Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C@H:12]([NH:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[Na+].C(O)(=O)C.S(Cl)([Cl:39])=O>CO.C1(C)C=CC=CC=1.O>[ClH:39].[C:2]1([C@H:12]([NH:14][CH2:15]/[CH:16]=[CH:17]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NCCC(=O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one hydrochloride (V) (100.0 g, 245.182 mmol) is suspended in cold methanol (50 ml) at −10° C. and, subsequently, a solution of sodium borohydride (4.6 g, 121.597 mmol), 30% w/w aqueous sodium hydroxide (35.5 g, 266.250 mmol) and water (30 ml) is added slowly in order to keep the internal temperature below 0° C. The reaction mixture is stirred at 0° C. for 0.5 hrs, then quenched by addition of acetic acid (36.7 g, 611.157 mmol), allowed to reach room temperature and added with water (280 ml). The volatile solvent is distilled off under vacuum at 40° C., then MTBE is charged (400 ml). The organic layer is separated and washed with water (3×50 ml). Then the free base is liberated by addition of sodium hydroxide (aq. 30% w/w; 48.8 g, 366.0 mmol) up to pH=12-13, and the organic layer is washed with water (3×50 ml). MTBE is distilled off under vacuum and flushed with toluene. The reaction mixture is then cooled down to 20° C. and a solution of thionyl chloride (30.5 g, 256.367 mmol) in toluene (60 ml) is charged drop-wise over two hours. The mixture is then stirred at 30° C. for 3 hours and once reaction goes to completion the volatiles are removed under vacuum at 60° C. Then toluene is restored and the reaction mixture is cooled to 20° C. Diisopropyl ether (200 ml) is added and the reaction mixture is refluxed at 80° C. for 1 hour, then cooled down to 20° C. The resulting thick suspension is filtered, the solid is washed with a 2:1 vol/vol toluene/diisopropyl ether (60 ml), followed by MTBE (3×60 ml). The so-formed thick suspension is heated up to 50° C., stirred for 20 minutes and then cooled down to 5° C. 65.0 g of a 98.4:1.6 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydro-chloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)-prop-2-en-1-amine hydrochloride (XI) is obtained as a white powder after exsiccation at 55° C. under vacuum.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[NH:18][C@@H:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][C@@H:17]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1[C@H](Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TFA (68.5 g, 601 mmol) was added dropwise at 0° C. to a solution of tert-butyl 1,3-(S)-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (13.5 g, 31.0 mmol) in CH2Cl2 (93 ml) and the mixture was stirred at this temperature for 15 min. After warming to RT, the reaction mixture was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted with aqueous saturated NaHCO3 solution to pH 7-8, the organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was distilled off. The workup was carried out by means of column chromatography and afforded 1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 7.8 g (75%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=O)(C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1.C(=O)([O-])O.[Na+].[ClH:34].O1CCOCC1>CN(C)C=O>[ClH:34].[CH:24]1([CH2:27][O:13][C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C1C[C@H](OCC2CC2)CN1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 16 mmol) in dry dimethylformamide at 0° C. was added sodium hexamethyldisilazide (3.5 g, 19 mmol) and after stirring for 5 min cyclopropylmethyl bromide (2.38 g, 17.6 mmol) was added and the mixture was stirred for 40 min at 0° C., then at room temperature for 3 h. After further addition of 1.5 g sodium hexamethyldisilazide and 1.4 g cyclopropylmethyl bromide the mixture was heated at 100° C. for 1 h. After addition of aqueous sodium hydrogencarbonate, the mixture was extracted 3 times with dichloromethane, the solvents were evaporated and the crude mixture was dissolved in dichloromethane (20 ml) and 4 M hydrogen chloride in dioxane (42 ml, 168 mmol). After addition of aqueous hydrochloric acid the organic layer was discarded and the aqueous layer was freeze-dried to give 2.89 g of crude (S)-3-cyclopropylmethoxy-pyrrolidine hydrochloride which was used in the next step without further purification. LC/MS (method 7): Rt=0.34 min; m/z=142.1 (M+H+).
Reaction SMILES: [O-]CC.[Na+].CO[C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:8]>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[C:15](=[O:22])[NH:14][C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:7]=1[OH:8])=[O:18])[CH3:21]
Reactant: CCOC(=O)CC(=O)Nc1ccsc1C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Yield: 54 %

Procedure:
Sodium ethoxide (0.67 g, 9.29 mmol) was added to a solution of 3-(2-ethoxycarbonyl-acetylamino)-thiophene-2-carboxylic acid methyl ester (1) (2.18 g, 7.74 mmol) in anhydrous ethanol and refluxed overnight. The solution was cooled and excess solvent was distilled off The residue was dissolved in water and acidified by cold diluted HCl solution. The solids formed were filtered, washed by water, and dried under vacuum at room temperature to yield 1.0 g (55%) of 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as white solid. MP 218° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 6.96 (d, J=5.6 Hz, 1H), 8.07 (d, J=5.6 Hz, 1H) ppm; MS m/z=240 amu (M++1).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
m-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with ether (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-m-tolyl-urea (0.7 g, 76%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.23 (s, 3H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.6 Hz, 1H), 6.70-6.77 (m, 2H), 7.05-7.17 (m, 2H), 7.25 (s, 1H), 7.75-7.88 (m, 3H), 8.70 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.19, 21.99, 30.93, 38.71, 48.86, 114.90, 118.25, 121.85, 121.95, 127.18, 128.46, 131.60, 133.66, 134.71, 137.73, 140.18, 140.30, 155.22, 167.01, 167.59, 169.82, 172.76; Anal. calcd. for C22H20N4O5+0.5H2O: C, 61.53; H, 4.93; N, 13.05. Found: C, 61.87; H, 4.72; N, 12.92.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:1]#[N:2])[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccccc3C#N)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Cyanobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(C2OCCO2)cc1
Reactant: NC(=O)c1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2)cn1
Temperature: 25 °C

Procedure:
Dissolve 4-[1,3]dioxolan-2-ylphenol (Part C2, 0.471 g, 2.85 mmol) in DMF (89.5 mL). Add NaH (80% in mineral oil) (0.128 g, 4.28 mmol). Stir at room temperature for about an hour before adding 5-fluoropyridine-2-carboxamide (0.400 g, 2.85 mmol). Heat at 80° C. for 4.5 hours before concentrating to dryness to form 5-(4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:21][C:20]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])[NH:3]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)CC1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(4-ethoxycarbonyl-1-piperidinyl)benzaldehyde analogous to the procedure of Example (2-1), m.p. 221°-223° C., crystallized from MeOH.
Reaction SMILES: [O:1]([C:8]1[C:13]2[C:14]([NH2:17])=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1n[nH]c2ccnc(Oc3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNc2n[nH]c3ccnc(Oc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a stirred solution of the compound prepared in Example 434 (0.217 g,) in toluene (12 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (0.205 g). The mixture was evaporated in vacuo to remove water from imine formed. Sodium triacetoxyborohydride (0.244 g) was added, followed by acetic acid (0.4 mL). After stirring at room temperature for 1 hour, the reaction mixture was quenched with methanol slowly, to decompose excess borohydride, and then concentrated in vacuo. Ethyl acetate, was added to the residue and then washed with aqueous saturated sodium bicarbonate, dried, evaporated in vacuo to provide the title compound (0.262 g) with the following physical data.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:13])[CH2:11]Cl)=[C:5]([CH:14]([CH3:16])[CH3:15])[CH:4]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:13])[CH2:11][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[C:5]([CH:14]([CH3:16])[CH3:15])[CH:4]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(CCl)Cc1ccc(CCl)cc1C(C)C
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(CCl)cc1C(C)C)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 150 °C
Yield: 67.1 %

Procedure:
A mixture of 24 g of 3-(p-1-chloromethyl-1-methylethylphenyl)-2-methylpropyl chloride and 32 g of cis-2,6-dimethylmorpholine is heated for 4 hours at 150° C. The crude product is dissolved in chloroform, washed several times with water, and dried over Na2SO4, the solvent is evaporated and the residue is distilled. There is obtained 21 g of N-[3-(p-1-chloromethyl-1-methylethylphenyl)-2-methylpropyl]-2,6-cis-dimethylmorpholine (active ingredient no. 1); b.p. (0.1 mm) 165°-166° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C>[CH3:29][O:30][C:31](=[O:35])[C@@H:32]([NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:34]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 94.6 %

Procedure:
(S)-2-{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (863 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (750 mg), L-alanine methyl ester hydrochloride (293 mg), HBTU (870 mg), and DIEA (500 uL).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][CH2:3]1.O.NN>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCC(CCCCN)CC1
Reaction time: 18 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-[4-(1-methyl-piperidin-4-yl)-butyl]-isoindole-1,3-dione (2.67 g, 8.89 mmol) in EtOH (50 mL) was added excess hydrazine hydrate (15 mL). After 18 h, the mixture was filtered and the filtrate was diluted with satd aq. NaHCO3 (20 mL) and water (20 mL). The mixture was extracted with CHCl3 (3×50 mL) and the combined organic layers were dried (Na2SO4) and concentrated to provide 1.36 g (90%) of a yellow oil, which was used in the next step without further purification.
Reaction SMILES: C([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:19])[CH:5]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.[I-].[K+]>ClCCl>[C:38]([O:40][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:19])[CH:5]=1)(=[O:39])[CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)cc1C
Temperature: 40 °C
Reaction time: 19 h

Procedure:
A solution of ethyl 2-(4-acetyl-2-methylphenoxy)-2-methylpropanoate (intermediate 8, 37.33 g) in dichloromethane (650 ml) was treated with 4-toluenesulphonic acid (2.75 g) followed by m-chloroperbenzoic acid (60.5 g) and the mixture warmed to 40° C. and stirred under nitrogen for 19 hours. The cooled mixture was treated with dichloromethane (350 ml) and the resulting mixture added to aqueous potassium iodide (1000 ml, 10% solution). The organic layer was collected and washed twice with water and brine, then dried over sodium sulfate, filtered and the filtrate concentrated to give the title compound as an orange oil.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]#[N:23])=[CH:12][CH:11]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[NH:41][N:40]=[N:39][N:23]=4)=[CH:14][CH:15]=3)[C:7]3[CH:24]=[C:25]([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=5[N:30]=4)[CH:26]=[C:27]([CH3:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:27]=[O:28])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][OH:28])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(-c3cncc(C=O)c3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Oc2nc(-c3cncc(CO)c3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of Compound 26a (200 mg, 0.40 mmol) in THF (5 mL) at 0° C. was added LiBH4 solution (2.0 M in THF) (0.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature over 2 h. The resultant mixture was diluted with water. The mixture was extracted with EtOAc (3×), and the organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 26b (71.5 mg; 35% yield). 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.80-7.94 (m, 1H), 7.13-7.16 (m, 2H), 6.91-6.94 (m, 2H), 5.83 (br. s, 0.6H), 5.06 (br. s, 0.4H), 4.71 (s, 2H), 4.18-4.26 (m, 1H), 3.84 (s, 3H), 3.86 (br. s, 0.6H), 3.50 (br. s, 0.4H), 3.37-3.40 (m, 2H), 3.15-3.20 (m, 2H), 2.06-2.15 (m, 1H), 1.90-1.98 (m, 2H), 1.77-1.86 (m, 1H), 1.43-1.49 (m, 9H); MS: m/z 508.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:24](=[O:25])[C:23]5=[C:29]([Cl:32])[CH:30]=[CH:31][C:21]([Cl:20])=[C:22]5[C:27]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Solvent: ClCCl
Product: O=C1c2c(Cl)ccc(Cl)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles) and 3,6-dichlorophthalic anhydride (2.01 gm; 9.27 mmoles) in dichloromethane (DCM, 50 ml) was stirred at room temperature for hr. White precipitates formed and the TLC of the reaction mixture showed that there was no starting amine remaining. The solvent was stripped down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column. (SiO2; 30 gm) and the column was eluted with a solution of 1% CH3OH in DCM. The desired product thus obtained weighed 2.29 gm (54%). Recrystallization from hot ethanol yielded 2.15 gm of white crystals, m.p.=163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:12][C:13]2[N:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 4-fluorobezylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (56% yield). 1H NMR (500 MHz, CDCl3) δ 8.13, 7.78, 7.66, 7.60, 7.33, 7.21, 7.09, 6.83, 4.50, 3.91-4.00, 3.73-3.80, 3.34-3.48, 3.05-3.22. MS (ES+) m/z 503 (M+1).