Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[F:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][O:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][O:28][CH2:27][C:26]3[CH:37]=[CH:38][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:32][CH2:33]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: Fc1ccc(COCCC2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccc(F)cc3)CC2)c1
Temperature: 99 °C
Yield: 80.2 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (264 mg, 0.74 mmol) and 4-[2-(4-fluorobenzyloxy)ethyl]piperidine (193 mg, 0.81 mmol, 1.1 equiv.) in anhydrous toluene (4 mL) were added successively sodium tert-butoxide (106 mg, 1.11 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (13.5 mg, 15 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 25.6 mg, 44 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. 3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-fluorobenzyloxy)ethyl]-1-piperidinyl]pyridine (305 mg, 80%) was obtained as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH:15]([CH:16]=[N:17][O:18][CH3:19])[CH:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH3:19][O:18][N:17]=[CH:16][CH:15]1[C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH:14]1[CH2:13][NH:12][CH2:11]2
Reactant: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CON=CC1C2CNCC12c1ccc(Cl)c(Cl)c1
Yield: 219.5 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.40 g, 6.23 mmol) obtained in step-1 of example 7 in dry DCM (40 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde O-methyl oxime (1.95 g, 97%) as a white solid as a mixture of isomers.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][CH2:6][CH:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[Br:2][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH3:5]
Reactant: BrP(Br)Br
Reactant: CCCCCC(O)CC
Product: CCCCCC(Br)CC
Temperature: 100 °C
Yield: 106.2 %

Procedure:
To 8 ml (23 g, 85.3 mmol) of phosphorus tribromide was added dropwise 15 g (115.4 mmol) of 3-octanol over a 1/2 hr period. The resulting solution was heated at 100° C. (oil bath) for 2 hr, after which time the reaction mixture was cooled and poured into 200 ml ice-water which was extracted with CHCl3 (3×120 ml). The combined organic extracts were washed with 5% Na2S2O3 (2×200 ml), H2O (200 ml), sat'd aq. NaHCO3 (2×200 ml), H2O (200 ml), and sat'd aq. NaCl (200 ml), and dried over MgSO4. After the removal of the solvent under reduced pressure, the residue was distilled (bp 78°-80° C./18 Torr, lit. bp 84.4°-85.1° C./20 Torr (18)) to give 17.5 g (78.58%) of pure 3-bromooctane which exhibited C-Br band at 797 cm-1 in the IR spectrum (18). NMR(CDCl3): δ1.0 (6H, t, CH3), δ1.31 (6H, broad singlet, --CH2), δ1.75 (4H, q, ##STR13## δ3.90 (1H, m, >CHBr).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.[H][H]>CO.[Pd]>[NH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC1(c2ccccc2)CCNCC1
Yield: 102.8 %

Procedure:
3.2 ml of 12N hydrochloric acid solution are added to a solution of 5 g of 4-amino-1-benzyl-4-phenylpiperidine in 25 ml of methanol, followed by addition of 0.5 g of 10% palladium-on-charcoal (50% water) and hydrogen overnight, at atmospheric pressure and at 40° C. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in 15 ml of water, basified by addition of 3.8 ml of 10N sodium hydroxide solution and left stirring. Sodium chloride crystals are added to the aqueous phase and the mixture is extracted twice with 25 ml of dichloromethane. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. 3.4 g of the expected product are obtained. b) A solution of 2.83 g of potassium carbonate in 2.8 ml of water is added to a solution of 4 g of compound of formula (III) obtained in Example 1 in 9.2 ml of toluene and 8 ml of methyl isobutyl ketone, followed by addition of 1.6 g of 4-amino-4-phenylpiperidine, and this mixture is heated at 70° C. for 12 hours. After cooling the reaction mixture to room temperature, 16 ml of water are added and the phases are then separated by settling. The organic phase is washed twice with 16 ml of water and is acidified by adding a solution of 1.5 ml of 12N hydrochloric acid in 16 ml of water, and the phases are then separated by settling. The acidic aqueous phase is washed twice with 10 ml of toluene, the aqueous phase is basified by adding 2 ml of 10N sodium hydroxide solution and is extracted twice with 30 ml of toluene. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. 4 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [I-:1].[Na+].[CH:3]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(#N)C>[CH:3]1([C:9]([I:1])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [I-]
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Solvent: CC#N
Product: O=C(I)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
In 80 ml of acetonitrile is dissolved 6 g of sodium iodide and, then, 5 g of cyclohexanecarbonyl chloride is added dropwise to the solution under ice-cooling. This mixture is stirred at 0° C. for 30 minutes. Then, insoluble matters are removed by filtration and the filtrate is concentrated under reduced pressure. To the residue is added 20 ml of petroleum ether and insoluble matters are removed by filtration and the filtrate is subjected to distillation under reduced pressure to obtain 5.0 g of cyclohexanecarbonyl iodide. Yield: 61%. B.p. 75°-80° C./5 mmHg [b.p. 103°-105° C./11 mmHg according to "Bull. Chem. Soc. Japan" 34, 480 (1961)].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31]Cl>[NH4+].[Cl-]>[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31][N:19]1[C:14]2([CH2:21][CH2:22][N:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]1=[O:20]
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CN2C(=O)CCCC23CCN(c2cnc4ccccc4n2)CC3)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
To a solution of 9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (80 mg, 0.27 mmol) in THF (5 mL) sodium hydride 95% (32 mg, 0.81 mmol) was added and the mixture was stirred for 10 min at rt. Then 2,5-dimethylbenzylchloride (70 mg, 0.35 mmol) was added and the reaction mixture was heated at 60° C. over 18 h. Saturated aqueous NH4Cl solution (40 mL) was added and the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by reversed phase preparative HPLC (column Zorbax eclipseXDB C18, flow 20 mL/min, mobile phase 0.1% TFA in water (A): acetonitrile (B) gradient) to yield the title compound (49 mg, 22%). [1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.88 (d, 1H), 7.70-7.55 (m, 2H), 7.48-7.35 (t, 1H), 7.05-6.85 (m, 2H), 6.72 (s, 1H), 4.55 (s, 2H), 4.55-4.39 (m, 2H), 3.12 (t, 2H), 2.65 (t, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 2.20-1.88 (m, 6H), 1.85-1.63 (m, 2H); LCMS RtE=1.64 min, [M+H]+=415.2].
Reaction SMILES: [S:1]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[CH2:4][S:3][CH2:2]1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:5]4[CH2:4][S:3][CH2:2][S:1][CH:6]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)CC1=CSCSC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)CC3=CSCSC3)CC12
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(1,3-dithiin-5-yl)acetic acid (1.23 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 20 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (80 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(1,3-dithiin-5-yl)acetyl]-4-perhydroisoindolone (1.94 g) melting at 211° C. is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]([O:15]CC)=O)=[O:10].[OH-].[Na+]>CO>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:15])[CH2:12][NH:11][C:9]1=[O:10]
Reactant: CCOC(=O)CNC(=O)Nc1ccccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CNC(=O)N1c1ccccc1I
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of ethyl N-{[(2-iodophenyl)amino]carbonyl}glycinate (6 g) in MeOH was treated with aqueous NaOH (2M, 17.5 ml) and stirred under nitrogen for 0.5 h at 20° C. The reaction mixture was quenched by adding aqueous 2M HCl (20 ml) and water. The white solid obtained was collected by filtration and then was dissolved in dioxane (30 ml) and treated with p-toluenesulfonic acid (750 mg). The mixture was heated and stirred at 100° C. for 16 h. The solvent was removed under reduced pressure, the residue was diluted in EtOAc and washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography on Biotage (40 g) eluting with dichloromethane:EtOAc (95:5 to 85:15) to give the title compound (1.68 g). LCMS RT=2.07 min.
Reaction SMILES: [F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][CH2:4][S:5]([C:7]1[S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)=[O:6].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[F:1][C:2](=[C:16]([F:17])[F:18])[CH2:3][CH2:4][S:5]([C:7]1[S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)(=[O:27])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(CCC(F)=C(F)F)c1nc2cnccc2s1
Solvent: ClCCl
Product: O=S(=O)(CCC(F)=C(F)F)c1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
2-(3,4,4-trifluoro-but-3-enylsulfinyl)-thiazolo[4,5-c]pyridine (0.1 g) was dissolved in methylene chloride (5 ml), m-chloroperbenzoic acid (0.07 g) was added and the mixture was stirred at room temperature for 2 hours. The mixture was washed with 1% aqueous sodium metabisulfite, aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using methylene chloride:ethyl acetate (85:15) to give the product as a brown semi-solid (0.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:25]3[CH:26]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]4)[N:22]=[C:23]([NH2:37])[N:24]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:8]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)COc1cccc(Cl)c1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)COc3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from (3-chlorophenoxy)acetyl chloride (Lancaster, Cat. #L18427) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=493.2/495.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[C:12]([CH2:14][C@@H:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:18]=[C:17](C2C=CC(C#N)=CC=2)[C@H:16]1C)#[N:13]>>[C:12]([CH2:14][C@@H:15]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[N:18]=[C:10]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[C@H:16]1[CH3:17])#[N:13]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: C[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N
Product: C[C@@H]1C(c2ccc(C#N)cc2F)=NN(c2ccc(O)cc2)[C@H]1CC#N

Procedure:
4-((4S,5S)-5-(Cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-3-fluorobenzonitrile was prepared from 3-fluoro-4-formylbenzonitrile following the procedure for the preparation of 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (91G): LC-MS [M+H] 335.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCCC(=O)O)cc2)CC(C)(C)C1
Yield: 94.7 %

Procedure:
The hydrolysis conditions described for 191 was followed. A solution of ethyl 4-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoate (222) (0.760 g, 1.7 mmol) in THF/EtOH (1:1, 40 mL) was treated with 1 N NaOH (20 ml, excess) at 70° C. for 1 h. The reaction mixture was poured into 20% aqueous HCl (200 mL). The precipitated product was filtered and dried under reduced pressure to afford 0.68 g (95%) of compound 223 as an off-white solid. mp 203-204° C. 1H NMR (300 MHz, CD3OD): δ 7.05 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.06 (quintet, J1=13.5, J2=6.9 Hz, 2H), 2.00 (d, J=4.2 Hz, 4H), 1.31 (s, 2H), 0.94 (s, 12H). LCMS (ESI): m/z 421 (M−H)−. Anal. Calcd for C27H34O4, C, 76.75; H, 8.11. Found: C, 75.63; H, 8.03.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:37][C:38]1[N:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:37][C:38]1[N:43]=[CH:42][C:41]([CH2:44][O:18][C:15]2[CH:16]=[CH:17][C:10]3[O:9][C:8]([CH:7]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=4)[CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:12]([CH3:13])[C:11]=3[CH:14]=2)=[CH:40][CH:39]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccc(Cl)nc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.39 g) synthesized in Example A155(1) was dissolved in tetrahydrofuran (5 mL), 6-chloro-3-pyridinemethanol (140 mg), tributylphosphine (0.35 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.36 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.32 g, 66%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.CCO>CC(C)=O.CCOCC.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a suspension of 2-t-butylphenol (20.00 g, 0.133 mol) and K2CO3 (36.80 g, 0.266 mol) in 260 mL of anhydrous acetone was added a neat solution of dimethylsulfate (17.63 g, 0.140 mol) dropwise through a syringe over 5 minute at RT under argon. The resulting thick suspension was stirred over night at RT and 100 mL of EtOH was added. After 1 hour, the mixture was diluted with ether and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried with MgSO4. After filtration, the solvents were removed and dried under high vacuum to give afford 2-t-butylanisole (16.99 g, 78% yield). 1H NMR (300 MHz, CDCl3): δ 1.40 (s, 9H), 3.86 (s, 3H), 6.88–6.96 (m, 2H), 7.18–7.26 (m, 1H), 7.31 (dd, J1=7.5 Hz, J2=1.2 Hz, 1H).
Reaction SMILES: C[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[H-].[Na+].CI>CN(C)C=O>[NH:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[CH:2]1
Reactant: Cc1nc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: c1cc2[nH]cnc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-1H-imidazo[4,5-c]pyridine in 50 ml of dimethylformamide was added 1.43 g of 50% sodium hydride in oil followed, after 20 minutes, by 1.86 ml of methyl iodide. After stirring at room temperature overnight, the solvent was concentrated in vacuo and the residue treated with chloroform and filtered. Removal of the chloroform gave a brown solid which was chromatographed on 150 g of silica gel using 5% methanol in chloroform as the eluent giving 774 mg of a less polar isomer and 356 mg of the desired 1H-imidazo[4,5-c]pyridine isomer.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:42])[C:8]2[N:9]=[CH:10][N:11]([C@@H:14]3[O:18][C@H:17]([CH2:19][CH:20]([P:28](=[O:31])([OH:30])[OH:29])[S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:16]([F:32])[C@H:15]3[O:33]C(=O)C3C=CC=CC=3)[C:12]=2[N:13]=1)(=O)C>N.CO>[NH2:4][C:5]1[NH:6][C:7](=[O:42])[C:8]2[N:9]=[CH:10][N:11]([C@@H:14]3[O:18][C@H:17]([CH2:19][CH:20]([P:28](=[O:29])([OH:31])[OH:30])[S:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:16]([F:32])[C@H:15]3[OH:33])[C:12]=2[N:13]=1
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: N
Solvent: CO
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Reaction time: 12 h
Yield: 100 %

Procedure:
Compound 35.16 (12 mg, 0.019 mmol) was dissolved in 7 N NH3 in MeOH (5 mL) and stirred for 12 h under nitrogen. The solvent was removed under reduced pressure and the residue was washed with 3×10 mL acetonitrile. The acetonitrile washings are filtered and the solid residue was redissolved in methanol, filtered and concentrated under reduced pressure. The residue gives compound 35.17 in greater than 90% purity (9.2 mg, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:29]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:26][CH2:27][CH3:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Reactant: CCCNCC1CC1
Product: CCCN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with propyl(cyclopropylmethyl)amine to give 8-chloro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 34 8-Nitro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-phenyl-4-H-s-triazolo[4,3-a][1,4]-benzodiazepine
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)CN1CCOCC1
Agent: Cl
Product: O=C(CN1CCOCC1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-morpholinoacetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.42-8.46 (m, 1H), 7.96-8.08 (m, 2H), 7.75-7.79 (m, 1H), 7.64-7.69 (m, 4H), 4.27-4.28 (m, 2H), 3.79-3.94 (m, 4H), 3.34-3.38 (m, 4H); MS (APCI+) M/Z 399 (M+H)+.