Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]([CH3:27])([CH3:26])[CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:22][C:13]1[C:12]2=[N:11][N:10]([CH2:23][CH2:24][CH3:25])[C:9]([CH2:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:27])[CH3:26])=[C:21]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
Methanesulfonyl chloride (232 μL, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3 hours at 0° C., the solution was stirred for 2 days at ambient temperature. To the solution was added 2 M aqueous sodium carbonate. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid. The crude product was purified by IFC (silica gel, elution with 10% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to provide a white foam that was crystallized from acetonitrile, isolated by filtration, and dried to yield 600 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white solid, mp 130-139° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=23)=[CH:29][CH:28]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(-c3ccc(CN)cc3)c2n1
Yield: 73 %

Procedure:
The Suzuki coupling of (S)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (4-(aminomethyl)phenyl)boronic acid under the same conditions as described in example 5.6.5 to give 73% of the titled compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.44 (br. s., 9 H) 1.90 (dd, J=9.92, 5.51 Hz, 1 H) 1.96-2.11 (m, 3 H) 3.35-3.45 (m, 4 H) 4.07-4.21 (m, 3 H) 6.33 (br. s., 1 H) 7.46 (d, J=8.38 Hz, 2 H) 8.19 (br. s., 2 H) 8.25-8.36 (m, 2H); LRMS (ESI) m/e 423.0 [(M+H)+, calcd for C23H30N6O2 422.0].
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7]>>[C:1]([CH2:2][NH:5][CH:6]([CH3:7])[C:8]([OH:10])=[O:9])#[N:4]
Reactant: C[C@H](N)C(=O)O
Reactant: N#CCO
Product: CC(NCC#N)C(=O)O

Procedure:
One suitable reaction scheme for the synthesis of an intermediate starting with alanine is shown in Scheme I. In step(a) alanine is contacted with glycolonitrile to form 2-(cyanomethylamino)propionic acid (I). The molar ratio of alanine to glycolonitrile is generally about 1:1 with a slight excess of glycolonitrile preferred. ##STR2##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(#N)C.[I-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 92.9 %

Procedure:
4,6-Dichloropyrimidine (149 mg, 1 mmol), 4-chlorophenol (135 mg, 1.05 mmol), potassium carbonate (166 mg, 1.2 mmol) and sodium iodide (7.5 mg, 0.05 mmol) were stirred in acetonitrile (3 mL) at 20° C. under an atmosphere of nitrogen for 16 h. The reaction was poured onto 1 N aqueous sodium hydroxide solution and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (224 mg, 93%) was obtained as a pale-yellow solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]2=[O:24])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)[C:12](=[O:24])[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@H](N2CCN(C(=O)OC(C)(C)C)CC2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](C(=O)O)CC2)C(=O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
t-Butyl 4-[trans-4-(methoxycarbonyl)cyclohexyl]-3-oxopiperazine-1-carboxylate (385 mg) obtained in Reference Example 71 (3) is dissolved in methanol (8 ml), and thereto is added 1 N aqueous sodium hydroxide solution (3.4 ml) under ice-cooling. The reaction solution is stirred at room temperature for 20 hours and concentrated under reduced pressure. Water and chloroform are poured to the residue, and aqueous layer is acidified by addition of 2 N hydrochloric acid. The organic layer is separated, washed with saturated brine and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure to give the title compound (375 mg).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:16][CH:15]=3)=[O:13])=[C:10]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36]C)[S:9][C:8]=2[CH:38]=1.Cl.CCOCC>C(Cl)Cl.CC(O)C.C(Cl)(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:19]=3)=[O:13])=[C:10]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])[S:9][C:8]=2[CH:38]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3OC)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)sc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Prepare the HCl salt of [6-methoxy-2-(2-methoxy-benzyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone by adding sat. HCl/Ether to a solution in CH2Cl2. Concentrate to dryness and redissolve in CH2Cl2 (5 mL). Cool this solution to 0° C. and add BBr3 (1 mL). Stir for 2 h while warming to r.t. Quench the reaction with sat. NaHCO3 and dilute with i-PrOH/CHCl3 (1:3). Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2) to afford [6-hydroxy-2-(2-hydroxy-benzyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (300 mg, 54%, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)O)[CH:17]=[CH:18][C:13]=3[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:19]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)([C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCc1nnnn1-2
Reactant: O=S(Cl)Cl
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCc1nnnn1-2
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4H-tetrazolo[1,5-a][1,4]benzodiazepine-8-methanol (see Example B9) (0.0015 mol) in thionyl chloride (10 ml) was stirred at 5° C. for 5 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 8-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-4H-tetrazolo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[C:16](=O)[C:15]([CH3:25])(C2CCCCC2)[CH2:14]3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[CH2:16][C:15]([CH2:25][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:14]3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2cccc3c2C(=O)C(C)(C2CCCCC2)C3)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)cc(-c2cccc3c2CC(CC2CCCCC2)=C3)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 183.5 %

Procedure:
25.3 g (76.1 mmole) 7-(3′,5′-Dimethylphenyl)-2-cyclohexyl-methyl-indan-1-one were dissolved in 90 ml toluene in a 500 ml-roundbottom flask equipped with a reflux condenser. 3.17 g (1.1 eq.) sodium borohydride were added. Then 13.3 ml (4.35 eq.) methanol were added at 50° C. and the mixture was stirred for 3 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 90 ml of toluene. After addition of 0.3 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent afforded 22.1 g (92%) of the desired indene as a slightly offwhite oil. 1H-NMR (400 MHz, CDCl3): δ=7.35 (d, 1H, aromatic), 7.24 (m, 1H, aromatic), 7.15 (m, 3H, aromatic), 7.01 (s, 1H, aromatic), 6.68 (s, 1H, C═CH), 3.37 (s, 2H, benzylic), 2.39 (s, 6H, PhCH3), 2.36 (d, 2H, CH2Cy), 1.74-0.91 (m, 11H, aliphatic) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>CC(N(C)C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:16]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1ccccc1N
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 0 °C
Yield: 16.3 %

Procedure:
2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) were heated with stirring in DMAC (20 ml) at 80° C. for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, then dried and purified by column chromatography (silica gel-ethyl acetate/n-hexane) to afford 43 (0.3 g, 15.0%) and 61 (1.4 g, 75.2%) as pale yellow powder. Yield, mp, and spectral data are given in Table 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:34][C:10]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1
Reactant: ClCc1cscn1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 20 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a white solid in 20% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.78 (s, 3H), 2.23 (s, 3H), 3.41 (dt, 1H), 3.58 (dt, 1H), 4.87 (m, 1H), 5.25 (s, 2H), 7.11 (d, 1H), 7.21 (d, 1H), 7.29 (d, 1H), 7.53 (d, 1H), 7.63 (dd, 1H), 7.69 (t, 1H), 7.76 (d, 1H), 8.23 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.96 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([CH3:20])=[C:10]([NH:12]C(=O)OC(C)(C)C)[N:11]=[C:5]2[CH:4]=1.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:12][C:10]1[N:11]=[C:5]2[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:21])[CH:8]=[CH:7][N:6]2[C:9]=1[CH3:20]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2cc(C(F)(F)F)ccn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N)nc2cc(C(F)(F)F)ccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 17-C (0.221 g, 0.7 mmol) was dissolved in 4N HCl in dioxane (7 mL) and the reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated in vacuo to give compound 17-D as a light yellow solid; MS m/z (M+H+) 216.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:42]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:43])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(F)cnc32)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCOCC5)C4)n3)c3cc(F)cnc32)cc1
Reaction time: 1 h

Procedure:
(1S,3R)—N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (50 mL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additional two hours. The resulting precipitate was collected by filtration, washed with water (3×50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 40 g column using EtOAc/DCM 20-100%, to provide 2.0 g of N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide as a white solid.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>O>[CH:1]1([O:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][CH:21]3[O:23][CH2:22]3)=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(CCOC2CCCCC2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(OCC2CO2)ccc1CCOC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
13.3 g (0.06 mol) of 4-(2-cyclohexyloxyethyl)-phenol, 3.04 (0.076 mol) of sodium hydroxide pellets and 50 cc of water are introduced into a round-bottomed flask. The mixture is stirred at ambient temperature and, when the solution has become homogeneous, 18.6 g (16 cc, 0.2 mol) of epichlorohydrin are introduced. The stirring is continued at ambient temperature for 16 hours. Extraction is carried out with diethyl ether and the organic phase is washed with water. It is dried over magnesium sulphate and the ether is driven off. This gives an oil, which is used directly in the next step.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:31])(C)=C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][CH2:19][N:18]1[C:17]2[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:16]=2[N:15]=[C:14]1[CH2:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4][C:5]1=[O:31]
Reactant: C=C(C)n1c(=O)n(Cc2nc3cc(C(=N)N)ccc3n2CCC(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C(=N)N)ccc21
Yield: 95.6 %

Procedure:
2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (20 mg, 0.05 mmol) was dissolved in 30% TFA/CH2Cl2 and stirred at reflux for 1 h. The solvent was removed and the residues triturated with ether to give 18 mg (99%) of 1-(3-methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carboxamidine as a white solid as the TFA salt.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[CH:17]=[CH:18][C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[C:2]=[O:3])=[CH:12][C:11]=1[CH:17]=[CH:18][C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]
Reactant: CC(Cl)OC(=O)C=Cc1cc(N)ccc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)OC(=O)C=Cc1cc(N=C=O)ccc1Cl

Procedure:
108.8 g of trichloromethyl chloroformate were added to a suspension of 130 g of 4-chloro-3-(α-chloroethoxycarbonylethenyl)-aniline in 1200 ml of toluene. The stirred mixture was refluxed for 16 hours. After the resulting precipitate had been separated off, the solvent was removed under reduced pressure, the residue was stirred with petroleum ether and the precipitate was removed and dried.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:27])[CH:11]([C:20]1(O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CN=CC=1.O=S(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>N1C=CC=CC=1.O>[CH2:1]([O:8][N:9]1[C:20]2([CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C1(O)CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C12CCOCC2
Temperature: 57 °C
Reaction time: 6 h

Procedure:
N-(Benzyloxy)-N2 -(t-butoxycarbonyl)-α-(4-hydroxy-2,3,5,6-tetrahydro-4-pyranyl)glycinamide (1.9 g, 5 mmoles) in 20 ml of dry pyridine under argon was treated with 1.05 g (6.5 mmoles) of pyridine-sulfur trioxide and heated to 57° C. for 2 hours. The volatiles were removed in vacuo. Dry acetonitrile was added and evaporated four times, and the residue was treated with a solution of 5 g (36 mmole) of potassium carbonate in 12.5 ml of water, followed by 40 ml of ethyl acetate. The mixture was heated to reflux with vigorous stirring for 6 hours. The mixture was cooled, diluted with water, and the layers separated. The organics were washed with 3% potassium bisulfate and brine, dried (sodium sulfate) and evaporated to a solid. Chromatography on 350 ml of LPS-1 in hexane:ethyl acetate (1:1) and evaporation of the pure product fractions (Rf=0.56 in same solvent) gave a solid. Trituration with isopropyl ether and air drying gave the product as a white solid, 0.78 g, melting point 144°-146° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.C(OCC)C.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Reactant: CCCCN
Solvent: CCOCC
Solvent: CO
Product: CCCCNc1ccc2cccc([N+](=O)[O-])c2n1
Temperature: 78 °C
Yield: 90 %

Procedure:
2-chloro-8-nitroquinoline (0.20 g; 0.96 mmol) is suspended in 9.5 ml of 1-butylamine and the medium is heated under reflux (78° C.) for 15 hours. The yellow solution obtained is subsequently concentrated under vacuum. The crude reaction product is taken up in a minimum volume of CH3OH and poured over 3 ml of diethyl ether. After centrifugation, butyl ammonium chloride crystals are removed and the supernatant is concentrated under reduced pressure to yield N-butyl-8-nitro-2-quinoline amine in the form of a yellow oil (0.21 g; 0.86 mmol, yield=90%). NMR-1H (250 MHz, CDCl3) δ, ppm: 7.83 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.77 (d, 3J (H, H)=9.0 Hz, 1H); 7.69 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.14 (m, 1H), 6.67 (d, 3J (H, H)=9.0 Hz, 1H); 5.07 (s large, 1H); 3.47 (m, 2H); 1.60 (m, 2H); 1.39 (m, 2H); 0.93 (t, 3J (H, H)=7.5 Hz, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.8 (Cq); 145.6 (Cq); 140.2 (Cq); 136.7 (CH); 131.5 (CH); 124.7 (CH); 124.1 (CH); 119.7 (CH); 113.3 (Cq); 41.3 (CH2); 31.5 (CH2); 20.2 (CH2); 13.8 (CH3). MS (CID, NH3): m/z=246 (MH+). Analysis (%) for C13H15N3O2: calculated C, 63.66. H, 6.16. N, 17.13. found C, 63.33. H, 6.21. N, 16.64.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[C:11](=[N:13]/O)/[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:16])([CH3:15])[O:3]1>CC(O)=O.[Zn]>[NH2:13][CH:11]([C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:15])([CH3:16])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)[CH3:12]
Reactant: C/C(=N\O)c1ccc2c(c1)B(O)OC2(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of crude compound (E)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone oxime (0.93 mmol) and zinc dust (260 mg, 4.0 mmol) in AcOH (8 mL) was heated to 40° C. and stirred for 0.5 h. LC-MS showed SM disappeared. The reaction mixture was used for next reaction directly without being purified.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[F:38][C:39]([F:53])([F:52])[CH2:40][O:41][C:42](=O)[O:43]N1C(=O)CCC1=O.FC(F)(F)CO.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1>C([O-])([O-])=O.[K+].[K+].C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[F:38][C:39]([F:53])([F:52])[CH2:40][O:41][C:42](=[O:43])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(OCC(F)(F)F)ON1C(=O)CCC1=O
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCC(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (0.09 g, 0.17 mmol, product of example 8) in K2CO3 1M (3 mL) and THF (1 mL) was added carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2,2,2-trifluoroethyl ester (0.05 g, 0.20 mmol), prepared from 2,2,2-trifluoroethanol, N,N′-disuccinimidyl carbonate and triethylamine in tetrahydrofuran. The mixture was stirred to room temperature for 24 h. Ethyl acetate was added and the organic layer was washed with water, then dried with MgSO4 and concentrated. The residue was purified by flash chromatography eluting with a mixture of hexane/EtOAc. The yield obtained was 10%.