Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCN(CC)CC.[NH2:45][CH2:46][CH2:47][OH:48].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](=[O:34])[NH:45][CH2:46][CH2:47][OH:48])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: NCCO
Reactant: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)NCCO)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-(L-leucyloxy)-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzoic acid (24, 130 mg, 0.26 mmol), Et3N (78 mg, 0.78 mmol) and 2-amino ethanol (24 mg, 0.39 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The separated organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 70 mg (54%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH3:7])(=[O:5])=[O:4].[H-].[Na+].[CH3:10][C:11]1([CH3:22])[O:20][C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:13]2[O:21][CH:12]12.CCCCCCC>CS(C)=O.C(OCC)(=O)C>[OH:21][CH:12]1[C:11]([CH3:22])([CH3:10])[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]1[CH2:1][NH:2][S:3]([CH2:6][CH3:7])(=[O:5])=[O:4]
Reactant: CCS(=O)(=O)NC
Reactant: CC1(C)Oc2ccncc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: CCS(=O)(=O)NCC1c2cnccc2OC(C)(C)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A solution of 480 mg (3.5 mmol) of N-methylethylsulfonamide in 0.75 ml DMSO (dimethylsulfoxide) is added to a suspension of 27 mg (0.7 mmol) of NaH (60% strength) in 1.5 ml of DMSO. After stirring at room temperature for 2 h, a solution of 0.48 g (2.7 mmol) of 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclo-propa[a]naphthalene (prepared analogously to G. Burell et al. J. Med. Chem. 33 (1990) 3023-3027) in 6 ml of DMSO is added dropwise. The mixture is heated at 60° C. for 4 h and then stirred overnight at room temperature. The reaction mixture is added to ice water and extracted with ethyl acetate. After removing the solvent in vacuo, the solid obtained is stirred with a mixture of heptane and ethyl acetate and filtered off with suction. 400 mg (67%) of ethanesulfonic acid (3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)methylamide are obtained as a solid (m.p. 163° C.).
Reaction SMILES: Cl.N[OH:3].[OH-].[K+].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][N:7]=1>C(O)C>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([NH2:17])=[O:3])=[CH:8][N:7]=1
Reactant: N#Cc1cnnc2ccccc12
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cnnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.76 g of hydroxylamine hydrochloride was added to a stirred solution of 0.72 g of 85% aqueous potassium hydroxide in 25 ml of absolute ethanol at room temperature. The mixture was stirred at room temperature for 20 minutes, then 1.55 g of 27C was added and the mixture was heated at reflux for 3 hours, held overnight at room temperature, and filtered. The filtrate was stripped of solvent to give a dark oil, from which a yellow solid precipitated on standing. The solid was separated, and stirred in hot ethyl acetate. The resulting mixture was filtered, the solvent was stripped from the filtrate and the residue was recrystallized from ethanol to give 27, as a yellow solid, m.p.: 223° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1csc(N2CCN(C)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2nc(CO)cs2)CC1

Procedure:
The reaction described in Preparation 15 was repeated, but using 4.0 g of ethyl 2-(4-methyl-1-piperazinyl)-thiazole-4-carboxylate, 0.6 g of lithium aluminum hydride and 50 ml of tetrahydrofuran, giving the title compound as white prisms.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH:27]1([C:30]([O:26][CH:23]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=5)[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:24][CH3:25])=[O:31])[CH2:29][CH2:28]1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.7 %

Procedure:
A mixture of 1-[9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (112 mg, 0.272 mmol), cyclopropanecarboxylic acid (35.1 mg, 0.408 mmol), 4-dimethylaminopyridine (49.8 mg, 0.408 mmol), triethylamine (76 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg, 0.544 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 13 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (93.5 mg, 0.195 mmol, 72%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14]C(=O)OC(C)(C)C)[C:9]=2[CH:22]=[O:23])=[C:4]([F:24])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:24])[C:9]=1[CH:22]=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a stirred solution of tert-butyl (4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-yl)carbamate (0.9 g, 2.57 mmol) in CH2Cl2 (15 mL) was added TFA (3.95 mL, 51.3 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (15 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude 2-amino-4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.6 g, 2.40 mmol, 41% yield) was carried into the next step without further purification. LCMS (ESI) m/e 251.0 [(M+H)+, calcd for C12H9ClFN2O 251.0]; LC/MS retention time (Method C): tR=1.67 min.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[S:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[N+:15]([C:12]1[S:11][C:10]([NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:14][CH:13]=1)([O-:17])=[O:16]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCC(=O)Nc1ncc([N+](=O)[O-])s1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2Cl2 (7 mL). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then added and the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mL) and extracted with 1M NaOH (3×30 mL). The combined aqueous layers were washed with EtOAc (20 mL) then acidified with 12M HCl and subsequently extracted with EtOAc (5×20 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (1.13 g, 54%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 1.82 (quint., J=7.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S+H]+260.0336. found 260.0344. Method B with 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (30 mg, 0.12 mmol) afforded the title compound VPC161276 (23 mg, 46%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 2.61 (t, J=7.2 Hz, 4H), 1.97 (quint., J=7.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 162.0, 142.8, 141.5, 34.0, 19.3; HRMS (ESI) calcd for [C11H10N6O6S2+H]+ 387.0176. found 387.0185.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:18]=[CH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1CN(Cc1ccccc1)C2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
A solution of 2-benzyl-4-bromoisoindoline (16.7 g, 58.0 mmol) and tributyl(vinyl)tin (20.3 mL, 69.6 mmol) in PhMe (400 mL) was degassed by bubbling nitrogen gas through the solution for 0.25 h. Tetrakis(triphenylphosphine)palladium (0) (1.30 g, 1.16 mmol) was added, and the resulting solution heated in a 100° C. oil bath under nitrogen for 24 h. The contents of the reaction flask were cooled, evaporated and subjected to flash column chromatography eluting with hexane/EtOAc 95/5 to give after evaporation the title compound as a pale oil that turned pink on standing. LRMS (ESI) m/z 236 [(M+H)+; calcd for C17H18N: 236].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[Li].Cl.[CH3:16][O:17][C:18](=[O:23])[C@H:19]([CH2:21][OH:22])[NH2:20].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:20][C@H:19]([C:18]([O:17][CH3:16])=[O:23])[CH2:21][OH:22])=[O:13])[S:10][C:3]=12
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](CO)NC(=O)c1cc2nccc(Cl)c2s1
Yield: 54.2 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (2.69 g, 12.25 mmole), SOCl2 (10 ml), L-serine methyl ester hydrochloride (2.86 g, 18.4 mmole) and Et3N (5.12 ml, 37.7 mmole) in a manner as previously described for example 9d to give a white solid (2.09 g, 54%). 1H NMR (300 MHz, CDCl3) δ8.61 (1H, d, J=5.1 Hz), 8.02 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.89 (1H, m), 4.15 (2H, m), 3.84 (3H, m).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:7].O.NN>C(O)C>[NH2:17][CH2:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:46])([F:1])[F:45])[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=2)[C@H:9]([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:10]1)=[O:15]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Yield: 55.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethyl-carbonyl)piperazine (250 mg), hydrazine hydrate (50 mg) in ethanol (5 ml) was heated under reflux for 2 hours. The resulting precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was washed with aqueous 1N sodium hydroxide solution and then purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (4:1) to afford (2R)-4-(2-aminoacetyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (110 mg).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[CH2:8]([NH2+:15][CH:16]1[CH2:21][CH2:20][CH:19]([C@H:22]([CH3:40])[C@H:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([N:26]2[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]2)=[O:25])[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[C:36]([O:35][C:33](=[O:34])[NH:32][C@H:23]([C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]1)=[O:25])[C@H:22]([CH:19]1[CH2:20][CH2:21][CH:16]([N:15]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:2])[CH2:17][CH2:18]1)[CH3:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@@H](C1CCC([NH2+]Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](C1CCC(N(C)Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step A (0.25 g, 0.54 mmol) in methanol (6 mL) was added a 37% aqueous solution of formaldehyde (0.10 mL, 1.62 mmol), followed by sodium triacetoxyborohydride (0.46 g, 2.16 mmol). After 3 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo, affording the title compound as a clear oil. This material was used without further purification. LC/MS 476.5 (M+1).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([NH2:39])=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([NH:39][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: FC(F)(F)c1cccc(-c2cccn3nc(Cl)nc23)c1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc(C(F)(F)F)c5)cccn4n3)cc2CC1

Procedure:
7-[8-(3-Trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(3-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.272 g, 914 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.360 g, 1.37 mmol) in a manner analogous to Example 311a and 311b to give product (0.203 g, 44%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.83 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.95 (d, 1H), 7.82 (m, 2H), 7.50 (m, 2H), 7.15 (t, 1H), 7.05 (d, 1H), 3.45 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H). MS=524 (MH)+.
Reaction SMILES: [CH3:1]N(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)=[CH:9][CH:8]=1.[H-].[Na+].CI>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:1])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:14]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(F)cc2)C1
Yield: 88 %

Procedure:
To an N,N-dimethylformamide solution (3.9 mL) of tert-butyl [1-(4-fluorophenyl)pyrrolidin-3-yl]carbamate (195 mg, 0.70 mmol) synthesized in Reference Synthesis Example 79, sodium hydride (28 mg, 0.70 mmol, purity 60%) and methyl iodide (44 μL, 0.70 mmol) were added at 0° C. and the resultant solution was stirred at room temperature for 1 day. To the reaction solution, the same amounts of sodium hydride and methyl iodide were further added and the resultant mixture was stirred for 1 day. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography (hexane/ethyl acetate=9/1) to obtain the title compound (181 mg, yield 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:20][C:15]2[CH:14]=[CH:13][C:12]([C:21](=[O:23])[CH3:22])=[C:11]([OH:10])[C:16]=2[CH2:17][CH2:18][CH3:19])=[CH:4][CH:5]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(Cl)nc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
Add 5-chloromethyl-2-chloropyridine (4.12 g, 25.4 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (4.94 g, 25.4 mmol) in dimethylformamide (40 mL). After 10 minutes add potassium carbonate (5.27 g, 38.1 mmol) and cesium carbonate (8.28 g, 25.4 mmol). Stir at room temperature for one hour, and then heat to 70° C. for 2 hours. Cool, partition between ethyl acetate (300 mL) and water (300 mL). Wash twice with water, brine, dry, and concentrate. Dissolve the crude solid in dichloromethane, and add hexane (70 mL) slowly. Triturate and filter to afford the title compound as an orange powder (2.95 g, 36%): 1H NMR (CDCl3) δ 0.94 (t, 3H), 1.55 (sextet, 2H), 2.58 (s, 3H), 2.67 (t, 2H), 5.14 (s, 2H), 6.47 (d, 1H), 7.38 (d, 1H), 7.60 (d, 1H), 7.73 (d, 1H), 8.47 (s, 1H), 12.75 (s, 1H).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[C:18]=2[CH:19]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Temperature: 0 °C

Procedure:
95 G. of 1-carbethoxy-4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine are stirred together with 1,000 ml. of ethyleneglycol, 77 g. of potassium hydroxide and 10 ml. of water on a bath of 160° for 6 hours. The reaction mixture is poured over ice water and extracted with ether. The ether extract is washed with water, dried and evaporated, whereby 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine is obtained as a red-brown viscous oil. After recrystallization from acetone/petroleum ether the product is obtained as crystals having a melting point of 125°-127°.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[C:6]1([C:12]([CH:14]=O)=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>O>[C:6]1([CH:12]2[CH2:14][NH:4][CH2:1][CH2:2][NH:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=CC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: c1ccc(C2CNCCN2)cc1
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
To a stirring solution of ethylenediamine (1.2 g, 20.0 mmol) in IMS (10 mL) was added a solution of phenylglyoxal hydrate (3.0 g, 20.0 mmol) in IMS (20 mL) dropwise. The resultant solution was stirred at room temperature for 3 hours and then sodium borohydride was added and the reaction mixture stirred over the weekend. Water (25 mL) was added and stirring continued for 15 minutes then the ethanol was removed by evaporation. A further amount of water (25 mL) was added and the solution was extracted with DCM (×3) then the combined organics were washed with brine, dried and the solvent evaporated. The material was purified by column chromatography using a silica II cartridge, eluting with 0-20% ammonia in methanol to afford 2-phenyl-piperazine as a pale yellow-orange solid (1.9 g). LCMS m/z 163.36 [M+H]+ R.T.=0.34 min (Analytical Method 6).