Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH2:27])=[O:26])[CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([NH2:27])=[O:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: NC(=O)C1CCCNC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCCC(C(N)=O)C3)s2)noc1C(F)(F)F
Yield: 97 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3-piperidinecarboxamide by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (120 mg, 97%). 1H NMR (DMSO-d6) 1.36-1.49 (m, 1 H), 1.55-1.75 (m, 2 H), 1.89-1.93 (m, 1 H), 2.35 (d, J=1.8, 3 H), 3.03 (br s, 2 H), 4.10 (br s, 2 H), 6.90 (s, 1 H), 7.37 (s, 1 H), 7.51 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1 H). 19F NMR −62.2. LC/MS 5.54 min, [M+1]+ 388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CCN)c3cc(Cl)ccc32)cn1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) in pyridine (10 ml) is added acetic anhydride (0.13 ml), and the mixture is stirred at 80° C. for 2 hours, and then stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted hydrochloric acid, water, and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylamino-ethyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (91 mg) as white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([C:25]2[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([C:25]2[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31]([O:9][C@H:4]3[CH2:5][C@@H:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]3)=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)Cl
Reactant: CC1CC(O)CC(C)(C)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(C(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1

Procedure:
5 g of 3,3,5-trimethylcyclohexanol, CIS form, and then 3.5 g of triethylamine dissolved in 10 ml of chloroform are added to 50 ml of pure chloroform. 12 g of 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl chloride diluted in a few ml of chloroform are then added slowly to the solution at low temperature. The mixture is refluxed for three hours and then, after cooling, the organic layer is washed successively with a normal solution of hydrochloric acid, sodium hydroxide and then distilled water. It is evaporated under reduced pressure and the residue is then chromatographed on a silica column with a mixture of petroleum ether and ethyl acetate and finally recrystallized from ethanol to give the title derivative in the form of attractive white crystals melting at 65° C., which in thin layer chromatography give a single spot of Rf 0.45 in the solvent system described in Example 1.
Reaction SMILES: C1COCC1.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CCCCC.CCOCC>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To 250 mL of THF was added 14 g (67 mmol) of 6-bromoquinoline and 44 mL (88 mmol) of 2M butyllithium in pentane was added at -70° under argon. The reaction was stirred for 15 minutes and 28.4 g (87.2 mmol) of tributyltin chloride was added at such a rate that the temperature remained below -60° . When addition was complete, the mixture was allowed to warm to -50° at which point the dark orange color characteristic of the anion became light amber. The mixture was stirred for 14 hrs at -70° and poured into ice-water and ether. The layers were separated, the ether layer washed with water, dried with magnesium sulfate, filtered and concentrated. The resultant oil was chromatographed on a silica gel column (30 cm ×6 cm) using 30% ether in hexane to provide 17.8 g (63%) of 6-quinolinyltributylstannane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]1[C:17]2[NH:18]C(=O)[O:20][C:21](=O)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C[Al](C)C.Cl>C1(C)C=CC=CC=1>[NH2:18][C:17]1[C:12]([O:11][CH3:10])=[CH:13][CH:14]=[CH:15][C:16]=1[C:21]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[CH3:9])=[O:20]
Reactant: Cc1c(N)cccc1Br
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol) and 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) in toluene (20 mL) was treated with 2 M trimethylaluminum in toluene (3.24 mL, 6.47 mmol) at 0° C. The mixture was stirred at room temperature for 10 minutes, then was heated at 70° C. overnight. The mixture was cooled to room temperature, treated with 1N aqueous HCl and extracted 3 times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide as a white solid (302 mg, 35% yield). Mass spectrum m/z 335, 337 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.72 (d, J=7.3 Hz, 2H), 7.46 (dd, J=8.0, 0.8 Hz, 1H), 7.17-7.10 (m, 2H), 6.90 (dd, J=7.9, 0.9 Hz, 1H), 6.72-6.66 (m, 1H), 5.88 (br. s., 2H), 3.92 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[C:17](O)=[O:18]>>[OH:10][CH2:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:17](=[O:18])[C:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[N:1]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc(CO)cc1N
Product: O=c1[nH]c2ccc(CO)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with (3,4-Diamino-phenyl)-methanol and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Hydroxymethyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:22])=[N:11][C:12]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]([CH3:37])[C:18](=[O:20])[CH:17]([O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:22])[N:11]=2)[CH3:21])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc(OC(C)C(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 12 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][C:14]1[N:15]([C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:16]=[CH:17][N:18]=1>O1CCOCC1>[CH3:13][C:14]1[N:15]([C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Cc1nccn1-c1cccc(N)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 70.1 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 0.215 mmol) in dioxane was added 3-(2-methyl-1H-imidazol-1-yl)aniline (90 mg, 0.520 mmol). The mixture was heated in microwave (200 W) for 50 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 48 mg 5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70% yield). LCMS (M+1=319)
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Cl:37][C:38]1[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl.CN1C(=O)CCC1>O1CCOCC1>[ClH:37].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Cl)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (40 mg, 164 μmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-6-methylnicotinamide (51 mg, 181 μmol) were suspended in 1,4-dioxane (1 mL). 4M HCl in 1,4-dioxane (0.16 mL, 0.333 mmol) was added and the reaction was irradiated (CEM personal microwave, 300 W) to a temperature of 160° C. for 60 min. The reaction was cooled to ambient temperature and NMP (1 mL) was added. The reaction mixture was re-heated to 160° C. (microwave irradiation, 300 W) for an additional two hours. The 1,4-dioxane was removed by rotary evaporation and the residue was partitioned between 10% aq. NaHCO3 solution (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted EtOAc (2×10 mL). The combined organic layers were washed with 10% LiCl (20 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative (RP) HPLC Chromatography (YMC S5 ODS, 20×100 mm, 10 minute gradient from 33% to 90% aqueous methanol with 0.1% TFA). The fractions containing the desired product were combined and concentrated. The purified material was dissolved in MeOH (1 mL), acidified with 4 N HCl in 1,4-dioxane (0.10 mL) and concentrated. The resulting salt was triturated with hot EtOAc and collected by filtration to afford a brown solid (4.4 mg, >97% HPLC purity). 1H NMR (DMSO-d6) δ 3.15 (s, 3H), 6.48 (s, 1H), 6.69 (d, 1H, J=6.10 Hz), 6.91 (d, 1H, J=7.63 Hz), 7.06-7.21 (m, 1H), 7.31-7.44 (m, 2H), 7.46-7.64 (m, 3H), 8.12-8.42 (m, 3H), 10.41 (s, 1H), 10.96 (s, 1H), 12.58 (s, 1H); MS(ESI+) m/z 490.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3/[CH:11]=[N:12]/C(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)=[N:7][O:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].I[CH2:41][CH:42]1[CH2:44][CH2:43]1.Cl>O1CCCC1.CC(C)=O>[Br:1][C:2]1[CH:33]=[CH:32][C:5]2[C:6]([C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3[CH:11]([NH2:12])[CH2:41][CH:42]3[CH2:44][CH2:43]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ICC1CC1
Reactant: Fc1ccc(C(/N=C/c2ccccc2-c2noc3cc(Br)ccc23)c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: NC(CC1CC1)c1ccccc1-c1noc2cc(Br)ccc12
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of (E)-N-(2-(6-bromobenzo[d]isoxazol-3-yl)benzylidene)-1,1-bis(4-fluorophenyl)methanamine (Compound 8) (1.34 g) in dry tetrahydrofuran (15 mL) under nitrogen was cooled to −78° C. with stirring and a 1M solution of potassium tert-butoxide in tetrahydrofuran (3.2 mL) added dropwise. Solution turned dark purple. After 20 min (iodomethyl)cyclopropane (1.45 g) was added in one portion and solution slowly warmed to room temperature, stirred at this temperature for 1.5 h then quenched by the addition of water (10 mL) and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated to leave a dark red gum that was dissolved in acetone (20 mL) and an aqueous 2N HCl solution (15 mL) added and the mixture stirred overnight. The acetone was removed by evaporation and the aqueous solution extracted with dichloromethane. The aqueous solution was made basic with sodium bicarbonate and extracted with dichloromethane, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. SCX purification (eluting with methanol then ammonia in methanol) followed by flash chromatography on silica eluting with 0 to 5% methanol in dichloromethane gave the title product (0.39 g).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](O)=[O:48].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:13]([NH:17][C:18]([C@@H:20]1[C:24]([CH3:25])([CH3:26])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:47](=[O:48])[CH2:46][O:45][C:44]1[C:43]([CH3:42])=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:54])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: Cc1cccc(C)c1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)COc2c(C)cccc2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
EDC-HCl (63 mg) was added to a solution of the compound obtained in Step 2 of Example 17 (127 mg), 2,6-dimethylphenoxyacetic acid (54 mg), and HOBt (41 mg) in DMF, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixture of EtOAc and n-hexane to obtain the title compound (130 mg).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1.C=O.[CH3:33]CCCCC.CCOC(C)=O>CC(O)=O>[CH3:33][N:2]([CH3:1])[C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CCCCCC
Reactant: [BH3-]C#N
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)cc4)cc3)sc2c1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)cc4)cc3)sc2c1
Yield: 7 %

Procedure:
Prepared as described in the Amination section using sodium cyanoborohydride (0.44 g, 6.95 mmol), 4-amino-N-[4-(6-methylbenzothiazol-2-yl)-phenyl]-benzamide (0.50 g, 1.39 mmol) and paraformaldehyde (0.42 g, 13.9 mmol) in AcOH (8 ml) to give the title compound (0.04 g, 7%) as a colourless solid after work-up and flash chromatography (3:1 Hexane/EtOAc).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[CH:22]=[O:23])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 12.96 g (60 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 300 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 52.35 ml, (123 mmol) 2.35M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 4.64 ml, (60 mmol) of N,N-dimethylformamide dropwise. The reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 5.72 g of the title compound as a white solid, m.p. 101.5°-103° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH:15]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:31]([C:33]1[CH:55]=[CH:54][C:36]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:51](=[O:53])[CH3:52])=[CH:35][CH:34]=1)=O.[NH:56]1[CH:60]=[CH:59][CH:58]=[CH:57]1>>[C:51]([O:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36]1[CH:54]=[CH:55][C:33]([C:31]2[C:60]3[NH:56][C:57]([C:15]([C:14]4[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=4)=[C:57]4[N:56]=[C:60]([C:15]([C:14]5[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=5)=[C:60]5[NH:56][C:57](=[C:15]([C:14]6[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:17]=6)[C:57]6[CH:58]=[CH:59][C:60]=2[N:56]=6)[CH:58]=[CH:59]5)[CH:59]=[CH:58]4)=[CH:58][CH:59]=3)=[CH:34][CH:35]=1)(=[O:53])[CH3:52]
Reactant: CC(=O)OCCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: c1cc[nH]c1
Reactant: CCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCC)c1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(-c2c3nc(c(-c4cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c4)c4ccc([nH]4)c(-c4cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c4)c4nc(c(-c5ccc(OCCCCCCCCCCCCOC(C)=O)cc5)c5ccc2[nH]5)C=C4)C=C3)c1

Procedure:
The title compound was prepared according to the method described in Example 24 above from 3,5-didecyloxy-benzaldehyde (see Example 13), acetic acid 12-(4-formyl-phenoxy)-dodecyl ester (see Example 6) and pyrrole.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[OH:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([N:25]2[CH2:2][CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:8][CH2:9]3)[C:20]2=[O:22])[CH2:27][CH2:28]1
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@H](O)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (4.80 g, 0.0150 mol), trans-4-aminocyclohexanol hydrochloride (2.5 g, 0.016 mol) and triethylamine (3.3 mL, 0.024 mol) in 1,2-dichloroethane (30.0 mL) was stirred at room temperature for 30 min. To the mixture was added sodium triacetoxyborohydride (7.9 g, 0.038 mol) with stirring. The mixture was stirred at room temperature for 1 h, then was heated at 80° C. for 2 h. After cooling, the mixture was diluted with dichloromethane, and washed with 1N HCl solution, NaHCO3 (7.5%), water, and brine successively, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give benzyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (4.20 g, 72.0%).
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18](N)[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[CH2:22]=O.[BH3-][C:25]#[N:26].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:26]([CH3:25])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: NC1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Into a 25-mL round-bottom flask containing a solution of 1-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (400 mg, 1.24 mmol, 1.00 equiv) in methanol (15 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at room temperature. Then NaBH3CN (152 mg, 2.42 mmol, 2.00 equiv) was added and the resulting solution was stirred for additional 2 h at ambient temperature and diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (450 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (30% CH3CN up to 64.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (380 mg, 87%) as a white solid. MS (ES, m/z): 351 [M+H]+; 1H NMR (300 MHz, CD3OD): δ 4.95 (1H, d), 4.15-4.05 (1, M), 3.01-2.96 (4H, m), 2.59-2.49 (2H, m), 2.32 (6H, s), 2.29-2.23 (3H, m), 1.96 (2H, d), 1.56-1.40 (2H, m), 1.30-1.21 (2H, m).