added portionwise and the reaction mixture heated at 70°-80° C. with constant stirring, for 4 hours. The solution was filtered hot, solvents were removed, and the residue was washed with water; chloroform used to extract the compound was removed in vacuo. A thick oil was crystallized from ether-hexanes after passing through a flush with ethyl acetate on silica gel. The product precipitated as a white solid, yield 1.0 g., m.p. 55°-57°.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]([CH3:17])[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:24]>>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]([CH3:17])[S:9]([CH2:12][C:13]([NH2:24])=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CS(=O)(=O)N(C)C(c1ccccc1)c1ccccc1
Reactant: N
Product: CN(C(c1ccccc1)c1ccccc1)S(=O)(=O)CC(N)=O
Yield: 90 %

Procedure:
The subtitle compound (2.62 g, 90%) was prepared as a white solid from aqueous ammonia solution (10 ml, s.g.=0.88) and methyl (N-diphenylmethyl-N-methylsulfamoyl)acetate (from step (a), 3.05 g, 9.2 mmol), using the method of Example 1(b). m.p. 110-115° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[O:8][C:7]2[C:2]([N:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:22][CH2:23][CH2:24]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1cncc(C(Oc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1

Procedure:
To a solution of 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (150 mg, 0.438 mmol) and 3,4-dihydro-2H-1,4-benzoxazine (59 mg, 0-438 mmol) in dry dioxane (5 mL) was added sodium t-butoxide (63 mg, 0.658 mmol), bis(tri-t-butylphosphine)palladium(0) (22 mg, 0.044 mmol). The mixture was heated to 100 C for 6 h. The reaction was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 4-[3-(dipyridin-3-ylmethoxy)pyridin-2-yl]-3,4-dihydro-2H-1,4-benzoxazine (2-3). LRMS m/z (M+H) Calcd: 397.5, found: 397.1.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4](F)[CH:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCNc1cc(Br)ccc1C(=O)OCc1ccccc1
Temperature: 75 °C
Yield: 14.1 %

Procedure:
Phenylmethyl 4-bromo-2-fluorobenzoate (Example 192, 315 mg, 1.02 mmol) was combined with n-butylamine (110 μl, 1.12 mmol, 1.1 eq.) and solid cesium carbonate (1.66 g, 5.1 mmol, 5.0 eq.) in anhydrous methyl sulfoxide (4 mL) and heated at 75° C. for 1.5 hours. The reaction was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a yellow oil (52 mg, 14%): 1H NMR (300 MHz, CDCl3) δ7.76 (d, 1 H), 7.71 (broad s, 1 H), 7.41-7.32 (m, 5 H), 6.80 (s, 1 H), 6.63 (d, 1 H), 5.26 (s, 2 H), 3.16-3.10 (m, 2 H), 1.69-1.60 (m, 2 H), 150-1.38 (m, 2 H), 0.95 (t, 3 H); MS m/z 362.0 and 364.0 (MH+ and MH+2).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH:25]=O)=[C:23]([F:30])[CH:22]=1.O>ClCCl>[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:23]([F:30])[CH:22]=1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1cc(Br)cc(F)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
Pyrrolidine (25 mL, 0.30 mol) and sodium triacetoxyborohydride (64 g, 0.30 mol) were added in portions to a stirred solution of Intermediate 18a, 4-Bromo-2,6-difluorobenzaldehyde (53.5 g, 0.24 mol) in dichloromethane (500 mL) on ice bath. The reaction mixture was intensively stirred for 12 h at RT. Water (400 mL) was added followed by addition of 5M aq. NaNSO4 to attain pH ˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH ˜10, and extracted with CHCl3 (2×300 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 (100 g) and evaporated in vacuo to give the title compound (52.5 g, 79%, 0.19 mol). LC/MS data: 275.9 and 277.9 (M+H)+ (calculated for C11H12BrF2N, 276.13). 1H NMR data (DMSO-d6): 7.40-7.48 (m, 2H, Ar—H), 3.66 (s, 2H, Ar—CH2), 2.38-2.46 (m, 4H pyrrolidine (CH2)2N), 1.61-1.71 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[CH3:55][N:56]([CH3:67])[C:57](=[O:66])[O:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][C:11]1([C:14](=[O:15])[NH:65][C:61]2[CH:62]=[CH:63][CH:64]=[C:59]([O:58][C:57](=[O:66])[N:56]([CH3:55])[CH3:67])[CH:60]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CN(C)CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1-(tert-Butoxycarbonyl)-4-(2-(dimethylamino)ethyl)piperidine-4-carboxylic acid from step B (100 mg, 0.33 mmol), HATU (175 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.116 mL, 0.67 mmol) were stirred in isopropyl acetate for 10 minutes. 3-aminophenyl dimethylcarbamate (90 mg, 0.5 mmol) was added, and the reaction was stirred at 85° C. for 2 hours, cooled to room temperature, stirred overnight, and then diluted with EtOAc, washed with sat. aq. Na2CO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum, to give the title compound as a viscous oil. MS (ES+) [M+H]+=463.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([S:15](=[O:18])(=[O:17])[NH2:16])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C>Cl>[ClH:14].[Cl:14][C:8]1[C:7]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:6]2[C:11]([CH2:12][CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCc2ccc(Cl)c(S(N)(=O)=O)c2C1
Agent: Cl
Product: NS(=O)(=O)c1c(Cl)ccc2c1CNCC2

Procedure:
2-Acetyl-7-chloro-8-sulfamyl-1,2,3,4-tetrahydroisoquinoline is hydrolyzed in refluxing 10% hydrochloric acid (60 ml.) for 2.5 hours. The reaction mixture is evaporated and the residue treated with methanol amd ether. The solid is filtered off to give 7-chloro-8-sulfamoyl-1,2,3,4-tetrahydroisoquinoline hydrochloride. The hydrochloride is treated with ammonium hydroxide as in Example 9 to give 7-chloro-8-sulfamoyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH2:32][CH2:33][N:34]([CH3:41])[CH:35]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48](Cl)=[O:49]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:48](=[O:49])[CH2:47][C:43]5[S:42][CH:46]=[CH:45][CH:44]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[O:31][CH2:32][CH2:33][N:34]([CH3:41])[CH:35]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN1CCC(N(C)CCOc2cc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)ccc2Cl)C1
Product: CN1CCC(N(C)CCOc2cc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)ccc2Cl)C1
Yield: 55 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[4-chloro-3-({2-[methyl(1-methyl-3-pyrrolidinyl)amino]ethyl}oxy)phenyl]-2-pyrimidinamine using 2-thienylacetyl chloride as described in Example 10, Step E to give a brown solid in 55% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.7 (s, 2H) 2.8 (m, 5H) 3.0 (d, J=14.5 Hz, 4H) 3.1 (s, 2H) 3.8 (s, 1H) 3.9 (s, 1H) 3.9 (s, 2H) 4.0 (s, 1H) 6.5 (d, J=5.3 Hz, 1H) 6.9 (s, 2H) 6.9 (s, 3H) 7.1 (m, 2H) 7.2 (m, 3H) 7.4 (m, 2H) 7.5 (d, J=8.6 Hz, 1H) 7.7 (d, J=20.0 Hz, 1H) 7.9 (s, 1H) 8.3 (d, J=5.1 Hz, 1H) 8.8 (d, J=6.4 Hz, 1H) 9.7 (s, 1H) 10.4 (s, 1H). ES-LC/MS m/z 693 [M+H]+.
Reaction SMILES: [N:1]([C:4]([F:16])([F:15])[C:5]([F:14])([O:9][C:10]([F:13])([F:12])[F:11])[C:6]([O-:8])=[O:7])=[N+:2]=[N-:3].[Na+].S(OC)(O[CH3:22])(=O)=O>>[N:1]([C:4]([F:15])([F:16])[C:5]([F:14])([O:9][C:10]([F:12])([F:13])[F:11])[C:6]([O:8][CH3:22])=[O:7])=[N+:2]=[N-:3]
Reactant: COS(=O)(=O)OC
Reactant: [N-]=[N+]=NC(F)(F)C(F)(OC(F)(F)F)C(=O)[O-]
Agent: [Na+]
Product: COC(=O)C(F)(OC(F)(F)F)C(F)(F)N=[N+]=[N-]
Yield: 84 %

Procedure:
The resulting solution, which contained sodium 3-azido-2-trifluoromethoxytrifluoropropionate, was stirred with 69.3 g (0.55 mole) of dimethyl sulfate for 3 hr. until an initial exothermic reaction subsided. Volatiles were removed at 50° (2 mm, 2.6×10-1 kPa), and the resulting crude ester was fractionated to yield 111.8 g (84%) of methyl 3-azido-2-trifluoromethoxytrifluoropropionate, bp 38°-41° (24 mm, 2.1 kPa). IR (CCl4): 3010, 2960, and 2850 (sat'd CH); 2150 (N3), 1780 (C=O), and 1100-1250 cm-1 (C-F). NMR (CCl4): 1H 3.89 ppm (s, OCH3); 19F-56.0 (d, JFF 8.6 Hz, 3F, OCF3) and -131.6 ppm (q of t, JFF 8.6, 5 Hz, 1F, CF) with an AB for CF2N3 at -8333 and -8521 Hz (d, JFF 5.0 Hz, 1F) and -8548 and -8763 Hz (d, JFF 5.6 Hz, 1F).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35]([O:37]C)=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35]([OH:37])=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N(CC(C)C)C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 4 h
Yield: 123.3 %

Procedure:
Methyl 3-[(tert-butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alaninate (200 mg) was dissolved in tetrahydrofuran-methanol (1:2, 18 ml), 2 M aqueous sodium hydroxide solution (0.95 ml) was added and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and solvent was evaporated under reduced pressure to give the object compound (240 mg).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35](I)[CH3:36].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:35]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:36]
Reactant: CCI
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Ethyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et). 1H NMR (CDCl3): 1.18 (3H), 1.27 (3H), 1.42 (9H), 1.49 (1H), 1.95 (1H), 2.62 (1H), 2.85 (2H), 3.94 (1H), 4.16 (2H), 4.36 (1H), 7.26 (2H), 7.35 (1H), 7.45 (2H), 7.55 (2H), 7.59 (2H).
Reaction SMILES: F[C:2](F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH3:2])[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(C)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting formaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.55 (t, J=5.4, 1H), 7.65 (t, J=6.5, 2H), 7.34 (ddd, J=3.7, 7.6, 10.9, 2H), 7.29-7.25 (m, 1H), 4.42-4.28 (m, 1H), 3.22 (d, J=10.5, 1H), 2.91 (dd, J=2.2, 9.0, 0.5H), 2.65 (dt, J=6.7, 17.3, 1H), 2.53 (dd, J=2.5, 9.2, 1H), 2.46 (dd, J=4.4, 10.2, 0.5H), 2.42-2.35 (m, 0.5H), 2.30 (d, J=8.8, 1.5H), 2.25 (dd, J=2.8, 9.0, 0.5H), 2.19 (s, 1.5H), 2.16-2.05 (m, 3.5H), 1.85 (td, J=6.2, 12.0, 1H), 1.75 (dd, J=6.6, 13.8, 0.5H), 1.63 (dt, J=7.0, 15.3, 0.5H), 1.39 (dt, J=8.1, 14.4, 1H), 1.31 (dt, J=2.9, 9.4, 0.5H), 1.22 (dd, J=6.5, 11.7, 3H), 0.71 (dd, J=2.9, 6.7, 3H); MS (ESI+) m/z 301 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:15][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NC1CCCC1
Product: Clc1cc(Cl)nc(NC2CCCC2)n1
Yield: 35.2 %

Procedure:
2,4,6-Trichloropyrimidine is reacted with cyclopentylamine according to the method of Example 3. The less polar 2-(cyclopentylamino)-4,6-dichloropyrimidine is obtained in a yield of 35.2%, m.p.:48°-52° C.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([C:15](=O)[C:16]([OH:18])=[O:17])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:14][CH2:13]1.[OH-].[K+]>Cl>[Br:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:14][CH2:13]1
Reactant: O=C(O)C(=O)c1ccc(SC2CC2)c(Br)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccc(SC2CC2)c(Br)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
To hydrazine monohydrate (16.9 mL) was added [3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetic acid (15 g) under ice-cooling, followed by stirring at 80° C. for 10 minutes. To the reaction mixture was added potassium hydroxide (8.22 g), followed by stirring at 80° C. for 20 minutes and then stirring at 100° C. overnight. After leaving it to be cooled at room temperature, concentrated hydrochloric acid (50 mL) was added thereto under ice-cooling, followed by extraction with chloroform (50 mL×3). The organic layer was sequentially washed with 1 M hydrochloric acid (50 mL×2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain [3-bromo-4-(cyclopropylsulfanyl)phenyl]acetic acid (13.5 g) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.[SH:17][CH2:18][CH2:19][OH:20].CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([S:17][CH2:18][CH2:19][OH:20])=[CH:3][CH:4]=1
Reactant: OCCS
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1ccc(SCCO)cn1
Temperature: 110 °C
Reaction time: 17 h
Yield: 95.7 %

Procedure:
In a 100 mL round-bottomed flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (502 mg, 1.59 mmol), 2-mercaptoethanol (124 mg, 112 μl, 1.59 mmol), xantphos (46.1 mg, 79.6 μmol) and Hunig's base (411 mg, 556 μl, 3.18 mmol) were combined with dioxane (10.0 ml) to give a light yellow solution. Pd2(dba)3 (36.4 mg, 39.8 μmol) was added and the mixture was evacuated and filled with argon. The reaction mixture was heated to 110° C. and stirred for 17 h under argon. The reaction mixture was cooled to 25° C., concentrated in vacuo and partitioned between 1M HCl and EtOAc. Separated and basified aqueous with 3M NaOH. The aqueous layer was extracted with EtOAc (3×125 mL). The organic layers were combined, washed with sat NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo to a light yellow solid. The solid was dried under vacuum at 25° C. for 21 hrs to afford 0.259 g (96%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 7.94 (d, J=2.3 Hz, 1H), 7.45 (dd, J=8.7, 2.3 Hz, 1H), 6.40 (d, J=8.7 Hz, 1H), 6.03-6.20 (m, 2H), 4.77 (t, J=5.7 Hz, 1H), 3.37-3.51 (m, 2H), 2.67-2.76 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH:7]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=O)=O.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C)C=O>[CH2:25]([O:24][CH:7]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][N:43]1[C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]2[C:39]1=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OCCCCCCCCCCCCCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC(CN1C(=O)c2ccccc2C1=O)OCCCCCCCCCCCCCC
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Crude O-(2,3-dimyristyloxypropyl) methanesulphonate 3 (14.2 g, 25.3 mmol) and potassium phthalimide (13.9 g, 75.0 mmol) were flushed with nitrogen and dissolved in anhydrous N,N-dimethylformamide (250 ml). The reaction was left to stir at 70° C. overnight under a constant stream of nitrogen. The N,N-dimethylformamide was removed on the rotary evaporator using a high vacuum pump instead of the usual aspirator. The residue was dissolved in chloroform (300 ml) and transferred to a separatory funnel with a chloroform rinse (50 ml), then washed with distilled water and ethanol (3×300 ml distilled water, 50 ml ethanol). The combined aqueous washes were back-extracted with chloroform (2×100 ml). The combined organic layers were dried with magnesium sulfate and the chloroform was removed on the rotary evaporator. TLC (30% ether-hexane, developed in Molybdate) indicated that the starting material had reacted to form product. This reaction yielded 13.5 g of crude N-(2,3-dimyristyloxypropyl)phthalimide 4.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C.O>C(OCC)(=O)C.CCCCCC.[Fe]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CSc1ccc(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(Oc3ccc(N)cc3)ncn2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
N-(6-(4-Nitrophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (620 mg, 1.75 mmol), iron powder (489 mg, 8.75 mmol) and ammonium chloride (936 mg, 17.5 mmol) were suspended in an ethanol (16 ml)-water (4 ml) mixed solvent and the suspension was heated and stirred at 80° C. for 1 hour. Upon completion of the reaction, the reaction mixture was filtered with celite and washed in an ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (392 mg, 1.21 mmol, 69%) as colorless crystals.