Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([OH:15])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>C1COCC1>[CH:11]1([O:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCC2)nc1

Procedure:
A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and cyclobutanol (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0° C. while NaH (1.18 g, 46.7 mmol) was added in three portions over ˜10-20 s under air (Caution: Extensive gas evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at “rt” for 1 h. The reaction was concentrated under reduced pressure at 80° C., taken up in 0.75 M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1×100 mL, 1×50 mL). The combined organic layers were dried (Na2SO4), concentrated, taken up in MeOH (2×100 mL) and concentrated under reduced pressure at 60° C. to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 80%). 1H NMR (300 MHz, CDCl3) δ 9.04 (dd, J=2.84 and 0.40 Hz, 1H), 8.33 (dd, J=9.11 and 2.85 Hz, 1H), 6.77 (dd, J=9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H).
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([OH:23])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:57][C:58]([F:74])([F:73])[CH2:59][NH:60][CH2:61][C:62]1[CH:63]=[C:64]2[C:69](=[CH:70][CH:71]=1)[C@H:68]([NH2:72])[CH2:67][CH2:66][CH2:65]2>C1COCC1>[S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([NH:72][C@H:68]1[C:69]2[C:64](=[CH:63][C:62]([CH2:61][NH:60][CH2:59][C:58]([F:57])([F:73])[F:74])=[CH:71][CH:70]=2)[CH2:65][CH2:66][CH2:67]1)=[O:23])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: N[C@@H]1CCCc2cc(CNCC(F)(F)F)ccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CNCC(F)(F)F)ccc32)cc1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (214 mg, 0.64 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (340 μl, 1.92 mmol, 3.0 eq.) and HATU (292 mg, 0.77 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((2,2,2-trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A53) (0.64 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 0.7% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 22% (80 mg, 0.14 mmol); MS, Rt=3.2 min; m/z=575.0 [MH]+
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:15]=1[CH:16]=O)[CH3:13].[BH3-]C#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH2:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([CH2:12][CH3:13])[C:15]=1[CH2:16][NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCc1cccc(CC)c1C=O
Reactant: Cc1nc2cccc(N)c2[nH]1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCc1cccc(CC)c1CNc1cccc2nc(C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Amino-2-methylbenzimidazole (0.79 g, 5.4 mmol) and 2,6-diethylbenzaldehyde (1.1 g, 6.6 mmol) were dissolved in methanol (30 ml). ZnCl2 (0.9 g, 6.6 mmol) and subsequently NaBH3CN (0.42 g, 6.6 mmol) in small portions were added and the mixture was refluxed under argon for 3 hours and was stirred at room temperature for 16 h. The mixture was poured over an aqueous 1M NaOH solution (50 ml). The resultant yellow suspension was extracted with DCM and the organic solution was washed with brine, dried over Na2SO4 and then evaporated under reduced pressure. The oily residue (1.8 g) was purified by crystallization from a mixture of ethyl acetate and acetonitrile to give 0.65 g (41%) of the title compound.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.[CH2:20]=[O:21]>C1COCC1>[OH:21][CH2:20][C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of tert-butyl cyclopropylsulfonylcarbamate (30 g, 136 mmol) in 750 mL of THF was added dropwise butyllithium (1.6 M in hexane, 212 mL, 339 mmol) over 30 min at −78° C. and the resulting mixture was stirred at −78° C. for 1 h. Formaldehyde gas was generated from para-formaldehyde (by heating at 180° C.) and was purged into the above reaction mass for 30 min at −30° C. The reaction was stirred at the same temperature for 1 h, then allowed to warm to room temperature. The reaction was quenched with aqueous ammonium chloride solution and diluted with water. The resulting mass was washed with ethyl acetate and the aqueous layer was acidified to pH ˜2 and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated under reduced pressure to get desired compound (27 g, 79%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.90 (sb, 1H), 4.95 (sb, 1H), 3.75 (s, 2H), 1.42 (s, 9H), 1.27 (m, 2H), 1.08 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:20]I>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][CH:14]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:13]1[I:20]
Reactant: Nc1c(Br)cccc1C1C=CCCC1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cccc2c1NC1C(I)CCCC21
Reaction time: 3 h

Procedure:
To the 2-bromo-6-cyclohex-2-en-1-ylaniline mixture (0.85 g, 3.4 mmol) above in dichloromethane (50 mL) was added sodium bicarbonate (2.3 g, 27 mmol) followed by iodine (3.5 g, 14 mmol). The reaction was stirred for 3 hours and then diluted with dichloromethane (100 mL). The organic phase was washed with a 10% w/w aqueous solution of sodium thiosulfate, washed with brine, and was dried by passing through a hydrophobic frit. The organic solution was concentrated to leave crude 8-bromo-1-iodo-2,3,4,4a,9,9a-hexahydro-1H-carbazole. MS m/z 378, 380 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([N:19]([CH2:21][C:22]([OH:24])=O)[CH3:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)[N:33]2[CH2:36][C:35](=[CH:37][S:38]([CH2:41][C:42]3[CH:43]=[C:44]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)[CH:45]=[CH:46][CH:47]=3)(=[O:40])=[O:39])[CH2:34]2)=[CH:28][CH:27]=1>ClCCl>[C:15]([O:14][C:12](=[O:13])[N:19]([CH2:21][C:22]([N:51]1[CH2:52][CH2:53][N:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][S:38]([CH:37]=[C:35]3[CH2:34][N:33]([CH:32]([C:29]4[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=4)[C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=4)[CH2:36]3)(=[O:39])=[O:40])[CH:43]=2)[CH2:49][CH2:50]1)=[O:24])[CH3:20])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine and then 10 cm3 of dichloromethane are successively added, at a temperature close to 20° C., to 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a temperature close to 20° C., the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 5 cm3 of dichloromethane. The combined filtrates are washed with 20 cm3 of water, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 143 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm). A mixture of rotamers is observed at room temperature; 1.31 and 1.41 (2s, 9H in total), 2.78 and 2.81 (2s, 3H in total), 2.93 (2s, 3H), from 3.10 to 3.25 (unresolved complex, 4H), from 3.45 to 3.65 (mt, 4H), 3.80 (mt, 2H), 4.06 and 4.09 (2s, 2H in total), 4.19 (mt, 2H), 4.78 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:26]([N:28](CC)CC)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:28][CH3:26])[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCC3)n2)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N2CCC2)n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
0.20 9 (0.00059 mol) of 4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 0.4 g (0.00588 mol) of methylamine hydrochloride and 2.28 ml (0.0176 mol) of triethylamine and stirred in an autoclave at 130° C. for 8 hours. The reaction mixture was freed from solvent and the residue was chromatographed on silica gel with methanol/dichloromethane 1:19. There was obtained 0.053 g (27%) of 4-amino-N-(2-azetidin-1-yl-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as light beige crystals; m.p.: >260° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20]Cl)=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3cc(Br)ccc3c21
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A solution of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.65 g, 20.8 mmol) in DMF (20 mL) was added dropwise via addition funnel to a solution of N-hydroxyphthalimide (4.07 g, 25.0 mmol) and triethylamine (4.3 mL, 31.2 mmol) in DMF (20 mL). The addition funnel was rinsed with DMF (20 mL) and the rinse was added to the reaction solution, which was stirred at room temperature. After 30 minutes, a precipitate formed. The viscous mixture was stirred at room temperature overnight, then diethyl ether (150 mL) was added. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 7.44 g of 2-{[4-amino-7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione, which contained some triethylamine hydrochloride. The filtrate was concentrated to yield 8.5 g of a brown oil, which was found to contain product and was combined with the material from above and used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10])([O-:3])=[O:2].C[O-].[Na+].[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>CO>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH:13][C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Reactant: O=C(Cl)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
5-nitroisatoic anhydride (20.8 g, 0.1 mol) ) was heated to reflux with sodium methoxide (0.5 g, 0.01 mol) in methanol (600 mL). After 1 h, the solvent was evaporated under vacuum and the residue dissolved in 1,2-dichloroethane (400 mL), washed with cold water and dried over MgSO4. Cyclopropanecarbonyl chloride (20.9 g, 0.2 mol) was added to the solution and then heated at 80° C. for 4.5 h. The mixture was allowed to cool and water (200 mL) was added under vigorous stirring. After 0.5 h, the stirring was interrupted and the phases separated, the C2H4Cl2 layer washed with sodium bicarbonate solution and dried over MgSO4. Evaporation of the solvent afforded 2-(cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester (21.7 g, 0.082 mmol). This material was dissolved in methanol (500 mL) and 10% Pd/C (2.2 g) was added. The flask was then flushed with H2 and stirred at room temperature and at 1 atm. After 5 h reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the combined filtrate evaporated to dryness to give the pure title compound as a grey solid (18.0 g, 0.077 mol).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)#[CH:25]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1-c1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-fluorobenzene. MS (+ESI) m/z: 391.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[N:12]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][CH:21]=2)[CH2:14][CH2:13]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc([N+](=O)[O-])c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 1-(2-methoxy-6-nitrophenyl)-4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepane (250 mg), 5% Pd/C (20 mg) in 50 mL of ethyl acetate was subjected to a Parr shaker at 65 psi of hydrogen for 16 hours. More 5% Pd/C (10 mg) was added and the reaction continued for another 16 hours. Filtration through celite followed by flash chromatography (0 to 10% MeOH in ethyl acetate) gave 3-methoxy-2-[4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepan-1-yl]-phenylamine (210 mg, 90%). MS (ES) m/z 395.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[N:7]([CH2:16][CH2:17][CH2:18][O:19]S(C)(=O)=O)[C:6]=2[CH:24]=1.[O:25]=[C:26]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]2[NH:27]1.C(=O)([O-])[O-].[K+].[K+].[ClH:46]>C(O)C.CO.O>[OH2:19].[ClH:1].[ClH:46].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[N:7]([CH2:16][CH2:17][CH2:18][N:37]3[CH2:38][CH2:39][C:34]4([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]5[NH:27][C:26]4=[O:25])[CH2:35][CH2:36]3)[C:6]=2[CH:24]=1
Reactant: O=C1NC2CCCCN2C12CCNCC2
Reactant: CS(=O)(=O)OCCCN1c2ccccc2CCc2ccc(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: O=C1NC2CCCCN2C12CCN(CCCN1c3ccccc3CCc3ccc(Cl)cc31)CC2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 5 g of 3-chloro-5-(3-methylsulfonyloxypropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, 4 g of 1,2,3,5,6,7,8,8a-octahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine, 4 g of potassium carbonate and 4 g of water in 40 ml of ethanol is stirred at 60° C. for 4 hours. The upper layer is separated and concentrated, and the residue is dissolved in 100 ml of toluene. The toluene solution is washed with water, dried, concentrated to about 15 ml and allowed to stand. The precipitated crystals are collected by filtration and recrystallized from ethanol. The crystals thus obtained are dissolved in methanol, and methanolic hydrochloric acid is added to give 1'-[3-(3-chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-1,2,3,5,6,7,8,8a-octahydro-2-oxo-imidazo[1,2-a]pyridine-3-spiro-4'-piperidine dihydrochloride monohydrate, m.p. 261° C. This product is dried at 120° C. under reduced pressure for 4 hours to give the anhydrous product as white crystals, m.p. 271° C., 4.3 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:29])=[CH:23]3)[CH:11]=1>>[CH3:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([NH:19][C:16]1[CH:15]=[CH:14][N:13]=[C:12]3[CH:11]=[C:10]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[S:18][C:17]=13)=[CH:28][CH:27]=2
Reactant: OB(O)c1cccs1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccs5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-thiophene-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.01 (d, 1H), 7.39 (d, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.26 (d, 1H), 7.01 (dd, 1H), 6.94 (dd, 1H), 6.53 (d, 1H), 6.09 (s, 1H), 2.39 (s, 3H); RP18-HPLC RT: 5.78 minutes; API MS: 362 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:3]=1[F:23].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([NH2:11])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:3]=1[F:23]
Reactant: O=[N+]([O-])c1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Reaction time: 1.5 h

Procedure:
For scale up synthesis, a solution of (4,5-difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodo-phenyl)-amine (165 g) and NH4Cl in 2.5 L of THF and 2.5 L of water was cooled to between 0° C. and 5° C. Zinc dust was added (portionwise) at a temperature of less than 25° C. (exothermic during first half of addition) over 30 minutes. The addition of zinc dust resulted in a color change from yellow to dark purple and to pale yellow. Complete conversion was achieved with the addition of NH4Cl (50 g) and zinc (60 g), followed by vigorous stirring for 20 minutes and a further 1.5 hours. Purity was 89.5%. The suspension was filtered and rinsed with 1 L of water and 1.5 L of THF. The combined solution was concentrated to remove THF (87.7% purity). 3 L of EA was added with stirring for 30 minutes. The layers were separated; the EA layer was washed with 2 L of water twice and then dried of MgSO4. The EA was filtered and concentrated to dryness. The crude was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, 1H), 7.46 (dd, 1H), 7.40 (bs, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 6.11 (t; 1H); 5.33 (bs, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH3:24])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:11]=1.CC1C=C(C=CC=1)N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:54][CH2:55][C:56]([N:58]1[CH2:63][CH2:62][CH:61]([O:64][C:65]2[CH:70]=[C:69]([F:71])[CH:68]=[CH:67][C:66]=2[Cl:72])[CH2:60][CH2:59]1)=[O:57]>CN(C=O)C.O>[Cl:72][C:66]1[CH:67]=[CH:68][C:69]([F:71])=[CH:70][C:65]=1[O:64][CH:61]1[CH2:62][CH2:63][N:58]([C:56](=[O:57])[CH2:55][NH:54][C:21]([C:19]2[N:18]=[N:17][N:16]([C:12]3[CH:11]=[C:10]([CH3:24])[CH:15]=[CH:14][CH:13]=3)[CH:20]=2)=[O:23])[CH2:59][CH2:60]1
Reactant: Cc1cccc(-n2cc(C(=O)O)nn2)c1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(-n2cc(C(=O)NCC(=O)N3CCC(Oc4cc(F)ccc4Cl)CC3)nn2)c1
Reaction time: 0.03 h
Yield: 75.3 %

Procedure:
DIPEA (171 mg, 1.32 mmol) was added to a stirred solution of 1-m-tolyl-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-methylaniline) in DMF (5 mL) followed by HOBt (44 mg, 0.32 mmol) and EDCI (141 mg, 0.73 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone (105 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the precipitate was collected The solid obtained was purified by recrystallisation from a solvent system EtOAc:hexane:MeOH (2:8:0.2) to afford 103 mg (74.1% Yield) of 1-m-tolyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 472, 96.02%. 1H NMR (300 MHz, DMSO-d6): δ 8.5 (t, 1H), 7.86 (s, 1H), 7.8 (d, 1H), 7.54-7.44 (m, 2H), 7.38-7.24 (m, 4H), 6.88 (t, 1H), 4.9 (m, 1H), 4.3 (d, 2H), 3.8 (m, 2H), 3.5 (s, 2H), 2.4 (s, 3H), 2.1 (d, 2H), 1.8 (d, 2H).