Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1L). The phases are separated and the aqueous phase is extracted with heptane (2×1L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ7.48 (dd, J=5.7, 2.4 Hz, 1H), 6.20 (d, J=5.7 Hz, 1H), 4.95-4.99 (m, 1H), 2.72 (dd, J=18.2, 6.0 Hz, 1H), 2.25 (dd, J=18.2, 2.3 Hz, 1H), 0.88 (s, 9H), 0.11 (s, 6H); 13C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57,100).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33]Br)=[C:27]3[N:35](C(OC(C)(C)C)=O)[C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:50])[CH:22]=2)(OC(C)(C)C)=O.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[Br:50][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[C:27]3[NH:35][C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]2=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 2 H), 8.67 (s, 1 H), 8.28 (d, J=2.0 Hz, 2H), 7.51-7.40 (m, 4 H), 4.30 (t, J=6.6 Hz, 2 H), 3.56 (t, J=4.6 Hz, 4 H), 2.52 (t, J=7.2 Hz, 2 H), 2.44-2.32 (m, 4 H), 2.11-2.00 (m, 2 H); MS (ESI) m/z 556.0 (M−H)−
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([OH:16])=[O:15])[C:3]1=[O:17].[CH2:18]([CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].[ClH:37]>C(O)(=O)C.CO>[ClH:37].[C:14]([CH2:13][N:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8][CH:2]([NH:1][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]1=[O:17])([OH:16])=[O:15]
Reactant: NC1CCc2ccccc2N(CC(=O)O)C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (10.0 g) and ethyl benzylpyruvate (26.4 g) in acetic acid (75 ml) and methanol (75 ml) was stirred at room temperature under nitrogen for 1 hour. Sodium cyanoborohydride (3.4 g) in methanol (25 ml) was added dropwise over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Concentrated hydrochloric acid (4 ml) was added dropwise, and the mixture stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. The residue was partitioned between 150 ml of water and 50 ml of ether and adjusted to pH 9 with 40% sodium hydroxide. The layers were separated and the ether layer was discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3×75 ml of ethyl acetate. The organic portions were dried (magnesium sulfate) and concentrated to dryness. Hydrogen chloride gas was bubbled into a solution of the crude product in 310 ml of methylene chloride for 5 minutes. The solution was evaporated and the residue was stirred in 225 ml of ether. The product was collected by filtration to give a 70:30 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from ethanol/ethyl acetate (1:3) to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride melting at 246°-8° (dec.) and corresponding to the racemic isomer B.
Reaction SMILES: C(Cl)CCl.N1([C:10]2[N:11]=[CH:12][C:13]3[CH:18]([C:19](O)=O)[CH2:17][CH2:16][C:14]=3N=2)C=NN=N1.FC1C(C#N)=C(C)C([C@@H]2OC[C@H]3CNCCN3C2)=CC=1>ClCCl>[NH:11]1[C:10]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C1CCc2nc(-n3cnnn3)ncc21
Agent: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Solvent: ClCCCl
Solvent: ClCCl
Product: c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
EDC (2.24 g, 11.68 mmol) was added to a suspension of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (2.51 g, 9.73 mmol) and 6-fluoro-2-methyl-3-[(3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40C-1] (2.81 g, 10.21 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at RT for 1.5 hours. Most of the solvent was evaporated. The residue was dissolved in EtOAc and washed with water, NaHCO3 solution and brine, dried (Na2SO4), filtered, and the solvent evaporated to afford a crude mixture of the two diastereomers. The crude product was purified on silica (220 g cartridge) with gradient elution from CH2Cl2 (solvent A) to 50% CH2Cl2:MeOH 90:10 (solvent B) to afford a mixture of the title diastereomers which were separated by chiral preparative SFC HPLC (SFC on Chiralpak IC column, Diacel Chemical Industries, LTD., 30×250 mm, 60% 2:1 MeOH:MeCN/CO2, 70 mL/min., 100 bar, sample in DCM/MeCN, 35C, 254 nm) to afford the separated aza-indane diastereomers: Isomer 2A, faster eluting, and Isomer 2B, slower eluting. Stereochemical assignment at the aza-indane chiral center was made by X-ray crystallography of the slower eluting isomer. Isomer A was dissolved in 1 mL acetonitrile and 1 eq. 1 M HCl in ether was added, and. the solid was filtered to yield the hydrochloride salt. Isomer 2A HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.04 (s, 1H); 8.72 (s, 0.4H); 8.68 (s, 0.6H); 7.81-7.88 (m, 1H); 7.25-7.31 (m, 1H); 5.12 (t, 1H); 4.63-4.75 (m, 1.5H); 4.40-4.46 (m, 1H); 4.33-4.38 (dd, 0.5H); 4.23-4.28 (dd, 0.5H); 3.72-3.90 (m, 2H); 3.42-3.52 (m, 3H); 3.14-3.28 (m, 3H); 2.84-3.1 (m, 2H); 2.86-2.97 (m, 1H); 2.73-2.82 (m, 1H); 2.60 (s, 3H); 2.50-2.35 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 462 (M+H−N2): The HCl salt of Isomer 2B was made in a similar fashion. Isomer 2B HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.0 (s, 1H); 8.7 (s, 1H); 7.82-7.86 (dd, 1H); 7.29 (t, 1H); 5.26 d, 1H); 4.66-4.76 (m, 1H); 4.49-4.54 (m, 1H); 4.45-4.59 (m, 1H); 4.35 (d, 0.5H); 3.90-4.03 (m, 1H); 3.76-3.88 (m, 0.5H); 3.11-3.43 (m, 5.5H); 2.88-3.00 (m, 0.5H); 2.70-2.82 (m, 1H); 2.63 (s, 3H); 2.21-2.40 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 42 (M+H−N2).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[CH3:20][NH:21][CH3:22].C(OCC)(=O)C>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (1.31 mmole, 0.350 g) was dissolved in 2 ml THF and cooled to 0° C. Dimethylamine (1 ml) was added. The solution was stirred at room temperature for 20 minutes. Ethyl acetate was added. The organic phase was washed with water, dried over sodium sulfate, and concentrated to yield 270 mg of 5-(2-cyanophenyl)-2-dimethylaminomethyl-1H-benzimidazole.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].FC(F)(F)C1C=CC(C(=O)C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1.CN1CCOCC1.[OH:37][CH:38]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=1)[C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)=[O:40]>ClCCl>[Br:1][CH2:2][C:3]([O:40][CH:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=1)[C:38]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH3:56])=[CH:53][CH:54]=1)=[O:37])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Agent: O=C(c1ccc(C(F)(F)F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCc1ccc(C(=O)C(OC(=O)CBr)c2ccc(CC)cc2)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completion. After 1 h, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone as a pale-yellow oil which was carried on directly. A portion of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone (3.15 g, 8.09 mmol) was treated with anhydrous sodium carbonate (0.86 g, 8.09 mmol), sodium iodide (0.12 g) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (2.0 g, 8.09 mmol) in anhydrous acetonitrile (120 mL) and the resulting mixture was heated to 80° C. for 5 h before it was cooled and concentrated down in vacuo. Purification of the residue by flash chromatography on silica gel with absolute ethyl acetate gave 3.40 g (76%) of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl) amino]carbonyl]-methyl]-1-piperazineacetate as pale-yellow foam. A portion of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl)amino]carbonyl]-methyl]-1-piperazineacetate (2.50 g, 4.50 mmol) was dissolved in glacial acetic acid (75 mL) and ammonium acetate (1.65 g, 22.5 mmol) was added. The mixture was gently refluxed under nitrogen for 6 h before the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N sodium hydroxide solution (until basic) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with ethyl acetate followed by 10% methanol in ethyl acetate) and yielded 0.61 g (22%) of the oxazole product I as a white solid and 0.85 g (30%) of the imidazole product I as a white solid after salt formation with ethereal hydrogen chloride.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([O:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([N:46]3[CH2:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[NH:48][C:47]3=[O:57])[CH2:42][CH2:41]2)=[O:39])[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:11][C:10]=1[CH3:58])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10]([CH3:58])=[CH:11][C:12]([CH2:16][C@@H:17]([O:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([N:46]3[CH2:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[NH:48][C:47]3=[O:57])[CH2:44][CH2:45]2)=[O:39])[C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[O:19])=[CH:13][C:14]=1[CH3:15]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
80 mg (0.10 mmol) ethyl 1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 10 mL EtOH were combined with 30 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 1 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+](=[CH2:21])=[N-]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH3:21])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1
Reactant: C=[N+]=[N-]
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(O)c1

Procedure:
An ethereal solution of 2-(2-hydroxy-4-biphenylyl) propionic acid was treated with excess diazomethane and the resulting mixture evaporated to dryness under reduced pressure. The resulting product was triturated with light petroleum, b.p. 40° - 60°C., collected by filtration and dried. The product was recrystallised twice from light petroleum (b.p. 80° - 100°C.) to give methyl 2-(2-hydroxy-4-biphenylyl)propionate, m.p. 105.5° - 107.5°C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:24])[CH:18]=1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (300 g, 1.46 mol), and TEA (300 g, 3 mol) in DCM (4 L) was added 6-chloropyrimidine-4-carbonyl chloride (250 g in 2 L of DCM) slowly at −60° C. over 1 h. After the addition was complete, the mixture was then allowed to warm to 10° C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (2 L). The organic phase was collected, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined product weight of 970 g, yield: 49%. 1H NMR (400 MHz, MeOD-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.2 Hz, 1H), 5.51 (s, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.6 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].S(Cl)(Cl)=O.Cl[C:17](SCl)=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:17]=[O:18])(=[O:10])=[O:9]
Reactant: O=C(Cl)SCl
Reactant: NS(=O)(=O)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C=NS(=O)(=O)c1ccccc1Cl

Procedure:
In a flask equipped with a stirrer, reflux condenser and nitrogen bubbling apparatus, were mixed 5 g (0.03 mole) o-chlorobenzenesulfonamide, 50 ml (0.686 mole) thionyl chloride and 2 drops of pyridine. Then 3.9 g (0.03 mole) chlorocarbonylsulfenyl chloride was slowly added.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:19])[CH:3]=1.[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][NH:26][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:19])[CH:3]=1)[CH3:22]
Reactant: CN(C)CCCN
Reactant: Cc1cc(Cl)nc(NCC(C)OC(C)C)c1[N+](=O)[O-]
Product: Cc1cc(NCCCN(C)C)nc(NCC(C)OC(C)C)c1[N+](=O)[O-]

Procedure:
5.75 parts of 6-chloro-2-isopropoxypropylamino-4-methyl-3-nitropyridine, 5 parts of dimethylaminopropylamine and 20 parts of alcohol are heated at 90° to 100° C for 12 hours. The excess amine and alcohol are distilled off in vacuo and the residue is extracted with chloroform. After distilling off the solvent from the chloroform solution, 6-dimethylaminopropylamino-2-isopropoxypropylamino-4-methyl-3-nitropyridine is obtained as a yellow substance.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]=2)[CH:6]=[C:5]1[C:44]([O:46]C)=[O:45])(C)C.[Li+].[OH-].Cl.[CH2:51]1[CH2:55]OC[CH2:52]1>>[CH:51]([C:5]1([C:44]([OH:46])=[O:45])[CH2:6][C:7]([C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]=2)=[CH:8][NH:4]1)([CH3:55])[CH3:52]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)cn1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C1(C(=O)O)CC(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)=CN1
Temperature: 25 °C
Yield: 97 %

Procedure:
Methyl 1-isopropyl-4-(4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-1 H-pyrrole-2-carboxylate (200 mg, 0.32 mmol) was dissolved in THF (8 mL). A 1 N LiOH solution (8 mL) was introduced and resulting mixture was refluxed for 12 hours. After cooling to room temperature, the mixture was neutralized to pH 7 with 5 N HCl. THF was removed at reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4 and concentrated to give the crude desired product as a yellow solid (190 mg, 97%). LC-MS (Method F): m/z=613.4 [M+H]+; 6.19 min. 1H-NMR (500 MHz, CDCl3): δ 7.74 (s, 1H), 7.53 (d, J=6.0, 1H), 7.30-7.37 (m, 9H), 7.23 (s, 1H), 7.16 (d, J=7.5, 6H), 5.79 (d, J=6.0, 1H), 5.41-5.48 (m, 2H), 3.91 (d, J=11.5, 2H), 3.49 (t, J=11.0, 2H), 2.15 (d, J=12.0, 2H), 1.72-1.79 (m, 2H), 1.42 (d, J=7.0, 6H).
Reaction SMILES: C(OC([N:11]1[CH2:18][C@H:17]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:23]([O:22][C:20]([NH:19][C:13]12[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CNC2
Yield: 107.5 %

Procedure:
A 10% palladium-carbon catalyst (about 50% wet, 115 mg) was added to a solution of (+)-(1R*,5S*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (575 mg, 1.595 mmol) in methanol (20 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for two hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (388 mg) as a colorless transparent gummy solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:6]
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: NCC(=O)NCC(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:37])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:25]3[CH2:24][C:23]([C:18]4[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=4)([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=3)=[CH:29][C:30]=2[CH3:37])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Cl)n1
Yield: 68.8 %

Procedure:
In a solution of 0.10 g of 2-amino-6-chloropyridine and 0.16 g of pyridine in 5 mL of dichloromethane, a solution of 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 5 mL of dichloromethane was added at room temperature with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.25 g of the aimed product as colorless resinous substance.