Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:7]23[CH2:8][CH:4]([CH2:5][CH:6]2[CH:9]=[CH2:10])[CH2:3][CH:2]13.ClC1C=C(C=CC=1)C(O)=[O:16]>ClCCl>[O:1]1[C:7]23[CH2:8][CH:4]([CH2:5][CH:6]2[CH:9]=[CH2:10])[CH2:3][CH:2]13.[O:1]1[C:7]23[CH2:8][C:4]4([O:16][CH:3]4[CH:2]12)[CH2:5][CH:6]3[CH2:9][CH3:10]
Reactant: O=C(O)c1cccc(Cl)c1
Agent: C=CC1CC2CC3OC13C2
Solvent: ClCCl
Product: CCC1CC23CC14OC4C2O3

Procedure:
After stirring 18 hrs at <4° C., KI-starch paper test for peroxide was negative. GC analysis showed little change in product mix: 28% VNB, 44% EVNBA, and 27% diepoxy. After confirming that additional mCPBA would react preferentially with VNB instead of EVNBA, an additional 877 g of mCPBA (for a total of 5085 g, 22.69 mol) was added in three portions as the solid to the reaction mixture. Additional dichloromethane was added only to rinse in the solids. The addition of solid mCPBA caused a temperature drop to 4° C., which was then followed by a gentle exotherm that caused the temperature to rise to 7° C. GC analysis showed 4% VNB, 63% EVNBA, and 32% diepoxy. KI-starch paper test was positive for peroxide. The reaction mixture was stirred an additional 39 hrs at <12° C. KI-starch paper test was negative for peroxide. GC analysis showed 1.4% VNB, 70% EVNBA, and 26% diepoxy isomers. The reaction mixture was split into two portions. 16.4 liters of saturated sodium bicarbonate solution and ˜1 kg of solid sodium bicarbonate was added to each portion. When the solutions did not clear, an additional 1000 g sodium bicarbonate was added to each, followed by 9 L water. The mixtures were stirred for 30 minutes until both had cleared. The phases were separated and the dichloromethane phase was decanted from the undissolved sodium bicarbonate. Each organic phase was washed with 2×16 L brine to pH 7. The undissolved sodium bicarbonate was dissolved with 50 L water, causing separation of ˜4 L of dichloromethane. After separating the phases, the aqueous phase was extracted with 2×4 L dichloromethane. The dichloromethane portions were washed with 2×12 L brine to pH 6. All dichloromethane portions were combined and rotary evaporated to give 2654 g of yellow liquid containing some solids. GC analysis showed 1.0% VNB, 75.7% EVNBA, and 20.2% diepoxy isomers. NMR analysis indicated the composition to be 3.1% m-chlorobenzoic acid, 55.5% EVNBA, 14.6% dichloromethane, and 26.7% diepoxy isomers. The crude product was filtered and then vacuum distilled through a 14-inch Vigreux column to yield 1,002 g (>99%)-3-epoxy-5-vinylnorbornane (EVNBA) and 109.08 (99.6%) 3-epoxy-5-ethylepoxynorbornane (diepoxides).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-dimethyl-2-nitrobenzene (151.2 g) is dissolved in 500 ml of CH2Cl2 and cooled to below 0° C. in a methanol ice bath. Sulfuric acid (200 ml) is added dropwise maintaining a temperature at below 0° C. After the sulfuric acid addition is complete, fuming nitric acid (86 ml) is added dropwise at a rate which maintains the temperature between -5° to -2° C. After the addition is complete the mixture is stirred at -3° to -5° C. for 2 hours. 200 ml of water are carefully added to the aqueous acidic layer and after cooling to room temperature is extracted with 600 ml of CH2Cl2. The extracts are combined and washed with 600 ml of H2O saturated NaCl solution and dried overnight. The mixture is filtered and the filtrate concentrated to give 192.2 grams of a yellow solid, M.P. 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][S:25]([C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:31]5[S:32][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 25.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 5-(methylsulfonyl)thiophene-2-carboxylic acid (47 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (41 mg, 26%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.[CH3:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[C:36]([OH:43])[CH:37]=[CH:38][CH:39]=2)[N:34]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][O:43][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[N:34]=[C:33]([CH3:32])[CH:42]=[CH:41]3)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (50 mg), 2-methyl-8-hydroxyquinoline (17 mg) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 1 day. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[4-(methylcarbamoyl)-cinnamoylaminomethyl]pyrrole (40 ml) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:15]2[C:14](=[CH:13][C:12]([O:11][CH3:10])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH2:20][CH2:21][NH:22]1
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(CCN)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(c1ccccc1Cl)NCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-chlorobenzaldehyde (0.5 M in dichloromethane) (800 μl) and 2-(3,4-dimethoxy-phenyl)-ethylamine (0.25 M in dichloromethane) (800 μl) was added trifluoroacetic acid (150 μl). The mixture was shaken at room temperature for 12-24 hours then evaporated to dryness. Toluene (1 ml) was added the mixture vortexed and re-evaporated to dryness. The residue was dissolved in methanol (1.5 ml) and dichloromethane (1 ml) and filtered through a SCX cartridge (Bakerbond JT7090-07, aromatic sulfonic acid). The cartridge was washed with methanol (3 ml) the product eluted with 0.5 M ammonia solution (5 ml). Product containing fractions were combined and evaporated to dryness. Toluene (1 ml) was added the mixture vortexed and re-evaporated to dryness to give 1-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline which was used directly in the next step.
Reaction SMILES: [CH2:1]([Li])CCC.[PH4+].[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([CH:22]=O)=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([CH:22]=[CH2:1])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To a suspension of 15.14 g of methyltriphenylphosphonium bromide in tetrahydrofuran, cooled to -78° C., is slowly added 21.73 ml of 1.95M n-butyllithium in hexanes. The reaction mixture is allowed to warm to room temperature and stirred until all of the phosphonium salt dissolves. This takes approximately 30 minutes. The reaction mixture is cooled to -78° C. and 1.95 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde added in one portion as a solid. The reaction mixture is allowed to warm to room temperature and stirred for 18 hours. The reaction mixture is quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried with MgSO4 and concentrated in vacuo to a residue which is purified by chromatography on silica gel using 1:3 ethyl acetate-hexanes to give 2.48 g of the desired product as a solid. CI mass spec 229 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:42][CH3:43])=[CH:11][C:12]2[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:17]([O:26][CH:27]3[C:32]([OH:33])=[C:31]([OH:34])[C:30]([OH:35])=[C:29]([OH:36])[O:28]3)[C@@H:16]3[CH2:37][CH2:38][CH2:39][N:15]3[C:14](=[O:40])[C:13]=2[CH:41]=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CCCCCC>[C:22]([O:21][C:19]([N:18]1[C:12]2[CH:11]=[C:10]([O:42][CH3:43])[C:9]([OH:8])=[CH:41][C:13]=2[C:14](=[O:40])[N:15]2[CH2:39][CH2:38][CH2:37][C@H:16]2[C@@H:17]1[O:26][CH:27]1[C:32]([OH:33])=[C:31]([OH:34])[C:30]([OH:35])=[C:29]([OH:36])[O:28]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)N1CCC[C@H]1[C@H](OC1OC(O)=C(O)C(O)=C1O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2c(cc1O)C(=O)N1CCC[C@H]1[C@H](OC1OC(O)=C(O)C(O)=C1O)N2C(=O)OC(C)(C)C
Yield: 89.3 %

Procedure:
A catalytic amount of 10% palladium on carbon (380 mg) was added to a solution of THP protected compound 6 (3.8 g, 7 mmol) in absolute alcohol (30 mL). The reaction mixture was hydrogenated for 3 h at 35 Psi. When the reaction was complete as indicated by TLC (SiO2, 50% EtOAc-hexane) the reaction mixture was filtered through Celite, and removal of excess solvent under reduced pressure afforded the phenol 7 (2.8 g, 6.25 mmol, 90% yield, mixture of diastereomers from THP protecting group) as a white solid: [α]20D=+52° (c=0.183, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 18H, Boc), 1.48-1.68 (m, 6H, THP), 1.69-1.88 (m, 6H, THP), 1.91-2.18 (m, 8H, 1-H, 2-H), 3.44-3.75 (m, 8H, 3-H, 11a-H, THP), 3.84-4.02 (m, 8H, 7-OMe, THP), 4.96-5.09 (m, 1H, THP), 5.10-5.18 (m, 1H, THP), 5.69-5.76 (d, 1H, 11-H), 5.77-5.87 (d, 1H, 11-H), 6.03 (s, 1H, OH), 6.14 (s, 1H, OH), 6.49 (s, 1H, 9-H), 6.86 (s, 1H, 9-H), 7.28 (s, 1H, 6-H), 7.32 (s, 1H, 6-H); 13C NMR (CDCl3, 400 MHz): δ 19.8, 20.5, 23.1, 23.2, 25.2, 25.3, 28.1, 28.2, 28.8, 29.1, 30.8, 31.2, 46.2, 55.9, 56.1, 59.9, 60.1, 63.3, 64.6, 80.9, 88.1, 91.1, 95.2, 100.4, 112.6, 113.3, 113.6, 114.2, 127.1, 129.0, 145.0, 145.3, 148.1, 148.5, 155.1, 167.1, 167.3; IR (neat): 3306, 2946, 1703, 1632, 1511, 1453, 1394, 1368, 1334, 1274, 1212, 1163, 1116, 1023 cm−1; MS (FAB) m/z (relative intensity) 471 ([M+Na]+., 5), 449 (M+., 100), 246 (50), 393 (22).
Reaction SMILES: [N+:1]([C:4]1[CH:27]([CH3:28])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)=[C:16]([NH:25][CH3:26])[CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:29])[C:5]=1[CH3:30])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:27]([CH3:28])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)=[C:16]([NH:25][CH3:26])[CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:29])[C:5]=1[CH3:30]
Reactant: CNc1cc(CC2(C)CC3C(=C(C)C(C)=C([N+](=O)[O-])C3C)O2)ccc1-c1ccn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1cc(CC2(C)CC3C(=C(C)C(C)=C(N)C3C)O2)ccc1-c1ccn[nH]1
Yield: 91.3 %

Procedure:
To 0.26 g of 5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl) pyrazole, 10 ml of ethanol was added and 0.43 g of stannous chloride dihydrate and 3 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 2 hours. The reaction solution was poured into water, neutralized with a sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 0.22 g of the objective product (melting point: 113-117° C.)
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].O=O.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].CC(C)=[O:14]>[Mo].CO.O>[CH3:1][CH:2]([CH3:4])[CH3:3].[C:7]([O:11][OH:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)O
Reactant: CC(C)=O
Agent: [Mo]
Agent: CC(C)C
Agent: O=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OO
Temperature: 137.77777777777777 °C
Yield: 22 %

Procedure:
The oxidation zone is in a pressurized reactor which is partially filled with a liquid reaction mixture comprising 5 ppm of soluble molybdenum catalyst. The liquid reaction mixture can be deemed to be about 66% isobutane and about 34% of a liquid mixture of oxidate, comprising products and byproducts. Fresh isobutane is injected and recycle isobutane is injected into the liquid reaction mixture. An oxygen-containing gas is injected into the liquid reaction mixture. The reactor is maintained at 700 psig and at 280° F. The average residence time for the isobutane in the reactor is about 4 hours, and the extent of conversion of the isobutane is about 34%. The yields of byproducts and products from such oxidation of isobutane correspond to about 66% tertiary butyl alcohol (TBA), about 22% tertiary butyl hydroperoxide (TBHP), about 6% acetone, about 6% of a mixture comprising about 2% water, about 1.5% methanol and minor amounts of related components. About 1% of the isobutane is converted to carbon dioxide with a measurable amount of carbon monoxide.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Br:33])[CH:31]=3)[NH:26][CH:25]=2)O)=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(#N)C>[Br:33][C:30]1[CH:31]=[C:32]2[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[N:17][CH:18]=3)=[CH:25][NH:26][C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncc(Br)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cc1

Procedure:
To {5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-chloro-benzyl)-carbamic acid tert-butyl ester (45, 180.0 mg, 0.33 mmol) in acetonitrile (30.0 mL) were added trifluoroacetic acid (2.0 mL, 0.026 mol) and triethylsilane (4.0 mL, 0.025 mol). The reaction was heated to reflux for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0038, 120 mg, 85.2%). MS (ESI)[M+H+]+=427.2, 429.2.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[P:24](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:24](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[O:25][CH3:26]
Reactant: Oc1cc(Cl)c2nc3ccccc3cc2c1
Reactant: CCCSP(=O)(Cl)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OC)Oc1cc(Cl)c2nc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-chloroacridine (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-methyl S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-methyl O-(4-chloroacridin-2-yl) S-propyl phosphorothioate.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>O>[NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]([CH:20]=[O:22])=[CH:2]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ccncc12
Yield: 4.65 %

Procedure:
A solution of 1H-pyrrolo[3,2-c]pyridine (2.95 g, 25 mmol) and hexamethylenetetramine (5.26 g, 37.50 mmol) in acetic acid (25 mL) and water (50 mL) was heated under reflux for 4 hours. The reaction mixture was evaporated and the residue was purified by MPLC silica chromatography, elution gradient 5 to 10% ammonia-methanol in DCM. Product containing fractions were evaporated to dryness and triturated with MeCN to afford 1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (0.170 g, 4.65%) as a white crystalline solid.
Reaction SMILES: [C:1]1([CH:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](O)CCO)C=CC=CC=1>CCCCCC.CC(O)C>[C:1]1([C:7](=[O:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCC(O)c1ccccc1
Agent: OCC[C@H](O)c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C(CCO)c1ccccc1

Procedure:
Determination of the absolute configuration, optical purity and reaction yield of 1-phenyl-1,3-propanediol or a derivative thereof in the examples was determined by high pressure liquid chromatography (column: Chiral Cell OB, manufactured by Daisel Chemical Co., eluent: hexane/2-propanol (8/2), flow rate: 0.7 ml/min, detection: UV 210 nm). The reaction yield represents the mole percentage of (S)-1-phenyl-1,3-propanediol produced per mole of 1-phenylpropan-3-ol-1-one added as starting material.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.CS([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)(=O)=O.[N-]=C=O.ClC1C=CC(CC2CC3N(CC(N)C)C(CC3)C2)=CC=1>C(Cl)Cl>[CH:22]12[CH2:23][CH2:18][CH:19]([CH:5]([OH:11])[CH2:21]1)[CH2:20][NH:24]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: CC(N)CN1C2CCC1CC(Cc1ccc(Cl)cc1)C2
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Product: OC1CC2CCC1CN2
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To a solution of triphosgene (0.22 g, 0.33 eq.) in CH2Cl2 was added 3-methane-sulfonyl-phenylamine hydrochloride (0.5 g, 2.4 mmol), followed by the dropwise addition of TEA (0.37 ml, 1.1 eq.). The mixture was heated to 40° C. for 30 min. It was allowed to cool to rt and stirred for an additional 45 min. The isocyanate solution was then added to a solution of 2-[3-(4-chlorobenzyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-1-methyl-ethylamine (0.18 g, 0.6 mmol) (prepared according to the procedure described in example 4, steps 1 to 4) in 6 ml of CH2Cl2. The mixture was stirred overnight at rt. It was diluted with CH2Cl2 and the organic layer was washed with Na2CO3 (sat.) twice, NaCl (sat.) and dried over Na2SO4. The crude mixture was purified on a silica-gel column with 1% iPrNH2, 9% MeOH in EtOAc to give 55% of Example 5 (M+: 490).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH3:72])[N:67]=2)[OH:65])=[CH:60][CH:59]=1>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:57][C:58]4[CH:63]=[CH:62][C:61]([CH:64]([OH:65])[C:66]5[CH:71]=[CH:70][CH:69]=[C:68]([CH3:72])[N:67]=5)=[CH:60][CH:59]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Cc1cccc(C(O)c2ccc(N)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc(C)n4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid 0.5 g (1.05 mmole) and 1-hydroxybenzotriazole (0.35 g) in DMF (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution were added a solution of (4-aminophenyl)(6-methylpyridin-2-yl)methanol (0.29 g) and triethylamine (0.60 ml) in DMF (5 ml) and 4-dimethylaminopyridine (1 flake) and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 95) (378.9 mg) as pale yellow amorphous.